TYPE DIABETES – COMPLICATIONS, PATHOGENESIS, AND ALTERNATIVE TREATMENTS Edited by Chih-Pin Liu Type Diabetes – Complications, Pathogenesis, and Alternative Treatments Edited by Chih-Pin Liu Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work Any republication, referencing or personal use of the work must explicitly identify the original source As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher No responsibility is accepted for the accuracy of information contained in the published chapters The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book Publishing Process Manager Sandra Bakic Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright illustrart, 2011 Used under license from Shutterstock.com First published November, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Type Diabetes – Complications, Pathogenesis, and Alternative Treatments, Edited by Chih-Pin Liu p cm ISBN 978-953-307-756-7 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part Diabetes Mellitus and Complications Chapter The Study of Glycative and Oxidative Stress in Type Diabetes Patients in Relation to Circulating TGF-Beta1, VCAM-1 and Diabetic Vascular Complications Vladimir Jakus, Jana Kostolanska, Dagmar Michalkova and Michal Sapak Chapter Diet, Lifestyle and Chronic Complications in Type Diabetic Patients 21 S.S Soedamah-Muthu, S Abbring and M Toeller Chapter Lipid Disorders in Type Diabetes Bruno Vergès Chapter Prevalence of Type Diabetes Correlates with Daily Insulin Dose, Adverse Outcomes and with Autoimmune Process Against Glutamic Acid Decarboxylase in Adults 61 Mykola Khalangot, Vitaliy Gurianov, Volodymir Kovtun, Nadia Okhrimenko, Viktor Kravchenko and Mykola Tronko Part Psychological Aspects of Diabetes 45 83 Chapter Type I Diabetes in Children and Adolescents Laura Nabors, Phillip Neal Ritchey, Bevin Van Wassenhove and Jennifer Bartz 85 Chapter Inadequate Coping Attitudes, Disordered Eating Behaviours and Eating Disorders in Type Diabetic Patients 95 Ricardo V García-Mayor and Alejandra Larraga Chapter Predictors of Adherence, Metabolic Control and Quality of Life in Adolescents with Type Diabetes 119 M Graỗa Pereira, A Cristina Almeida, Liliana Rocha and Engrácia Leandro VI Contents Chapter Part Chapter Contributing Factors to Poor Adherence and Glycemic Control in Pediatric Type Diabetes: Facilitating a Move Toward Telehealth 141 Joseph P H McNamara, Adam M Reid, Alana R Freedland, Sarah E Righi and Gary R Geffken Perspectives of Diabetes Pathogenesis 159 Fulminant Type Diabetes Mellitus in IRS-2 Deficient Mice 161 Toshiro Arai, Nobuko Mori and Haruo Hashimoto Chapter 10 Obesity in the Natural History of Type Diabetes Mellitus: Causes and Consequences 181 Fernando Valente, Marília Brito Gomes and Sérgio Atala Dib Chapter 11 Meta-Analysis of Genome-Wide Association Studies to Understand Disease Relatedness 199 Stephanie N Lewis, Elaine O Nsoesie, Charles Weeks, Dan Qiao and Liqing Zhang Chapter 12 Cytokine-Induced -Cell Stress and Death in Type Diabetes Mellitus 213 Lisa Vincenz, Eva Szegezdi, Richard Jäger, Caitriona Holohan, Timothy O’Brien and Afshin Samali Chapter 13 A Novel L-Arginine/L-Glutamine Coupling Hypothesis: Implications for Type Diabetes 241 Paulo Ivo Homem de Bittencourt Jr and Philip Newsholme Part Identification and Monitoring of Diabetes Mellitus 285 Chapter 14 Diabetes Type and 2: What is Behind a Classification? 287 Adriana Mimbacas and Gerardo Javiel Chapter 15 The Enlarging List of Phenotypic Characteristics That Might Allow the Clinical Identification of Families at Risk for Type Diabetes 305 Elena Matteucci and Ottavio Giampietro Chapter 16 Altering Trends in the Epidemiology of Type Diabetes Mellitus in Children and Adolescents 323 Elisavet Efstathiou and Nicos Skordis Chapter 17 Genetic Testing of Newborns for Type Diabetes Susceptibility – The MIDIA Study 337 Kjersti S Rønningen Contents Part Alternative Treatments for Diabetes 363 Chapter 18 Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus 365 Momir Mikov, Hani Al-Salami and Svetlana Golocorbin-Kon Chapter 19 Role of Vitamin D in the Pathogenesis and Therapy of Type Diabetes Mellitus 403 Agustin Busta, Bianca Alfonso and Leonid Poretsky Chapter 20 Honey and Type Diabetes Mellitus 423 Mamdouh Abdulrhman, Mohamed El Hefnawy, Rasha Ali and Ahmad Abou El-Goud Chapter 21 Fatty Acid Supply in Pregnant Women with Type Diabetes Mellitus 437 Éva Szabó, Tamás Marosvưlgyi and Tamás Decsi Chapter 22 Therapeutic Modelling of Type Diabetes 461 Nilam Nilam, Seyed M Moghadas and Pappur N Shivakumar VII Preface Diabetes is a leading cause of death in many countries affecting both the young and old at an alarming rate worldwide Due to the destruction of insulin-producing beta islet cells by the body’s own immune system, type diabetes is the most common metabolic and endocrinal disease among children Finding a cure for this disease has been a major challenge for both basic science and clinical investigators Owing to rapid research progress in the field, we now have a better knowledge in understanding the cellular and molecular basis responsible for diabetes, the associated complications, and alternative treatments for this chronic inflammatory disease This book is intended as an overview of recent progress in type diabetes research worldwide, with a focus on different research areas relevant to this disease These include: diabetes mellitus and complications, psychological aspects of diabetes, perspectives of diabetes pathogenesis, identification and monitoring of diabetes mellitus, and alternative treatments for diabetes In preparing this book, leading investigators from several countries in these five different categories were invited to contribute a chapter to this book We have striven for a coherent presentation of concepts based on experiments and observation from the authors own research and from existing published reports Therefore, the materials presented in this book are expected to be up to date in each research area Complications, such as those lead to severe cardiovascular