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Management of Type 2 Diabetes Mellitus

The goals of therapy for type 2 DM are similar to those in type 1. While glycemic control tends to dominate the management of type 1 DM, the care of individuals with type 2 DM must also include attention to the treatment of conditions associated with type 2 DM (obesity, hypertension, dyslipidemia, cardiovascular disease) and detection/management of DM-related complications. DM-specific complications may be present in up to 20–50% of individuals with newly diagnosed type 2 DM. Reduction in cardiovascular risk is of paramount importance as this is the leading cause of mortality in these individuals.

Pharmacological Interventions

Hypoglycemic agents

If the patient is not able to achieve target glycemic control with weight management and exercise, then pharmacologic therapy is indicated.

Based on their mechanisms of action, glucose-lowering agents are subdivided into agents that increase insulin secretion, reduce glucose production, increase insulin sensitivity, and enhance GLP-1 action. Glucose-lowering agents (with the exception of α-glycosidase inhibitors and an amylin analogue) are ineffective in type 1 DM and should not be used for glucose management of severely ill individuals with type 2 DM. Insulin is sometimes the initial glucose-lowering agent.

1) Insulin Secretagogues

Insulin Secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cells. These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years), who have residual endogenous insulin production.  Various examples of Insulin Secretagogues are as follows-

a) Sulfonylurea—first generation

  • Chlorpropamide
  • Tolazamide
  • Tolbutamide

b ) Sulfonylurea—second generation

  • Glimepiride
  • Glipizide
  • Glipizide (extended release)
  • Glyburide
  • Glyburide (micronized)

c) Nonsulfonylureas

  • Repaglinide
  •  Nateglinide

Insulin Secretagogues are generally well tolerated. All of these agents, however, have the potential to cause profound and persistent hypoglycemia, especially in elderly individuals. Hypoglycemia is usually related to delayed meals, increased physical activity, alcohol intake, or renal insufficiency.

2) Biguanides

Metformin is representative of this class of agents. It reduces hepatic glucose production through an undefined mechanism and improves peripheral glucose utilization slightly.

Metformin reduces fasting plasma glucose and insulin levels, improves the lipid profile, and promotes modest weight loss.The major toxicity of metformin, lactic acidosis, can be prevented by careful patient selection.

3) α-Glycosidase Inhibitors

α -Glycosidase inhibitors (acarbose and miglitol) reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion. Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia.

4) Thiazolidinediones

Thiazolidinediones reduce insulin resistance. These drugs bind to the PPAR-γ (peroxisome proliferator-activated receptor- γ) nuclear receptor. The PPAR- γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and appear to reduce insulin resistance indirectly by enhancing fatty acid storage and possibly by increasing adiponectin levels Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance

Rosiglitazone, Pioglitazone belong to this category.

5) Glucagon like peptide–1 agonists

GLP-1 agonists (ie, exenatide, liraglutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying. The use of a GLP-1 in addition to metformin and/or a sulfonylurea may result in modest weight loss

6) Amylinomimetics

Pramlintide acetate is an amylin analog that mimics the effects of endogenous amylin, which is secreted by pancreatic beta cells. This agent delays gastric emptying, decreases postprandial glucagon release, and modulates appetite.

7) Insulin Therapy in Type 2 DM

Insulin should be considered as the initial therapy in type 2 DM, particularly in lean individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in individuals who are hospitalized or acutely ill. Insulin therapy is ultimately required by a substantial number of individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes.

Non pharmacological Interventions

a) Weight reduction

Treatment is directed toward achieving weight reduction, and prescribing a diet is only one means to this end. Behavior modification to achieve adherence to the diet—as well as increased physical activity to expend energy—is also required.

b) Diet

A well-balanced, nutritious diet remains a fundamental element of therapy. The American Diabetes Association (ADA) recommends about 45–65% of total daily calories in the form of carbohydrates; 25–35% in the form of fat (of which less than 7% are from saturated fat), and 10–35% in the form of protein. In patients with type 2 diabetes, limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. Patients with type 1 diabetes or type 2 diabetes who take insulin should be taught “carbohydrate counting,” so they can administer their insulin bolus for each meal based on its carbohydrate content. In obese individuals with diabetes, an additional goal is weight reduction by caloric restriction).

The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily, and individuals with LDL cholesterol more than 100 mg/dL should limit dietary cholesterol to 200 mg daily. High protein intake may cause progression of renal disease in patients with diabetic nephropathy; for these individuals, a reduction in protein intake to 0.8 kg/day (or about 10% of total calories daily) is recommended.

c) Dietary fiber

Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary “fiber.” Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit 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 retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

d) Artificial and other sweeteners

Aspartame (NutraSweet) consists of two major amino acids, aspartic acid and phenylalanine, which combine to produce a sweetener 180 times as sweet as sucrose. A major limitation is that it is not heat stable, so it cannot be used in cooking. Saccharin (Sweet ‘N Low), Sucralose (Splenda), and Acesulfame potassium (Sweet One) are other “artificial” sweeteners that can be used in cooking and baking.

Fructose represents a “natural” sugar substance that is a highly effective sweetener, induces only slight increases in plasma glucose levels, and does not require insulin for its metabolism. However, because of potential adverse effects of large amounts of fructose on raising serum cholesterol, triglycerides, and LDL cholesterol, it does not have any advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.

Sugar alcohols, also known as polyols or polyalcohol, are commonly used as sweeteners and bulking agents. They occur naturally in a variety of fruits and vegetables but are also commercially made from sucrose, glucose, and starch. Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). They are not as easily absorbed as sugar, so they do not raise blood glucose levels as much. Therefore, sugar alcohols are often used in food products that are labeled as “sugar-free,” such as chewing gum, lozenges, hard candy, and sugar-free ice cream. However, if consumed in large quantities, they will raise blood glucose and can cause bloating and diarrhea.


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