Effect of insulin-glipizide combination on skeletal muscle capillary basement membrane width in diabetic patients.

This study investigated the long-term effect of insulin or the combination of insulin and an oral hypoglycemic compound (glipizide) on the skeletal muscle capillary basement membrane width in insulin-requiring diabetic patients. Seventy diabetic patients were randomized to treatment with either insulin-placebo or insulin-glipizide (5 mg/d) for 3 years. Of these, only 61 patients completed the study; 27 patients received insulin-placebo and 34 patients received insulin-glipizide. Three skeletal muscle (quadriceps femoris) biopsies were performed in all patients over a 3-year period. Glycosylated hemoglobin A1 was determined every 100 +/- 20 days, including plasma glucose levels. Muscle capillary basement membrane width was quantitated by a previously described method. After approximately 16 months, glycosylated hemoglobin A1 decreased significantly in each group from its baseline (P < 0.001 insulin-glipizide group and P < 0.025 insulin-placebo), although no statistically significant difference was seen between the two groups. After 3 years this decrease was statistically significant (P < 0.001) only in the insulin-glipizide group. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups. In spite of the significant decrease in glycosylated hemoglobin A1 in both groups after 14 to 16 months, only muscle capillary basement membrane width in the insulin-glipizide group decreased significantly compared with baseline. Patients receiving insulin-placebo showed a gradual increase in the muscle capillary basement membrane width, which after 3 years was significantly higher than baseline (P < 0.02). Although the mechanisms by which the addition of glipizide to insulin treatment reduced the thickening of the muscle capillary basement membrane are not clearly understood, the current findings suggest that diabetic microangiopathy is not necessarily progressive and that prophylaxis may be attained.

Diabetic microangiopathy in KK mice. VI. Effect of glycemic control on renal glycoprotein metabolism and established glomerulosclerosis.

Twenty-three nonobese KK mice with abnormal tolerance to glucose, hyperinsulinemia with insulin resistance and human diabetic-like nephropathy were treated with either saline (12 mice) or glipizide, an oral hypoglycemic compound, 1 mg/kg, (11 mice) from 120 to 360 days of age. These mice develop significant increases in mesangial volume and matrix by 40 days of age. Oral glucose tolerance (OGTT), glucosyltransferase and N-acetyl-beta-glucosaminidase (enzymes involved in synthesis and degradation of kidney glycoproteins, respectively) in the kidney and serum, 24-hr proteinuria, and light microscopy studies of the kidney were performed. Glipizide-treated mice improved their OGTT. There was no difference in body weight; however, a 16% decrease (P less than 0.05) in kidney weight was observed in glipizide-treated mice. Both enzymes were significantly increased in the kidneys of mice treated with glipizide. No difference in serum enzymes was found between the two groups of mice. About 58% of the saline-treated mice had moderate glomerulosclerosis. By contrast, only 27% of glipizide-treated mice had moderate glomerulosclerosis. Also, a significant decrease in proteinuria was found in glipizide-treated mice. These data suggest that glipizide improves glucose metabolism, decreases kidney size, prevents kidney glycoprotein and mesangial matrix accumulation, and reduces proteinuria in type II diabetic KK mice. This indicates that good glycemic control prevents further progression of established diabetic nephropathy in animals.

Diabetic nephropathy. An update.

Nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus. In the United States, diabetes accounts for one fourth of new cases of end-stage renal disease each year. Complication rates and costs are much higher for diabetic than for nondiabetic patients with end-stage renal disease. Despite numerous studies, the pathophysiology of diabetic renal disease is not completely understood. We reviewed the current status of the structural, functional, biochemical, pathogenetic, and treatment modalities of diabetic renal disease and examined future therapeutic interventions.

Sulfonylurea-induced decrease of muscle capillary basement membrane thickness in diabetes.

Three muscle biopsies were performed in 53 overt type 2 diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an increased capillary basement membrane width in muscle. Thirty-five patients received glipizide and 18 received placebo. In the patients receiving placebo, the mean of the muscle capillary basement membrane width increased from 158.7 +/- 11.5 nm (SEM) to 170.9 +/- 14.7 nm (P = NS), but in those receiving glipizide the value decreased from 192.9 +/- 13.2 nm to 161.0 +/- 10.2 nm (P = 0.02). Plasma glucose and glycosylated hemoglobin A1 decreased significantly (P less than 0.001) after 2 years in patients receiving glipizide. In 15, mean glycosylated hemoglobin A1 reached a normal range, and mean basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). These findings are consistent with the hypothesis that effective response to oral medication can decrease the basement membrane thickening, suggesting that diabetic microangiopathy is not necessarily progressive.

