Diabetes mellitus

INTRODUCTION

Diabetes mellitus (DM) is traditionally described as a syndrome of disordered metabolism with hyperglycemia due either to an absolute insulin deficiency or reduction of its biologic effectiveness or both. DM is coming as a global epidemic especially in Asian counties. India is now called as the diabetic capital of the world.

CLASSIFICATION

NIH Diabetes Data Group, in 1979, traditionally divided diabetes into two main types viz. – non-insulin dependent DM (NIDDM) and insulin dependent DM (IDDM). In 1997, the ADA and WHO recommended a change in classification, with etiology being the defining criteria. This classification has introduced the terms, type 1 and type 2 diabetes mellitus, to replace IDDM and NIDDM, respectively.

DIAGNOSIS AND CLINICAL PRESENTATION

Type 1 Diabetes Mellitus

It is a severe disorder and is associated with ketosis in untreated state. The disorder is homogenous and can
occur at any age, although it is most common in lean young individuals who usually present with dramatic symptoms. The disease is characterized by insulinopenia, low C-peptide and elevated glucagon indicating specific b-cell defect. The b-cell defect is most commonly due to autoimmune attack, while in approximately 5% subjects no cause is identifiable. If not treated with insulin the disorder can be fatal, i.e. the patients are dependent on insulin for their survival (5a).

Type 2 Diabetes Mellitus

It is considered to be a heterogeneous disorder, which afflicts individuals who have relative insulin deficiency, coupled with insulin resistance. The individuals are usually obese adults, not requiring insulin to prevent ketoacidosis. They may need exercise, diet, and oral hypoglycemic agents to control glycemia till late in the natural history of the disease, when insulin may be needed. Recently, however, type 2 DM has been found also to occur at a younger age. Some investigators consider type 2 DM to be a facet of Syndrome X (Reaven’s syndrome) comprising of hyperinsulinemia, dyslipidemia, hypertension and hyperglycemia.

Other specific types of diabetes

There are several other types of diabetes, which could result from genetic defects of pancreatic function, pancreatic disease, endocrinopathies, chemicals, abnormalities in insulin action, infections, mutations in the insulin receptor, mutations of mitochondrial DNA and other genetic syndromes.

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Hypertension in Diabetes

Hypertension is a common accompaniment of type 2 diabetes and sets in the course of type 1 diabetes. Hypertension magnifies many fold the damage to the target organs (kidneys, heart, eyes etc) in diabetics and hence needs significant attention. Drug treatment in addition to lifestyle intervention is recommended to reach the prescribed goals by ADA and AHA (BP< 130/85 mm of Hg). Various drug trials on hypertensive diabetics are Appropriate Blood Pressure Control in Diabetes (ABCD), Fosinopril vs. Amlodipine Cardiovascular Events Randomized Trial (FACET), Irbesartan Diabetic Nephropathy Trial (IDNT). In perspective because of their efficacy, lesser side effects and good metabolic profile, ACE inhibitors rank as first-line treatment in both type 1 and type 2 diabetes.

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Management approach to a patient wıth dıabetes mellitus

TYPE 1 Diabetes Mellitus

All patients with type 1 DM should be exclusively on insulin therapy. The preferred form of therapy is basal bolus therapy which involves one (or more) injections of intermediate acting insulin and premeal bolus of regular insulin. Recently intermediate acting insulin has often been replaced with a long acting analogue (glargine or detemir) and the regular insulin with a short acting analogue (lispro or aspart). There are no fixed formulae for dose calculation and regular self home monitoring of blood glucose is used guide dose changes. Monitoring should be performed before and 2 hours after all major meals and also at 3.00 AM. The frequency of testing depends on the stability of control and consistency of lifestyle. Younger children, adolescents and professionals with unpredictable meal schedule must monitor more frequently to guide therapy and attain optimal   control. Adults with a consistent dietary regimen and daily schedule may monitor less frequently. Dose changes must never be made in response to a single abnormal blood glucose value. Ideally a trend of 3 or more abnormal values at the same monitoring point necessitates a dose change. The fasting blood glucose value dictates the dose of the night time long/intermediate acting insulin while each premeal blood glucose value reflects effect of the previous injection dose of the short acting analogue / regular insulin. The doses should be titrated to attain premeal blood glucose value of 70-120 mg/dl and a 2 hour post meal value of < 140 mg/dl.


TYPE 2

Pharmacotherapy should be initiated in patients with type 2 DM once a medical nutrition therapy and exercise has been unable to reach the goals. Metformin is the drug of choice in obese patients with type 2 diabetes while sulfonylureas are the preferred agents for lean patients with type 2 DM. Metformin is administered usually after the meal to minimize the gastrointestinal side effects. Dose escalation of metformin should be done at 4 weekly intervals with a maximum daily dose of 2-2.5 grams per day. Sustained release preparations of metformin are now available enabling single daily dosing. Glibenclamide, gliclazide and glipizide are administered twice a day, prior to breakfast and dinner while glimepiride can be given as a single daily dose. The escalation of the dose of sulfonylurea should not be done at intervals earlier than 7-14 days and this may be increased further in the case of glimepiride. In case the level of glycemia attained by a half maximal dose of sulfonylurea is unacceptable, it is preferable to add metfomin, or a thiazolidinedione rather than increasing the dose of sulfonylurea.

