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(BQ) Part 2 book Textbook of diabetes presents the following contents: Microvascular complications in diabetes, macrovascular complications in diabetes, other complications of diabetes, diabetes in special groups, delivery and organization of diabetes care, future directions.
7 Microvascular Complications in Diabetes 35 Pathogenesis of Microvascular Complications Ferdinando Giacco & Michael Brownlee Diabetes Research Center, Departments of Medicine and Endocrinology, Albert Einstein College of Medicine, NY, USA Keypoints • Microvascular complications are caused by prolonged exposure to hyperglycemia • Hyperglycemia damages cell types that cannot downregulate glucose uptake, causing intracellular hyperglycemia • Intracellular hyperglycemia damages tissues by five major mechanisms: increased flux of glucose and other sugars through the polyol pathway; increased intracellular formation of advanced glycation end-products (AGEs); increased expression of the receptor for AGEs and its activating ligands; activation of protein kinase C isoforms; and overactivity of the hexosamine pathway • A single process – increased mitochondrial production of oxygen free radicals – activates each of these mechanisms • Persistent consequences of hyperglycemia-induced mitochondrial superoxide production may also explain the continuing progression of Overview of diabetic complications All forms of diabetes are characterized by hyperglycemia, a relative or absolute lack of insulin action, and the development of diabetes-specific pathology in the retina, renal glomerulus and peripheral nerve Diabetes is also associated with accelerated atherosclerotic disease affecting arteries that supply the heart, brain and lower extremities As a consequence of its diseasespecific pathology, diabetes mellitus is now the leading cause of new blindness in people 20–74 years of age and the leading cause of end-stage renal disease (ESRD) in the developed world Survival of patients with diabetic ESRD on dialysis is half that of those without diabetes More than 60% of patients with diabetes are affected by neuropathy, which includes distal symmetrical polyneuropathy, mononeuropathies and a variety of autonomic neuropathies causing erectile dysfunction, urinary incontinence, gastroparesis and nocturnal diarrhoea Diabetic accelerated lower extremity arterial disease in conjunction with neuropathy Textbook of Diabetes, 4th edition Edited by R Holt, C Cockram, A Flyvbjerg and B Goldstein © 2010 Blackwell Publishing • • • • tissue damage after improvement of glycemic levels (“hyperglycemic memory”) Different individual susceptibility to microvascular complications have been linked to polymorphisms in the superoxide dismutase gene Hyperglycemia-induced mitochondrial reactive oxygen species production impairs the neovascular response to ischemia by blunting hypoxia-inducible factor transactivation Hypertension accelerates microvascular damage by increasing intracellular hyperglycemia through upregulation of the glucose transporter Potential mechanism-based therapeutic agents for diabetic microvascular complications include transketolase activators, poly(ADPribose) polymerase inhibitors and catalytic antioxidants accounts for 50% of all non-traumatic amputations in the USA Diabetes and impaired glucose tolerance increase cardiovascular disease (CVD) risk three- to eightfold Thus, over 40% of patients hospitalized with acute myocardial infarction (MI) have diabetes and 35% have impaired glucose tolerance Finally, new blood vessel growth in response to ischemia is impaired in diabetes, resulting in decreased collateral vessel formation in ischemic hearts, and in non-healing foot ulcers The focus of this chapter is on the microvascular complications comprising retinopathy, nephropathy and peripheral neuropathy Much of the impact of chronic diabetes falls on the microcirculation [1,2] With long-standing disease, there is progressive narrowing and eventual occlusion of vascular lumina, resulting in impaired perfusion, ischemia and dysfunction of the affected tissues Several processes contribute to microvascular occlusion One of the earliest is increased vascular permeability, allowing extravasation of plasma proteins that accumulate as periodic acid–Schiff-positive deposits in the vessel walls In addition, the extracellular matrix elaborated by perivascular cells such as pericytes (retina) and mesangial cells (glomerulus) is increased, brought about by changes in synthesis and turnover of its component proteins and glycosaminoglycans As a result, the basement membrane is thickened in many tissues, including retinal capillaries and the vasa nervorum, while mesangial matrix is 555 Part Microvascular Complications in Diabetes Role of hyperglycemia in microvascular complications Overall, diabetic microvascular complications are caused by prolonged exposure to high glucose levels This has been established by large-scale prospective studies for both type diabetes (T1DM) by the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study [DCCT/ EDIC] [12] and for type diabetes (T2DM) by the UK Prospective Diabetes Study [UKPDS] [13]) Similar data have been reported by the Steno-2 study [14] Because every cell in the body of people with diabetes is exposed to abnormally high glucose concentrations, why does hyperglycemia selectively damage some cell types and not others? The targeting of specific cell types by generalized hyperglycemia reflects the failure of those cells to downregulate their uptake of glucose when extracellular glucose concentrations are elevated Cells that are not directly susceptible to direct hyperglycemic damage such as vascular smooth muscle show an inverse relationship between extracellular glucose concentrations and glucose transport In contrast, vascular endothelial cells, a major target of hyperglycemic damage, show no significant change in glucose transport rate when glucose concentration is elevated, resulting in intracellular hyperglycemia (Figure 35.1) These differences are caused in part by tissue-specific differences in expression and function of different glucose transporter (GLUT) proteins [15] Mechanisms of hyperglycemia-induced damage There are nearly 2000 publications supporting five major mechanisms by which hyperglycemia causes diabetic complications: Increased flux of glucose and other sugars through the polyol pathway; 556 (a) 2DG Uptake (Fold over basal) Smooth muscle cells 5.5 22 (b) 2DG Uptake (Fold over basal) expanded in the renal glomerulus Hypertrophy and hyperplasia of endothelial, mesangial and arteriolar smooth muscle cells also contribute to vessel wall thickening Finally, increased coagulability of the blood and adhesion of platelets and leukocytes to the endothelial surface lead to microthrombus formation and luminal occlusion The progressive narrowing and blockage of diabetic microvascular lumina are accompanied by loss of microvascular cells In the retina, diabetes induces apoptosis of Müller cells and ganglion cells [3], pericytes and endothelial cells [4] In the glomerulus, widespread capillary occlusion and declining renal function are associated with podocyte loss In the vasa nervorum of diabetic nerves, endothelial cell and pericyte degeneration occur [5] and appear to precede functional abnormalities of peripheral nerves [6] Increased apoptosis of cells in the retina, renal glomerulus and peripheral neurons is a prominent feature of diabetic microvascular tissue damage [7–11] and may also cause damage to adjacent cells Endothelial cells 5.5 22 Medium glucose (mmol/L) Figure 35.1 Lack of downregulation of glucose transport by hyperglycemia in cells affected by diabetic complications (a) 2-Deoxyglucose uptake in vascular smooth muscle cells pre-exposed to 5.5 or 22 mmol/L glucose (b) 2-Deoxyglucose uptake in aortic endothelial cells pre-exposed to 5.5 or 22 mmol/L glucose Data from Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S, Moller DE, et al Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells Diabetes 1993; 42:80–89 Increased intracellular formation of advanced glycation endproducts (AGEs); Increased expression of the receptor for AGEs (RAGE) and its activating ligands; Activation of protein kinase C (PKC) isoforms; and Overactivity of the hexosamine pathway Despite this, the results of clinical studies in which one of these pathways is blocked have been disappointing This led to the hypothesis in 2000 that all five mechanisms are activated by a single upstream event: mitochondrial overproduction of the reactive oxygen species (ROS) superoxide as a result of intracellular hyperglycemia This provides a unifying hypothesis for the pathogenesis of diabetic complications Increased polyol pathway flux The polyol pathway is based on a family of aldoketo reductase enzymes which can utilize as substrates a wide variety of sugarderived carbonyl compounds and reduce these by nicotinic acid Pathogenesis of Microvascular Complications Chapter 35 ROS Toxic aldehydes Figure 35.2 The polyol pathway When glucose concentration is normal, aldose reductase reduces toxic aldehydes generated by reactive oxygen species (ROS) to inactive alcohols With intracellular hyperglycemia, it can also reduce glucose to sorbitol Both reactions use nicotinic acid adenine dinucleotide phosphate (NADPH) as a co-factor When aldose reductase activity is sufficient to deplete reduced glutathione (GSH), oxidative stress is augmented Sorbitol-dehydrogenase (SDH) oxidizes sorbitol to fructose using NAD+ as a co-factor GSSG, glutathione disulfide (oxidized glutathione) Increased glucose adenine dinucleotide phosphate (NADPH) to their respective sugar alcohols (polyols) The classic representation holds that glucose is converted to sorbitol, and galactose to galactitol Sorbitol is then oxidized to fructose by the enzyme sorbitol dehydrogenase (SDH), with NAD+ being reduced to NADH (Figure 35.2) The first and rate-limiting step of the polyol pathway is governed by aldose reductase, which is found in tissues such as nerve, retina, lens, glomerulus and blood vessel wall In these tissues, glucose uptake is mediated by GLUT proteins other than GLUT-4 and so does not require insulin; intracellular glucose concentrations therefore rise in parallel with hyperglycemia Several mechanisms have been proposed to explain how hyperglycemia-induced increases in polyol pathway flux could damage the tissues involved These include sorbitol-induced osmotic stress, decreased cytosolic Na/K+-ATPase activity, increased cytosolic NADH/NAD+, and decreased cytosolic NADPH It was originally suggested that intracellular accumulation of sorbitol, which does not diffuse easily across cell membranes, could result in osmotic damage, but it is now clear that sorbitol levels in diabetic vessels and nerves are far too low to this Another early suggestion was that increased flux through the polyol pathway led to decreased phosphatidylinositol synthesis, and that this inhibited Na/K+-ATPase activity The latter abnormality does occur in diabetes, but has recently been shown to result from hyperglycemia-induced activation of PKC which increases the production of two inhibitors of Na/K+-ATPase, arachidonate and prostaglandin E2 [16] It has also been suggested that the reduction of glucose to sorbitol by NADPH (Figure 35.2) consumes the latter NADPH is a co-factor required to regenerate reduced glutathione (GSH); as GSH is an important scavenger of ROS, this could induce or exacerbate intracellular oxidative stress Indeed, overexpression Inactive alcohols Aldose reductase SDH Sorbitol Fructose NAD+NADH NADPH NADP+ Glutathione reductase GSSG GSH of human aldose reductase increased atherosclerosis in diabetic mice and reduced the expression of genes that regulate regeneration of GSH [17] Reduced GSH is depleted in the lens of transgenic mice that overexpress aldose reductase and in diabetic rat lens compared with non-diabetic lens [18,19] It has also been recently demonstrated that decreased glutathiolation of cellular proteins is related to decreased nitric oxide (NO) availability in diabetic rats which would decrease S-nitrosoglutathione (GSNO) Restoring the NO levels in diabetic animals increases glutathiolation of cellular proteins, inhibits aldose reductase activity and prevents sorbitol accumulation Moreover, hyperglycemia can also inhibit glucose-6-phosphate dehydrogenase, the major source of NADPH regeneration, which may further reduce NADPH concentration in some vascular cells and neurons [20] In diabetic vascular cells, however, glucose does not appear to be the substrate for aldose reductase, because the Michaelis constant (Km) of aldose reductase for glucose is 100 mmol/L, while the intracellular concentration of glucose in diabetic retina is 0.15 mmol/L [21,22] Glycolytic metabolites of glucose such as glyceraldehyde-3-phosphate, for which aldose reductase has much higher affinity, may be the physiologically relevant substrate Increased intracellular AGE formation AGEs are formed by the reaction of glucose and other glycating compounds (e.g dicarbonyls such as 3-deoxyglucosone, methylglyoxal and glyoxal) with proteins and, to a lesser extent, nucleic acids The reactions proceed through a series of stages that are initially reversible and yield early glycation products, but eventually undergo irreversible changes that markedly impair the structural, enzymatic or signaling functions of the glycated proteins (Figure 35.3) A familiar example of this process yields glycated hemoglobin (HbA1c) AGEs are found in increased amounts in 557 Part Microvascular Complications in Diabetes to glyoxal [30], the decomposition of an Amadori product to the 3-deoxyglucosone, or the fragmentation of glyceraldehyde-3phosphate to yield methylglyoxal [31] All these reactive intracellular dicarbonyls react readily with uncharged amino groups of intracellular and extracellular proteins to form AGEs Methylglyoxsal is the major intracellular AGE precursor [32,33] Glucose Endothelial cell Matrix Intracellular protein glycation AGE precursors Proteins mRNA Intracellular transducer AGE receptor Integrins AGE plasma proteins AGE receptor ROS NK-κB Growth factors and cytokines Macrophage/ mesangial cell Figure 35.3 Increased production of intracellular advanced glycation end-products (AGE) precursors damages cells by three mechanisms: modification of intracellular proteins; modification of the extracellular matrix (upper panel); and interactions with AGE receptors such as RAGE in endothelial cells and macrophages NFκB, nuclear factor κB; ROS, reactive oxygen species extracellular structures of diabetic retinal vessels [23–25] and renal glomeruli [26–28], where they can cause damage through the mechanisms described below These AGEs were originally thought to