diseases, caused by diabetes due to chronic inflammation have attracted intensive research in recent years This section contains four chapters that discuss diabetes mellitus-caused complications due to the effect of glycative and oxidative stress, varied diet and life style, lipid disorders, and daily insulin doses Better knowledge in these areas may help those who are affected by diabetes to reduce disease-associated long-term complications and to improve their life quality Type disease usually occurs at young age and can have significant impact on those affected Therefore, managing this disease becomes a very challenging daily task for the patients themselves and for their close family members Frustration may occur while patients deal with their disease conditions, making adherence and proper glycemic control a challenge To help address these challenges, four chapters discuss psychological aspects of diabetes, which provide updated and useful information regarding psychological factors related to diabetes in children and adolescents, how to X Preface avoid inadequate coping attitudes and maintain good eating behaviors, and how to improve adherence, metabolic control, and quality of life While many aspects of how type diabetes may occur are discussed elsewhere, five chapters are included in this book to address some unique or alternative perspectives of diabetes pathogenesis For example, a chapter discusses the effect of IRS-2 gene on fulminant type diabetes in animal models Another chapter discusses the role of obesity in the natural history of type diabetes Other factors, such as cytokinesinduced beta cell death and the effect of L-Arg/L-Glu coupling on diabetes, are the topics of two other chapters respectively Aided by recent progress in genomic studies, the fifth chapter discusses the use of meta-analysis of genome-wide association studies to better understand disease relatedness Due to the nature of the disease, it is not an easy task to identify disease risk or susceptibility early in life The classification between type vs type diabetes has also become less clear nowadays as increasing number of adults can develop symptoms of type diabetes Four chapters provide insightful discussion addressing this important issue A chapter discusses evidence showing altering trends in the epidemiology of type diabetes in children and adolescents Thanks to recent research progress and better understanding of diabetes pathogenesis, a chapter discusses a more comprehensive list of phenotypic markers that may help clinical identification of families at risk Another chapter suggests that genetic testing of newborns may also be a possibility to help identify disease susceptibility and distinguish different types of diabetes Finding a cure for type diabetes remains a major challenge and ultimate goal for diabetes basic and clinical research Currently, insulin injection is the gold standard for disease treatment The use of insulin pump therapy has provided continuous subcutaneous insulin infusion for patients A chapter provides an overview of mathematical modeling of using pump therapy as a management strategy for diabetes therapy In seeking better treatments for this disease, recent studies suggest that it may be promising approaches using alternative medicine in therapies Four chapters discuss findings in this area and suggest new aspects of using alternative medicine approaches to treat or ameliorate the disease conditions These include the potential use of bile acid and probiotics, vitamin D, honey and fatty acids Finally, we would like to thank all the authors who have contributed to this book While there is no doubt that this book may have omitted some important findings in diabetes field, we hope the information included in this book will be useful for both basic science and clinical investigators We also hope that diabetes patients and their family will benefit from reading the chapters in this book Dr Chih-Pin Liu The Beckman Research Institute of the City of Hope, Duarte, California, USA 456 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments Min, Y., Ghebremeskel, K., Lowy, C., Thomas, B & Crawford, MA (2004) Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes Diabetologia, Vol.47, No.1, (January 2004), pp 75-81, ISSN 0012-186X Min, Y., Lowy, C., Ghebremeskel, K., Thomas, B., Offley-Shore, B & Crawford, M (2005a) Unfavorable effect of type and type diabetes on maternal and fetal essential fatty acid status: a potential marker of fetal insulin resistance The American Journal of Clinical Nutrition, Vol.82, No.6, (December 2005), pp 11621168, ISSN 0002-9165 Min, Y., Lowy, C., Ghebremeskel, K., Thomas, B., Bitsanis, D & Crawford, MA (2005b) Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women Diabetic Medicine: a Journal of the British Diabetic Association, Vol.22, No.7, (July 2005), pp 914-920, ISSN 0742-3071 Min, Y., Nam, JH., Ghebremeskel, K., Kim, A & Crawford, M (2006) A distinctive fatty acid profile in circulating lipids of Korean gestational diabetics: a pilot study Diabetes Research and Clinical Practice, Vol.73, No.2, (August 2006), pp 178-183, ISSN 01688227 Mohan, IK & Das, UN (2001) Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids Nutrition, Vol.17, No.2, (February 2001), pp 126-151, ISSN 0899-9007 Morris, MC., Evans, DA., Bienias, JL., Tangney, CC., Bennett, DA., Wilson, RS., Aggarwal, N & Schneider, J (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease Archives of Neurology, Vol.60, No.7, (July 2003), pp 940946, ISSN 0003-9942 Mozaffarian, D., Psaty, BM., Rimm, EB., Lemaitre, RN., Burke, GL., Lyles, MF., Lefkowitz, D & Siscovick, DS (2004) Fish intake and risk of incident atrial fibrillation Circulation, Vol.110, No.4, (July 2004), pp 368-373, ISSN 0009-7322 Mozaffarian, D., Ascherio, A., Hu, FB., Stampfer, MJ., Willett, WC., Siscovick, DS & Rimm, EB (2005) Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men Circulation, Vol.111, No.2, (January 2005), pp 157164, ISSN 0009-7322 Murano, Y., Funabashi, T., Sekine, S., Aoyama, T & Takeuchi, H (2007) Effect of dietary lard containing higher alpha-linolenic acid on plasma triacylglycerol in rats Journal of Oleo Science, Vol.56, No.7, (July 2007), pp 361-367, ISSN 1345-8957 National Diabetes Statistics, 2011, Available from http://diabetes.niddk.nih.gov/ dm/pubs/statistics/ Nikkari, T., Räsänen, L., Viikari, J., Akerblom, HK., Vuori, I., Pyörälä, K., Uhari, M., Dahl, M., Lähde, PL., Pesonen, E & Suoninen, P (1983) Serum fatty acids in 8-year-old Finnish boys: correlations with qualitative dietary data and other serum lipids The American Journal of Clinical Nutrition, Vol.37, No.5, (May 1983), pp 848-854, ISSN 0002-9165 Noaghiul, S & Hibbeln, JR (2003) Cross-national comparisons of seafood consumption and rates of bipolar disorders The American Journal of Psychiatry, Vol.160, No.12, (December 2003), pp 2222-2227, ISSN 0002-953X Fatty Acid Supply in Pregnant Women with Type Diabetes Mellitus 457 Norris, JM., Yin, X., Lamb, MM., Barriga, K., Seifert, J., Hoffman, M., Orton, HD., Barón, AE., Clare-Salzler, M., Chase, HP., Szabo, NJ., Erlich, H., Eisenbarth, GS & Rewers, M (2007) Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type diabetes JAMA : the Journal of the American Medical Association, Vol.298, No.12, (September 2007), pp 1420-1428, ISSN 00987484 Ortega-Senovilla, H., Alvino, G., Taricco, E., Cetin, I & Herrera, E (2009) Gestational diabetes mellitus upsets the proportion of fatty acids in umbilical arterial but not venous plasma Diabetes Care, Vol.32, No.1, (January 2009), pp 120-122, ISSN 01495992 Pettitt, DJ., Lawrence, JM., Beyer, J., Hillier, TA., Liese, AD., Mayer-Davis, B., Loots, B., Imperatore, G., Liu, L., Dolan, LM., Linder, B & Dabelea, D (2008) Association between maternal diabetes in utero and age at offspring's diagnosis of type diabetes Diabetes Care, Vol.31, No.11, (November 2008), pp 2126-2130, ISSN 01495992 Plourde, M & Cunnane, SC (2007) Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements Applied Physiology, Nutrition, and Metabolism, Vol.32, No.4, (August 2007), pp 619-634, ISSN 1715-5312 Racine, RA & Deckelbaum, RJ (2007) Sources of the very-long-chain unsaturated omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid Current Opinion in Clinical Nutrition & Metabolic Care, Vol.10, No.2, (March 2007), pp 123-128, ISSN 1363-1950 Radesky, JS., Oken, E., Rifas-Shiman, SL., Kleinman, KP., Rich-Edwards, JW & Gillman, MW (2008) Diet during early pregnancy and development of gestational diabetes Paediatric and Perinatal Epidemiology, Vol.22, No.1, (January 2008), pp 47-59, ISSN 0269-5022 Ramsammy, LS., Haynes, B., Josepovitz, C & Kaloyanides, GJ (1993) Mechanism of decreased arachidonic acid in the renal cortex of rats with diabetes mellitus Lipids, Vol.28, No.5, (May 1993), pp 433-439, ISSN 0024-4201 Ruiz-Gutierrez, V., Stiefel, P., Villar, J., García-Donas, MA., Acosta, D & Carneado, J (1993) Cell membrane fatty acid composition in type (insulin-dependent) diabetic patients: relationship with sodium transport abnormalities and metabolic control Diabetologia, Vol 36, No.9, (September 1993), pp 850-856, ISSN 0012-186X Salem, N Jr., Wegher, B., Mena P & Uauy, R (1996) Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants Proceedings of the National Academy of Sciences of the United States of America, Vol.93, No.1, (January 1996), pp 49-54, ISSN 0027-8424 Schaefer, EJ., Bongard, V., Beiser, AS., Lamon-Fava, S., Robins, SJ., Au, R., Tucker, KL., Kyle, DJ., Wilson, PW & Wolf, PA (2006) Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study Archives of Neurology, Vol.63, No.11, (November 2006), pp 1545-1550, ISSN 0003-9942 458 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments Seigneur, M., Freyburger, G., Gin, H., Claverie, M., Lardeau, D., Lacape, G., Le Moigne, F., Crockett, R & Boisseau, MR (1994) Serum fatty acid profiles in type I and type II diabetes: metabolic alterations of fatty acids of the main serum lipids Diabetes Research and Clinical Practice, Vol.23, No.3, (April 1994), pp 169-177, ISSN 0168-8227 Shin, CS., Lee, MK., Park, KS., Kim, SY., Cho, BY., Lee, HK., Koh, CS & Min, HK (1995) Insulin restores fatty acid composition earlier in liver microsomes than erythrocyte membranes in streptozotocin-induced diabetic rats Diabetes Research and Clinical Practice, Vol.29, No.2, (August 1995), pp 93-98, ISSN 0168-8227 Soriguer, F., Serna, S., Valverde, E., Hernando, J., Martín-Reyes, A., Soriguer, M., Pareja, A., Tinahones, F & Esteva, I (1997) Lipid, protein, and calorie content of different Atlantic and Mediterranean fish, shellfish, and molluscs commonly eaten in the south of Spain European Journal of Epidemiology, Vol.13, No.4, (June 1997), pp 451563, ISSN 0393-2990 Soulimane-Mokhtari, NA., Guermouche, B., Saker, M., Merzouk, S., Merzouk, H., Hichami, A., Madani, S., Khan, NA & Prost, J (2008) Serum lipoprotein composition, lecithin cholesterol acyltransferase and tissue lipase activities in pregnant diabetic rats and their offspring receiving enriched n-3 PUFA diet General Physiology and Biophysics, Vol.27, No.1, (March 2008), pp 3-11, ISSN 0231-5882 Sun, Q., Ma, J., Campos, H., Hankinson, SE., Manson, JE., Stampfer, MJ., Rexrode, KM., Willett, WC & Hu, FB (2007) A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease Circulation, Vol.115, No.14, (April 2007), pp 1858-1865, ISSN 0009-7322 Szabó, É., Boehm, G., Beermann, C., Weyermann, M., Brenner, H., Rothenbacher, D & Decsi, T (2007) trans Octadecenoic acid and trans octadecadienoic acid are inversely related to long-chain polyunsaturates in human milk: results of a large birth cohort study The American Journal of Clinical Nutrition, Vol.85, No.5, (May 2007), pp 13201326, ISSN 0002-9165 Szabó, É., Boehm, G., Beermann, C., Weyermann, M., Brenner, H., Rothenbacher, D & Decsi, T (2010a) Fatty acid profile comparisons in human milk sampled from the same mothers at the sixth week and the sixth month of lactation Journal of Pediatric Gastroenterology and Nutrition, Vol.50, No.3, (March 2010), pp 316-320 ISSN 02772116 Szabó, É., Soltész, Gy & Decsi, T (2010b) Long-chain polyunsaturated fatty acid supply in diabetes mellitus, In: Handbook of Type Diabetes Mellitus, L Aucoin, T Prideux (Ed.), pp 265-295, Nova Science Publishers Inc., ISBN: 978-1-60741-311-0, New York, USA Tam, WH., Ma, RC., Yang, X., Ko, GT., Tong, PC., Cockram, CS., Sahota, DS., Rogers, MS & Chan, JC (2008) Glucose intolerance and cardiometabolic risk in children exposed to maternal gestational diabetes mellitus in utero Pediatrics, Vol.122, No.6, (December 2008), pp 1229-1234, ISSN 0031-4005 Tanakol, R., Yazici, Z., Sener, E & Sencer, E (1999) Fatty acid composition of 19 species of fish from the Black Sea and the Marmara Sea Lipids, Vol.34, No.3, (March 1999), pp 291-297, ISSN 0024-4201 Fatty Acid Supply in Pregnant Women with Type Diabetes Mellitus 459 Thomas, B., Ghebremeskel, K., Lowy, C., Min, Y & Crawford, MA (2004) Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women European Journal of Clinical Nutrition, Vol.58, No.11, (November 2004), pp 14921497, ISSN 0954-3007 Thomas, B., Ghebremeskel, K., Lowy, C., Offley-Shore, B & Crawford, MA (2005) Plasma fatty acids of neonates born to mothers with and without gestational diabetes Prostaglandins, Leukotrienes, and Essential Fatty Acids, Vol.72, No.5, (May 2005), pp 335-341, ISSN 0952-3278 Thomas, B., Ghebremeskel, K., Lowy, C., Crawford, M & Offley-Shore, B (2006) Nutrient intake of women with and without gestational diabetes with a specific focus on fatty acids Nutrition, Vol.22, No.3, (March 2006), pp 230-236, ISSN 0899-9007 Tilvis, RS & Miettinen, TA (1985) Fatty acid compositions of serum lipids, erythrocytes, and platelets in insulin-dependent diabetic women The Journal of Clinical Endocrinology and Metabolism, Vol.61, No.4, (October 1985), pp 741-745, ISSN 0021972X Tilvis, RS., Helve, E & Miettinen, TA (1986) Improvement of diabetic control by continuous subcutaneous insulin infusion therapy changes fatty acid composition of serum lipids and erythrocytes in type (insulin-dependent) diabetes Diabetologia, Vol.29, No.10, (October 1986), pp 690-694, ISSN 0012-186X Vidgren, HM., Louheranta, AM., Agren, JJ., Schwab, US & Uusitupa, MI (1998) Divergent incorporation of dietary trans fatty acids in different serum lipid fractions Lipids, Vol.33, No.10, (October 1998), pp 955-962, ISSN 0024-4201 Wijendran, V., Bendel, RB., Couch, SC., Philipson, EH., Thomsen, K., Zhang, X & LammiKeefe, CJ (1999) Maternal plasma phospholipid polyunsaturated fatty acids in pregnancy with and without gestational diabetes mellitus: relations with maternal factors The American Journal of Clinical Nutrition, Vol.70, No.1, (July 1999), pp 53-61, ISSN 0002-9165 Wijendran, V., Bendel, RB., Couch, SC., Philipson, EH., Cheruku, S & Lammi-Keefe, CJ (2000) Fetal erythrocyte phospholipid polyunsaturated fatty acids are altered in pregnancy complicated with gestational diabetes mellitus Lipids, Vol.35, No.8, (August 2000), pp 927-931, ISSN 0024-4201 Williams, C., Birch, EE., Emmett, PM., Northstone, K & Avon Longitudinal Study of Pregnancy and Childhood Study Team (2001) Stereoacuity at age 3.5 y in children born full-term is associated with prenatal and postnatal dietary factors: a report from a population-based cohort study The American Journal of Clinical Nutrition, Vol.73, No.2, (February 2001), pp 316-322, ISSN 0002-9165 Winkler, C., Hummel, S., Pflüger, M., Ziegler, AG., Geppert, J., Demmelmair, H & Koletzko, B (2008) The effect of maternal T1DM on the fatty acid composition of erythrocyte phosphatidylcholine and phosphatidylethanolamine in infants during early life European Journal of Nutrition, Vol.47, No.3, (April 2008), pp 145-152, ISSN 1436-6207 Yen, CH., Dai, YS., Yang, YH., Wang, LC., Lee, JH & Chiang, BL (2008) Linoleic acid metabolite levels and transepidermal water loss in children with atopic dermatitis Annals of Allergy, Asthma & Immunology : Official Publication of the American College of 460 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments Allergy, Asthma, & Immunology, Vol.100, No.1, (January 2008), pp 66-73, ISSN 10811206 Yuan, JM., Ross, RK., Gao, YT & Yu, MC (2001) Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China American Journal of Epidemiology, Vol.154, No.9, (November 2001), pp 809-816, ISSN 00029262 Zhao, J., Del Bigio, MR & Weiler, HA (2009) Maternal arachidonic acid supplementation improves neurodevelopment of offspring from healthy and diabetic rats Prostaglandins, Leukotrienes, and Essential Fatty Acids, Vol.81, No.5-6, (NovemberDecember 2009), pp 349-356, ISSN 0952-3278 22 Therapeutic Modelling of Type Diabetes Nilam Nilam1, Seyed M Moghadas2 and Pappur N Shivakumar3 1Department of Mathematics, Delhi Technological University, Delhi for Disease Modelling, York University, Toronto, Ontario 3Department of Mathematics, University of Manitoba, Winnipeg, Manitoba 1India 2,3Canada 2Centre Introduction In this Chapter, we are mainly concerned with mathematical modelling (using differential equations) of controlled continuous subcutaneous infusion of insulin in Type diabetes using pumps It occurs mainly in children where controlling levels of sugar is entirely dependent on external infusion of insulin Type I diabetes is a result of loss of beta-cell functions in the body due to an autoimmune reaction There is vast literature concerning continuous infusion of insulin where feedback is intermittent and the dosage is adhoc Other ways of combating Type I diabetes include transplantation of insulin producing tissues or introducing artificial beta cells We mathematically model the sugar concentration in the body and use it to dovetail a previously medically prescribed sugar concentration curve The modelling, for the first time, aids the continuous infusion of insulin based upon individuals requirements in terms of the curve of decay of sugar concentration in a prescribed time For each individual, depending on many personal factors like obesity, age, kidney functions, etc., a prescription is made of the desirable curve of sugar concentration from its highest level to the