Thiazolidinediones are preferred as add-on therapy when sulfonylureas alone are not achieving acceptable glycemic control and metformin is either contraindicated or not tolerated.  Further, when a combination of maximal dose of sulfonyurea and metformin do not lead to euglycemia, thiazolidinediones can be added as a third agent.  A combination of the two insulin sensitizers is also a probable therpeutic option in obese patients with type 2 diabetes.

The newer secretogogues being quicker in onset and short acting need to be dosed t 5-10 minutes before major meals. They provide a better postprandial control and can be used accordingly in people with postprandial hyperglycemia and those with erratic meal schedule. During the course of type 2 DM the response to therapy goes off temporally and gradually necessitating increasing the number of oral agents and their doses. Finally most of type 2 DM cases may only be controlled adequately by using insulin therapy either alone or in recommended combinations with oral hypoglycemic agents.

Management of Lipid disorders

Most common cause of mortality and morbidity in diabetes (both type 1 and 2) is atherosclerotic cardiovascular disease owing to several risk factors, hyperlipidemia being the most prominent. Diabetic dyslipidemia is characterized by mild hypertriglyceridemia, low HDL and elevated LDL, the latter being in small, dense and oxidized (atherogenic) form. Both ADA and American Heart Association (AHA) recommend LDL cholesterol lowering as first priority followed by raising HDL and lowering triglycerides as 2nd and 3rd priority respectively. Both agencies recommend LDL goal and TG goals of 100 mg/dl and 200 mg/ dl respectively. HDL goal, however are different (ADA > 45 mg/dl and AHA 35 mg/dl). Five lipid lowering trials have examined and demonstrated a positive benefit of statins on CHD in diabetics. These trials are: The Scandinavian  Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE),Long Term Intervention with Pravastatin in Ischemic Disease (LIPID), Air Force/Texas Coronary Atherosclerosis Programme(AF-CAPS) and Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial ( VA-HIT)  and  used statins and fibric acid derivatives. Drug therapy for HDL and triglyceride are taken up only after behavioral modification (i.e. weight loss, increased physical activity, and smoking cessation) has been tried.

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Insulin

Insulin is the only therapy available for patients with type 1 diabetes.  Insulin is also required in patients with type 2 diabetes who have developed sulfonylurea failure or those who are undergoing an acute infective or operative event, which has destabilized metabolic control. Insulin replacement in patients with type 1 dia­betes has been less than optimal because it is not possible to completely reproduce the normal physio­logic pattern of insulin secretion into the portal vein. The problem of achieving optimal insulin delivery remains unsolved with the present state of tech­nology. Subcutaneous injections do not reproduce the physiologic patterns of insulin secretion; how­ever, with the help of appropriate modifications of diet and exercise and careful monitoring of capil­lary blood glucose levels at home, it is possible to achieve acceptable control of blood glucose by using multiple injections. In some patients, a portable in­sulin infusion pump may be required for optimal control. With the development of highly purified hu­man insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site.

Table 4: Characteristics of currently used preparations of human insulin and insulin analogues

Type of insulin	Onset of action	Peak effect	Dosing interval	Time point to monitor effect
Mealtime                                 (min)                      (min)
Lispro (rapid acting)	5-15	30-90	At meal	2 hr
Aspart(rapid acting)	5-15	60-120	At meal	2-3 hr
Regular(short acting)	30-60	120-240	30-45 min premeal	4 hr
Background                            (hrs)                     (hrs)
NPH(intermediate acting)	2-4	4-6	Twice daily	8-12 hr
Ultalente (long acting)	3-5	Limited peak	Twice daily	10-12 hr
Glargine (long acting)	2-4	Peakless	Once daily	Fasting glucose
Detemir	2-4	Peakless	Twice daily	Fasting glucose

 

Table 4 indicates commercial insulin preparations that differ with regard to their time of onset and duration of biologic action. It is important to recognize that values given for time of onset of action, peak effect, and du­ration of action are only approximate ones and that there is great variability in these parameters from pa­tient to patient and even in a given patient depending on the size of the dose, the site of injection, the de­gree of exercise, the avidity of circulating anti-insulin antibodies, and other less well defined variables.

Human insulin is now produced by recombinant DNA techniques (biosyn­thetic human insulin). Improvements in purifica­tion techniques for insulin have reduced or elimi­nated contaminating insulin precursors that were ca­pable of inducing anti-insulin antibodies. "Purified" insulin is defined as containing less than 10 ppm of proinsulin, whether extracted from animal pancreas or produced from biosynthetic proinsulin. All human and pork insulins currently available con­tain less than 10 ppm of pro insulin and are labeled as "purified." The more highly purified insulins currently in use preserve their potency quite well; therefore, refrigera­tion while in use is not necessary. During travel, re­serve supplies of insulin can be readily transported for weeks without significant loss of potency pro­vided they are protected from extremes of heat or cold. At present, insulins in the USA are available only in a concentration of 100 units/ml (U 100) while in India both U 100 and U40 are available, and dispensed in 10-mL vials. Four principal types of insulin are available: (1) Ul­trashort-acting insulin, with very rapid onset and short duration of action; (2) short-acting insulin, with rapid onset of action; (3) intermediate-acting insulin; and (4) long-acting insulin, with slow onset of action (Table 4).

Ultra-short-acting and short-acting in­sulins are dispensed as clear solutions at neutral pH. All other commercial insulins have been specifically modified to obtain more prolonged action. They are dispensed as opaque suspensions at neutral pH with either protamine (derived from fish sperm) in phos­phate buffer (NPH) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins), ren­dering the insulin insoluble. These preparations are designed for subcutaneous use.