arise from non-enzymatic reactions between extracellular proteins and glucose; however, the rate of AGE formation from glucose is orders of magnitude slower than that induced by glucose-derived dicarbonyl precursors generated intracellularly, and it now seems likely that raised intracellular glucose is the primary initiating event in the formation of both intracellular and extracellular AGEs [29] AGEs can arise intracellularly from the autooxidation of glucose 558 Intracellular effects of AGEs Intracellular production of AGE precursors can damage cells by three general mechanisms First, intracellular proteins modified by AGEs have altered function Secondly, extracellular matrix components modified by AGE precursors interact abnormally with other matrix components and with matrix receptors (integrins) which are expressed on the surface of cells Finally, plasma proteins modified by AGE precursors bind to AGE receptors on cells such as macrophages; binding induces the production of ROS, which in turn activates the pleiotropic transcription factor, nuclear factor κB (NFκB), causing multiple pathologic changes in gene expression [34] It has been recently demonstrated that AGE modification of intracellular protein can be involved in diabetic retinopathy In diabetes, retinal capillary formation is regulated by complex context-dependent interactions among pro- and anti-angiogenic factors [35,36], including angiopoietin-2 (Ang-2) When vascular endothelial growth factor (VEGF) levels are insufficient, Ang-2 causes endothelial cell death and vessel regression Diabetes induces a significant increase in retinal expression of Ang-2 in rat [37], and diabetic Ang-2 +/− mice have both decreased pericyte loss and reduced acellular capillary formation [38] Moreover, in mouse kidney endothelial cells, high glucose causes increased methylglyoxal modification of the corepressor mSin3A Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc-transferase, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine This modification of Sp3 causes decreased binding to a glucoseresponsive GC-box in the Ang-2 promoter, resulting in increased Ang-2 expression Increased Ang-2 expression induced by high glucose in renal endothelial cells increased expression of intracellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in cells and in kidneys from diabetic mice and sensitized microvascular endothelial cells to the proinflammatory effects of tumor necrosis factor α (TNF-α) [39] Effects of AGEs on extracellular matrix AGE formation alters the functional properties of several important matrix molecules Collagen was the first matrix protein in which glucose-derived AGEs were shown to form covalent intermolecular bonds This process is partly mediated by H2O2 production [40,41] With type I collagen, this cross-linking causes expansion of molecular packing [42], while AGE formation on type IV collagen from basement membrane inhibits the normal lateral association of these molecules into a network-like structure by interfering with binding of the non-collagenous NC1 domain to the helix-rich domain [43] AGE formation on laminin Pathogenesis of Microvascular Complications Chapter 35 prevents the molecules from self-assembling into a polymer and also decreases binding with type IV collagen and heparan sulfate proteoglycan [44] These AGE-induced cross-links alter tissue function, notably in blood vessels AGEs decrease elasticity in arteries from diabetic rats, even after vascular tone is abolished, and increase fluid filtration across the carotid artery [45] In vitro, AGE formation on intact glomerular basement membrane increases its permeability to albumin in a manner that resembles the abnormal permeability of diabetic nephropathy [46,47] AGE formation on extracellular matrix also interferes with the ways in which cells interact with the matrix For example, methylglyoxal modification of type IV collagen’s cell-binding domains decreases endothelial cell adhesion and inhibits angiogenesis [48] AGE formation on a 6-amino acid, growth-promoting sequence in the A chain of the laminin molecule markedly reduces neurite outgrowth [49], while AGE modification of vitronectin reduces its ability to promote cell attachment [50] In addition, matrix glycation impairs agonist-induced Ca2+ increases which might adversely affect the regulatory functions of endothelium [51] Receptor-mediated biologic effects of AGEs AGE-modified proteins in the circulation can affect a range of cells and tissues Specific receptors for AGEs were first identified on monocytes and macrophages Two AGE-binding proteins isolated from rat liver, identified as OTS-48 (60 kDa) and 80K-H (90 kDa) [52], are both present on monocytes and macrophages; antisera against either protein block AGE binding [53] AGE protein binding to this receptor stimulates macrophages to produce cytokines, including interleukin-1, TNF-α, transforming growth factor β (TGF-β), macrophage colony-stimulating factor and granulocyte–macrophage colony-stimulating factor, as well as insulin-like growth factor I (IGF-I) These factors appear to be produced at concentrations that can increase glomerular synthesis of type IV collagen and induce chemotaxis and proliferation of both arterial smooth muscle cells and macrophages [54–62] The macrophage scavenger receptor type II (class A), galectin-3 and CD36 (a member of the class B macrophage scavenger receptor family) have also been shown to recognize AGEs [63–67] AGE receptors have also been identified on glomerular mesangial cells In vitro, AGE protein binding to its receptor on mesangial cells stimulates secretion of platelet-derived growth factor which in turn mediates mesangial cells to produce type IV collagen, laminin and heparan sulfate proteoglycan [68,69] Vascular endothelial cells and other cell types also express specific AGE receptors (RAGEs), notably 35-kDa and 46-kDa AGE-binding proteins that have been purified to homogeneity [70–72] The N-terminal sequence of the 35-kDa protein is identical to lactoferrin, whereas the 46-kDa AGE-binding protein is a novel member of the immunoglobulin superfamily, containing three disulfide-bonded immunoglobulin homology units RAGE have been shown to mediate signal transduction via generation of ROS, activation of NFκB, and p21 ras [73–75] AGE signaling can be blocked in cells by expression of RAGE antisense cDNA [76] or anti-RAGE ribozyme [77] It has been also recently demonstrated that a RAGE–NFκB axis operates in diabetic neuropathy by mediating functional sensory deficits [78] In endothelial cells, AGE binding to its receptor alters the expression of several genes, including thrombomodulin, tissue factor and VCAM-1 [79–81] These effects induce procoagulatory changes on the endothelial cell surface and increase the adhesion of inflammatory cells to the endothelium In addition, endothelial AGE receptor binding appears to mediate in part the increased vascular permeability induced by diabetes, probably through the induction of VEGF [82–85] RAGE deficiency attenuates the development of atherosclerosis in the diabetic apoE(−/−) model of accelerated atherosclerosis Diabetic RAGE(−/−)/apoE(−/−) mice had significantly reduced atherosclerotic plaque area These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment, decreased expression of proinflammatory mediators, including the NFκB subunit p65, VCAM-1, and monocyte chemotactic protein (MCP-1) and reduced oxidative stress [86] It is important to note that more recent studies indicate that AGEs at the concentrations found in diabetic sera are not the major ligand for RAGE Rather, several pro-inflammatory protein ligands have been identified, which activate RAGE at low concentrations These include several members of the S100 calgranulin family and high mobility group box (HMGB1), all of which are increased by diabetic hyperglycemia Binding of these ligands with RAGE causes cooperative interaction with the innate immune system signaling molecule toll-like receptor (TLR-4) [87,88] Increased protein kinase C activation The group of PKCs consist of at least 11 isoforms that are widely distributed in mammalian tissues The activity of the classic isoforms is dependent on both Ca2+ ions and phosphatidylserine and is greatly enhanced by diacylglycerol (DAG) Persistent and excessive activation of several PKC isoforms might also operate as a third common pathway mediating tissue injury induced by hyperglycemia and associated biochemical and metabolic abnormalities This results primarily from enhanced de novo synthesis of DAG from glucose via triose phosphates, whose availability is increased because raised intracellular glucose levels enhance glucose flux through the glycolytic pathway [89–92] Finally, recent evidence suggests that the enhanced activity of PKC isoforms could also result from the interaction between AGEs and their cell-surface receptors [93] Hyperglycemia primarily activates the β and δ isoforms of PKC, both in cultured vascular cells [94–96] and in the retina and glomeruli of diabetic animals [91,92,93], but increases in other isoforms have also been found, such as PKC-α and PKC-ε isoforms in the retina [89] and PKC-α and PKC-δ in the glomerulus of diabetic rats [97,98] (Figure 35.4) 559 Part Microvascular Complications in Diabetes Hyperglycemia DAG PKC ET-1 VEGF eNOS TGF-β PAI-1 NFκB NAD(P)H oxidases Collagen Fibronectin ROS Fibrinolysis Blood-flow abnormalities Vascular permeability Angiogenesis Capillary occlusion Vascular occlusion Pro-inflammatory gene expression Multiple effects Figure 35.4 Activation of protein kinase C (PKC) by de novo synthesis of diacylglycerol (DAG) and some of its pathologic consequences eNOS, endothelial NO synthase; ET-1, endothelin-1; NADPH, nicotinic acid adenine dinucleotide phosphate; NFκB, nuclear factor κB; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor In early experimental diabetes, activation of PKC-β isoforms has been shown to mediate the diabetes-related decreases in retinal and renal blood flow [99], perhaps by depressing the production of the vasodilator NO and/or increasing endothelin-1, a potent vasoconstrictor Overactivity of PKC has been implicated in the decreased NO production by the glomerulus in experimental diabetes [100] and by smooth muscle cells in the presence of high glucose levels [101], and has been shown to inhibit insulinstimulated expression of endothelial NO synthase (eNOS) in cultured endothelial cells [102] Hyperglycemia increases the ability of endothelin-1 to stimulate mitogen activated protein kinase (MAPK) activity in glomerular mesangial cells, and this occurs by activating PKC isoforms [103] The increased endothelial cell permeability induced by high glucose in cultured cells is mediated by activation of PKC-α [104]; activation of PKC by high glucose also induces expression of the permeability-enhancing factor VEGF in smooth muscle cells [105] 560 In addition to mediating hyperglycemia-induced abnormalities of blood flow and permeability, activation of PKC may contribute to the accumulation of microvascular matrix protein by inducing expression of TGF-β1, fibronectin and type IV collagen in both cultured mesangial cells [106,107] and in glomeruli of diabetic rats [97] This effect also appears to be mediated through the inhibition of NO production by PKC [108] Hyperglycemiainduced activation of PKC has also been implicated in the overexpression of the fibrinolytic inhibitor, plasminogen activator inhibitor (PAI-1) [109], and in the activation of NFκB in cultured endothelial cells and vascular smooth muscle cells [110,111] Increased hexosamine pathway flux Several data suggest that hyperglycemia could cause diabetic complications by shunting glucose into the hexosamine pathway [112–115] Here, fructose-6-phosphate is diverted from glycolysis to provide substrates for reactions that utilize UDP-N- Pathogenesis of Microvascular Complications Chapter 35 Glucose Glycolysis Glucose Gluc-6-P Fruct-6-P GFAT Glu, Glucosamine-6-P UDPGlcNac OGT Figure 35.5 The glucosamine pathway Glucosamine-6-phosphate is generated from fructose-6-phosphate and glutamine, by glutamine: fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of this pathway Glucosamine6-phosphate is converted to UDP-Nacetylglucosamine (UDP-GlcNac), which can glycosylate transcription factors and thus enhance transcription of genes including plasminogen activator inhibitor (PAI-1) and transforming growth factor β1 (TGF-β1) OGT, O-linked N-acetylglucosamine (GLcNac) transferase acetylglucosamine, particularly the formation of O-linked N-acetylglucosamine This pathway has been shown to have an important role in hyperglycemia-induced and fat-induced insulin resistance [116–118] The rate-limiting step in the conversion of glucose to glucosamine is regulated by glutamine : fructose-6phosphate amidotransferase (GFAT), and inhibition of this enzyme blocks hyperglycemia-induced increases in the transcription of both TGF-α [112] and TGF-β1 [113] It is not entirely clear how increased glucose flux through the hexosamine pathway mediates hyperglycemia-induced increases in the gene transcription of key genes such as TGF-α, TGF-β1 and PAI-1, however, it has been shown that the transcription factor Sp1 regulates hyperglycemia-induced activation of the PAI-1 promoter in vascular smooth muscle cells [119], raising the possibility that covalent glycation of Sp1 by Nacetylglucosamine to form its O-GlcNacylated derivative could explain how hexosamine pathway activation might operate Virtually every RNA polymerase II transcription factor examined is O-GlcNacylated [120], and this glycosylated form of Sp1 appears to be more transcriptionally active than its nonglycosylated counterpart [121] A fourfold increase in Sp1 O-GlcNacylation (caused by inhibition of the enzyme O-GlcNac-β-N-acetylglucosaminidase) resulted in a reciprocal ac lcN O G – PO TGF-β PAI-1 mRNA 30% decrease in the level of serine/threonine phosphorylation of Sp1; thus, O-GlcNacylation and phosphorylation may compete to modify the same sites on Sp1 (Figure 35.5) [122] GlcNac modification of Sp1 may regulate other glucoseresponsive genes in addition to TGF-β1 and PAI-1 Glucoseresponsive transcription of the acetylcoenzyme A carboxylase gene (the rate-limiting enzyme for fatty acid synthesis) is regulated by Sp1 sites, and post-transcriptional modification of Sp1 may similarly be responsible [123,124] Because so many RNA polymerase II transcription factors are O-GlcNacylated [120], others in addition to Sp1 may be regulated by reciprocal modification (glycosylation vs phosphorylation) at key serine and threonine residues and so cause gene transcription to be glucose-responsive In addition to transcription factors, many other nuclear and cytoplasmic proteins can be modified by OGlcNac moities perturbing their