PRACTICE OF MEDICINE Insulin Therapy : Practical Points UC Kansra*, S Sircar** Insulin is a polypeptide composed of two chains of aminoacids : the A - chain has 21amino acids and B - chain has 30 amino acids. The two chains are linked with each other by two cysteine disulphide bonds between CYS A 7 and CYS B7 and second bond between CYS A 20 and CYS B19. There is an additional intra-chain disulphide bond connecting cysteine between A 6 and A 11. Insulin is essential for normal carbohydrate, protein, and fat metabolism. Type 1 diabetics do not produce enough insulin to sustain life, hence are dependant upon exogenous insulin for survival. On the other hand type 2 diabetics are not dependent upon insulin for survival but many patients will require supplemental insulin for adequate control especially during times of stress and illness. In our country about 95% of patients have type 2 diabetes. At present there are about 25-30 million diabetic patients in India and this number is projected to increase to 50 million by 2010. Therefore the burden of type 2 diabetes is very large. It is estimated that 25- 30% of type 2 diabetes patients usually require supplemental insulin after few years of OHA (oral hypoglycaemic agents) therapy on regular basis and most of them will require insulin at one time or another in their lifetime either during surgery or acute illness. Hence, the number of type 2 patients on insulin outnumber the patients of type 1 who are dependent upon insulin for their survival. UKPDS study shows that diet alone is ineffective in 90% of patients after one year and by 6th year 50% of patients will need insulin for proper control as 10-20% patients develop secondary failure to OHA every year 1 . Goals of insulin therapy 1. Elimination of prime glycosuric symptoms. 2. Prevention of ketoacidosis. 3. Restoration of lean bodymass. 4. Improvement in exercise and work performance. 5. Reduction of frequent infections. 6. Decrease in foetal malformations, maternal and foetal morbidity. 7. Delay, arrest, or prevention of micro and macrovascular complications. 8. Improvement in the sense of well being. Insulin preparations and characteristics Insulin can be classified into different categories based on parameters such as (a) Species; (b) Purity; (c) Physical Characteristics; (d) Potency; and (e) Time, Duration, and Effect. A) Species: It is either derived from animal pancreas or produced by genetic engineering methods. Depending upon molecular structure, insulin is classified as human, porcine, or bovine. Porcine insulin differs from human by one amino acid, whereas bovine differs by three amino acids. Bovine insulin is most immunogenic, whereas human is the least. In India, either human or porcine insulins are available whereas bovine preparations have been recently withdrawn from the market. Molecular structure 2 SPECIES A-CHAIN B-CHAIN Immunogenecity A-8 A-10 B-30 HUMAN Threonine Isoleucine Threonine Least PORCINE Threonine Isoleucine Alanine Intermediate BOVINE Alanine Valine Alanine Most B) Purity-measured in terms of proinsulin content Conventional < 3000 ppm – Not available Highly purified < 10 ppm * Senior Physician & Diabetologist, Safdarjung Hospital, New Delhi-110 029 ** Consultant Physician & Diabetologist D-656, CR Park, New Delhi-110 019. 286 Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 Monocomponent < 1 ppm – all human insulins are monocomponent. C) Physical characteristics: The solution can be either clear or cloudy. All regular, soluble, or crystalline insulins are clear solutions whereas all long acting insulins like NPH, lente, or ultra- lente are cloudy solutions. All insulins except conventional bovine have neutral pH. Conventional bovine insulin was acidic and is not available for clinical use at present. D) Potency: In India all types of insulins are available as 40 units/ml in 10 ml vials. 