Short-Acting Insulins:  Regular insulin is short-acting, soluble crystalline insulin, whose hypoglycemic effect appears within 15-30 minutes after subcutaneous injection, peaks at 1-3 hours, and lasts for about 5-7 hours when usual quantities, eg, 5-15 units, are administered. Soluble insulin hexamerizes on being injected into subcutaneous tissue, and needs to dissociate back to a monomeric state, before it can be absorbed in to the circulation and commence action.  Regular insulin is the only type that can be administered intra­venously or used in continuous subcutaneous infu­sion pumps. Regular insulin or the short acting analogues are particularly useful in the treatment of diabetic ketoacidosis and when the insulin require­ment is changing rapidly, such as after surgery or during acute infections.

Intermediate-Acting Insulin:

1. Lente insulin: This is a mixture of 30% short-acting with 70% ul­tralente insulin. Its onset of action is delayed to 2-4 hours, and its peak response is generally reached in about 8-10 hours. Because its duration of action is often less than 24 hours (with a range of 18-24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. The su­pernatant of the lente suspension contains an excess of zinc ions, which may precipitate regular insulin if it is added to lente.

2. NPH (neutral protamine Hagedorn, or isophane) insulin-is an in­termediate-acting insulin in which the onset of action is delayed by combining two parts of soluble crys­talline zinc insulin with one part protamine zinc in­sulin. The mixture is reported to have equivalent con­centrations of protamine and insulin, so that neither is in excess ("isophane"). The peak action and duration of action of NPH insulin are similar to those of lente insulin, however, in contrast to lente insulin, regular insulin retains its solubility and independent rapid ac­tion when mixed with NPH. Flocculation of suspended particles may occasion­ally "frost" the sides of a bottle of NPH insulin or "clump" within bottles from which multiple small doses are withdrawn over a prolonged period. This instability is a rare phenomenon and might occur less frequently if NPH human insulin were refrigerated when not in use and if bottles were discarded after 1month of use. Patients should be vigilant for early signs of frosting or clumping of the NPH insulin, be­cause it indicates a pronounced loss of potency. Sev­eral cases of diabetic ketoacidosis have been reported in patients with type 1 diabetes who had been inadver­tently injecting this denatured insulin.

 Long-Acting Insulin: Ultralente insulin a relatively insoluble crystal of zinc and insulin sus­pended in an acetate buffer. Its onset of action is quite delayed, with peak effects at 8-14 hours and duration of action of up to 36 hours. It is generally recommended that the daily dose of Ultralente be split into two equal doses given every 12 hours. This is needed in type 1 patients to achieve basal insulin levels throughout the 24 hours, which are comparable to that achieved in normal subjects by basal endogenous se­cretion or by the overnight infusion rate programmed into insulin pumps.

Insulin Analogues

Short Acting Analogues: The first commercially available short acting analogue was insulin lispro. This analogue is synthesized by interchanging proline with lysine at positions 28 and 29 in the B chain of insulin. Another short acting analogue, insulin aspart, has been formed by substituting aspartic acid for the proline at position 28 of the B chain. These analogues appear to be similar to insulin in terms of their binding characteristics to the insulin and IGF-I receptors and equally potent in terms of glu­cose-lowering activity. The short acting analogues have a faster onset, and shorter duration of action compared with regular insulin.  They can be injected just prior to the meal (“shoot and eat”) as opposed to the recommended 30 minutes gap before meals for regular insulin.  The circulating concentration of the short acting analogues declines to undetectable levels by approximately 4 hours after the injection (25).

Long Acting Insulin Analogues:  The insulin mole­cule has also been modified in an effort to develop long­ acting insulin analogues to ensure a smooth prolonged basal control. One such analogue, insulin glargine, has a glycine substitution for asparagine at position A21 and two arginine additions at the end of the B chain. These substitutions result in a shift of the iso­electric point of human insulin from pH 5.4 toward pH 7.0, making the insulin less soluble at the neutral pH of the injection site. This insulin is administered as a clear solution at a slightly acidic pH. After injec­tion, the change to a more neutral pH causes precipi­tation of the insulin at the injection site and forms a slow-release depot. Glargine appears to provide a basal insulin level last­ing for about 24 hours. Another analogue, insulin detemir has been synthesized by removing threonine at position B30 of insulin, and acylating the e-amino group of lysine B29 with a 14-carbon myristoyl fatty acid.  The fatty acid modification allows insulin detemir  to reversibly bind albumin, resulting in delayed absorption and prolonged action. Insulin detemir needs to be injected twice a day to ensure coverage of the 24 hour period. Both the long acting analogues can be described as “peakless” insulins (26).

Insulin Mixtures: Since intermediate insulin require several hours to reach adequate therapeutic levels, their use in type I patients requires sup­plements of regular insulin preprandially. It is well established that insulin mixtures containing increased proportions of lente to regular insulin may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and par­tially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (eg, I part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular in­sulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are pre­scribed. For convenience, regular or NPH insulin may be mixed together in the same syringe and in­jected subcutaneously in split dosage before breakfast and dinner. It is recommended that the regular in­sulin be withdrawn first, then the NPH insulin. No at­tempt should be made to mix the insulins in the syringe, and the injection is preferably given immedi­ately after the syringe is loaded. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or insufficient manual dexterity.