normal function and regulation One example relevant to diabetes is the inhibition of eNOS activity by O-GlcNacylation at the Akt site of eNOS protein [125– 127] Hyperglycemia also increases GFAT activity in aortic smooth muscle cells which increases O-GlcNac modification of several proteins in these cells [128] Overall, activation of the hexosamine pathway by hyperglycemia may result in many changes in both gene expression and in protein function that 561 Part Microvascular Complications in Diabetes together contribute to the pathogenesis of diabetic complications Recently, increased modification of key signaling molecules by O-GlcNAc was shown to cause reduced insulin signal transduction [129] Pathway selective insulin resistance in vascular cells and resultant overactivation of the MAPK pathway by hyperinsulinemia could contribute further to diabetic microvascular damage [130] Intracellular glucose oxidation begins with glycolysis in the cytoplasm, which generates NADH and pyruvate Cytoplasmic NADH can donate reducing equivalents to the mitochondrial electron-transport chain via two shuttle systems, or it can reduce pyruvate to lactate, which leaves the cell to act as a substrate for hepatic gluconeogenesis Pyruvate can also be transported into the mitochondria where it is oxidized by the tricarboxylic acid (TCA) cycle to produce CO2, H2O, four molecules of NADH and one molecule of reduced flavine adenine dinucleotide (FADH2) Mitochondrial NADH and FADH2 provide energy for ATP production via oxidative phosphorylation by the electron transport chain Electron flow through the mitochondrial electron transport chain is effected by four enzyme complexes, plus cytochrome c and the mobile carrier ubiquinone, all of which lie in the inner mitochondrial membrane [137] NADH derived from both cytosolic glucose oxidation and mitochondrial TCA cycle activity donates electrons to NADH : ubiquinone oxidoreductase (Complex I) which ultimately transfers its electrons to ubiquinone Ubiquinone can also be reduced by electrons donated from several FADH2-containing dehydrogenases, including succinate : ubiquinone oxidoreductase (Complex II) and glycerol-3phosphate dehydrogenase Electrons from reduced ubiquinone are then transferred to ubiquinol : cytochrome c oxidoreductase (Complex III) by the Q cycle which generates ubisemiquinone radicals [138] Electron transport then proceeds through cytochrome c, cytochrome c oxidase (Complex IV) and, finally, molecular oxygen Electron transfer through Complexes I, III and IV extrudes protons outwards into the intermembrane space, generating a proton gradient that drives ATP synthase (Complex V) as protons A single process underlying different hyperglycemia-induced pathogenic mechanisms: mitochondrial superoxide production Specific inhibitors of aldose-reductase activity, AGE formation, RAGE ligand binding, PKC activation and hexosamine pathway flux each ameliorate various diabetes-induced abnormalities in cell culture or animal models, but it has not been clear whether these processes are interconnected or might have a common cause [99,131–134] Moreover, all the above abnormalities are rapidly corrected when euglycemia is restored, which makes the phenomenon of hyperglycemic memory conceptually difficult to explain It has now been established that all of the different pathogenic mechanisms described above stem from a single hyperglycemiainduced process, overproduction of superoxide by the mitochondrial electron-transport chain [135,136] Superoxide is the initial oxygen free radical formed by the mitochondria which is then converted to other, more reactive species that can damage cells in numerous ways [137] To understand how this occurs, mitochondrial glucose metabolism is briefly reviewed (Figure 35.6) Glucose-derived reactive oxygen species originate from the mitochondrial electron transport system ΔμH+ ΔμH+ H+ H+ H+ H+ H+ ATP synthase I III e– Q– II e– IV Cyt c e– e– FAD NAD+ FADH2 H20 Heat O2 NADH ATP O2– 562 UCP O2 ADP + Pi Figure 35.6 Mitochondrial metabolism Flow of electrons (e−) through the electron transport chain in the inner mitochondrial membrane pumps H+ ions into the intermembrane space; superoxide is generated as a consequence of one electron leak H+ ions can pass back across the inner membrane along their concentration gradient, either via ATP synthase (to produce ATP) or via uncoupling proteins (UCP) When intracellular hyperglycemia increases electron flux by generating more NADH and FADH2, more superoxide is produced Cyt c, cytochrome c; Q, ubiquinone Index MAPK8IP1 (IB1) gene 196 Marchal de Calvi, Charles 4, Mas receptor 643, 645 masoprocol 1032, 1033 maternal factors, T1DM etiology 144 maternally inherited diabetes and deafness (MIDD) 253–5 clinical features 254, 254–5 differential diagnosis 246, 255 management 255 pathogenesis 155, 253–4 matrix metalloproteinases (MMPs), foot ulcers 734–5 maturity-onset diabetes 25 maturity-onset diabetes of the young (MODY) 27, 153–5, 193, 244–51 extrapancreatic features 250, 250 genetic etiology 153, 193–4, 244–7 molecular mechanisms 154 relevance to T2DM 194 glucokinase (MODY 2) 153, 193, 194, 247–9 blood glucose levels 247, 248 clinical features 247–8 differential diagnosis 246, 248 management 248 pregnancy and 249, 249, 889 history of recognition 12 HNF1A (MODY 3) 193, 193–4, 249–51 clinical features 249–50 differential diagnosis 246, 250 management 251 pregnancy and 251 HNF1B (MODY 5) see renal cysts and diabetes HNF4A (MODY 1) 193, 193–4, 249–51 clinical features 249–50 differential diagnosis 250 management 251 pregnancy and 251 INS (MODY 7) 193, 194 IPF-1 (MODY 4) 193, 194 NEUROD1 (MODY 6) 193, 194 subtypes 153, 193, 247 transcription factor 153, 154, 249–51 clinical features 248, 249–50 differential diagnosis 247, 250, 250 management 251 pregnancy and 251 Maudsley, Henry 940 Mauriac syndrome 284 Mauritius, T2DM 54 MB09975N 1036 MB39890A 1036 meals children with diabetes 865–6 frequency 128–9 in-flight 392 insulin injections with 435, 435 restaurant 128 see also eating; food intake; post-prandial state Medi-Tag labels 391 Medic Alert bracelets 391 Medica 16 1039 medical errors, hospital inpatients 518, 518 medications, diabetic see antidiabetic agents medroxyprogesterone acetate, depot 267, 753 megaloblastic anemia, thiamine responsive 256 Meggitt–Wagner ulcer classification 733–4, 734, 735 meglitinides (glinides) 456, 463–5 adverse effects 465 cautions and contraindications 456, 464–5 chemical structure 465 combination therapy 465, 473–4, 474, 500 drug interactions 457 efficacy 465 indications 464–5 mode of action 455, 464, 464, 1021–2, 1022 older people 934 pharmacokinetics 464, 465 renal failure 608 see also nateglinide; repaglinide MEK (MAPK/ERK kinase) 109 Melanesian populations 55 melanin-concentrating hormone (MCH) 134 melanocortin-3 (MC3) receptors 133–4 melanocortin-4 receptors (MC4R) 133–4 gene mutations 229, 230 α-melanocyte stimulating hormone (α-MSH) 133 melatonin 204 melatonin receptor 1B 204 melioidosis 838–9, 843 mellitus, origin of term menopause, age at 891 Mensing approach to education 341–2, 342 mental illness see psychiatric disorders Menzel, Ruth 18 Mering, Josef von 7, 13, 14 mesenteric artery occlusive disease 717 mesial temporal sclerosis 816–17 metabolic control see glycemic control metabolic modulators, congestive heart failure 690, 692 metabolic rate, resting (RMR) 230 metabolic syndrome 176, 923 definition 176, 176 fructose consumption and 129 global burden 72 gout 794 HIV/AIDS 840 hypertension 658–60, 659 NAFLD and 176, 177, 178 older people 922 pathogenesis 184, 184–5 platelet hyperactivity 702 psychotic disorders 948 stroke risk 701 T2DM risk 46, 176 metabolism adaptation to pregnancy 890–1 disturbances in diabetes 215–22 neural and hormonal control 134 nutrient 131 see also fatty acid oxidation; glucose metabolism metaglidasen 1033, 1035 Metaglip see metformin–glipizide combination 131 I-metaiodobenzylguanidine scanning 289 metanephrine, serum 289 metformin 456, 456–60 adverse effects 460 cautions and contraindications 419, 456, 458–9 chemical structure 457 chronic kidney disease 608 combination therapy 459, 473–4, 500–1 DPP-4 inhibitors 506 exenatide 504 fixed-dose pills 474, 501 development 17, 456–7 dosage 459 drug interactions 416, 457 efficacy 459–60 formulations 459 gestational diabetes 908 HIV lipodystrophy 840 hypoglycemia induction 414 indications 458–9 inherited lipodystrophies 258 initial monotherapy 498, 498, 501–2 insulin therapy with 459–60 lipid-lowering effects 459, 677 metabolic and vascular effects 457, 457–8, 458, 459 mode of action 455, 457–8, 458 older people 933 pharmacogenetic studies 206–7 pharmacokinetics 458 polycystic ovary syndrome 294, 459 pregnancy 906 prevention of T2DM 61, 460, 500–1 prior gestational diabetes 909 psychotic disorders 949–50 regular review 459 skin reactions 786 stroke prevention 702 metformin–glibenclamide combination 474 metformin–glipizide combination 474 metformin–pioglitazone combination 474, 501 metformin–replaglinide combination 474 metformin–rosiglitazone combination 474, 501 metformin–sitagliptin combination 474 metformin–vildagliptin combination 474, 506 methicillin-resistant Staphylococcus aureus (MRSA) colonization 848 foot infections 737 necrotizing fasciitis 849 methyl palmoxirate 1039 α-methyldopa 419, 902 methylglyoxal hyperglycemia-mediated production 563, 639, 640 modifications 558, 567, 640 3-methylhistidine excretion 221 metoclopramide, gastroparesis 769 metoprolol congestive heart failure 691, 691 diabetogenic effects 268 hypertension 664–5 metyrapone, Cushing syndrome 287 Mexican Americans diabetes in old age 923–4 T2DM frequency 51 T2DM susceptibility genes 197–8 Mexico, costs of diabetes 78 Meyer-Schwickerath, Gerd 18 mianserin 273 miconazole 415 microalbuminuria cardiovascular disease risk 602, 603 children 872 definitions 600 hypertension and 603, 660–1 management 606–7 natural history 600–1, 601 pregnancy and 898, 903 prevention 605–6 transient 600 microaneurysms, retinal see retinal microaneurysms microangiopathy cerebral 818 skin manifestations 780 stroke pathophysiology 702 1105 Index microarray gene expression studies, T2DM 192–3 Micronesian populations 55 micronutrients 347, 349, 353 microsomal triglyceride transfer protein (MTP) 676 microtubules GLUT-4 vesicle trafficking 112 insulin secretion 91 microvascular complications alcohol consumption and 389 associations between 603 determinants of individual susceptibility 565–7 global burden 71–2 hypertension and 567, 661 management 329–30 MODY 250 pancreatic diabetes 302 pathogenesis 555–68 AGE receptors 559 AGEs 557–9, 558 glycemic memory 563–5, 565 hemodynamic factors 567 hexosamine pathway flux 560–2 hyperglycemia-induced damage 556–67 mitochondrial superoxide production 562–3, 564 neovascular response to ischemia 567 polyol pathway flux 556–7, 557 potential therapies based on 567–8 protein kinase C activation 559–60, 560 unifying hypothesis 563, 564 physical activity and 360 pregnancy and 897–8 presentation of diabetes with 318–19 psychologic reactions 811–12 role of hyperglycemia 556, 556 T2DM, benefits of intensive therapy 454, 454 see also nephropathy, diabetic; neuropathy, diabetic; retinopathy, diabetic mid-frequency external muscle stimulation 630 Middle East, T2DM 54–5, 55 miglitol 471–2, 1020 chemical structure 471, 1021 mode of action 472, 1020 pharmacokinetics 472 mineral supplements 353, 1035 Minkowski, Oskar 7, 7, 13, 14 miscarriage 892 Misuse of Drugs Act 1971 389, 389–90 mitiglinide (KAD-1229) 1022, 1022, 1023 mitochondria AMPK promotion of biogenesis 120 function in obesity 232–3 glucose metabolism 562, 562–3 hyperglycemia-induced superoxide production 562, 562–3, 564, 565 mitochondrial DNA mutations 155, 253–4 polymorphisms 155 mitogen activated protein kinase (MAPK) pathway 109 MK-0431 see sitagliptin mobile phone-based telecommunication systems 990–2, 991 models of diabetes care chronic care model (CCM) 1071, 1071–7 concepts 986 different resource settings 986–97 future 1070–8 MODY see maturity-onset diabetes of the young 1106 Mogensen, Carl-Erik 18 monitoring glycemic control 399–408, 437–8 children 870–1 clinical practice 327–8, 403–7 community setting 406–7 frequency in practice 970–2, 974 future outlook 407–8 gestational diabetes 405–6 history 16, 18 hospital setting 406 importance of regular 977–9, 978 rationale 399 resource-poor settings 407 T1DM 404–5, 437 T2DM 405, 437–8 telemedicine systems 990–2, 991 tests and their characteristics 400–3 monocyte chemotactic protein (MCP-1) 233, 233, 234–5 monocytes, impaired function 836, 837 monogenic diabetes 153–6, 245–59 associated with insulin resistance 256–9 clinical presentation 315, 889 clinical subtypes 245, 246 differential diagnosis 246 with extrapancreatic features 250, 251, 253, 253–6 lipodystrophies 257–9 molecular testing 259 neonatal 26, 246, 251–3 with pancreatic exocrine dysfunction 256 relevance to adult-onset T2DM 193–5 without extrapancreatic features 245–51, 246 monogenic obesity 229 mononeuropathies limb 618 presentation of T2DM with 319 truncal 618, 619 monosodium glutamate 130 mood disorders 940–4 during course of diabetes 810–11 see also anxiety; bipolar disorder; depression morphine, painful neuropathy 630 morpholinoguanide BTS67582 1022, 1023 mortality alcohol consumption and 388, 388 elderly people 929–30 global 73–4, 74 psychotic disorders 946 T1DM 40 T2DM 57–8 motion sickness 392 motivational interviewing 338, 989, 1073 motor dysfunction, peripheral neuropathy 617 motor vehicle accidents 381, 382 mouth ulcers, islet transplant recipients 1056 MRSA see methicillin-resistant Staphylococcus aureus mSin3A, methylglyoxal modification 558 MTNR1B gene 201, 204 mTOR complex (mTORC1) 119 mTOR complex (mTORC2) 119 mTOR signaling pathway 119–20 Mucor 841 mucormycosis (zygomycosis) 841 as presenting feature 316 rhinocerebral 782, 841, 843 multidisciplinary management 324, 324–5, 975–9 chronic care model 1072 cost-effectiveness 979 different resource settings 988–9 evolving concept 975 foot problems 739 hospital inpatients 519 patient empowerment and self-care 976–7 protocol driven care 976, 977 retinopathy 579 risk stratification 976–7 see also diabetes care team multiple endocrine neoplasia type (MEN1) acromegaly 279 glucagonoma 291 somatostatinomas 291 muraglitazar 649, 1034 Murlin, Richard 13 Murphy sign 847 muscle, skeletal AMPK actions 120 contraction, stimulating glucose uptake 113–14, 182 insulin action 112–14, 113 insulin resistance 181–2 insulin-stimulated glucose transport 112–13 lipid accumulation 232 wasting, at presentation of diabetes 315, 316 muscle stimulation, mid-frequency external 630 muscular fitness 359 musculoskeletal disorders 789–99 MUSE (transurethral alprostadil) 750 Mycareteam 996 mycophenolate mofetil diabetogenic effects 272 islet transplantation 1054, 