100 units/ml vials as well as pen cartridges are also available but care should be taken to use appropriate or potency matching syringe. For patients having insulin resistance even 500 - 5000 units/ml preparations are available. E) Time Duration and effect 3 Insulin Type Synonyms Retardant Time of Effect Hours Onset Peak Duration Unmodified Soluble None 0.25-1 1.5-4 5-9 Regular H] Short Acting P] same B] NPH Isophane Protamine 0-5-2 3-6 8-14 H] P] same B] Lente Mixture of 30% Zinc H 1-2 3-8 7-14 Semilente (an P 1-2 3-8 7-16 amorphous precipitate B 1-5-3 5-10 10-24 of Insulin with Zinc ions) with 70% Ultralente Insulin Zinc H 2-3 4-8 8-14 Ultralente An Insoluble Crystal B 3-4 6-12 12-28 of Zinc and Insulin Insulin Lispro None 5-15 1-2 4-5 Analogues Minutes 10/90 Premixed 25/75 Protamine 0.25-1.5 3-6 8-14 30/70 and 50/50 (H- Human, P- Porcine, B- Bovine) Unmodified and lispro insulins do not have any retardant hence have rapid onset of action, early peak and short duration of action. NPH has protamine or fishsperm as retardant, whereas lente and ultralente have Zn as retardant. Lente is a mixture of ultra and semilente in the ratio of 70:30. Only soluble or regular insulin is to be used by intravenous route. NPH and lente are used in once a day, basal, or twice a day regimen. Ultralente is best for basal regimen. Lispro has advantage over other insulins as it can be given with meals because of rapid onset and short duration of action. It is most suitable for old persons and children as their eating habits are often erratic. Normally, insulin is stored in vials as hexamers and requires degradation to dimers and monomers for absorption. Since in lispro insulin there is interchange of proline and lysine at 28 Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 287 and 29, hence it remains in monomeric or diameric form and is thus rapidly absorbed. Pre- mixed insulins are usually available in a wide range, but 25/75 & 30/70 are most popular. If pre-mixed is with lente, then because of presence of Zn almost 50% of crystalline insulin changes to lente but this problem does not exist when regular insulin is mixed with NPH. Almost all available combinations are with NPH 4 . Storage of insulin All insulin preparations are required to be stored in a cool and dark place; otherwise their potency is lost, as it is temperature dependent. At 4 degree C it loses only 2% potency over years. At 25 degree C 2% loss occurs in 6 months. At 40 degree C 2% loss occurs in one week and 5% in one month. Therefore the extremes of temperature, that is, <2 and >30 degree C should be avoided 5 . Therefore, keep insulin preparations away from direct sunlight, in a cool and dark place. Do not keep in a freezer compartment. The vial in current use can be easily kept at room temperature in a dark place without losing any potency, as most patients will consume it within one month. If kept in a freezer, then before injecting it should be taken out and kept at room temperature for at least 1/2 an hour, otherwise injection will be painful if cold insulin is injected. In rural areas or when refrigerator is not available, it is advisable to put the vial in plastic bag, tie a rubber band and keep it in wide mouth bottle filled with water or in an earthen pitcher. During travel Ideally keep the insulin in a flask with ice, or in a hand bag, or a proper container if outside temperature is less than 30 ° C. Never keep insulin in the glove compartment of a car. Absorption of insulin Except lispro, all insulins in vials are in hexamer form and need to be changed to monomeric form before absorption and it is the rate-limiting step in absorption. Usually there is a lag period of at least 10-15 minutes before insulin appears in circulation. Insulin analogue is most rapidly absorbed followed by human, porcine, and bovine in descending order 6 . Factors affecting absorption - can be either physiological or structural A) Capillaries at injection site Higher density of capillaries enhances absorption. Absorption is rapid from the abdominal wall followed by upper arm and thigh in descending order as abdominal wall has high density of capillaries. It also depends upon their functional status, that is, open or closed capillaries at the site. Capillary density and functional status decrease in lipo- dystrophy and atrophy. Obesity and smoking also cause a decrease in density and affect functional status of capillaries 7 . Exercise and massage, increased local temperature, and better hydration result in better absorption. Absorption is better with intramuscular as compared to subcutaneous route. B) Insulin concentration and dose 40 u/ml is faster absorbed as compared to 100 u/ml insulin. Higher the dose, slower is the absorption 8 . Hence the onset and duration of action of same type of insulin can vary depending upon the physiological and structural factors at the injection site. Mixing insulins Usually premixed solutions in a wide range are available, but at times one has to mix short and long acting insulins. Expect bovine insulin, all are at neutral pH and can be easily mixed. Pre-mixed are with NPH as lente is not suitable because presence of Zn changes 50% of crystalline insulin to lente. Technique Wipe the top of vial with 70% isopropyl alcohol. 