It has been demonstrated that insulin lispro can be acutely mixed with either NPH or ultralente insulin without affecting its rapid absorption. Premixed preparations of insulin lispro and NPH insulin are un­stable because of exchange of insulin lispro with the human insulin in the protamine complex. Conse­quently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate acting insulin composed of isophane complexes of protamine with insulin lispro has been developed and given the name NPL (neutral protamine lispro). Premixed combina­tions of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75) have been tested. Pre­liminary results suggest that 25% NPL:75% insulin lispro given before each meal is effective in control­ling postprandial hyperglycemia while providing ef­fective basal coverage.


Methods of Insulin Administration

A. Insulin Syringes and Needles: Single unit syringes (those with a needle fixed to the syringe to minimize dead space) are available for injection of insulin. Their finely honed 27- or 28-gauge, and more recently even 30- gauge attached needles have greatly re­duced the pain of injections. They are light, not sus­ceptible to damage, and convenient when traveling. Two lengths of needles are available: short (8 mm) and long (12.7 mm). Long needles are preferable in obese patients to reduce the variability of insulin ab­sorption. Disposable syringes may be reused until blunting of the needle occurs (usually after three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable, since it can dissolve the silicon coating and increase the pain of skin puncturing.

To facilitate treatment of patients who are adher­ing to a regimen of multiple preprandial injections of regular insulin that supplement a single injection of long-acting insulin delivered by a conventional syringe, portable pen injectors have been introduced. These pen-sized devices contain cartridges of U 100 regular human insulin and retractable needles, thereby eliminating the need for insulin vials and syringes during the day. Cartridges containing insulin lispro, regular insulin, NPH insulin and pre-mixed insulin are available for use with these pens.

B. Sites for Injection: Any part of the body covered by loose skin can be used as an injection site, including the abdomen, thighs, upper arms, flanks, and upper outer quadrants of the buttocks. In general, regular insulin is absorbed more rapidly from upper regions of the body such as the arm area or the ab­domen rather than from the thighs or buttocks. Exer­cise appears to facilitate insulin absorption when the injection site is adjacent to the exercising muscle. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohyper­trophy occurs owing to repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain patients with type 1 diabetes if injection sites are rotated in­discriminately over different areas of the body. Con­sequently, diabetologists recommend limiting injec­tion sites to a single region of the body for a particular time of the day and rotating sites within that region. It is possible that some of the stability of glycemic control achieved by infusion pumps may be related to the constancy of the site of infusion from day to day. For most patients the ab­domen is the recommended site for injection, since it provides a considerable area in which to rotate sites and there may be less variability of absorption with exercise than when the thigh or deltoid areas are used. The effect of anatomic sites appears to be much less pronounced with the shorter acting insulin analogues.

C. Insulin Delivery Systems: Efforts to ad­minister insulin by "closed loop" systems (glucose­controlled insulin infusion systems [Biostator] have been successful in acute situations such as diabetic ketoacidosis or during surgery. However, chronic use is precluded by the bulkiness of the computerized pump and by the need for continuous aspiration of blood for the external glucose sensor that activates the appropriate insulin or glucose infusion.

Several small portable "open loop" devices for the delivery of insulin are in the market. These devices contain an insulin reservoir and a pump programmed to deliver regular insulin subcutaneously; they do not contain a glucose sensor. With improved methods for self-monitoring of blood glucose at home (see below), these pump systems are becoming increas­ingly popular. These pumps are small (about the size of a pager) and easy to program. They have many features, including the ability to record a number of different basal rates throughout a 24-hour period and adjust the time over which bolus doses are given. They are able also to detect pressure build-up if the catheter is kinked. Im­provements have also been made in the infusion sets. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected so the pa­tient can remove the pump temporarily (eg, for bathing). The great advantage of continuous subcu­taneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion -should maintain a constant blood glucose level between meals.

CSII therapy is appropriate for patients who are motivated, mechanically adept, educated about dia­betes (diet, insulin action, treatment of hypo- and hy­perglycemia), and willing to monitor their blood glu­cose, four to six times a day. Known complications of CSII include ketoacidosis, which can occur when in­sulin delivery is interrupted, and skin infections. An­other major disadvantage is the cost and the time de­manded of physicians and staff in initiating therapy. Patients use either regular insulin or short-acting analogues in the pumps. Reports suggest that subjects using insulin lispro have lower HbAlc values and improved postprandial glucose control with the same frequency of hypoglycemia. There does remain a concern that in the event of pump failure, insulin lispro could result in more rapid onset of hyperglycemia and ketosis. The published results suggest that insulin requirements are lower and there is less hypoglycemia with this form of insulin de­livery compared with intensive insulin therapy by injections.

Intranasally administered soluble insulin is rapidly absorbed when given along with a detergent sub­stance to facilitate adsorption. Preliminary clinical trials have demonstrated its efficacy in reducing post-prandial hyperglycemia in subjects with type 1 diabetes. However, its absorption is limited to less than 10% of the administered nasal dose. This reduces its cost-effectiveness, and most manufacturers have dis­continued clinical trials until more progress is made in improving its bioavailability. Inhalers that can provide more precise delivery of drugs have been de­veloped, and inhaled insulin is currently in phase III trials.

Pancreatic islet cells have been successfully transplanted in genetically similar strains of rodents with experimental diabetes; however, this approach has not yet been successful in humans because of dif­ficulties in preparing and maintaining viable islets and because of immunologic rejection of the tissue. Pancreas transplantation at the time of renal trans­plantation is becoming more widely accepted. Pa­tients undergoing simultaneous pancreas and kidney transplantation have a 74% chance of pancreatic graft survival and a 92% chance of renal graft survival after I year. Routine use of pancreatic transplantation in the absence of a need for renal transplantation should only be considered in those rare patients who fail all other insulin therapeutic approaches and who have life-threatening complications related to their lack of metabolic control.  Islet cell transplant has also been tried with success especially for patients with brittle type 1diabetes.  The limited availability of donor tissue limits the utility of these procedures.

