The a-glucosidase inhibitors primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from the gastrointestinal tract. They act by competitively inhibiting a-glucosi-dases, a group of enzymes in the intestinal brush border epithelial cells that includes glycoamylase, sucrase, mal-tase, and dextranase. The prolongation of the intestinal absorption of carbohydrates results in a blunted insulin response, keeping postprandial hyperglycemia under control. To be effective, a-glucosidase inhibitors must be taken before or with meals. Theoretically, the a-glucosidase inhibitors are most beneficial in patients with mild to moderate diabetes whose diet is more than 50% carbohydrates. a-Glucosidase inhibitors are not approved for used in type I diabetes.
Acarbose (Precose) is an oligosaccharide derivative that has a higher affinity for the a- glucosidase enzymes than do other dietary oligosaccharides. Systemic absorption of acarbose is very low (~2%), with most being broken down in the intestine to several metabolites. About half of the orally administered acarbose is excreted unchanged in the feces, while the remainder, some of which is systemically absorbed, is renally excreted. Acarbose may be associated with hepatotoxicity in rare instances.
Miglitol (Glyset) is another a-glucosidase inhibitor, but in contrast to acarbose, miglitol is systemically absorbed prior to its activity in the small intestine. It also appears to inhibit the enzymes sucrase and maltase to a greater extent than does acarbose. It does not undergo metabolism and is renally excreted unchanged.
Gastrointestinal disturbances (loose stools, flatulence, and abdominal cramping) are the most frequently observed side effects of the a-glucosidase inhibitors. These effects can be minimized by starting patients on a low dose and then slowly advancing the dose as tolerance develops; curtailment of carbohydrate consumption also can alleviate these effects. Patients should be counseled that these side effects will occur and that tolerance should develop; otherwise, compliance will be low and about one-third of patients will stop their medication. Unlike the sulfonylureas, insulin, and the thia-zolidinediones, a-glucosidase inhibitors do not cause weight gain. Insulin levels do not change in the presence of a-glucosidase inhibitors, so fasting hypoglycemia does not occur when a-glucosidase inhibitors are used as monotherapy. Although the a-glucosidase inhibitors may be used as monotherapy, they are usually used in combination with metformin, sulfonylureas, or insulin. Under the best circumstances, a-glucosidase inhibitors can be expected to promote a 0.5 to 1% reduction in a patient's hemoglobin A1c. Leaving aside their gastrointestinal side effects, a-glucosidase inhibitors appear to be relatively safe.
^ Study Questions
1. The main reason metformin should not be used in patients with renal failure is that
(A) It increases the risk of lactic acidosis.
(B) It increases the risk of ketoacidosis.
(C) It causes development of congestive heart failure.
(D) It causes hepatic necrosis.
(E) It causes hypoglycemia.
2. All of the following statements are true EXCEPT
(A) Lispro insulin displays a similar affinity and action with the insulin receptor.
(B) Lispro insulin has a slower onset of action than glargine insulin.
(C) Premixed 70/30 insulin is composed of 70% NPH and 30% regular insulin.
(D) Glucagon is a hormone that counteracts many of the metabolic effects of insulin.
(E) Glargine insulin has a longer duration of action than lispro insulin.
3. Hypoglycemia is rarely seen with these drugs when used as monotherapy EXCEPT:
4. All of the following are true statements about the thiazolidinediones EXCEPT
(A) Thiazolidinediones may be hepatotoxic in some individuals.
(B) Thiazolidinediones increase the number of insulin receptors on the cell membrane surface.
(C) Thiazolidinediones bind a nuclear receptor in tissue termed PPAR-7, which augments the expression of insulin-regulated genes.
(D) Thiazolidinediones take many days to weeks to begin exerting a blood glucose-lowering effect in diabetics.
(E) The most common side effects of thiazolidine-diones are weight gain and edema.
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