1056 new-onset T1DM 1011 side effects 1056–7 mydriatics 419 myelopathy, diabetic 619 myocardial dysfunction diastolic 685, 692 pathophysiology 687–8, 688 systolic 685 see also heart failure, congestive myocardial function, assessment 690 myocardial infarction acute (AMI) glucose lowering therapy 499–500, 515 hyperglycemia 515 in pregnancy 899 T2DM presenting with 317–18 GLP-1 therapy after 481 metformin therapy and 459 older people 928 rosiglitazone-related risk 467, 468 Myocardial Infarction National Audit Programme (MINAP), UK 515 myocardium, energy production 687–8, 689 myoinositol 893 myosin, insulin secretion 91 myotonic dystrophy 259 n-3 fatty acids see omega-3 fatty acids N-acetylglucosamine (GlcNac) 561–2 NADH mitochondria 562, 562 polyol pathway 556–7, 557 NADPH, polyol pathway 556–7, 557 NADPH oxidases 235 effects of hyperglycemia 560 NAFLD see non-alcoholic fatty liver disease nailfold infections 781, 781 nails, yellow 783 nalidixic acid 273 nasogastric tubes (NGT), acute stroke 705 Index nateglinide 464 adverse effects 465 chemical structure 465 efficacy 465 indications and contraindications 465 older people 934 pharmacokinetics 464, 465 renal failure 608 National Diabetes Data Group (NDDG) 24, 25, 27–8 national diabetes programs, implementation 986–7 National Diabetes Support Group (now NHS Diabetes) 517 National Health and Nutritional Examination Surveys (NHANES) 970, 971 National Institute for Health and Clinical Excellence (NICE) 990 depression screening 943 gestational diabetes screening 319, 907–8 patient education guidance 340 pre-pregnancy glycemic targets 901, 901 pregnancy in diabetes 889, 906–7 tocolysis in diabetic pregnancy 271 treatment targets 328, 328 National Institute of Innovation and Implementation (NHSIII) 517–18, 519 National Service Framework for Diabetes, UK 516–17 National Urban Diabetes Survey, India 54 Native Americans, T2DM 51 natural history of diabetes, historical perspective 11–13 natural killer (NK) cells, β-cell destruction 145 Nauru 55 nausea, in gastroparesis 765 NBI-6024 1009, 1011 necrobiosis lipoidica diabeticorum (NLD) 775, 775–6, 776 necrolytic migratory erythema 291, 291, 783, 783 necrotizing fasciitis 781–2, 849 as presenting feature 316 needle phobia 954 negative pressure wound therapy (NPWT) 737–8 Nelson syndrome 287–8 neonatal diabetes 26, 246, 251–3 genetic etiology 251, 252 genetic testing 253 permanent see permanent neonatal diabetes transient 251, 251, 252–3 neonatal progeroid syndrome 258 neonates of diabetic mothers 896–7 of parents with glucokinase MODY 249 see also children; infants neovascularization anterior segment 592, 593 pathogenesis 567, 591 retinal see retina, neovascularization nephrology, referral to 608–9, 609 nephropathy, diabetic 599–609 age-related increase 926 association with other diabetic complications 602–3 cardiovascular disease association 602–3, 603 cardiovascular risk management 607–8, 608 contraindicated drugs 419 definitions 599–600 dietary protein intake 348, 353, 607 economic costs 75 foot ulceration risk 730 genetic factors 566–7, 602 global burden 72, 73 historical milestones 4, 9, 13, 18 hypertension and 603, 660–1, 666 insurance and 386–7 islet transplantation and 1056, 1058 management 606–9 microvascular complications and 603 natural history 600, 600–2 organization of care 609 pregnancy 609, 898–9 prevention 330, 604–6, 605 regular review 329–30 risk factors 602, 602 screening 330, 603–4 children 872 pre-pregnancy 903 T1DM 600–1, 601 management 606, 606–7 prevention 605, 605 T2DM 601–2 classic 601–2 management 606, 607 non-classic 602 prevention 605, 605–6 see also chronic kidney disease nerve biopsy, sural 624, 624 nerve conduction velocity (NCV), measurement 622, 623 nerve growth factor gene therapy 1068 nesidioblastosis, chronic pancreatitis 300, 300 Netherlands, T2DM 53 Nettleship, Edward 4, neural processing, slowed 816, 817 neural tube defects (NTDs) 893, 899 neurocognitive dysfunction see cognitive dysfunction NEUROD1 gene 193, 194 neurogenin (Ngn3)+ β-cell progenitors 1048 neurologic features hyperosmolar hyperglycemic syndrome 317 permanent neonatal diabetes 252 neurological examination 620, 621 Neuropad test 620, 621, 732 neuropathic pain 615–16 assessment 622 clinical features 616–17, 618–19 non-pharmacologic treatment 630–1 pharmacologic treatment 626–30, 627 see also painful diabetic neuropathy neuropathy, diabetic 615–31 classification 615, 616 diagnostic assessment 620–5 exercise recommendations 373 focal and multifocal 618–19 foot infections 838 foot ulceration 729–30 global burden 72 historical descriptions 4, 8–9 islet transplantation and 1056 older people 927 painful see painful diabetic neuropathy pathogenic mechanisms 620 patient education 732 presentation of T2DM with 319 proximal see amyotrophy, diabetic regular review 329 treatment 625–31, 627 see also autonomic neuropathy; distal symmetrical sensory/sensorimotor polyneuropathy; peripheral neuropathy, diabetic Neuropathy Disability Score 620–2 Neuropathy Symptom Score 620–2 neuropeptide Y (NPY) 87 as candidate autoantigen 148 control of energy balance 133 regulation of insulin secretion 98 neuropeptides food intake regulation 133–4 regulating insulin secretion 97–8 neuropsychologic dysfunction 815–19 neurotransmitters food intake regulation 133 regulating insulin secretion 97 neutral protamine Hagedorn (NPH) insulin 430 development 17 pregnancy 905 T2DM 434, 508, 509–10 neutrophils, impaired function 836, 837 new vessel formation see neovascularization new vessels elsewhere (NVE) 583, 584, 591 new vessels on and/or within disc diameter of the disc (NVD) 583, 584, 591 New York Heart Association (NYHA) classification 685 New Zealand incidence of T1DM 33, 34 T2DM prevalence 55 NFκB see nuclear factor κB NHS Diabetes (formerly National Diabetes Support Group) 517 niacin see nicotinic acid NICE see National Institute for Health and Clinical Excellence nicorandil 463 nicotinamide new-onset T1DM 1008 T1DM prevention 1002, 1006, 1007 nicotinic acid (niacin) 676–7, 677 chemical structure 1039 glycemic effects 272, 418, 1039 nicotinic acid adenine dinucleotide see NADH nicotinic acid adenine dinucleotide phosphate see NADPH NIDDM1/CAPN10 gene (calpain-10 gene) 164, 197, 198–9, 201 Niemann–Pick C1-like protein 676 nifedipine, hypertension 665 night-eating syndrome 128 nitrates diabetogenic potential 38 phosphodiesterase inhibitor interactions 749 nitric oxide (NO) anti-atherogenic effects 640 erectile dysfunction 743–4, 744, 746 gastrointestinal complications 763 insulin action 183 penile erection 743 reduced production 560 stroke pathophysiology 701 nitric oxide synthase, endothelial see endothelial nitric oxide synthase nitrites, diabetogenic potential 38 nitrogen excretion, urinary 220–1 NN2211 see liraglutide NN9535 485 NNC 25–0926 1036 nocturia 314 non-alcoholic fatty liver disease (NAFLD) metabolic syndrome and 176, 177, 178 pathogenesis 178–80 see also fatty liver non-alcoholic steatohepatitis (NASH) 176, 177 1107 Index non-arteritic anterior ischemic optic neuropathy (NAION) 748 non-communicable diseases (NCD) 69 non-esterified fatty acids (NEFA) see free fatty acids non-insulin-dependent diabetes mellitus (NIDDM) 25 see also type diabetes non-obese diabetic (NOD) mouse, prevention studies 1002, 1005, 1008, 1011, 1065 non-payment models 1076 non-steroidal anti-inflammatory drugs (NSAIDs) contraindications 419 hyperglycemic effects 273 Noorden, Carl von 8, 10 norepinephrine (noradrenaline) concentrations in diabetes 221 excess in pheochromocytoma 288 food intake regulation 133 islet nerve terminals 87 regulation of insulin secretion 97–8 response to hypoglycemia 530 normetanephrine, serum 289 North America distribution and trends 70 T2DM 50–2 nortriptyline depression 815 hyperglycemic effects 272 painful neuropathy 627 NOTCH2 gene 201, 201 Novorapid® see insulin aspart NPH insulin see neutral protamine Hagedorn (NPH) insulin nuclear factor κB (NFκB) 111 hyperglycemia-mediated activation 558, 560, 560 inflammation in obesity 234 O-glycosylation 119 p65 subunit, epigenetic changes 565, 566, 639–40 RAGE-mediated activation 641 nurses chronic care model 1072 diabetes educator see educators, diabetes diabetes inpatient specialist (DISN) 517, 519, 520 diabetes specialist (DSN) 519, 961 facilitating transition to adult care 884 initiating insulin therapy 437, 437 insulin prescribing and delivery errors 518–19 integrated diabetes centers 962 low resource settings 988, 989 patient education 326, 961 practice 961 nutrient(s) -induced insulin secretion 92, 92–5 metabolism and storage 131–2 regulation of food intake 132 sensing, and insulin action 118–21 nutrition early life see fetal malnutrition neonates of diabetic mothers 896–7 T1DM etiology and 39 see also diet; food intake Nutritional Intervention to Prevent Diabetes study 1005–6, 1006 nutritional management see dietary management O-linked N-acetylglucosamine (O-GlcNac) 561–2 1108 O-linked N-acetylglucosamine (O-GlcNac) ase 119 O-linked N-acetylglucosamine transferase (OGT) 119, 561 obesity 227–38 adipose tissue hypoxia 235 adipose tissue inflammation 181, 234–5 adipose tissue secretory function 233–4 alcohol consumption and 388 bariatric surgery 238 β-cell function 166–7, 232–3 body fat distribution 227–8 central (abdominal; android) 180 assessment 228 ethnic specific values 176 insulin resistance 180, 182 T2DM development 236 T2DM risk 46, 228 Cushing syndrome 285 diagnosis and classification 227–8, 228 diffuse idiopathic skeletal hyperostosis 795 drugs promoting 130, 237–8 endoplasmic reticulum stress 235 environmental factors 127–31, 231, 231 etiology 126–34 epidemiologic model 127–31 homeostatic model 131–4 fetal programming/epigenetics 127, 230 genetic factors 126–7, 229–30 gestational diabetes 891 gynoid 180 infection susceptibility 837 insulin resistance 167, 179, 179, 182, 232–6 insulin secretion 164, 232–3 liver fat content 179, 180 monogenic 229 osteoarthritis 795 oxidative stress 235 pathophysiology 230 pregnancy and 892, 896, 899 weight gain targets 907 regional patterns 56, 57 stroke risk 701 T2DM and epidemiologic studies 46, 228, 229 management 237–8 metformin therapy 458–9 pathophysiologic mechanisms 232–6, 236 treatment 236–8, 496–7 see also antiobesity drugs; body weight; weight reduction octreotide chemical structure 1036 diabetic diarrhea 770 drug-induced hypoglycemia 412, 414 glycemic effects 271 suppression of glucagon 1036 offloading devices Charcot neuroarthropathy 738 foot ulcers 735 offspring of diabetic mothers birth weight 894 diabetes risk 897 neonatal complications 896–7 obesity risk 127 renal transplant recipients 899 Ogle, William OGTT see oral glucose tolerance test okadaic acid 1037, 1037 olanzapine, diabetogenic effects 272, 929, 949 older people 922–36 acute metabolic complications 925–6 in care homes 935, 935 chronic diabetic complications 926–8 cognitive dysfunction 819, 928, 928 diagnosis of diabetes 930 disability 929, 930–1 epidemiology of diabetes 923, 923–4, 924 etiology of diabetes 924–5 exercise 360, 371 insulin treatment 934, 934–5 lifestyle modification 933 management of diabetes 930–5, 931 aims 933 cardiovascular risk 932–3 modern strategy 935–6, 936 prioritizing care 930, 930–1, 931 treatment targets 931–2, 932 mental illness 928–9 mortality 929–30 oral antidiabetic agents 456, 933–4 presentation of diabetes 314, 930, 930 special needs 923 T1DM 934–5 T2DM 922, 923 management 930–5 pathogenesis 924, 924, 924–5 treatment targets 931–2, 932 omega-3 (n-3) fatty acids 39, 348, 352, 1005–6 omentin 1032 ophthalmoplegia, diabetic 618 ophthalmoscopy binocular indirect 579 direct 579 opiates 389–90 Opie, Eugene L 13, 14 opioid receptors, food intake regulation 133 opioids, painful neuropathy 627, 629–30 optic neuropathy, non-arteritic anterior ischemic (NAION) 748 optical coherence tomography (OCT) 580, 581 maculopathy 584, 588 oral antidiabetic agents 452–74, 455 acute stroke 704 cautions and contraindications 456 combination therapies 497–510 colesevelam 506–7 fixed-dose pills 473–4, 474, 499 with incretin mimetics 504–6 with insulin 508–10 older people 934, 934, 935 oral agents only 499–503 rationale 498–9 dose adjustments for exercise 373 driving restrictions 382, 384 drug interactions 413, 414, 414–15, 457 gestational diabetes 908 history 16, 17 inducing hypoglycemia 411–14, 412 initial monotherapy 498, 498 lipid-lowering effects 677 modes of action 455, 455 older people 456, 933–4 pharmacogenetic studies 206–7 pre-pregnancy 902 pregnancy 456, 906 regular review 327 skin reactions 785, 785–6 stroke prevention 702 travelers 393 see also biguanides; gliptins; α-glucosidase inhibitors; meglitinides; sulfonylureas; thiazolidinediones; specific agents oral candidiasis 781 Index oral contraceptive pill (OCP) contraception in diabetes 753 diabetogenic effects 267–8 oral glucose tolerance test (OGTT) acromegaly 280, 282 assessing β-cell function 161, 161 children 861 diagnosis of diabetes 28, 29 gestational diabetes 30 MODY 247, 250 post-myocardial infarction 317–18 prediction of T1DM 1005 problems with 29 screening for diabetes 320 oral insulin, T1DM prevention 1002, 1006, 1006, 1007, 1007–8 oral insulin administration 431, 432 oral rehydration fluid 870 orexin A (hypocretin) 134 organic cation transporter (OCT1) gene 207 organizations, diabetes 20 organochlorines, body fat stores 130 orlistat glucose-lowering effects 473 prevention of T2DM 497 serum lipid effects 677 T2DM 238, 496–7 orthoses, foot 732 osteoarthritis 795 osteomyelitis 850 foot 737, 850 diagnosis 736, 737 treatment 737 malignant otitis externa 841 osteoporosis 796–9 epidemiology 796, 797 hormone replacement therapy 755 investigation and management 799 pathogenesis 796–9, 798 osteoprotegerin (OPG) 647–8, 738 other specific types of diabetes 26, 26–7 otitis externa, malignant 781, 841 outcome expectancy 820–1 ovarian cysts, islet transplant recipients 1056 overweight 228 etiology 126–34 environmental/epidemiologic model 127–31 epigenetic factors 127 homeostatic model 131–4 genetic factors 126–7, 229–30 metformin therapy 458–9 T2DM risk 228, 229 see also obesity oxcarbazepine, painful neuropathy 629 oxidative stress diabetic pregnancy 892–3 impaired insulin action 121 obesity 235 renin angiotensin system and 645 oxycodone, painful neuropathy 627, 629–30 oxygen-regulated protein of 150 kDa (ORP150) 235 oxymetholone 272 P32/98 1027, 1027 p90 ribosomal protein S6 kinase (p90 S6 kinase) 109 Pacific Islands, T2DM 55–6 paclitaxel 416 painful diabetic neuropathy 615–16 acute 618 clinical features 616–17 depression and 943 focal and multifocal 618–19 non-pharmacologic treatment 630–1 older people 927 pharmacologic treatment 626–30 see also neuropathic pain Pakistan costs of diabetes 77 T2DM 54 pamidronate, Charcot neuroarthropathy 738, 793 pancreas artificial 448–9, 1051 donor organs, shortages 1059 endocrine