Generation Sulfonylurea Research Articles

Kidney disease in KK mice: effect of glipizide.

We previously demonstrated that glomerulosclerosis and proteinuria can be prevented by control of blood glucose levels either by insulin or glyburide in genetically diabetic KK mice (1,2). Also, we demonstrated that poor control of glucose despite treatment with glyburide did not prevent glomerulosclerosis in a subset of KK mice (2). This reinforces the impact of glycemic control in the prevention of diabetic nephropathy. The purpose of the present study is two-fold: 1) to evaluate the efficacy of another second generation sulfonylurea compound, glipizide, in controlling blood glucose levels in KK mice; and 2) to investigate the relationship between glucose control and structural, biochemical and functional characteristics of kidney disease in KK mice.

Activation of pyruvate dehydrogenase complex (PDC) of rat heart mitochondria by glyburide

The effects of the second generation sulfonylurea, glyburide, on the pyruvate dehydrogenase multienzyme complex (PDC) of rat myocardial tissue were examined using rat ventricular slices and isolated mitochondria. Therapeutic concentrations (10 −7 to 10 −6M) of glyburide produced a 30% increase in the decarboxylation of [1 −14C] pyruvate by the PDC of ventricular tissue. Addition of glyburide to intact rat heart mitochondria stimulated activity of the PDC in a time- and concentration-dependent manner. Half-maximal stimulation of the enzyme occurred with 6 × 10 −5M glyburide and maximal activation of the enzyme was achieved with 1 × 10 −4M glyburide. At the height of stimulation, PDC activities were 6-fold greater than those observed under control conditions with succinate alone. When mitochondria were disrupted by sonication or freezethawing, glyburide produced no stimulation of pyruvate decarboxylation. We conclude that glyburide directly stimulates the decarboxylation of pyruvate by the PDC of the myocardium. Furthermore, the presence of intact mitochondria is necessary for the stimulatory action of glyburide on the PDC.

New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus

In the present review we have examined recent data concerning the pathogenetic factors known to contribute to the glucose intolerance in noninsulin-dependent diabetes mellitus (NIDDM). The following conclusions appear warranted: (1) insulin secretion in response to glucose is frequently, but not invariably, deficient in persons with fasting hyperglycemia. Basal insulin secretion, however, is normal and milder degrees of glucose intolerance can be associated with a normal or supernormal insulin response to glucose; (2) insulin resistance is almost uniformly present in patients with any degree of clinically detectable glucose intolerance. This insulin resistance is located both in the liver and in the peripheral tissues, principally the muscle; (3) hepatic resistance is present in the form of inappropriately high glucose production in the fasting state and deficient glucose uptake following glucose ingestion. Peripheral resistance manifests itself as reduced glucose uptake (mostly by muscle) after exposure to endogenous or exogenous insulin and reduced clearance of plasma glucose in the fasting state; (4) decreased binding of insulin to its cellular receptors is commonly found in patients with both chemical and overt diabetes. Insulin binding, however, may be normal in diabetic patients with severe insulin resistance. A significant postreceptor defect in glucose metabolism appears to be present in patients with marked fasting hyperglycemia; (5) a general conceptual framework for the pathogenesis of noninsulin-dependent diabetes mellitus is presented in which a defect (a) in the secretory activity of the beta cell, (b) in the interaction between the gastrointestinal tract and the liver, or (c) at the cellular level is in turn considered as the possible initiating event. Each pathogenetic sequence is discussed in the context of the available evidence and is tentatively associated with a clinical subset of patients. From the therapeutic standpoint, three measures are presently available that are capable of ameliorating the insulin resistance in NIDDM. First, a regular program of physical activity is very likely to improve glucose tolerance through an enhancement of insulin sensitivity. Second, the newer generation sulfonylurea agents appear to provide a promising means of improving the insulin resistance. Third, dietary modification may prove useful in reducing the fasting plasma glucose concentration toward normal levels. The value of weight reduction, high fiber diet, substitution of fructose for glucose, and alterations in the carbohydrate content of the diet are discussed.