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Diagnostic criteria for diabetes

The diagnostic criteria for diabetes mellitus are based on measuring venous plasma glucose in the fasting state and 2 hours after a 75 gram glucose load (recommended by the WHO).  The details of the diagnostic criteria are provided in Table 2.

Table 2. Diagnostic criteria for Diagnosis of Diabetes mellitus

Category	WHO	ADA
Impaired fasting glucose (IFG)	BGF=100 to < 126 mg/dl	BGF=100 to < 126 mg/dl
Impaired glucose tolerance (IGT)	2 hr post glucose > 140 mg/dl and < 200 mg/dl	-
Diabetes mellitus (DM)	BGF  >126 mg /dl  or 2 hr Post glucose ³ 200 mg/dl (OGTT)	BGF  >126 mg /dl or Casual = 200 mg/dl + Osmotic Symptoms
Normal	FPG=100 mg/dl and PP £140 mg/dl	FPG=100 mg/dl and PP £140 mg/dl

·        All values are venous plasma glucose

·        To convert mg/dl to mmol/L, divide by 18.

·        In case of an abnormal test result, the test should be repeated on a different day.

·        Oral glucose tolerance test (OGTT) is recommended by WHO and not by ADA for epidemiological purposes. 

MANAGEMENT OF DIABETES MELLITUS


Since DM is a disorder, which affects multiple organs in the body leading to morbidity and mortality, it needs a multidisciplinary approach involving dieticians, endocrinologists /diabetologists, cardiologists, nephrologists, ophthalmologists, chiropodists etc.


Non-pharmacological Therapy

Non-pharmacological measures including diet, exercise and stress alleviation are as important as pharmacological interventions for the management of diabetes.

Medical Nutrition therapy (MNT)

A proper diet remains a fundamental element of therapy in all patients with diabetes. However, in over half of cases, diabetics fail to follow their diet because of unnecessary complexity of di­etary instructions and poor understanding of the goals of dietary control by the patient and physician. Recently the Indian Council of Medical Research has published guidelines, which are similar to the widely practiced guidelines on MNT given by American Diabetes Association. For persons with type 2 diabetes recommendations for caloric distribution of proximate principles is as follows: 55-60% energy from carbohydrate, 10-15% from protein and 20-25% from fats. The patients are advised to limit their carbohydrate intake by avoiding refined foods, honey, jaggery, sugar, sweets etc and substituting non-cholesterologenic monoun­saturated oils such as olive oil, rapeseed oil or the oils in nuts. This maneuver is also indicated in patients with type 1diabetes on intensive insulin regimens in whom near-normoglycemic control is less achievable on diets higher in carbohydrate con­tent. For both types of dia­betes cholesterol intake should be restricted to 300 mg daily and saturated fats like ghee and butter should be no higher than <7% of total calories.  The remaining intake of fats should be in the form of equal amounts of polyunsaturated fat (n-6 and n-3 fatty acid containing sources) and monounsaturated fat. Stearic acid is the least cholesterologenic saturated fatty acid, since it is rapidly converted to oleic acid ­in contrast to palmitic acid (found in animal fat as well as coconut oil), which is a major substrate for cholesterol formation. Oils containing linoleic acid (n-6) such as groundnut, sesame, and rice bran should be used along with oils containing a linolenic acid (n-3) such as soyabean and mustard.  The optimal ratio of n-6: n-3 polyunsaturated fatty acids in the diet should be 5-10:1.

Dietary Fibre. Traditional Indian diet is rich in fibres as it contains whole grains (ragi, jowhar, barley, oats etc), whole pulses, soyabean, green leafy vegetables and fenugreek seeds. Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit time and may have bene­ficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to decrease gastric and intestinal transit so that glucose absorption is slower and hyperglycemia is diminished. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

Glycemic Index: Quantitation of the relative glycemic contribution of different carbohydrate foods has formed the basis of a "glycemic index" (GI), in which the area of blood glucose (plotted on a graph) generated over a 3-hour period following ingestion of a test food containing 50 g of carbohydrate is com­pared with the area plotted after giving a similar quantity of reference food such as glucose or white bread:

GI =                  Blood glucose area of test food             x 100

Blood glucose area of reference food

 In comparison to white bread with an index of 100, the mean GI of some foods is : baked potato, 135; table sugar (sucrose), 86; kidney beans, 54; ice cream, 52; and lentils, 43.

Artificial Sweeteners:  The nonnutritive sweetener saccharin is widely used as a sugar substitute and continues to be available in certain foods and beverages despite recent warnings about its potential long-term bladder carcinogenicity. Aspartame may prove to be the safest sweetener for use in diabetics (180 times as sweet as sucrose). A major limitation is its heat labiality, which precludes its use in baking or cooking. These should be used in moderation.

Fruits: Fruits (whole) are recommended in moderation (1-2 servings), however, very sweet fruits and fruit juices can be avoided.

Alcohol: Alcohol intake is best avoided and if used must be in moderation as it may worsen the dyslipidemia, neuropathy and glycemic control.

Common Salt: Up to 6 gms /day of is permitted. Restrict pickles, papad, chatni and salty processed foods.