tumors 290–2 extracts 9, 10, 11 fetal development, diabetic pregnancy 893–4 “internal secretions” 7, 9, 428 lineage reprogramming 1048–9 molecular pathways in development 154 preservation, for islet transplantation 1053 stem cells 1048 pancreas-duodenum homeobox-1 see Pdx-1 pancreas transplantation 1052 history 1051 see also islet transplantation pancreas–kidney transplantation 1052 pregnancy after 898–9 pancreatectomy, diabetes after 306 pancreatic calculi chronic pancreatitis 299, 300, 301 tropical calcific pancreatitis 303, 303 pancreatic carcinoma 306 association with diabetes 306 tropical calcific pancreatitis 303 pancreatic diabetes, fibrocalculous see fibrocalculous pancreatic diabetes pancreatic disease 26, 27, 298–307, 299 clinical presentation 315 pancreatic exocrine insufficiency after pancreatic surgery 306 chronic pancreatitis 300, 302 diarrhea 764–5 monogenic diabetes with 256 pancreatic polypeptide (PP) 87, 97 pancreatic surgery, diabetes after 306 pancreatitis acute 298–9, 299 GLP-1 analog-related 483, 484 chronic 299–302 alcoholic 299, 301, 303, 303, 387 causes 299 clinical features and diagnosis 300 diabetes in 302 investigations 300–2, 301 pathologic features 299–300, 300, 300 fibrocalculous see fibrocalculous pancreatic diabetes hereditary chronic 299 idiopathic 299 inherited lipodystrophies 257, 258 obstructive chronic 299 tropical calcific 156, 299, 302–3, 303, 304 panel reactive antibodies (PRA), after islet transplantation 1057 papaverine, intracavernosal injection 750 Papua New Guinea, T2DM 55 paracetamol 414–15 parasympathetic nervous system control of penile erection 743 gastrointestinal motor control 761, 761 islet cell innervation 87, 97 regulation of insulin secretion 97–8 tests of function 768 parathyroid hormone (PTH), hypersecretion 292–3 parenteral therapies, non-insulin 478–88 parents adolescents 876, 877 factors affecting glycemic control 822 fears and phobias 812–13 newly-diagnosed children 808–9 paronychia 781, 781 Parving, Hans-Henrik 18 patient(s) adherence to therapy see adherence barriers to achieving treatment targets 972–3 diagnostic consultation 313–14 education see education, patient “ideal” appointments 1077–8 involvement in health care and service development 331 partnership philosophy 324, 324 as team member 519 see also health care professional–patient relationship patient-centered care 324, 325, 989 future directions 1077–8 patient-centered educational approaches 336–7 patient-centered medical home 1077 Patient Health Questionnaire (PHQ-9) 943 Paulesco, Nicolas 10, 11, 428 Pavy, Frederick 4, 8–9 pay for performance (P4P) models 1076 PBX1 gene 199 PC-1 (ENNP1) 109–10, 195–6 gene 195–6, 201 as therapeutic target 1030 Pdx-1 (IPF-1) 194 effects of free fatty acids 167 gene transduction studies 1066 GLP-1 actions 479, 1024 intrauterine growth restriction and 894 regenerating pancreas 1048 PDX1 gene mutations see IPF1 gene mutations Pedersen, Jørgen 19, 19 pediatric patients see children pegaptanib 593–4 pegvisomant 281, 282 pelvic floor retraining 770 pelvic inflammatory disease (PID) 754 penile prostheses 751, 751 pentamidine β-cell toxicity 269, 269 induced hypoglycemia 414 people with diabetes see patient(s) peptide heat shock protein 60 (DiaPep277), newonset T1DM 1009, 1010 percutaneous endoscopic gastrostomy (PEG), acute stroke 705 percutaneous transluminal angioplasty (PTA) (and stenting) acute limb ischemia 716 complications 715 lower limb ischemia 713–14, 714 results 714, 715–16 perflurodecalin (PFC) 1053 perforating dermatoses 783–4, 784 pericytes, retinal 577 loss of 578, 578–9 perilipins 115 perimetry 580 perinatal risk factors, T1DM 39 1109 Index perindopril cardiovascular protection 646, 649 hypertension 665 nephropathy prevention 605–6 perinephric abscess 845 periodontal disease 841–2 as presenting feature 320 peripheral aneurysms 720 peripheral arterial disease (PAD) 710–20 acute lower limb ischemia 710, 716, 716–17 arms 717–18 asymptomatic stage 711 conservative management 713 critical ischemia see critical limb ischemia diagnosis 712, 712 foot ulceration 729, 729 functional pain see claudication incidence 710–11 interventional treatment 713–16, 714 lower limbs 710–16 older people 926, 927 pathophysiology 711 prognosis 712 renal and mesenteric arteries 717 stages 710 treatment 712–16 peripheral neuropathy, diabetic 615–31 alcohol consumption and 389 classification 615, 616 clinical assessment 620–3, 621, 731–2 clinical manifestations 616–20 CNS dysfunction 619, 619–20 diagnostic assessment 620–5 distal symmetric see distal symmetrical sensory/sensorimotor polyneuropathy electrodiagnostic measures 622, 623 epidemiology 615–16 exercise recommendations 373 focal and multifocal 618–19 nephropathy and 603 older people 927 painful see painful diabetic neuropathy pathogenic mechanisms 620 quantitative sensory testing 623, 624 skin biopsy 624–5, 625 sural nerve biopsy 624, 624 travel precautions 392 treatment 625–31, 627 see also neuropathy, diabetic peripheral vascular disease 710–23 see also peripheral arterial disease permanent neonatal diabetes (PNDM) 251, 252 causes 251, 252 clinical features 252 KATP 93, 246, 251, 252 management 252 peroxisome proliferator-activated receptor-α (PPAR-α) 501 peroxisome proliferator-activated receptor-α/γ (PPAR-α/γ) dual agonists 649, 1034 peroxisome proliferator-activated receptor-δ (PPAR-δ) agonists 1034 peroxisome proliferator-activated receptor-γ (PPAR-γ) 466, 466, 466–7, 501 agonists 1033, 1034, 1035, 1035 see also thiazolidinediones gene see PPARG gene regulation of bone metabolism 799 peroxisome proliferator-activated receptor-γ coactivator see PGC-1 peroxisome proliferator-activated receptor modulators, selective (SSPARM) 1034 1110 peroxisome proliferator response element (PPRE) 466, 466, 1034 persistent hyperinsulinemic hypoglycemia of infancy (PHHI) 93 person with diabetes see patient(s) personal identification 391 personality, metabolic control and 820–1 personality disorder 954 Petters, Wilhelm 13 pexelizumab 648 PGC-1 117, 118, 466 PGC-1α 193, 196, 1040 PGC-1β 193 phagocytosis, impaired 837 Phalen test 792 pharmacists 976, 1072 pharmacogenetics, T2DM in adults 206–7 phenformin 17, 457 phentermine 496 phentolamine closure of KATP channels 1022 intracavernosal injection 750 phenyl butyric acid 121 phenylpropanolamine 133 phenylthiazolium bromide 641 phenytoin 272 pheochromocytoma 288–90 phimosis, Candida 781 phlorizin 1039, 1040 phobias needle 954 treatment-induced 812–13 phorbol esters 1037 phosphatase and tensin homolog see PTEN phosphate therapy, diabetic ketoacidosis 550, 862 phosphatidylinositol (PtdIns) 107 phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) 107 accelerated catabolism 111 as therapeutic target 1028, 1031 phosphatidylinositol-3 (PI3) kinase (PI3K) 107 mTOR pathway activation 120 p85 subunit 107 p110 subunit 107 as therapeutic target 1028, 1030–1 phosphodiesterase (PDE 5) 744, 747 phosphodiesterase (PDE 5) inhibitors 747–9 adverse effects 748, 748 autonomic neuropathy and 419 cardiovascular safety 748–9 female sexual dysfunction 752 non-responsiveness 748, 749 phosphodiesterase (PDE) inhibitors, β-cell-specific 1026–7 phosphoenolpyruvate carboxykinase (PEPCK) 116–18 3-phosphoinositide-dependent protein kinase (PDK1) 107 phosphoinositol phosphatases 111 phospholipase A2, cytosolic (cPLA2) 94, 97 phospholipase C (PLC) activators 1027 regulation of insulin secretion 93–4, 96, 97 photography, retinal 329, 579 Phycomyces infections 782 physical activity defined 359 diabetic complications and 360, 360 insulin resistance and T2DM and 182 overweight/obesity and 129–30, 231 prevention of weight gain 131 see also exercise physical measures, painful diabetic neuropathy 630 physician–patient relationship see health care professional–patient relationship physicians (doctors) barriers to achieving treatment targets 973 clinical inertia 1070–1 hospital clinics 961 insulin prescribing and delivery errors 518 lifestyle advice 496 low resource settings 988 role in multidisciplinary team 325, 519, 976 see also general practitioners physiotherapy, frozen shoulder 791 phytophenols 1033 Pickup, John 17 Pima Indians diabetic nephropathy 601 intrauterine imprinting 127, 897 T2DM prevalence 51, 923 T2DM susceptibility loci 198 pinitol 1030, 1031 pioglitazone 466 adverse effects 468 cardiovascular safety 468, 503, 677, 678, 702 chemical structure 466, 1035 combination therapy 501–3 efficacy 467–8 indications and contraindications 467 older people 934 pharmacokinetics 467, 467 renal failure 608 serum lipid effects 468, 677 skeletal effects 503, 798, 798–9 pioglitazone–glimepiride combination 474, 501 pioglitazone–metformin combination 474, 501 piqûre diabetes pituitary adenomas ACTH secreting 284–5, 287 growth hormone-secreting 279, 280, 281, 282 pituitary adenylate cyclase-activating polypeptide (PACAP) 87, 98 placenta, effects of maternal diabetes 891 placental growth hormone 890 PLAGL1 gene 252 plant-derived compounds, potentiating insulin action 1033 plasma differentiation factor see PC-1 plasmapheresis, newly diagnosed T1DM 1001 plasminogen activator inhibitor (PAI-1) hyperglycemia-mediated induction 560, 561 insulin resistance 183 obesity 233, 234 platelet-derived growth factor (PDGF) therapy, foot ulcers 737 platelet hyperactivity 702 pluripotent stem cells, induced (iPS cells) 1048, 1049 pneumococcus see Streptococcus pneumoniae Pneumocystis jirovecii pneumonia drug-induced hypoglycemia 414 drug therapy 269 pneumonia 842–3 PNPLA3 gene 180 podiatry 732 POEMS syndrome 293 police custody 380, 386 pollutants, environmental, T2DM risk 47 polycystic ovary syndrome (PCOS) 293–4, 294 infertility 891 Index metformin therapy 294, 459 skin conditions 782 type A insulin resistance 257 polycythemia, neonatal 897 polydipsia 4, 314 polyglandular syndromes, autoimmune see autoimmune polyglandular syndromes polyglandular theory, von Noorden’s Polynesian populations, T2DM 55–6 polyol pathway 556–7, 557 poly(ADP-ribose) polymerase (PARP) 563 inhibitors 568 polytetrafluoroethylene (PTFE) grafts, peripheral bypass surgery 714, 715 polyuria clinic-based review 327 historical descriptions 3, 4, at presentation 314 popliteal aneurysms 720 porcine insulin 429, 430 portal vein thrombosis, islet transplantation 1052, 1056 Portuguese Association for the Protection of Poor Diabetics 20 positron emission tomography (PET), pheochromocytoma 289 post-absorptive state see fasting post-prandial hyperglycemia 216–17 α-glucosidase inhibitors 471–2, 473 antidiabetes agents targeting 500, 500 gliptins 469 meglitinides 464, 465 rapid-acting insulin analogs 431 T1DM 218 T2DM 177, 218–19 post-prandial state blood glucose monitoring 406 glucose metabolism 216–17, 217 T1DM 218 T2DM 177, 218–19 sources of hepatic fatty acids 178–9 post-transplantation diabetes mellitus (PTDM) 271–2 post-traumatic stress disorder (PTSD), parents 808–9 postoperative care 525–6 postural hypotension 661 potassium, serum diabetic ketoacidosis 549, 862 insulin-resistant states 183 potassium channels, ATP-sensitive see ATPsensitive potassium channels potassium therapy, diabetic ketoacidosis 550, 862 potato consumption 38–9 potential abnormality of glucose tolerance (PotAGT) 25 poverty 52–3, 79, 79 PPAR see peroxisome proliferator-activated receptor PPARG gene mutations, familial partial lipodystrophy 257 polymorphisms response to thiazolidinediones and 206 T2DM association 106, 164, 201 PPARGC1 gene polymorphism 196 pramlintide 132, 486–8, 500 chemical structure 486 human studies 486–8 side effects and drawbacks 488 prandial insulin releasers see meglitinides Prandimet see metformin–replaglinide combination prayer sign 789 pre-adipocytes 234–5 pre-diabetes see intermediate hyperglycemia pre-eclampsia 898 Pre-POINT trial 1006, 1006 pre-pregnancy care 331, 900–3 access to 900 evidence of effectiveness 900 folic acid supplementation 901 lifestyle advice 901–2 optimal glycemic control 900–1, 901 provision of information 900 review of medications 902 screening for diabetic complications 902–3 prefrontal cortex (PFC), control of food intake 133 pregabalin, painful neuropathy 627, 629 pregnancy 888–910 antenatal management 903–8 first trimester 906–7 second trimester 907 third trimester 907 continuous glucose monitoring 407, 904 diet 354, 354, 906–7 glycemic control 903–6 history 19 insulin treatment 904–5 lifestyle advice 906–7 oral antidiabetic agents 456, 906 autoimmune diseases and 899–900 β2-agonists for tocolysis 271 classification of diabetes 889–90 contraindications to 753 effect of maternal diabetes on 891–6 epidemiology of diabetes in 889–90 glucokinase MODY 249, 249, 889 HNF1A and HNF4A MODY 251 hypoglycemia risk 901, 903–4 intrapartum management 908–9 macrovascular complications and 899 management 900–10 metabolic changes gestational diabetes 891 normal women 890 pre-existing diabetes 891 nephropathy and 609, 898–9 obese women 892, 896, 899, 907 outcomes 889, 890, 892–7 physiologic insulin resistance 319, 890 planning 331, 900 postnatal management 909–10 presentation of diabetes in 319–20, 889, 891 retinopathy and 594–5, 897–8 risks to mother 897–900 smoking during 127 T1DM 889–90 antenatal care 906 breastfeeding 909 diabetes risk in offspring 897 glycemic management 903–5 intrapartum management 908–9 metabolic changes 891 nephropathy and 898 pre-pregnancy care 900, 901 retinopathy and 897–8 T2DM 889–90 antenatal care 906 diabetes risk in offspring 897 glycemic management 903, 905, 906 metabolic changes 891 pre-pregnancy care 901 stillbirths 896 timing and mode of delivery 908 White classification 890 see also gestational diabetes mellitus; offspring of diabetic mothers; pre-pregnancy care preoperative evaluation 523–4, 524 preproinsulin 88 gene see INS gene preretinal hemorrhages (PRH) 583, 584 prescriptions 961 presentations of diabetes see clinical presentations of diabetes PressureStat 732, 734 preterm delivery 908 diabetic nephropathy 898 preterm infants 896–7 prevention of diabetes after gestational diabetes 909–10 comprehensive approach 986–7 Internet-based systems 996 psychotic disorders 949–50, 950 T1DM 13, 860, 1005–11 historical studies 1001–2 identifying those at high-risk 1002, 1002–5 primary 1005–6, 1006 secondary 1006–8, 1007 tertiary 1008–11, 1009 T2DM 59, 60, 61 acarbose 61, 472 exercise 364–5 metformin 61, 460, 500–1 orlistat 497 thiazolidinediones 61, 468 weight loss 348 PREVFIN trial 1005, 1006 previous abnormality of glucose tolerance (PrevAGT) 25 priapism 750, 750 primary care 325, 960–1, 1071 capitation payments 1076 chronic care model 1077 communication with specialist care 964, 965–7 delivery system design 1072–3 erectile dysfunction management 751–2 low resource settings 987, 988 psychotic disorders 949 shared-care approach 962–3 technology-based clinical support 992, 993 traditional 961–2 see also community-based diabetes care; general