desired lowest level in a given period of time This fine tunes the delivery of insulin as it takes away much guesswork of amounts of insulin given intermittently or continuously Devices attached to continuous monitoring device will infuse insulin continuously and as per prescribed curve of reduction of sugar concentration Thus, the pumps delivery takes into consideration the time profile of the insulin release, with the release stopping after the prescribed values are attained The amount released in a dual wave shaped insulin bolus combining [8] both the usual normal and square wave methods The therapy described will be the forerunner of intense clinical research work.Mathematical models with numerical simulations and analysis based on experimental data can be more effective in terms of costs and an extraordinary amount of time dealing with diverse physiological situations This is particularly so in view of the complexities of the functions in the human body and incomplete existing knowledge This chapter provides an overview of mathematical modelling of type diabetes, with particular focus on pump therapy as a management strategy for continuous subcutaneous insulin infusion Previous models describing the mechanism of glucose metabolism have mostly focused on type diabetes, most notably the classical minimal model for explaining the profile of glucose concentration over time.[4,5] Here we summarize the conclusions of 462 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments these studies for management of diabetes, and attempt to lay out a framework for further development of these models to include pump therapy These models are often formulated as a system of differential equations that describes the profile of insulin release and the dynamics of glucose concentration over specified period of time In addition to providing background on existing modelling frameworks, the practical implications of their outputs are discussed The main goals are (a) formulation of the model using the pump mechanism (b) defining the parameters (c) profiling the insulin release (d) simulating using estimated parameter values and (e) modelling extensions to include obesity as it had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel The model consists of blood glucose concentration, remote insulin action and amount of insulin The model predictions include insulin secreted, if any, in pancreas, role of other organs, tissue uptake etc This chapter closes with future direction in mathematical modelling of type diabetes for optimal usage of external insulin and measuring insulin dependency with an insight into the role of obesity in developing diabetes Diabetes 2.1 What is diabetes? Diabetes is a global problem with devastating human, social and economic impact Diabetes is a growing epidemic threatening to overwhelm global healthcare services, wipe out some indigenous populations and undermine economies worldwide, especially in developing countries Today more than 250 million people worldwide are living with diabetes and by 2025, this total is expected to increase to over 380 million people Approximately 24 million people are diabetics in United States which is about percent of the total population The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity Diabetes is a highly prevalent disease in India where more than 35 million people suffer from diabetes Alarmingly, as much as 13 million cases remains undiagnosed which leads to long term complications The prevalence of diabetes is greater amongst the urban South Asian population (12-15%) compared to urban population in the West (6%).[9] That is why Diabetes has been one of the most important subjects for biomedical research for many years Diabetes Mellitus, commonly referred to as Diabetes, means sweet urine Consistently elevated levels of blood glucose lead to spillage to glucose into urine, hence the term sweet urine When the blood sugar level consistently runs too high in our blood stream, the condition is named as Diabetes In patients with Diabetes Mellitus, the absence or insufficient production of insulin by the liver causes hyperglycemia Diabetes Mellitus is a syndrome characterized by chronic hyperglycemia resulting from absence or relative impairment in insulin secretion and/or insulin action It can also be referred to as a condition characterized by the disturbances of carbohydrate, protein and fat metabolism, the way our bodies use digested food for growth and energy The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.[7] Diabetes is the most common endocrine disorder It is a chronic medical condition meaning it can last a lifetime which can be controlled but can not be cured completely Therapeutic Modelling of Type Diabetes 463 Human body functions best at a certain level of sugar in the blood stream Blood sugar levels are tightly controlled by insulin, the principal hormone that makes it possible for many cells (primarily muscle and fat cells) to use glucose from the blood It is manufactured by the beta cells of the pancreatic islets of Langerhans, a small section of the pancreas Secretion of insulin primarily occurs in response to increased concentration of glucose in the blood Insulin helps the glucose from food get into the body cells If body does not make enough insulin or if the insulin does not work the way it should, glucose can not get into the cells It stays in the blood instead and blood glucose level gets too high causing to have Diabetes Deficiency of insulin or its action plays a central role in all forms of diabetes There are three major forms of diabetes:[18] 2.1.1 Type diabetes Type diabetes is one of the most challenging medical disorder because of the demands it imposes on day-to-day life It was formerly known as insulin dependent diabetes mellitus (IDDM) or juvenile onset diabetes mellitus In this type of diabetes, the pancreas undergoes an autoimmune attack by the body itself and is rendered incapable of making insulin It is an autoimmune disorder, in which body’s own immune system attacks