Tobacco: Smoking and the use of tobacco in any form should be prohibited.

Physical activity: In type 2 diabetes a vigorous program of exercise to achieve weight reduction and its maintenance by close supervision of exercise program and calorie counting is central to the management. The total amount of calories prescribed must take into account the pa­tient's ideal body weight, life-style, and activity level. Exercise programme is individualized according to capacity, needs, suitability and disabilities. All diabetics should carry an I-card and a fast acting carbohydrate to minimize problems because of exercise induced hypoglycemia. The best form of exercise is a stepwise increase in aerobic exercises. Prior to an exercise schedule all diabetics need to be evaluated in detail to rule out any contraindication like CAD, proliferative diabetic retinopathy, autonomic neuropathy etc. Some tailor-made exercise regimens can be prescribed to such patients. Brisk walking for 30-60 minutes or equivalent should be enforced regularly. Yoga, a traditional Indian system getting international acceptance for stress coping skills is beneficial in diabetes as has been demonstrated in some studies. Some aspects of Yoga are-Asanas (involving postures), Pranayama (involving breath), Dhayana (meditation) and Bhavana (visualization) and need to be learnt under expert guidance.

Stress management: Diabetes being a stressful situation in life of an individual a holistic treatment plan should include positive behavior modification, healthy lifestyle, provision of family support, acquisition of coping skills and periodic counseling.

Pharmacological Therapy

Oral agents for the treatment of hyperglycemia

The drugs for treating type 2 diabetes fall into three categories. First, there are the drugs that primar­ily stimulate insulin secretion (insulin secretagogues). Second, there are drugs that sensitize tissues (primarily liver and adipose tissue) to the action of insulin (insulin sensitizers). Third, there are drugs that principally affect absorp­tion of glucose by retarding the enzymatic digestion of complex carbohydrates (Table 3).

Table 3. Characteristics of oral antidiabetic drugs.

Drug		Daily Dose / Dosing Frequency		Duration	Comment/Side effects
	Sulfonylureas				Commonly used, lower cost, effective in severe hyper-glycemia. Can be used in combinations. S/E: Hypoglycemia, wt gain, Contra-indicated if S Cr. >2 mg/dl.
	Glibenclamide	1.25- 20 mg OD / BID	Up to 24 hours
	Gliclazide	80-320 mg / BID	Up to 24 hours
	Glipizide	2.5- 40 mg /  OD/BID	6-12 hours
	Glimepiride	1-8 mg / OD	Up to 24 hours
	Meglitinide analogues  Repaglinide Nateglinide	0.5 - 4 mg / before major meals 60-240 mg / before major meals	3 hours		For mild hyperglycemia, variable meal schedule, post-prandial hyper-glycemia and renal insufficiency. High cost
	Biguandes Metformin	1-2.5 g with meals / 2 or 3 times daily	7-12 hours		No hypoglycemia, Weight neutral, post meal hyperglycemia; can be combined. S/E: GI, C/I if S Cr>1.5 mg/dl; age > 70 yrs; systemic diseases.
	Thiazolidinediones Rosigliltazone	4-8 mg /  OD/BID	24-30 hours		Beneficial in dyslipidemia; can be used in combinations. S/E: hepatotoxicity, wt. gain, anemia.
	Pioglitazone	15-45 mg / OD	30 hours
	Alpha-glycosidase inhibitors  Acarbose Voglibose	75-300 mg / in 3 divided doses with first bite of food	4 hours		S/E=GI, Hypoglycemia in combination with other agents, less potent and costly. Better for post meal, erratic meal schedule and combinations.
	Miglitol	75-300 mg in divided doses with first bite of food	4 hours

* Tolbutamide, chlorpropamide, acetoheximide and tolazamide are no longer in routine clinical

use.

Insulin secretogogues

Sulfonylureas
This group of drugs contains a sulfonic acid-urea nucleus that can be modified by chemical substitu­tions to produce agents that have similar qualitative actions but differ widely in potency. The proposed mechanisms of action of the sulfonylureas include: augmentation of insulin release from pancreatic b cells and  potentiation of insulin action on its target cells.

Specific receptors, consisting of two proteins, one that binds the sulfonylurea (SUR) and the other which is an ATP-sensi­tive potassium channel, are present on the surface of pancreatic b cells that bind sulfonylurea. It has been shown that activation of these receptors closes potassium channels, resulting in de­polarization of the b cell. This depolarized state per­mits calcium to enter the cell and actively promote insulin release.

Sulfonylureas are not indicated in ketosis-prone type 1 diabetes, since these drugs require functioning pancreatic b cells to pro­duce their effect on blood glucose. Moreover, clinical trials show no benefit from the use of sulfonylureas as an adjunct to insulin replacement in type 1 diabetic patients. The sulfonylureas seem most appropriate for use in the non-obese patient with type 2 diabetes whose hyperglycemia has not responded to diet therapy. In obese patients with mild diabetes and slight to moderate peripheral insensitivity to levels of circulating insulin, the primary emphasis should be on weight reduction. When hyperglycemia in obese diabetics has been more severe, with consequent im­pairment of pancreatic b cell function, sulfonylureas may improve glycemic control until concurrent mea­sures such as diet, exercise, and weight reduction can sustain the improvement without the need for oral drugs. Table 3 enlists various sulfonylureas along with their characteristics.