practitioners prison 380, 386 private specialist diabetes care 961–2 pro-opiomelanocortin (POMC) 133–4 PROactive trial 503 progeroid syndrome, neonatal 258 progesterone-only pill (POP) contraception in diabetes 753 hyperglycemic effects 267 progestogens (progestins) diabetogenic effects 267 long-acting depot 267, 753 prohormone convertases and 89, 91, 163 proinsulin autoantibodies 147 biosynthesis 1, 88–9, 90 discovery 15 gene see INS gene processing 89, 90, 91, 163 genetically engineered cells 1066 1111 Index proinsulin (cont.) secretion 89–90 split products 91, 163 proinsulin-based DNA vaccine (BHT-3021), new-onset T1DM 1009, 1011 proinsulin peptide, new-onset T1DM 1011 proinsulin : proinsulin conversion intermediate ratio, T2DM 164 prokinetic agents, in gastroparesis 769 propranolol, diabetogenic effects 268 prostacyclin synthase, therapies targeting 568 prostaglandin E1 see alprostadil prostaglandin E2 (PGE2), diabetic pregnancy 893 prostaglandins diabetic teratogenesis and 893 role in islet function 94–5 prostate cancer risk, and T2DM 194, 203 protamine insulinate 16 protamine isophane insulin 430, 430 protamine-zinc insulin 16–17, 430 protease inhibitors (PI), diabetogenic effects 46–7, 270–1, 840 protein dietary intake 353 in nephropathy 348, 353, 607 observed 350 recommendations 347, 348, 349 metabolism 220–1 protein kinase A (PKA) regulation of insulin secretion 95, 96 regulation of lipolysis 115 protein kinase B see Akt/protein kinase B protein kinase C (PKC) atypical (aPKC), insulin signaling pathway 108 conventional (cPKC) 108 glucose-mediated activation 559–60 inhibitors 1030, 1030 insulin receptor and IRS protein inhibition 110 insulin secretory role 95, 96 novel (nPKC) 108 regulation of insulin secretion 97 protein phosphatase (PP1), glycogen associated regulatory subunit 196 protein tyrosine phosphatase-1B (PTP-1B) gene variant 196 inhibitors 1030 modulation of insulin signaling 110 protein tyrosine phosphatases (PTPases) 110 proteinuria cardiovascular disease risk 602, 603 definitions 600, 658 hypertension and 603, 660–1 management 606–7 natural history 600–1, 601 pregnancy and 898 prevention 605–6 Prout, William pruritus 783 Pryce, Thomas Davies Pseudomonas infections 781, 841, 845 pseudotabes, diabetic 616 psoas abscess 847 psychiatric disorders 940–54 older people 928–9 psychologic distress 808–15 acute metabolic complications and 812 diabetic complications triggering 811–12 established diabetes 809–11 foot ulcer healing and 735 identification 824 1112 inherited lipodystrophies 258 interventions 814–15 management 330–1 newly-diagnosed diabetes 326–7, 808–9 see also anxiety; depression psychologic factors 807–25 diabetes management 810, 819–24, 820 impact of diabetes 808–15 see also cognitive dysfunction psychologic interventions, to improve adherence 823–4, 824 psychologic states 820, 821–2 psychologic support, painful neuropathy 630 psychologic traits 820–1 psychologist, pediatric 863, 864 psychomotor slowing 816, 817, 818 psychosexual counseling 747 psychosocial factors, depression and diabetes 942 psychotherapy depression 944 to improve adherence 823–4 psychologic distress 814 psychotic disorders 944–50 epidemiology 945 with established diabetes 950 management 948–50 mechanisms of link with diabetes 948, 948 mortality 946 prevention of diabetes 949–50, 950 as risk factor for diabetes 946–8 screening for diabetes 950 see also bipolar disorder; schizophrenia psychotropic agents, diabetogenic effects 272 PTEN 107, 111 as therapeutic target 1028, 1031 PTF1A gene mutations 251 PTPN1 gene variants 196 PTPN2 gene 143 PTPN22 gene 143, 144 pubertal growth, effects of diabetes 284, 284 PUVA therapy, necrobiosis lipoidica diabeticorum 776 pyelonephritis acute 844 emphysematous 845–6, 846 pyomyositis 849 pyriminil 270 quality assurance, blood glucose measurements 403 quality of care evaluation 970–2, 974 factors compromising 972–5 models of payment for improving 1076–7 quality of life 813–14 diabetes-specific 813–14 erectile dysfunction 746 general health-related 813 insulin pump therapy and 442 quantitative sensory testing (QST) 623, 624 quetiapine, diabetogenic effects 949 quinagolide 282 quinine/quinine derivatives 414 quinolone antibiotics 414 R1438 1027 Rab-GTPase-activating protein (GAP) 108 Rabson–Mendenhall syndrome 257 radio-immunoassay 15 radiocontrast media 419 radiotherapy, acromegaly 281, 282 Raf-1 kinase 109 RAGEs see receptors for advanced glycation end-products Rahbar, Samuel 18 ramipril cardiovascular protection 649 hypertension 665, 667 nephropathy prevention 605 older people 932 prevention of T2DM 59 stroke prevention 702 ranibizumab 593–4 RANKL inhibitors, Charcot joint 793 role in Charcot joint 738, 793 rapamycin see sirolimus Ras 109 Ras-p38 MAP kinase pathway 109 reactive oxygen species (ROS) atherogenic effects 639 diabetic pregnancy 892–3 impairment of insulin action 121 mechanisms of induction 558, 560 mitochondrial overproduction 562, 562–3, 565 obesity 235 renin angiotensin system and 645 therapies targeting 568 receptor activator of nuclear factor κB ligand see RANKL receptors for advanced glycation end-products (RAGEs) 559, 641 antagonists 642, 649 downstream effects of activation 641, 641 soluble (sRAGE) 642 RECORD trial 503 records, patient 988, 996 recreational drug use see drug use, recreational rectal balloon expulsion test 767 registries, diabetes 987–8, 1072, 1073–4, 1075 relaxation training 824 Removable Cast Walkers (RCW) 735 RENAAL study 607 renal artery stenosis (RAS) contraindicating ACE inhibitors 417 diagnosis 662, 663 management 717 renal cell carcinoma, HNF1B MODY 256 renal cysts and diabetes (RCAD) (HNF1B MODY; MODY5) 193, 255–6 clinical features 254, 255, 255–6 congenital malformations 892 renal disease chronic see chronic kidney disease diabetic see nephropathy, diabetic end-stage see end-stage renal disease HNF1B MODY 255–6 inherited lipodystrophies 258 renal failure contraindicated drugs 419 exenatide 482, 608 gliptins (DPP-4 inhibitors) 470, 608 maternally inherited diabetes and deafness 255 renal cysts and diabetes (HNF1B MODY) 255–6 retinopathy treatment and 593 sulfonylurea-induced hypoglycemia 412 renal function assessment 603–4, 662–3 effects of pregnancy 898 islet transplantation and 1056 Index staging of kidney disease 599–600, 600 see also creatinine, serum; glomerular filtration rate renal papillary necrosis 845 renal replacement therapy (RRT) 599 referral for 608–9, 609 renal threshold for glucose 314, 407 MODY 250 renal transplant recipients 851 pregnancy 898–9 renin angiotensin system (RAS) 642–6 classic pathway 642, 643 hypertension and 661 interaction with AGEs 642 novel aspects 642–3, 643 role in macrovascular disease 643–5, 644 renin angiotensin system (RAS) inhibitors cardiovascular protection 646 endothelial dysfunction and 645–6 nephropathy management 606–7 nephropathy prevention 605, 606 see also angiotensin II receptor blockers; angiotensin-converting enzyme (ACE) inhibitors repaglinide 464 adverse effects 414, 465 chemical structure 465 drug interactions 416 efficacy 465 indications and contraindications 464–5 older people 934 pharmacokinetics 464, 465 renal failure 608 repaglinide–metformin combination 474 repetition 359 resistance exercise 359 healthy individuals 360 intensity of 359 recommendations 371, 372, 372–3 T1DM 363–4, 364 T2DM 366–7, 368, 369–70 resistin 99, 1032 respiratory distress syndrome, neonatal 897 respiratory tract infections 842–3 rest pain 711 see also critical limb ischemia restaurants 128, 231 resting metabolic rate (RMR) 230 resveratrol 1032, 1033 retina 575 arteriolar abnormalities 583 blood flow 579 in pregnancy 897 ischemia 579 lesions associated with 590–1 new vessel formation 591 signs of severe 592 neovascularization appearances 583, 584, 591, 591 pathogenesis 591 photography 579 structure 577 venous abnormalities 583 retinal blood vessels 575, 577 basement membrane 577 thickening 578, 578 constriction in pregnancy 897 lesions 581–4 pathophysiologic changes 578, 578–9, 579 retinal capillaries acellular 579 increased permeability 579 microaneurysms see retinal microaneurysms weakening 579 retinal hemorrhage/microaneurysm (HMa) 582, 582 retinal hemorrhages 581–2, 582 classification of retinopathy 590, 590, 591, 591 larger 582, 582 small 581 retinal microaneurysms 581, 582 mild non-proliferative retinopathy 590, 590 pathophysiology 579, 579 retinoid X receptor (RXR) 466, 466, 1034 selective modulators 1034 retinoids, topical, necrobiosis lipoidica diabeticorum 776 retinol-binding protein (RBP-4) 234, 1032 retinopathy, diabetic (DR) 575–95 acromegaly and 282 advanced 591–3 age-related increase 578, 926 alcohol consumption and 318–19, 389 background 590, 590 classifications 584–93, 585–7 clinical assessment 579 contraindicated drugs 419, 419–20 depression as risk factor 812, 943 exercise recommendations 371, 373 genetic factors 567, 578 global burden 72 historical perspective 4, 8, 8, 13, 18, 575, 576 intravitreal VEGF inhibitors 593–4 investigations 579–80 islet transplant recipients 1055–6 laser treatment see laser treatment, retinal lesions 581–4, 582, 583, 584 low vision and blindness 595 maternally inherited diabetes and deafness 255 multidisciplinary management 579 nephropathy and 603 non-proliferative mild 585, 590 moderate and severe 585, 590–1 older people 926–7 pathogenic role of AGEs 558 pathophysiologic events 578, 578–9, 579 pre-proliferative 590–1 pregnancy and 594–5, 897–8 presentation of diabetes with 318, 318–19 prevention 927 proliferative (PDR) 591–3 classification 585 laser treatment 591–3, 592 low risk patients 592 with maculopathy 593 pathogenesis 591 psychologic reactions 811–12 as risk factor for CNS abnormalities 818 risk factors 575–8 screening 329, 580–1 children 873 low resource settings 988 older people 926–7 pre-pregnancy 902 shared-care approach 963 vitrectomy 594, 594 see also maculopathy, diabetic Reuting, Ruth 16 revascularization carotid 721–3 peripheral arterial disease 713–16, 714 rheumatic disorders 789–95 rheumatoid arthritis 795 rhinocerebral mucormycosis 782, 841, 843 Rhizopus 838, 841 ribosomal S6 kinase (S6K) 119–20 rictor 119 rifampicin 415, 416 rimonabant 496, 497, 678 effect on insulin action 1033 serum lipid effects 677 risk states, diabetes 25, 27–8 risk stratification 975–6 risperidone, diabetogenic effects 272, 929, 949 ritodrine, hyperglycemic effects 271 rituximab, new-onset T1DM 1009, 1010 rivoglitazone 1033, 1035 Rollo, John 4, 5–6, 6, Roma, Ernesto 20, 20 Root, Howard 18–19 rosiglitazone 466 adverse effects 468 cardiovascular safety 467, 468, 503, 677, 678, 702 chemical structure 466, 1035 combination therapy 501–3, 505 drug interactions 416, 467 efficacy 467–8 indications and contraindications 467 initial monotherapy 498, 498, 501–2 older people 934 pharmacokinetics 467, 467 prevention of T2DM 61 renal failure 608 serum lipid effects 468, 677 skeletal effects 503, 798, 798–9 rosiglitazone–glimepiride combination 474, 501 rosiglitazone–metformin combination 474, 501 rubella, congenital 38 rubeosis faciei 780 ruboxistaurin (LY333531) 1030, 1030 rural areas adolescents in 879, 885 model of care 988 see also urbanization Russia, T2DM 53 S100 calgranulin family proteins 559 S22068 1022, 1023 sacral agenesis 892 salbutamol, hyperglycemic effects 271 salicylates hypoglycemic effects 415 inhibition of IKKβ 111, 1030 saline infusions diabetic ketoacidosis 550, 862 hyperosmolar hyperglycemia 551 older people 925 salivation, excess, as presenting feature 320 Salmonella 849 salt intake 347, 353 Sanger, Frederick 13, 15, 15, 428 Sardinia, T1DM 33 sauna, subcutaneous insulin absorption 433 saxagliptin 468, 1026, 1027 chemical structure 1027 Scandinavia, T2DM 53 schizophrenia 944–50 case definition 945, 945 epidemiology 945 impact on overall functioning 945, 945 management 948–50 mechanisms of link with diabetes 948, 948 1113 Index schizophrenia (cont.) mortality 946 as risk factor for diabetes 946–8, 947 schools, diabetes management 864 scintigraphy, gastrointestinal motility assessment 762, 767 sclerodactyly 778 scleroedema of diabetes 778 Scott, Ernest 10 screening abdominal aortic aneurysms 720 chronic kidney disease 603–4, 604 depression 943 diabetes 320 after gestational diabetes 910 psychotic disorders 950 diabetic complications 328–30, 978 low resource settings 988 foot ulcers 731–2, 732 gestational diabetes 319, 907, 907–8 hypertension 661–2 nephropathy 330, 603–4 retinopathy see under retinopathy, diabetic seasonal affective depressive syndrome (SADS) 130 seasonal variations, diagnosis of T1DM 35, 35 secondary care 325 see also specialist care selective peroxisome proliferator-activated receptor modulators (SSPARM) 1034 selective serotonin reuptake inhibitors (SSRIs) depression 815, 944 older people 929 hyperglycemic effects 272 painful neuropathy 628 self-care behaviors 822–3 AADE7TM 334, 336 drafting a written plan 342 educational approach to changing 335–6 see also adherence self-efficacy 820–1, 878, 1073 self-management of diabetes automated feedback systems 993, 993 barriers to, adolescence 878 education see education, patient hospital inpatients 331, 406, 517 interactive feedback systems 991, 993–4, 994, 995 lack of appropriate support 1070–1 merged feedback systems 994–6 mobile phone-based systems 990–2, 991 patient empowerment 976–7 prevention of hypoglycemia 538–9 promotion during adolescence 878 psychologic processes 819–24, 820 support 1072, 1073 transition to, adolescents 877–8 self-monitoring of blood glucose (SMBG) 404, 437–8 adherence 822–3 childhood illness 869 children 870, 871 effectiveness 405 falsification of results 327 gestational diabetes 405–6 pre- and post-exercise 373–4 pregnancy 904 prevention of hypoglycemia 539 recommended frequency 978 recording of results 870 resource-poor settings 407 review at clinic 327 1114 T1DM 404 T2DM 405 technique 404, 404 telemedicine systems 990–2, 991 travelers 392 usefulness 406–7 semilente insulin 430 sensorimotor neuropathy clinical manifestations 616–18, 617 foot ulceration 730 see also distal symmetrical sensory/ sensorimotor polyneuropathy sensory deficits distal symmetric polyneuropathy 616, 617 foot ulceration risk 730 septic arthritis 850 serine–threonine phosphorylation, insulin receptor substrate proteins 110–11 serotonin, food intake regulation 133 serotonin noradrenaline reuptake inhibitors (SNRIs), painful neuropathy 627, 628–9 set (of resistance exercises) 359 sex differences see gender differences sex-related incidence, T1DM 32, 33 sexual (dys)function 743–55, 954 female 331, 752–5 male 743–53 management 331 see also erectile dysfunction SGLT2 see sodium-glucose co-transporter SGLT2 inhibitors 1039–40 SH2-domain-containing inositol phosphatases (SHIPs) 111, 1031 SH2-domain-containing proteins 106–7, 109 SH2-domain-containing tyrosine phosphatase (SHP2) 107 shared care 962–3, 