288 Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 Inspect the neutral soluble insulin vial for any suspended particles and if present discard it. Roll vial between palms and never shake it. First take lente insulin vial and inject air equivalent to dose. Withdraw the needle without draining the insulin. Now take plain insulin vial, inject air equal to dose and draw the required amount of insulin in syringe. Now draw the lente insulin in the syringe. If lente is drawn first and at the time of draining plain insulin if some amount of lente enters plain vial it will change plain to lente in the vial. Injection site For routine administration insulin is always given subcutaneously. IV, IV infusion, or IM routes are used only during ketoacidosis or stressful conditions. It can be injected in anterior abdominal wall, upper arm, thigh, and buttocks; the rate of absorption also declines in above order. Same site is used for at least one month and rotation is done within the same site rather than rotating to different sites with each injection (by an inch for each injection). Using same site decreases variability in day to day absorption. Rotation within the same area prevents lipodystrophy. Avoid a site with open wounds or blisters 9 . Injection technique If the injection site is clean, there is no need to clean the site with alcohol or spirit as there are bactericidal agents in insulin vial and as such injection site infections are very rare. But if antiseptic cleaning agent is used then let it evaporate before injecting insulin 10 . In thin or averagely built person, lift or grasp a fold of skin between thumb and index finger and inject at 45°or 90°. In obese person, full length injection at 90° is recommended. If there is pain or blood at injection site one must review the injection technique. Pain can be minimized by: a) Injecting when insulin is at room temperature b) Keep muscles at site relaxed. c) Penetrate skin quickly while inserting or withdrawing needle and do not change direction. d) Avoid air bubbles in the syringe 11 . Syringes and other delivery devices Insulin is available in two potencies, that is, 4O u/ml and l00 u/mI, and always use compatible syringe that is having 0-40 u/ml or 0-100 u/mI. In disposable insulin syringes there is no dead space hence insulin is not wasted. The needle used is very fine, of 29 G or 30 G, having either 8 mm or 12.7 mm length suitable for average and obese patients respectively 12 . Ideally, a syringe should not be reused but if reuse is desired, then after injection recap it and store properly at room temperature in appropriate box. There is no need to sterilise or clean with alcohol or spirit. The same syringe can be reused till the needle becomes blunt. Reuse is not advisable if personal hygiene is poor or open wounds are present 13 . Among the other devices Insulin Pens have become very popular. They are safe, accurate, convenient and most suitable for elderly and handicapped persons. They can be reused and only cartridges need to be replaced. Each cartridge contain 300 u of insulin. Other methods of administration are : a) Jet injection b) Insulin infusion pump c) Nasal Insulin Infuser d) Transdermal Insulin e) Oral Insulin Indications A. Absolute  Type 1 diabetic patients  GDM (Gestational Diabetes Mellitus)  Ketoacidosis B. Relative Type 2 diabetic patient with primary or secondary failure to OHA Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 289  Surgery under general anaesthesia  Type 2 diabetes with symptoms of glucose toxicity  Acute illness  Acute infections, e.g., Pneumonia, septicaemia, etc.  