The earlier generation sulfonylureas, like glibenclamide and chlorpopamide, have a long duration of action and high probability of inducing hypoglycemia. Agents like glipizide and gliclazide need more frequent dosing (2-3 times a day) due to a short duration of action. Glimeperide, the newer generation sulfonylurea is given once daily as monotherapy or in combination with other oral agents or insulin in a single daily dose of 1 mg/d (max.dose is 4 mg) . It has a long duration of effect with a half-life of 5 hours, al­lowing once-daily administration, which improves compliance. It is completely metabolized by the liver to relatively inactive metabolic products and is considered cardiac friendly.

Formulations which ensure 24 hour activity profile are also available for glipizide and gliclazide.  The hypoglycemic potency of the various sulfonylureas is quite similar.  It is therefore important to emphasize that if the maximal dose of a sulfonylurea does not result in eulgycemia, it is extremely unlikely that changing to another sulfonylurea will bring better results.  Further, for each sulfonylurea the decline in blood glucose for each unit increment in the dose is best seen till the half-maximal dose of the drug is reached.  After half maximal dose is achieved, further increase in the dose results in a smaller decline in blood glucose.

An area of controversy has been the possible cardiovascular effects of sulfonylureas because the ATP sensitive K+ channel, which is responsive to sulfonylurea action, is ubiquitous in its distribution. While some in vitro studies, animal experiments and short term human studies have suggested that earlier sulfonylureas like glibenclamide and tolbutamide may have adverse cardiovascular effects, none of the larger trials using sulfonylureas have provided epidemiological evidence for excess cardiovascular risk or death. The major concern for sulfonylureas, as a group is the likelihood of causing hypoglycemia and the tendency to cause weight gain. Since most sulfonylureas are metabolized in the liver and excreted through the kidney their use is prohibited in case of liver dysfunction and renal failure.

Meglitinides

Repaglinide and nateglinide are similar to sulfonylureas in their mechanism of action but lack the sulfonic acid-urea moiety. These are rapidly absorbed, undergo complete metabolism in the liver to inactive biliary products.  For repaglinide the starting dose is 0.5 mg three times a day 15 minutes before each meal (max. of 16 mg/day), while that for nateglinide is 60 mg three times a day. The drug may be useful for postprandial hyperglycemia, elderly and in patients with renal impairment. The short duration of their action also makes them useful and less likely to cause hypoglycemia in patients who have an inconsistent daily schedule with likelihood of long gaps between meals.

Insulin action sensitizers

Biguanides
Unlike sulfonylureas, the biguanides do not require functioning pancreatic b cells for reduction of hyperglycemia. Use of phenformin has been discontinued because of its associa­tion with the development of lactic acidosis in pa­tients with coexisting liver or kidney disease. Metformin (1,l-dimethylbiguanide hydrochloride) was introduced in France in 1957 as an oral agent for therapy of type 2 diabetes, either alone or in conjunc­tion with sulfonylureas. It received FDA approval in 1995 for use in the United States but has been used in most of the countries, including India, for over 4 decades. Metformin is reported to be less likely to produce lactic acidosis and has generally re­placed phenformin in the treatment of diabetics. The exact mecha­nism of action of metformin remains unclear but it may reduce hepatic gluconeogenesis, slow down gastrointesti­nal absorption of glucose and increase up­take by skeletal muscle. It re­duces both the fasting level of blood glucose and the degree of postprandial hyperglycemia in patients with type 2 diabetes but not in normal subjects. Metformin has a half-life of 1.5-3 hours. It can be used as monotherapy, an adjunct to diet, sulfonylureas, thiazolidinediones or insulin particularly in obese and dyslipidemic subjects. Metformin is relatively contraindicated in patients with cardiorespiratory insufficiency, impaired renal function, any state likely to be associated with tissue hypoxia, general anaesthesia, use of radiographic contrast media, and age of 70 years. Metformin is used to a maximum dose of 2550 mg daily. The most frequent side effects of metformin are gastrointestinal symptoms (anorexia nausea vomiting, abdominal discomfort, diarrhea). Absorption of vitamin B 12 appears to be reduced. Dermatologic or hematologic toxicity is rare. Lactic acidosis, though uncommon with metformin in con­trast to phenformin, is reported in cases with associated risk factors such as renal, he­patic, or cardiorespiratory insufficiency, alcoholism and advanced age.

Thiazolidinediones

This new class of anti-hyperglycemic agents sensitizes peripheral tissues to insulin by binding to a nuclear receptor called peroxisome prolifera­tor-activated receptor-gamma (PPAR-g). Observed subsequent effects include increased glucose transporter expression (GLUT I and GLUT 4), decreased free fatty acid lev­els, decreased hepatic glucose output, and increased differentiation of preadipocytes into adipocytes. Troglitazone, the first drug in this class was withdrawn because it caused acute liver failure. Two other drugs now in clinical use, rosiglitazone and pioglita­zone, are effective as monotherapy, as well as in combination with sulfonylureas, metformin, and insulin. Rosiglitazone therapy is associated with increases in total cholesterol, LDL cholesterol (14-18%), and HDL cholesterol (11-14%). Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cho­lesterol (12-19%) but did not result in a consistent change in total cholesterol and LDL cholesterol lev­els.. Anemia occurs in 3-4% of patients treated with these drugs, but this effect may be due to a dilutional effect of increased plasma vol­ume rather than a reduction in red cell mass. Weight gain occurs, especially when the drug is combined with a sulfonylurea or with insulin. The weight gain is a result of water retention and increase in adipose tissue, largely in the subcutaneous compartment.  The dosage of rosiglitazone is 4-8 mg daily and of pioglitazone 15-45 mg daily, and the drugs do not have to be taken with food. These two agents in clinical trials did not, unlike troglitazone, show evidence of drug-induced liver function test abnormalities or hepatotoxicity. The FDA has recommended, however, that patients should not initiate drug therapy with these agents if the ALT is 2.5 times greater than the upper limit of normal, and liver function tests should be performed once every 2 months for the first year and periodically thereafter.