1073 older people 935 shared savings payment models 1076 SHC protein 109 shift-work 385 shin spots 776–7, 777 short stature, maternally inherited diabetes and deafness 255 SHORT syndrome 258 shoulder, frozen 790–1 shoulder dystocia 908 sibutramine glucose-lowering effects 473 potentiating insulin action 1033 serum lipid effects 677 T2DM 238, 497 withdrawal 473, 497 sick day management, children 868–70 sickness absence rates 386 sildenafil 748, 748–9, 752 silicone, injected liquid, diabetic foot 733 simvastatin, cardiovascular benefits 674, 932 Singapore, T2DM 57 sirolimus (rapamycin) diabetogenic effects 272 effect on insulin action 120 islet transplantation 1053, 1054, 1058 new-onset T1DM 1011 side effects 1056 SIRT1 120, 1040 sirtuins 1040 sitagliptin 468, 1026, 1027 adverse effects 471 chemical structure 469, 1027 combination therapy 506 efficacy 470–1 indications 469–70 pharmacokinetics 469, 470 renal failure 470, 608 vs liraglutide 484, 484–5 sitagliptin–metformin combination 474 skeletal disorders 795–9 skin bioengineered substitutes 738 biopsy 624–5, 625 infections 780, 780–2, 848–9 temperature, self-monitoring 733 thickening, diabetic 777–8 xerotic (dry) 783 yellow discoloration 777 skin disorders 774–86 associated with diabetes 782, 782–4 iatrogenic 784–6 metabolic markers 774–9, 775 vascular 780, 780 skyrin 1036 SLC2A2 gene mutations 251 SLC30A8 gene 148 HbA1c levels and 205 T2DM 200–1, 201 sleep duration T2DM risk and 46 weight gain and 130 slit-lamp biomicroscopy 579 small-fiber neuropathies 616 small intestine assessment of function 768 bacterial overgrowth 764, 768, 770 dysfunction 764, 764–5 normal function 762–3 smoking 350 cessation hypertension 663 nephropathy 607–8 weight gain after 130 erectile dysfunction and 746, 747 inhaled insulin delivery and 448 preconception advice 901–2 during pregnancy 127 retinopathy and 578 SNARE proteins 91 social aspects of diabetes 380–95 economics 79, 79 newly diagnosed patients 326 Social Cognitive Theory 338–9 Social Learning Theory 338 social worker, pediatric 863, 864 socioeconomic disadvantage 52–3, 79, 79 socioeconomic gradient chronic diseases 71 obesity and T2DM 231 SOCS proteins 111 sodium dietary intake 347, 353 plasma, diabetic ketoacidosis 549 urinary excretion, insulin resistance 183 sodium channel blockers, painful neuropathy 629 sodium-glucose co-transporter (SGLT2) 1039, 1040 inhibitors 1019, 1039–40 soft drinks, calorically sweetened 128, 129, 231 soft tissue fibroproliferative disorders 789–92 infections 781–2, 848–50 somatostatin (SST) chemical structure 1036 Index regulation of insulin secretion 97 secretion in T2DM 169 somatostatin analogs acromegaly 271, 281, 281–2 glucagonoma 291 glycemic effects 271 inhibition of glucagon secretion 1036 see also octreotide somatostatinoma 291–2 somatropin see growth hormone (GH), recombinant human sorbitol induction of diarrhea 764, 770 polyol pathway 557, 557 sorbitol-dehydrogenase (SDH) 557, 557 SOS protein 109 South America incidence of T1DM 33, 34 T2DM 52 South-East Asia diabetes-related deaths 74 T2DM 57 SOX13 (ICA12) 148 Sp1 transcription factors mediating insulin action 117, 118 O-glycosylation 119, 561 specialist care 325, 961–3 communication with primary care 964, 965–7 hospital clinics 961 integrated 962 low resource settings 988 private 961–2 rationalization 963–4 shared care approach 962–3 spermine 1037, 1037 spine, diffuse idiopathic skeletal hyperostosis 795, 795–6 spironolactone hypertension 664, 667 nephropathy management 607 SREBP-1, regulation by insulin 114–15 SREBP-1c 118 SREBP transcription factors 118 Sri Lanka, T2DM 54 St Vincent’s Declaration 324, 324 Stages of Change Model 338 Staphylococcus aureus colonization 848 pneumonia 842–3 skin infections 781, 848 soft tissue infections 848, 849 Star trial 444–5 starch, inhibitors of digestion 1020, 1020 Starling curve of pancreas 175, 280 starvation regimen, Allen’s 9–10 STAT proteins 111 statins 418 cardiovascular protection 649, 674, 674 children 872 congestive heart failure 692 fibrates with 419 HDL-raising effect 676 older people 932 pregnancy 902 stroke prevention 701, 705 triglyceride-lowering effect 676 stearoyl-coenzyme A desaturase 678 steatorrhea 300, 306, 764 Steiner, Donald 13, 15 stem cell therapy 1045–9 stem cells adult 1046–7, 1066 defined 1046 embryonic see embryonic stem cells induced pluripotent (iPS) cells 1048 pancreatic 1048 Steno-2 study 18, 970, 975, 979 cardiovascular benefits 649 nephropathy 607–8, 608 neuropathy 625–6 stenosing tenosynovitis 791 sterol response element binding proteins see SREBP transcription factors Stevens–Johnson syndrome 785 stillbirths 894–6, 908 stomach pathophysiology of dysfunction 763–4 see also gastric emptying; gastroparesis Streptococcus pneumoniae (pneumococcus) infections 842, 848 vaccination 851 streptozocin (streptozotocin) 269 stress coping styles 821 management programs 824 metabolic control and 821–2 psychotic disorders 948 T1DM etiology 144 as trigger for diabetes 821 see also psychologic distress stress hormones see counter-regulatory hormones stress hyperglycemia 514–16 acute myocardial infarction 317, 515 acute stroke 318 benefits of glucose lowering 515, 516 childhood intercurrent illness 869–70 elderly 930 evidence of harm 515 glycemic targets 521, 521 intravenous insulin 520, 520–1, 521 management 519–22 pathophysiology 515–16 surgical patients 523, 850–1 see also in-hospital hyperglycemia stress ketosis 547 striae, Cushing syndrome 285, 286 stroke 698–706 acute treatment 703, 703–5 undiagnosed diabetes 318 cardioembolic 700 carotid stenosis and risk 721 epidemiology 698–701 diabetes 699–700 intermediate hyperglycemia 700–1 hemorrhagic 700 ischemic 699 pathophysiology 701–2 risk factors 698–9, 699, 700–1 lacunar 699, 699, 702 older people 926, 928 primary prevention 702–3 secondary prevention 705, 705–6 units 704–5 stromal-derived factor (SDF-1) 235, 567 students, university and college 394–5 subcutaneous insulin administration 432–4 absorption rates 433 alternative routes 431–2 children 863, 865 complications 433–4 historical milestones 17 injection devices 432, 432–3 injection site infections 785, 850 injection technique 432, 432 rotation of injection site 433 skin complications 434, 784–5 transition from intravenous route to 521, 521–2 see also continuous subcutaneous insulin infusion (CSII) pumps substance misuse 954 see also drug use, recreational succinate dehydrogenase subunit B (SDHB) mutations 288 succinate dehydrogenase subunit D (SDHD) mutations 288 succinic acid esters 1022–3 sucrose, dietary intake 347, 349, 351 sugars, dietary intake 347, 349, 351 suicidal ideation, adolescents 810 sulfamethoxazole 414 sulfonylurea receptor (SUR1) 93, 94, 197, 464, 1021, 1021–2 gene see ABCC8 (SUR1) gene meglitinide actions 464 novel agents acting on 1022, 1022 sulfonylurea actions 461, 461 tissue specificity 463 sulfonylurea receptor 2, A and B isoforms (SUR2A/B) 463, 464 sulfonylureas 456, 460–3, 500 acute stroke 704 adverse effects 463 cautions and contraindications 456, 462 chemical structures 460 combination therapies 462, 473–4, 499–500 fixed dose pills 474 insulin 499–500, 507, 508 Cushing syndrome 286 development 17, 460 driving restrictions 382, 384 drug interactions 414, 414–15, 457, 461–2 efficacy 463 HNF1A and HNF4A MODY 251 hypoglycemic effects 411–12, 462, 463, 500 older people 925–6, 933 prevention 539 indications 462 initiating therapy 462 lipid-lowering effects 463, 677 mode of action 93, 455, 461, 461, 1021–2, 1022 neonatal diabetes 252, 253 older people 933 pharmacogenetic studies 206–7 pharmacokinetics 461–2, 462 pregnancy 906 renal failure 419, 608 secondary failure of therapy 463 skin reactions 785, 785–6 surreptitious ingestion 416 weight gain 238, 463 superficial femoral artery, angioplasty and stenting 713–14, 714, 714 superoxide effects 563, 564 hyperglycemia-induced mitochondrial production 562, 562–3, 565 increased vascular production 645 therapeutic targeting 568 superoxide dismutase (SOD) 563 superoxide dismutase (SOD)/catalase mimetics 568 support groups, diabetes 327, 989 1115 Index suppressor of cytokine signaling (SOCS3) 111 SUR1 see sulfonylurea receptor SUR1 gene see ABCC8 (SUR1) gene sural nerve biopsy 624, 624 surgery 523–6 intra-operative care plans 525, 525 intra-operative management of glycemia 525 metabolic response 523 postoperative care and discharge 525–6 preoperative evaluation 523–4, 524 risk assessment 524, 524 same-day admissions/specific preparations 524 surgical decompression, painful neuropathy 631 surgical site infections 850–1 Sushrut (Susrata) (Hindu physician) 4, 4, sweating, indicator test 620, 621, 732 Sweden costs of diabetes 76 T1DM 33 T2DM 53 sweeteners, artificial 351 inducing diarrhea 764, 770 Symlin® see pramlintide sympathetic nervous system control of body fat stores 134 gastrointestinal motor control 761, 761 islet cell innervation 87, 97 regulation of insulin secretion 97, 98 tests of function 768 tone, insulin-resistant states 183 sympathoadrenal response to hypoglycemia 529, 530, 530 diabetes 531, 531, 532–5 synaptotagmins 91 syndrome X see metabolic syndrome synthalin 17 SYR-322 see alogliptin syringomas, clear cell 783 T-helper type 1/type responses 839 T lymphocytes adipose tissue 235 autoreactive β-cell destruction 145–6 identification 146 CD4+CD25+ regulatory 146 presentation of autoantigens 145 T1DM see type diabetes T2DM see type diabetes table-top sign 789 tacrolimus (FK506) diabetogenic effects 272 islet transplantation 1053, 1054, 1056, 1058 side effects 1056 tadalafil 748, 748–9 Tandemact see pioglitazone–glimepiride combination Tanzania, diabetes care services 960 targets, treatment see treatment targets taspoglutide 485, 1026 taste altered, as presenting feature 320 physiology 132 Tattersall, Robert 12 taxi drivers 384 TC10 109 TCF1 gene see HNF1A gene TCF2 gene see HNF1B gene TCF7L2 gene variants response to therapy 206–7 T2DM 165, 199–200, 201 1116 TCF14 gene see HNF4A gene team diabetes care see diabetes care team diabetes inpatient 519 pediatric diabetes care 863, 864 teamwork see multidisciplinary management Technosphere® insulin 448 telangiectasia, periungual 780 telemedicine 963, 990–2, 991, 1074 see also information and communications technology telepediatric service 885 television (TV) viewing 129–30 telmisartan cardiovascular protection 646, 649 hypertension 665 temperature self-monitoring, skin 733 tendamistate 1020 teplizumab, new-onset T1DM 1008, 1009 teratogenesis, mechanisms of 892–3 terbutaline, hyperglycemic effects 271 tesaglitazar 1034 testosterone control of body fat stores 134 replacement therapy 749 tetrahydrocannabinol 133 text messaging 885 THADA gene 201, 201 thalassemia, iron overload 306 theophylline, hyperglycemic effects 271 thiamine 568, 1035 thiamine responsive megaloblastic anemia 256 thiazide diuretics beta-blocker interactions 416 contraindications 419 diabetogenic effects 46, 268 glucocorticoid interactions 266 glycemic effects in diabetes 418 hypertension 664, 667 thiazolidinediones (TZD) (glitazones) 456, 465–8, 500 adverse effects 468 cardiovascular safety 467, 468, 503, 677, 678, 702 cautions and contraindications 456, 467, 503, 692 chemical structure 466, 1035 combination therapy 473–4, 474, 501–3, 504, 506 development 17 drug interactions 457, 467 efficacy 467–8 HIV/AIDS 840 hypoglycemic effects 414, 468 indications 467 inherited lipodystrophies 258 mode of action 121, 455, 466, 466, 466–7, 1034, 1035 necrobiosis lipoidica diabeticorum 776 new and investigational 1033 older people 934 pharmacogenetic studies 206 pharmacokinetics 467, 467 polycystic ovary syndrome 294 prevention of T2DM 61, 468 serum lipid effects 468, 677 skeletal effects 468, 503, 798, 798–9 skin reactions 786 weight gain 238 thioctic acid see lipoic acid thirst 314 Thompson, Leonard 10, 12, 427 thoracoabdominal neuropathy or radiculopathy 618, 619 thromboembolism prophylaxis acute stroke 705 older people 931–2, 932 thrombolytic therapy acute limb ischemia 716 acute stroke 703–4 diabetic retinopathy and 420 thrombosis, acute lower limb ischemia 716 thyroid disease, autoimmune 292, 293 children 873 pregnancy 899–900 thyroid function, pre-pregnancy screening 903 thyroid hormone, control of body fat stores 134 thyroid peroxidase (TPO) antibodies 873 thyrotoxicosis 292, 292 TIEG2/KLF11 gene 196 time trends, incidence of T1DM 35–6, 36 time zones, travel across 392–3, 393, 393 Tinel test 792 tissue plasminogen activator (t-PA), acute stroke 703, 704 tissue transglutaminase autoantibodies 873 TLK16998 1029, 1029 TNF-α see tumor necrosis factor α TNF-related apoptosis inducing ligand (TRAIL) 647–8 tocolysis, β2-agonists for 271 α-tocopherol 39, 1034 toe pressure 711 measurement 712, 712 tolbutamide chemical structure 460 development 17 drug interactions 415 hypoglycemic effects 411, 925–6 older people 933 pharmacokinetics 462 renal failure 608 toll-like receptor (TLR-4) 234 Tolstoi, Edward 17 torcetrapib 678 Torres Strait, diabetes care services 960 Total Contact Cast (TCC) 735, 793 toxins causing weight gain 130 diabetogenic 38–9, 47 T1DM etiology 144 TP4000 642 traditional medicines, inducing hypoglycemia 411, 413, 415 TRAIL (TNF-related apoptosis inducing ligand) 647–8 training, hospital staff 518 tramadol, painful neuropathy 627, 629 trandolapril, nephropathy prevention 605 trans-fats 347, 349, 352 transcription factor 7-like (TCF7L2) 200 gene see TCF7L2 gene transcription factors mutations associated with T2DM 196 causing MODY 153, 154, 249 pancreatic development 154 transcutaneous electrical nerve stimulation (TENS) 630 transfer to adult health care system 878 distinction from transition 876 transferrin saturation 305, 305 transformation of care 1077 Index transforming growth factor β (TGF-β) 560, 560, 561 transglutaminase autoantibodies 873 transient ischemic attack (TIA) 700 transient neonatal diabetes (TNDM) 251, 252–3 causes 251, 252 clinical features 252–3 management 253 transition 875–86 adolescence as time of 876 adolescent needs during 878–9 adolescent perspective 883 barriers 879 components 877–8 concept 875–6 definitions 875–6, 877 diabetes care setting 877–8 facilitators 879, 883, 883 future research 885 information and communication technology 885 models of care 879–83 in practice 883–5 as a process 876 quality processes 885 stages 880, 881–2 transition case coordinator (TCC) 880–3, 881, 882 transition clinics 880, 882 transketolase activators 567–8 TRANSLATE trial 960 transplantation diabetes after 271–2 infections after 851 see also islet transplantation; pancreas transplantation; renal transplant recipients travel 381, 391–4 food and drink 394 hot climates 393–4 intercurrent illness 394 long flights/crossing times zones 392–3, 393, 393 preparations 391–2, 392 recreational activities 394 Treat to Target Trial 509, 509 treatment targets 978 achievement in practice 