Active pulmonary tuberculosis  Acute MI, CVA  Diabetic nephropathy  Chronic liver disease, etc. Choice of insulin Soluble/Regular/Neutral It is the only insulin suitable for IV use. Useful for twice, basal-bolus, or CSII regimen for glycaemic control. To be used in acute stressful conditions and keto-acidosis. Extended acting Lente, NPH, ultralente, and premixed are suitable for once, twice, or basal bolus regimen. Ultralente is preferred for single bedtime injection and NPH for single before breakfast (BBF) injection. Lispro insulin - Best suited for post-prandial hyperglycaemia but can be used in place of regular in twice, basal bolus regimen, etc. Premixed insulins Premixed insulins are very popular and available in wide range. Regular is mixed with NPH as it is more stable. 30/70 and 25/75 are most popular and used in twice a day regimen. 50/50 is preferred for correction of post-prandial hyperglycaemia. Insulin regimens A. Once daily regimen It is most commonly used in type 2 diabetes patients with secondary failure to OHA and used in combination with OHA. Either lente, ultralente, or NPH is used. NPH is preferred before breakfast, whereas lente or ultralente before dinner. The regimen is not suitable for type 1 diabetes cases. B. Twice daily regimen It is the most commonly used regimen as it is suitable for most type l, 2, and GDM patients. It is very convenient as patient has to take only BBF and before dinner (BD) dose and there is no need to carry insulin to school or office. Usually both short and long acting insulins are used in combination, but in few cases only long acting insulin can be used alone but not the short acting. This regimen is not to be used in acute medical emergencies. Usually, of the total daily dose 2/3rd is given BBF and 1/3 before dinner; but depending upon eating habits and glycaemic status, dose can vary and even 50% can be given BBF and BD. Again, the usual ratio of long acting to short acting is 2/3:1/3 or 70:30. But in premixed insulins wide range is available from 10:90, 25:75 to 50:50. This regimen gives similar results as compared to multiple injections or CSII by pump. C. Basal bolus regimen In this regimen regular and intermediate acting insulin is used. Basal requirement is met by intermediate acting insulin given twice a day before breakfast and dinner. The regular insulin is given before each meal thrice a day. Out of the total daily requirement 50% is given as basal (intermediate) and 50% as regular insulin. The share of regular insulin (50%) is given as 20% BBF, 10% BL and 20% BD. It gives similar results as compared to twice a day but the only disadvantage is that the before lunch (BL) dose is to be taken at school or office. D. Continuous subcutaneous insulin infusion Only short acting insulin is used and is given by insulin pump which the patient has to wear throughout the day. It is neither practical, nor are the results better than twice daily or bolus regimen. 290 Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 During surgery All patients undergoing surgery, under general anaesthesia, require changing over to insulin from OHA and to regular insulin from intermediate acting insulin. Surgery should be scheduled in the morning. Omit BBF insulin. Do fasting blood sugar and put patient on GIK (Glucose-Insulin- Potassium) regimen according to blood sugar level at least one hour before starting surgery. The GIK regimen should continue at least one hour after the patient has taken the first post operative meal and patient is shifted to pre-surgery thrice a day insulin regimen 14 . During surgery do blood sugar at 1/2 hourly or one hourly interval as per the status of patient. Because of surgical stress, insulin requirements are more with intra-abdominal or thoracic surgery. CABG puts maximum surgical stress. The stress caused by laparotomy is much more than the stress caused by even whole body skin grafting. Glucose-Insulin-Potassium (GIK) Regimen Blood/Plasma Fluid Insulin Insulin KClmeq/100ml Glucose mg.