the beta cells in the islets of Langerhans of the pancreas destroying them or damaging them sufficiently to reduce insulin production The pancreas then produces little or no insulin At present, scientists not know exactly what causes the body's immune system to attack the beta cells, but it is believed that autoimmune, genetic, and environmental factors, possibly viruses, are involved It develops most often in children and young adults, but can appear at any age.Type diabetes, which predominately affects youth, is rising alarmingly worldwide, at a rate of 3% per year Some 70,000 children worldwide are expected to develop type diabetes annually If not diagnosed and treated with insulin, a person with type diabetes can lapse into a life-threatening diabetic coma, also known as diabetic ketoacidosis 2.1.2 Type diabetes Type diabetes, formerly called adult-onset diabetes or non-insulin- dependent diabetes mellitus (NIDDM), is the most common form of diabetes Type diabetes is responsible for 90 -95% of diabetes cases and is increasing at alarming rates globally as a result of increased urbanization, high rates of obesity, sedentary lifestyles and stress Type diabetes is increasingly being diagnosed in children and adolescents though it can occur at any age Millions of people don’t even know they have it because it can arise with minimal outward signs or symptoms It is diagnosed with insulin resistance in which the pancreas is producing enough insulin but for unknown reasons, the body can not use the insulin effectively This leads to a situation similar to type diabetes in which the pancreas can’t secrete enough insulin because of which glucose builds up in the blood and the body cannot make efficient use of its main source of fuel This form of diabetes is associated with obesity, older age, a family history of diabetes, a history of gestational diabetes, certain medications, impaired glucose metabolism, psychological factors, and physical inactivity Type diabetes can be controlled with exercise, diet and lifestyle modifications.[6] This type of diabetes may develop microvascular complications, which may lead to retinopathy, nephropathy and peripheral and autonomic nephropathies, and macrovascular complications include atherosclerotic coronary and peripheral arterial disease 464 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments 2.1.3 Gestational diabetes This type of diabetes develops just before or during the pregnancy Though the patient may have diabetes before the onset of the pregnancy, it is termed gestational only if it is first identified after the pregnancy has occurred Gestational diabetes is caused by the hormones of pregnancy which is produced when the placenta supports the growing fetus These hormones may interfere with the mother’s ability to produce and use her own insulin Usually this form of diabetes goes away after the delivery but women who have had gestational diabetes have a 20 to 50 percent chance of developing type diabetes within to 10 years especially those who require insulin during pregnancy and those who are overweight Untreated Gestational Diabetes Mellitus (GDM) can lead to fetal macrosomia, hypoglycemia, hypocalcemia and hyperbilirubinemia Also chances of cesarean delivery and chronic hypertension increases in women with GDM 2.2 History and causes of diabetes Diabetes is not a newly born disease, it has been with human race from long back but, we came to knew about it in 1552 B.C Since after than, many of Greek as well French physicians had worked on it and threw some light on the nature of disease, organs responsible for it etc Diabetes was recognized and categorized with complete details and its types, Type 1and Type in 1959 In 1870s, a French physician had discovered a link between Diabetes and diet intake, and then diabetic diet was formulated with inclusion of milk, oats and other fiber containing foods in 1900-1915 Dr Frederick Banting, Prof Macleod and Dr Collip discovered the function of insulin, its nature, along with its use started at the University of Toronto from 1920 -1923, who were awarded a Noble prize In 1922, 14 year old Leonard Thompson becomes the first human to receive insulin In the decade of 1940, it has been discovered that different organs like kidney and skin are also affected if diabetes is creeping from a long term A major turn in this research was in 1955, when the oral hypogycemic drugs had been manufactured Paul E Lacy, a JDRF – funded researcher at Washington University School of Medicine performs the first successful islets transplantation in diabetic animal models in 1976 The first experimental insulin pump was developed in 1979 which leads to further refined pumps to provide the infusion of insulin in a way which closely mimics the glucose response of human islets Since then, scientists are trying their best to produce results with the most impact Diabetes and its complications occur among Americans of all ages and ethnicities but the elderly and certain racial/ethnic groups are more commonly affected In comparison of non – Hispanic whites, African Americans and Hispanics/Latino Americans are about two times more likely to be affected by the disease It has been found that one tribe in Arizona has the highest rate of diabetes in the world, with about 50 percent of the adults between the ages of 30 and 64 with the disease Population of type diabetes sufferers has officially reached epidemic proportions Diabetes mellitus is developed when pancreatic tissue responsible for the production of insulin is absent because it is destroyed by disease such as chronic pancreatitis, trauma or surgical removal of pancreas It can also result from other hormonal disturbances such as excessive growth hormone production (acromegaly, in which a pituitary gland tumor at the base of the brain causes excessive production of growth hormone leading to hyperglycemia) and Cushing’s syndrome, in which the adrenal glands produce an excess of cortisol which promotes blood sugar elevation Several other factors that make it