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