Agents Hampering Intestinal Glucose Absorption

Alpha-Glucosidase Inhibitors

Acarbose and miglitol act as competitive inhibitors of intestinal brush border alpha-glucosidases, thus delaying the absorption of carbo­hydrates and reduce postprandial glycemic excursion. Both are po­tent inhibitors of glucoamylase, a-amylase, and sucrase. They are less effective on isomaltase and are ineffective on trehalase and lactase. Acarbose has the molecular mass and structural features of a tetrasaccharide, binds 1000 times more avidly to the in­testinal disaccharidases and very little (about 2%) crosses the microvillus membrane. The principal ad­verse effect, seen in 20-30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 diabetes patients with their diet prescriptions. The recommended starting dose of acarbose is 25 mg twice daily and can be gradually in­creased to 100 mg three times daily. However, most patients are unable to tolerate doses higher than 50 mg three times a day.  It should be given with the first mouthful of food in­gested. A slight rise in hepatic aminotransferases has been noted in clinical trials (5% versus 2% in placebo controls, and particularly with doses greater than 300 mg/d). Migli­tol is structurally similar to glucose, is absorbable and is similar to acarbose in terms of its clinical effects.  The starting dosage is 25 mg three times a day to a maintenance dose of 50 mg three times a day. Miglitol should not be used in renal failure since its clearance is impaired in this setting.

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Laboratory and home based monıtorıng of blood glucose

Blood glucose testing

Venous plasma or serum has the advantage over whole blood of providing values for glucose that are independent of hematocrit and reflect levels in the interstitial spaces.  For these reasons and because plasma and serum lend themselves to automated analytic procedures ­they are used in most laboratories. The glucose con­centration is 10-15 % higher in plasma or serum than in whole blood because structural components of blood cells are absent. Whole blood glucose determi­nations are seldom used in clinical laboratories but have been used by diabetic patients during self-moni­toring of capillary blood glucose, a technique widely accepted and recommended now the management of diabetes mellitus. Recently, however, many new reflectance meters have been     modified to directly record serum glucose rather than to calculate whole blood glucose concentrations.

Venous blood samples

The laboratory methods regularly used for deter­mining plasma glucose utilize enzymatic methods (such as
glucose oxidase or hexokinase), colorimetric methods (such as a toluidine), or automated methods. The automated methods utilize reduction of copper or iron compounds by reducing sugars in dialyzed serum. They are convenient but are not specific for glucose, since they react with other reducing sub­stances (which are elevated in azotemia or with high ascorbic acid intake). Samples should be collected in tubes containing sodium fluoride, which prevents glycolysis in the blood sample that would artifactually lower the mea­sured glucose level. If such tubes are not available, samples must be centrifuged within 30 minutes of collection and the plasma or serum stored at 4 °C.



Capillary blood samples

Several strip (glucose oxidase) based methods for use with portable, battery operated reflectance meters that give a digital readout are now available. First-generation reflectance meters required exact timing by the operator as well as careful removal of all traces of blood from the strip prior to reading of the colour. Second-generation devices have eliminated these two potential sources of technical error by providing automatic timing and allowing quantitation without removal of the blood. The tim­ing required for glucose measurements by these meters varies from 12 sec­onds to 45 seconds and as little as 2-5 mL of blood are needed for analysis by most meters. To monitor their own blood glu­cose levels, patients must prick their fingers with a 21-gauge lancet, a procedure that can be facilitated by a small plastic trigger device. Third-generation devices are presently in the de­velopmental stage and represent a noninvasive method relying on infrared absorption spectra, which allow quantitation of glycemia flowing through capil­lary beds of the finger or earlobe. Present pilot mod­els are relatively large and expensive, but they appear to be accurate and have the great advantage of elimi­nating painful pricks to the fingers (8,9).

Testing for Ketonuria / Ketonemia

Commercial products are available to test for the presence of ketones in the urine. Most strips utilize a nitroprusside re­action that measures only acetone and acetoacetate. Although these tests do not detect b-hydroxybutyric acid, which lacks a ketone group, the semi quantitative estimation of the other ketone bodies is nonethe­less usually adequate for clinical assessment of ketonuria. Other conditions besides diabetic ketoacidosis may cause ketone bodies to appear in the urine; these in­clude starvation, high-fat diets, alcoholic ketoacido­sis, fever, and other conditions in which metabolic re­quirements are increased. Serum ketone measurements, using strip-based technology has also now become available.

Glycosylated hemoglobin

Glycohemoglobin (GHb) is produced by a ke­to-amine reaction between glucose and the amino ter­minal amino acid of both beta chains of the hemoglo­bin molecule. The major form of glycohemoglobin (Hb A1C), which normally comprises only 4-6% of total hemoglobin, is abnormally elevated in diabetics. The glycosylation of hemoglobin is dependent on the concentration of blood glucose. The reaction is not reversible, so that the half-life of glycosylated he­moglobin relates to the life span of red cells (which normally circulate for up to 120 days). Glyco­hemoglobin generally reflects the state of glycemia over the preceding 8-12 weeks, thereby providing a method of assessing chronic diabetic control (10).

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