more likely that a person develop diabetes are as follows: Therapeutic Modelling of Type Diabetes       465 Age-older than 45 years Obesity Family history of diabetes in a first degree relative (parent or sibling) History with gestational diabetes mellitus Hispanic, Native American, African American, Asian American or Pacific Islander descent Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein HDL cholesterol 250mg/dl) 2.3 Symptoms and diagnosis of diabetes mellitus Diabetes mellitus (DM) has diverse intial presentations The early symptoms of diabetes are related to elevated blood sugar levels in the body and loss of glucose in the urine It usually presents with symptomatic hyperglycemia Common sign and symptoms may include any of the following:  Being very thirsty  Urinating often  Feeling very hungry or tired  Losing weight without trying  Repeated or slow healing infections  Having dry, itchy skin  Extreme fatigue  Blurred vision  Tingling or loss of feeling in the hands or feet 2.4 Biological terms commonly used in diabetes Insulin: An anabolic hormone, produced by the beta cells of the islets of Langerhans of pancreas in response of elevated blood sugar level in the body It helps to control the blood sugar level in the desirable range Glucose: Glucose is a simple sugar present in everyone’s body It is an essential nutrient that provides energy for the proper functioning of the body cells After meals, food is digested in the stomach and intestines The glucose in digested food is absorbed by the intestinal cells into the blood stream and is carried by the blood to all the cells in the body Glucose needs insulin to enter into the body as it can not get into the cells alone Glucagon: Glucagon is a hormone synthesized and secreted from alpha cells of the pancreatic islets used for carbohydrate metabolism Its secretion increases rapidly when the sugar level is too low in the body It maintains the level of glucose in the blood by binding to specific receptors on hepatocytes causing the liver to release its intracellular stores of glucose As these stores become depleted, glucagon then encourages the liver to synthesize glucose by gluconeogenesis which will be released to prevent the development of hypoglycemia, low sugar level Insulin Resistance: Sometimes the cells throughout the body become resistant to the insulin produced by the pancreas due to which it becomes difficult for the sugar to enter the cells This condition is known as insulin resistance Diabetic Ketoacidosis: It is a condition in which the cells of muscle, liver and other body parts are unable to take up glucose for producing energy due to the absence of insulin It is a 466 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments state of absolute or relative insulin deficiency aggravated by hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism To avoid starvation the body begins to break down fat for energy Fatty acids and ketone bodies are released due to the break down of fat causing chemical imbalance (metabolic imbalance) called Diabetic Ketoacidosis Moderate or large amounts of ketones in urine are dangerous They upset the chemical balance of the blood Chronic hyperglycemia: Chronic hyperglycemia means elevated blood sugar level in the blood 2.5 Treatment therapies for diabetes Type Diabetes is very serious, with a sudden and dramatic onset, usually in youth Type diabetes is an autoimmune condition, where the body attacks its own insulin producing cells The body’s immune cells, or white blood cells, include B cells and T cells B cells make antibodies and present ‘antigens’ to T cells, allowing them to recognize, and kill invaders People with Type diabetes must maintain an insulin-monitoring and insulin-injecting regimen for the rest of their lives as the islets of Langerhans are destroyed in this type of diabetes Treatment for type diabetes includes taking insulin shots or insulin pump to deliver insulin in the body, making wise food choices, exercising regularly and controlling blood pressure and cholesterol Type diabetes can be treated successfully with diet, physical activity and medication, if necessary.[23] Physical activity can help to control blood sugar levels and increases body’s sensitivity to insulin.[6] Also, it helps delays or stop heart diseases, a leading complication of diabetes Diet plays an extremely important role in controlling this type of diabetes Being overweight can increase the chances of developing type diabetes Usually GDM in pregnant women disappears itself after delivery 2.6 Mathematical model The first approach to measure the insulin sensitivity in vivo was introduced by Himsworth and Ker [24] and the first mathematical model to estimate the glucose disappearance and insulin sensitivity was proposed by Bolie In this model, he assumed that glucose disappearance is a linear function of both glucose and insulin The insulin secretion and disappearance is proportional to glucose and plasma insulin concentration respectively The main objective here is to prescribe a more accurate, but less simple, method of arranging the palatable composition of a diabetic diet The modified coupled differential equations for the plasma glucose and insulin concentration [1-14, 16-22], when the normal fasting level of plasma glucose is 70 - 120 mg/dl, are given as follows dg  l1hg  l2  g0  g  U  g0  g   l3F  t  dt (1) dh  l4  g  g0  U  g  g0   l5 h0  l6 I  t  dt (2) where, g(t) - plasma glucose concentration, h(t) - insulin concentration, li - sensitivity constants, i = 1,2,3,4,5,6, F(t) - food source input for plasma glucose, I(t) – insulin input and U(g0 - g) is unit step function 467 Therapeutic Modelling of Type Diabetes The insulin input I(t) will be given through injection at subcutaneous level at periodic intervals, which leaks its contents into the system over a period of time Therefore, I(t) may be defined as I t   t t  t0 b At t = t0, I(t) =  b where,     t0 t  t0 ,   t  t0  t0 t  t0  I t     t  t0  t  t0    t (3) ,  - quantity of injection, t0 – time of injection, t -time lag to maximum Food input source term, F(t), is the source for food input to the plasma glucose level, the contents of which are reduced in a simple exponential manner Therefore, F(t) may be modeled as Se   t t0  , t  t  F t    t  t0 0,  (4) where, S - quantity constant of meal,  - delay parameter For t  t0 , in non – diabetic case, F(t )  and I (t )  and for diabetic case, F(t )  , I (t )  A mathematical model for the dynamics of glucose concentration in patients with type diabetes using CSII [15] therapy as an external source of insulin has been developed by us We attempt to model the effect of an external source of insulin release, as a prescribed function of time, on glucose levels The model is then used to assess the optimal insulin release profile, and the threshold amount required to bring the level of glucose to within a normal physiological range To model the pump’s delivery of insulin, we take into account three major factors: (i) the total amount of insulin released over a specific period; (ii) the time profile of insulin release, f(t); and (iii) the glucose threshold concentration Gc, below which the pump stops releasing insulin The amount of insulin (TDD) is proportional to the total amount of glucose, whose concentration is assessed by the sensor in the pump’s controller This amount is released by the pump in a dual wave shaped insulin bolus which allows the patient to combine both normal and square wave techniques The body characteristics of the patient determine how much insulin is needed to maintain the glucose level within the normal physiological range after each meal The dual wave shape also provides a rapid increase in insulin plasma concentration, and sustained high circulating insulin levels while a meal is being consumed Here, we extend the minimal model to incorporate the above factors, which leads to the following differential equations: dG   X G  l1 (Gb  G ) , dt (5) 468 Type Diabetes – Complications, Pathogenesis, and Alternative Treatments dX   p1 X  p2 ( I  I b ), dt (6) dI   l2 (G  Gc ) f (t )  l3 ( I  I b ), dt (7) where G is the blood glucose concentration, X is an auxiliary function representing remote insulin action, and l is the insulin plasma concentration A description of the model parameters and their values are given in Table The important part of this extension is the first term of (7) which models all three factors mentioned above This term contributes to the insulin plasma when the glucose concentration exceeds the threshold Gc, and is defined as l (G(t )  Gc ) f (t ) if G(t )  Gc l2 (G  Gc )   if G(t )  Gc 0 (8) The function models the profile of insulin release from the pump, and the coefficient represents a scaling factor determining TDD of insulin released by the pump In the next section, we discuss different profiles of insulin release and compare their effects on the optimal control of glucose concentration The newer generation of pumps can be programmed to release insulin using three different bolus techniques A normal bolus can be used if small amounts of carbohydrates are consumed or if a correction to the blood glucose level outside the physiological range needs to be made A square wave profile is helpful when eating foods that are high in both fat/protein and carbohydrate (fat and protein delay the absorption of carbohydrates) If a normal bolus is given for a meal high in protein and fat concentrations, circulating insulin levels rise rapidly and may peak before the carbohydrates are absorbed This mismatch in insulin and blood glucose levels can result in postprandial hypoglycemia Therefore, a dual wave bolus, as a combination of the normal and square wave bolus techniques, can be introduced Using this technique, half of the insulin dose is given (over a short period of time) at the onset of the meal, and the remainder over a 2–4 h period The profile of a dual wave bolus is modeled as a function of time, f(t), in Eq (4) over a period of h (Fig 1(a)–(c)) Fig Profile of insulin release by the pump f(t), for 3h: HLL release; (b)LHL release; (c) LLH release, where H stands for high amount release of insulin and L stands for its low amount per hour f(t) is normalized so that H=L 469 Therapeutic Modelling of Type Diabetes S No Parameter Gb Gc Ib l1 l2 l3`` p1 p2 Description Base line value of glucose concentration in plasma Glucose threshold concentration in plasma Baseline value of insulin concentration in plasma The insulin dependent rate of tissue glucose uptake Scaling factor determining TDD of insulin The rate of decay for insulin in plasma The rate of spontaneous decrease of glucose uptake The rate of insulin – dependent increase in tissue glucose uptake due to insulin concentration excess over its baseline Value Unit 118 mg dl-1 100-107 mg dl-1 µU ml-1 10 Min-1 Variable min-1 µU mg-1 0.264 min-1 0.0107 min-1 0.007 min-2 µU ml-1 Table Description and values of the model parameters obtained from the published literature This particular work is published in Applied Mathematics and computation, 2007, pages 1476 – 1483 and has been cited by Kato, R, Munkhjargal, M and Takahashi, D “An autonomous drug release system based on chemo- mechanical energy conversion “Organic Engine” for feedback control of blood glucose”, Biosensors and Bioelecetronics in 2010 Vol 26(4), pages 1455 - 1459 2.7 Future work More advanced mathematical models can be formulated to explain the effects of obesity on diabetes, effects of exercise on management of type diabetes Parameters involving glucose sensors can be added to the insulin pump model for a better programmed insulin delivery by insulin pump References [1] D Araujo-Vilar, C.A Rega-Liste, D.A Garcia-Estevez, F Sarmiento-Escalona, V Mosquera-Tallon, J Cabezas-Cerrato, Minimal model of glucose metabolism: modified equations and its application in the study of insulin sensitivity in obese subject, Diabetes Res Clin Pract 39 (1998) 129–141 [2] R.N Bergman, L.S Phillips, C Cobelli, Physiologic evaluation of factors controlling 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