% 100 ml/hr. U/100ml U/500 ml <100 10% Dextrose 1 5 2 100-200 10% Dextrose 2 10 2 200-300 10% Dextrose 3 15 2 300-400 10% Dextrose 4 20 2 >400 N/Saline 4 20 2 Insulin dose to be reduced to half if 5% Dextrose is used. Insulin therapy for ketoacidosis The use of low dose insulin regimen either given by insulin infusion or intramuscularly is now the accepted regimen for keto- acidosis. The high dose regimen is no longer used as with low dose regimen there is less frequent hypokalaemia, hypoglycaemia, and more predictable response. Insulin is given as 6 u/hour by continuous IV infusion. Only short acting insulin is used. When the blood sugar falls to 250 mg% the normal saline is replaced with 10% dextrose and insulin infusion rate reduced to 4 u/hour. But if significant drop in plasma glucose is not observed after 2 hours of insulin infusion and if fluid replacement, blood pressure, and infusion lines are satisfactory, then double the infusion rate. Insulin can be given by IM route with dose of 6 u/hr but often a loading does of 20 u is required. If after 2 hours the fall in sugar is not satisfactory, either double the dose or start IV infusion. The acidosis and ketosis resolve more slowly than hyperglycaemia; hence, IV dextrose preferably 10% dextrose with insulin should continue till patient starts eating and shift to thrice a day regimen by subcutaneous route. It is advisable to increase the total daily dose by 20% of previous (before onset of ketoacidosis) insulin dose and after recovery discharge on previous or twice a day regimen. Insulin regimen in special group of patients 1. Elderly: Do not aim for strict glycaemic control. Twice a day or once a day regimen are most suitable. 2. Renal failure: There is considerable reduction in insulin requirement and twice daily or basal bolus regimens are suitable. 3. Recurrent hypoglycaemia: Insulin dose distribution needs to be reviewed rather Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 291 than the regimen. In some cases shifting evening dose to bedtime can prevent nocturnal hypoglycaemia. 4. Children: Same regimens are used as for adults. Intermediate insulin may be ab- sorbed faster. Twice a day is best suited as it eliminates injection at school. 5. Secondary diabetes: Due to pancreatic disease; usually have mild diabetes and can be managed with twice a day regimen. 6. Steroid and endocrine diabetes: They have marked insulin insensitivity and considerable endogenous insulin secretions. It may require high dose of insulin, but cessation of steroids often allows patient to come off insulin again. They are managed with twice daily regimen. Endocrinopathies cause mild diabetes which can be easily controlled with twice a day insulin regimen. 7. Pregnancy: Insulin dose will increase as pregnancy advances and balance of insulin changing to greater daytime requirement. There is sudden fall in insulin requirement after delivery. 8. Cirrhosis of liver: Marked insulin insensitivity during day but because of impaired gluconeogenesis, no difficulty in maintaining glucose concentration over night. Hence require preprandial injection regimen. Adjustment of insulin dosage For proper monitoring of control, the patient should be encouraged to do SMBG (Self monitoring of blood glucose). Ideally it should be done by using glucometer and only when glucometer is not available, gluco or dextro sticks can be used. Urine sugar testing is not reliable. Though expensive, HbA 1C is good for monitoring the control. Ideally plasma blood sugar should be done before and after each main meal and at bed time. Once good control is achieved the frequency is reduced to once or twice a week. Before attempting to readjust the insulin dosage, a good number of blood glucose readings should be available. If earlier control was good within last 3 months and there are no symptoms of hyperglyacemia or reasons to suggest poor control, the blood sugar should be repeated with same dosage and also do HbA 1C before attempting any change. The blood may also show 30-50% variation at any one time of the day on different days. Fasting and PP should be done on same day for better assessment. The guidelines for insulin dose adjustment are : 1. Do not change earlier than 2-3 days. 2. Change around 25% of any one preparation at one time. 3. Do not change more than 10-20% of total dose at one time. 4. Always modify the preceding dose. 5. Always review the dietary habits and injection technique of the patient before modification. 6. Reduce the dose by 15-20% at the time of discharge. Dose adjustment on changing from conventional to human insulin No dose adjustment is required if : Requirement <1 u/kg body wt. No lipodystrophy Patient can do SMBG. If patient is taking >1u/Kg body wt. then reduce dose of human insulin by 15-20% at the time of changing from conventional to human insulin and readjust the dosage. 