970–2, 971, 972, 973 barriers to achieving 972–5, 1070–1 cardiovascular risk factors 328, 932 history 16, 17–18 importance of attaining multiple 979 see also glycemic targets TrialNet 1012 triamcinolone, intravitreal 589–90 Tribbles (TRB) gene family 111–12 Trichophyton rubrum 782 tricyclic antidepressants (TCAs) depression 815 glycemic effects 272 painful neuropathy 627, 628 trigger finger 791 triglitazone 17 triglycerides 675–7 hormonal control of lipolysis 115 metabolism 220, 675–6 T2DM and insulin resistance 177, 178 serum elevated see hypertriglyceridemia genetic studies 205 liver fat content and 177, 178 treatment targets 328, 678 sources of intrahepatocellular 178–9 TRIGR trial 1005, 1006 trimetazidine, congestive heart failure 690, 692 troglitazone 465–6 prevention of T2DM 61 truncal neuropathy, diabetic 618, 619 TSPAN8-LGR5 gene 201, 201 TTP488 642 tuberculosis 843, 844 tuberous sclerosis complex (TSC) 120 tumor necrosis factor α (TNF-α) atherogenesis and 645 congestive heart failure 688 IRS1 inhibition 110 obesity and development of T2DM 233, 233, 234–5 pregnancy 890 stress-induced secretion 516 as therapeutic target 1031 tumor necrosis factor (TNF) inhibitors, Charcot joint 793 Turkey, T2DM 53 Turner, Robert 18, 18 twin studies obesity and overweight 229 T1DM 37, 37, 143 Twitter 885 type diabetes (T1DM) 25–6, 141–56 adolescence 876–7 autoimmune (type 1a) 25–6, 141–9, 142 associated conditions 293, 873–4 childhood 859–60, 860 brain structure and function in adults 817, 817–19 cardiovascular risk 672 care provision 964 childhood 859–74 clinical presentation 314–17, 315, 315 depression 941 eating disorders 950, 952 epidemiology 31–40 etiology 142, 142, 143–5, 839 environmental factors 37–40, 144, 144–5 genetic factors 36–7, 37, 143, 143–4 exercise 360–4, 367–74, 372 female fertility 891 first degree relatives (FDR)/high-risk children prediction of T1DM 1002, 1002–5 prevention of T1DM 1001–2, 1005–8 fractures 796–7, 797 future drug treatment 1001–12 gene therapy 1065–7 historical aspects 9, 11–13 hypertension see under hypertension hypoglycemia frequency 536, 536 idiopathic (type 1b) 26, 142, 152–6 incidence 32–6 by age 32, 32–3 geographical variations 33, 34, 70 seasonal variations 35, 35 by sex 32, 33 temporal trends 35–6, 36 within-country variations 34–5 insulin treatment 436 basal bolus regimen 435 history 427, 428 initiation 436–7 insulin pumps 440–1 premixed insulin 436 see also insulin treatment intervention in newly diagnosed 1008–11, 1009 islet transplantation 1050–60 metabolic disturbances 217–18, 220–1 monitoring glycemic control 404–5 mortality 40 nephropathy see under nephropathy, diabetic neuropathy 625 older people 934–5 partial remission (honeymoon) period 1001 immune-modulating therapy 1001–2 intervention studies 1008–11, 1009 pathogenesis 141–2, 145–9 historical studies 13 role of infections 839 phenotypes 152–6 pre-pregnancy care 900, 901 prediction 1002, 1002–5 autoimmune markers 1003–4 biochemical markers 1004–5 genetic markers 1003 pregnancy see under pregnancy prevention see under prevention of diabetes quality of life 813–14 slowly progressive see latent autoimmune diabetes of adults stem cell therapy 1045–9 Type Diabetes Prediction and Prevention (DIPP) trial 1007, 1008 type one-and-a-half diabetes see latent autoimmune diabetes of adults type diabetes (T2DM) 25, 26, 160–9 β-cell defects see under β-cell(s) cardiovascular risk 672 childhood 859–60, 860 clinical presentation 314–19, 315 combination therapies 497–510 efficacy 498, 499 fixed-dose pills 473–4, 474, 499 need for 497–8, 498 rationale 498–9 tolerability and convenience 498–9 congestive heart failure 685 depression 941–2 economics 58, 58–9, 60 epidemiology 45–60 etiology intrauterine factors 47, 166, 893–4 multifactorial nature 191–2 new concepts 202–3 role of infections 839–41 exercise 364–73, 368, 369–70, 372 female infertility 891 fractures 796, 797, 798 gene therapy strategies 1067 gene–environment interactions 191–2 genetics 164–5, 191–207 gestational diabetes as forerunner 890 health care burden 58–9 heterogeneity 160 historical aspects 9, 11–13 hypertension see under hypertension hypoglycemia frequency 536, 536–7 impact 57–9 incidence 51–2, 53, 56 insulin resistance see under insulin resistance insulin treatment 436, 507–10 with incretin mimetics 505, 506 initiation 434, 436–7, 507 insulin pumps 441 optimal 510 1117 Index type diabetes (T2DM) (cont.) with oral agents 459–60, 499–500, 507, 508–10 pregnancy 891, 901 premixed insulin 436, 508 regimens 434–5, 507, 507, 508–10 management 452–74, 494–510 aims/goals 453, 453, 495–6 algorithms 474, 474, 494–5, 495 combination pharmacotherapy 497–510 community and specialist levels 964 future drug treatment 1017–40 guidelines 437, 454–6 initial monotherapy 498, 498 insulin treatment see above intensive vs standard glycemic control 453, 453–4, 454 lifestyle advice 454, 496 models of care 1071 monitoring glycemic control 405 multidisciplinary approach 975–9 oral antidiabetic agents see oral antidiabetic agents pathophysiologic aspects 453–4 weight reduction 237–8, 496–7 metabolic disturbances 218–21 morbidity 57–8 mortality 57–8 natural history 162–3, 175, 175, 453, 453–4, 502 nephropathy see under nephropathy, diabetic neurocognitive dysfunction 819 neuropathy 625 non-insulin parenteral therapies 478–88 obesity and see under obesity older people 922, 923 management 930–5 pathogenesis 924, 924, 924–5 overlap with T1DM 152, 153 pathogenesis 161–9 pre-pregnancy care 901 pregnancy see under pregnancy prevalence 45, 494 factors affecting 47, 47, 48 projections 50 regional and ethnic patterns 48–57, 49, 50, 51, 70 prevention see under prevention of diabetes quality of life 814 risk factors 46, 46–7, 685 alcohol consumption 387, 387 breastfeeding and 909 common gene variants 205–6 depression as 811, 942 environmental 46–7, 231 obesity 46, 228, 229 psychotic disorders 947 recent emerging 46–7 risk stratification 975–6 types of diabetes, other specific 26, 26–7 tyrosine phosphorylation CAP/Cbl/TC10 pathway 108 insulin receptor 106 insulin receptor substrates 106–7 UAE see urinary albumin excretion UDP-N-acetylglucosamine (UDP-GlcNAc) 119, 560–1 UK Prospective Diabetes Study (UKPDS) 18, 453, 453–4, 454, 970 blood pressure control 667, 667 cardiovascular outcomes 638, 673, 673 1118 combination therapies 498, 498 metformin therapy 459, 501 nephropathy 605 progression of T2DM 502 retinopathy development 578, 927 risk stratification 976 stroke 702 sulfonylurea-induced hypoglycemia 463 UK Screening classification of retinopathy and maculopathy 586, 587, 590–1 ulceration foot see foot ulcers necrobiosis lipoidica diabeticorum 776 Ullrich, Axel 13, 15 ultralente insulin 430 ultrasound antenatal scanning 906, 907 B scan examination of eye 580 uncoupling protein-1 (UCP-1) 131, 563 uncoupling protein-2 (UCP-2) 167, 232 undiagnosed diabetes 70, 320 hospital inpatients 514–15 unemployment 73, 385–6 uniparental disomy, neonatal diabetes 252, 253 United Kingdom (UK) standards of inpatient care 516–17 T2DM prevalence 52–3 United Nations Resolution on Diabetes (2006) 985 United States (USA) costs of diabetes 58, 58–9, 77, 79 distribution and trends 70 driving regulations 384 T1DM 33, 34 T2DM 50–2 University Group Diabetes Program 17 University of Texas (UT) ulcer classification system 734, 734 University of Wisconsin solution (UW) 1053 university students 394–5 upper gastrointestinal endoscopy 765, 766 upper limb ischemia 717–18 urate, serum 794 urbanization 71 diabetes risk factors and 46, 47 T2DM prevalence and 49–50, 54–5, 56 uric acid metabolism, insulin resistance 183 urinary albumin excretion (UAE) chronic kidney disease staging by 599–600, 600 definitions 600 history of measurement 18 monitoring 604, 608 screening 603–4 trends over time 600, 600, 601, 601, 602 urinary albumin : creatinine ratio (ACR) 330, 604 urinary glucose testing drugs interfering with 420 monitoring diabetes 403, 407 at presentation of diabetes 314 screening for diabetes 320 urinary ketone testing childhood illness 869 diabetic ketoacidosis 547, 550 urinary tract infections (UTI) 844–7 clinical features 845 diagnosis 846 epidemiology and risk factors 844–5 microbiology 845 predisposing factors 838 treatment 846–7 urine ants clustering around 5, 320 tasting urokinase, intra-arterial, acute stroke 703–4 urotensin II (UT II) 647, 647 urticarial reactions, insulin 784 Uzbekistan, T2DM 53 vaccinations 851 Vacor 38 vacuum therapy, erectile dysfunction 750, 750–1 vagal neuropathy 763–4 vaginal candidiasis 752–3, 781 as presenting feature 316 vaginal dryness 752 vagovagal reflexes, GLP-1 actions via 480 valganciclovir 1054 valsartan, hypertension 665 vanadium salts 1030, 1035 vardenafil 748, 748–9 vascular dementia 819 vascular endothelial growth factor (VEGF) adipose tissue 235 gene therapy 1068 inhibitors, intravitreal therapy 593–4 retinal expression 558, 560, 560 vascular function, insulin-resistant states 183 vascular skin changes 780, 780 vascular smooth muscle cells (VSMC) pathogenesis of atherosclerosis 640, 641 retinal, death of 579 vascular surgery, open abdominal aortic aneurysms 719, 719–20 acute lower limb ischemia 716 lower limb ischemia 713, 714–15, 715 complications 715 older people 927 results 714, 715–16 vasoactive intestinal polypeptide (VIP) 87 regulation of insulin secretion 98 secreting tumors (VIPomas) 292 vasodilatation, impaired endothelium-dependent 183–4 vasodilators, autonomic neuropathy 419 vaspin 1032 VEGF see vascular endothelial growth factor vein grafts, peripheral bypass surgery 714, 715 venesection, therapeutic 305, 305–6 venlafaxine, painful neuropathy 628–9 venous beading, retinal 583, 583, 591, 591 venous insufficiency, lower limbs 780 venous loops, retinal 583, 583, 590 venous thromboembolism prophylaxis see thromboembolism prophylaxis verapamil, glycemic effects 268–9 vertebral artery stenosis 700 very low calorie diets (VLCD) 237, 347 very low density lipoprotein (VLDL) 675, 676 liver fat content and 177, 178 vesicle-associated membrane protein-2 (VAMP) 148 Veterans Affairs Diabetes Trial (VADT) 328, 454, 503, 625, 638 Viagra see sildenafil vibration perception threshold (VPT) 615, 625 Vibrio infections 849 Victoza® see liraglutide videoconferencing 885 vildagliptin 468, 1026, 1027 adverse effects 471 chemical structure 469, 1027 combination therapy 506 Index efficacy 471 indications 469–70 pharmacokinetics 469, 470 renal failure 470, 608 vildagliptin–metformin combination 474, 506 VIPoma 292 virilization, type A insulin resistance 257 viruses causing weight gain 130–1 T1DM etiology 38, 144, 839 T2DM etiology 839–41 visfatin 1032 visual blurring, at presentation of diabetes 316 visual field defects, driving and 383, 383 visual impairment driving and 382–3, 383 older people 926–7 presentation of diabetes with 318, 318–19 psychologic reactions 811–12 vitamin B1 (thiamine) 568, 1035 vitamin C (ascorbic acid) 420, 1034 vitamin D 353 supplements 497, 1005, 1006, 1034–5 T1DM etiology 39 vitamin E 39, 1034 vitamin K5 1037, 1037 vitamins 1034–5 antioxidant 353, 1034 vitiligo 782 vitrectomy 594, 594 vitreous hemorrhage (VH) 583 vitronectin, modification by AGEs 559 vocational driving licenses 384 voglibose 471–2, 1020 chemical structure 471, 1021 vomiting childhood intercurrent illness 870 diabetic ketoacidosis 316, 549 gastroparesis 765 vulvovaginal candidiasis 752–3, 781 as presenting feature 316 Wagener, Henry 13 waist circumference 228, 228 ethnic specific values 176 Wang Ying-lai 15 ward environment, hospital 518 warfarin, stroke prevention 705–6 water intake, guidance 128 Weichselbaum, Anton 13 weight, body see body weight weight gain antidepressant-induced 944 antipsychotic drug-induced 948 prevention 950, 950 drugs promoting 130, 237–8, 468 insulin-induced 237–8, 433 sulfonylurea-induced 238, 463 T2DM risk 228 targets in pregnancy 907 see also obesity; overweight weight loss (unintended) GLP-1 analog therapy 482, 483, 484, 485 peripheral neuropathy 618, 619 pramlintide therapy 488 presentation of diabetes with 314–16, 315, 315 weight lowering drugs see antiobesity drugs weight reducing diets 347–8 macronutrient distribution 348 obese patients with T2DM 237 weight reduction (intended) benefits in obesity 236–7 hypertension 663 insulin resistance and 179–80 liver fat content and 179–80 management of diabetes 346–8 obese patients with T2DM 237, 238 prevention of diabetes 348 triglyceride-lowering effects 677 weightlifting 372 see also resistance exercise Welsh Community Diabetes Study 926, 929 Werner syndrome 259 Western Pacific region diabetes-related deaths 74 T2DM 55–7 Western Samoa 55–6 WFS1 gene variants 194–5, 201 Whipple’s triad, hypoglycemia 529 White, Priscilla 19, 890 White classification, diabetes in pregnancy 890 Whitlock model for educational counseling 341, 342 WHO see World Health Organization Wilder, Russell 17 Willis, Thomas 5, 14, 942 Wilson, Clifford 4, 13 Wolcott–Rallison syndrome 256 Wolfram syndrome 194–5, 256, 293 wolframin 194–5 women contraception 753–4 genitourinary infections 752–3 hormone replacement therapy 754–5 sexual dysfunction 331, 752–3 see also gender differences Women’s Health Initiative (WHI) study 754, 796 Woodrow, John 14 work see employment World Health Organization (WHO) Alma Ata Declaration (1978) 959 classification of diabetes 25, 25, 27–8 diagnosis of gestational diabetes 30 diagnostic criteria 27, 28–9, 48 Innovative Care for Chronic Conditions (ICCC) framework 985, 985–6 St Vincent’s Declaration 324 wortmannin 120 wound healing diabetic foot 734–5 factors affecting 735 role of apoptosis 837 stress hyperglycemia and 516 xanthomas, eruptive 779, 779 Yalow, Rosalyn 13, 15, 15, 428 yellow nails 783 Young, Frank 14 young adult clinics 880, 882 young adults eating disorders 951, 952, 953 incidence of T1DM 32–3 leaving home 381, 394–5 T2DM incidence 53 see also adolescents young-onset diabetes familial 245, 246 heterogeneous etiologies 153 see also maturity-onset diabetes of the young; monogenic diabetes ZAC (PLAGL1) gene 252 ZFP57 gene 253 zinc lente insulin 430, 430 zinc supplements 1035 zinc transporter (ZnT8) 200 autoantibodies (ZnT8Ab) 146, 148, 1004 gene see SLC30A8 gene ZP10A 1026 Zuelzer, Georg 10, 11 zygomycosis see mucormycosis 1119 ... Sci U S A 20 00; 97: 122 22 122 26 Wallace DC Disease of the mitochondrial DNA Annu Rev Biochem 19 92; 61:1175 21 2 Trumpower BL The protonmotive Q cycle: energy transduction by coupling of proton... C-term H3 (a) H2A H2BK 123 36 14 H3K79 119 18 acK meR meK 23 12 16 20 12 15 20 H4 H2B qPCR for NFkB p65 mRNA level (arbitrary units) 300 (b) 20 0 * * * * 100 LG(6h) HG(6h) HG(6h)+LG(2d) HG(6h)+LG(4d)... cytoplasmic proteins in 123 124 125 126 127 128 129 130 131 1 32 133 134 135 136 137 138 139 vivo using the peptide O-GlcNAc-beta-N-acetylglucosaminidase inhibitor O- (2- acetamido -2- deoxy-d-glucopyranosylidene)