292 Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 Adjustment of Morning Dose Before Lunch Before Dinner a) Hyperglycaemia Increase short acting BBF Increase Intermediate (lente/NPH) BBF b) Hypoglycaemia Decrease short acting BBF Decrease intermediate (lente/NPH) BBF Adjustment to Evening Dose Before Dinner Before Breakfast a) Hyperglycaemia Increase Intermediate BBF Increase Intermediate before OR Dinner Add Short acting at Lunch b) Hypoglycaemia Decrease Intermediate BBF Decrease intermediate before dinner OR OR shift intermediate to bed time Omit short acting at Lunch OR Decrease short acting before dinner if dose is very high Complications of Insulin Therapy Hypoglycaemia Identification card. Carry 25-50 gm glucose while travelling even from home to place of work. Relatives and friends be taught to give Inj. glucagon. Allergy (Localised/Generalised). Lipoatrophy and Lipohypertrophy. Insulin oedema. Immunological insulin resistance. Insulin antibodies. Insulin resistance. Obesity and weight gain. Atherosclerosis, etc. Summary  Educate patient about the disease, need for insulin, and problem of hypoglycaemia and its management.  Should keep 25 gm glucose at home, place of work and carry while travelling.  All new patients requiring insulin for short period should be put on human insulin.  If patient already well controlled on conventional, no additional benefit with human insulins.  Always inspect vial before use.  Explain storage and mixing.  Teach and review injection technique yearly, and earlier if local site complications are present.  Insist on self injecting of insulin.  Set individual glycaemic goals.  Tight control not desired in elderly, ESRD, and patients with poor knowledge.  Encourage SMBG.  Only short acting can be given IV.  Once daily not preferred.  Twice daily/basal bolus/CSII/multiple injection regimen have similar results.  Adjust 15-20% of single preparation at one time. References 1. UK Prospective Diabetes Study Group: Intensive blood glucose control with sulphonylurea or insulin compared with conventional treatment and risk of complication in patients with Type 2 diabetes (UKPDS33). Lancet 1998; 352: 837-53. 2. Yue DK, Turtle Jr. New form of insulin and their use in treatment of diabetes. Diabetes 1977; 26: 341-7. 3. Homes PD, Alberti KGMM. Insulin Therapy Ed. Alberti KGMM et al. In International text book of Diabetes Journal, Indian Academy of Clinical Medicine  Vol. 1, No. 3  October-December 2000 293 Mellitus. England John Wiley & Sons 1992; 831-63. 4. Nolte MS, Poon V, Grodsky GM et al. Reduced solubility of short acting insulin when mixed with longer acting insulin. Diabetes 1983; 32: 1177-81. 5. Insulin Administration, American Diabetes Association. Diabetes Care 1999; 22 (Suppl. 1): S83-S86. 6. Sherwin RS, Kramer KJ, Tobin JD et al. A model of kinetics of insulin in man. J Clin Invest 1974; 53: 1481-92. 7. Hildebrandt P, Sejrsen P, Nielsen SL et al. Diffusion and polymerisation determines the insulin absorption from subcutaneous tissue in diabetic patients. Scand J Clin Lab Invest 1985; 45: 685-90. 8. Rosenzweig JL. Principles of Insulin therapy. Ed Kahn CR, Weir CC In Joslin’s Diabetes Mellitus. New Delhi. BI Waverly Pvt Ltd 1996; 13: 460-88. 9. For references from 9-13, American Diabetes Association. Continuous subcutaneous insulin infusion (Position Statement). Diabetes care 1999; 22 (Suppl.1): S87. ALEMBIC Presents Comprehensive Diabetic Range GLZ 80/40 (Gliclazide Tab) GLZ Plus (Gliclazide + Metformin) 80mg 500mg Forminal 500/850 (Metformin) ALA-100 (Alpha Lipoic Acid) Sionara 100/200 (Celecoxib 100/200mg Cap) & GOLD STANDARD IN ARTHRITIS MANAGEMENT With Best Compliments from . PRACTICE OF MEDICINE Insulin Therapy : Practical Points UC Kansra*, S Sircar** Insulin is a polypeptide composed of two chains of aminoacids : the. cartridge contain 300 u of insulin. Other methods of administration are : a) Jet injection b) Insulin infusion pump c) Nasal Insulin Infuser d) Transdermal Insulin e) Oral Insulin Indications A 2 >400 N/Saline 4 20 2 Insulin dose to be reduced to half if 5% Dextrose is used. Insulin therapy for ketoacidosis The use of low dose insulin regimen either given by insulin infusion or intramuscularly is