Disminución inducida por drogas del espesor de la membrana basal capilar en diabetes / Drug-induced decrease of muscle capillary basement membrane thickness in diabetes

Se realizaron tres biopsias musculares en 53 diabéticos no insulinodependientes durante un período de aproximadamente dos años. Al inicio 21 (40%) tuvieron un aumento en el espesor de la membrana basal capilar de músculo; 35 pacientes recibieron glipizida y 18 recibieron placebo. En los pacientes que recibieron placebo, la medida de espesor de la membrana basal capilar de músculo aumentó de 158,7 ñ 11,5 nm (SEM) a 170,9 ñ 14,7 nm (P = NS), pero en aquéllos que recibieron glipizida el valor disminuyó de 192,9 ñ 13,2 nm a 161,0 ñ 10,2 nm (P = 0,02). La glucosa plasmática y la hemoglobina glucosilada disminuyeron significativamente (P < 0,001) después de dos años en los pacientes que recibieron glicpizida. En 15, la media de la hemoglobina glucosilada A1 alcanzó un rango normal, mientras que el espesor medio de la membrana basal disminuyó a un nivel cercano al encontrado en sujetos sin diabetes (P = NS). Estos hallazgos concuerdan con la hipótesis de uqe la respuesta efectiva a la medicación oral puede disminuir el espesor de la membrana basal, sugiriendo que la microangiopatía diabética no es necesariamente progresiva

Disminución inducida por drogas del espesor de la membrana basal capilar en diabetes / Drug-induced decrease of muscle capillary basement membrane thickness in diabetes

Se realizaron tres biopsias musculares en 53 diabéticos no insulinodependientes durante un período de aproximadamente dos años. Al inicio 21 (40%) tuvieron un aumento en el espesor de la membrana basal capilar de músculo; 35 pacientes recibieron glipizida y 18 recibieron placebo. En los pacientes que recibieron placebo, la medida de espesor de la membrana basal capilar de músculo aumentó de 158,7 ñ 11,5 nm (SEM) a 170,9 ñ 14,7 nm (P = NS), pero en aquéllos que recibieron glipizida el valor disminuyó de 192,9 ñ 13,2 nm a 161,0 ñ 10,2 nm (P = 0,02). La glucosa plasmática y la hemoglobina glucosilada disminuyeron significativamente (P < 0,001) después de dos años en los pacientes que recibieron glicpizida. En 15, la media de la hemoglobina glucosilada A1 alcanzó un rango normal, mientras que el espesor medio de la membrana basal disminuyó a un nivel cercano al encontrado en sujetos sin diabetes (P = NS). Estos hallazgos concuerdan con la hipótesis de uqe la respuesta efectiva a la medicación oral puede disminuir el espesor de la membrana basal, sugiriendo que la microangiopatía diabética no es necesariamente progresiva (AU)

Delay of progression of diabetic microangiopathy.

Three muscle biopsies were performed in 53 overt type II diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an abnormally increased capillary basement membrane width in muscle. Thirty-five subjects received glipizide and 18, placebo. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups (P = NS). In the subjects receiving placebo, the mean width of the muscle capillary basement membrane increased (P = NS), but in those receiving glipizide, the mean decreased from 193 +/- 13 nm (SEM) to 161 +/- 10 nm (P = .02). Fasting plasma glucose and glycosylated hemoglobin A1 significantly decreased (P less than .001) after two years in those receiving glipizide. In 15 subjects, mean glycosylated hemoglobin A1 reached the normal range, and mean muscle capillary basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a 2-year significant decrease of muscle glucosyltransferase (synthesis) activity (P less than .01) in the glipizide-treated subjects as opposed to a significant increase (P less than .001) in those receiving placebo. Muscle N-acetyl-beta-glucosaminidase activity (degradation) was statistically increased (P less than .001) in those subjects taking glipizide, but decreased in those taking placebo (P less than .001).

Hereditary diabetes in the KK mouse: an overview.

Table III compares metabolic and morphologic characteristics of different species of control and KK mice. The C57BL/6J demonstrates no significant metabolic, clinical or histologic abnormalities. Our two highly inbred Swiss albino groups I and II also do not show significant glomerular lesions, although we found striking intolerance to glucose, hyperinsulinism, and obesity among them. Thus a genetic predisposition may be necessary in addition to various environmental factors to produce microangiopathy in KK mice. The yellow AY mouse is included in this table, since it is strikingly hyperinsulinemic and obese without concomitant vasculopathy such as the other mentioned control strains have. In conclusion, the KK mice develop chemical diabetes preceded by a stage of prediabetes and also demonstrate renal, retinal and neurologic complications similar to those seen in human diabetes. Of particular interest is the development of mild to moderate glomerulosclerosis in the prediabetic stage; with progression to severe glomerulosclerosis and attendant proteinuria later in life. With proper back-crossing, both hyperglycemia and glomerulosclerosis can be transmitted to normal control mice, suggesting that a specific genetic background is necessary for the development of diabetes and diabetic-like microangiopathy. We therefore suggest that the KK mouse serves as an ideal genetic animal for the study of non-insulin-dependent diabetes mellitus and its complications for rational prevention and therapy.

Enzyme activities as a predictor of diabetic vasculopathy.

Forty-one patients with chemical diabetes had three oral glucose tolerance tests and underwent muscle biopsy three times over a period of three years. Twenty-three received glipizide and 18 placebo. Those taking placebo had an increase in the mean muscle capillary basement membrane width (p = 0.01), but those taking glipizide showed a decrease (p = 0.01) to values no different from those of nondiabetic subjects. Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a three-year decrease (not significant) in muscle glucosyltransferase activity in the glipizide-treated patients, but a statistically significant difference (p less than 0.01) comparing the adjusted means of the two treatment groups. N-acetyl-beta-glucosaminidase activity was significantly increased in muscle from baseline values (p less than 0.01), with adjusted means also significantly different (p less than 0.01). The data suggest that changes in basement membrane and enzyme activities are correlated, and the latter may be a predictor to follow the development, progression, or regression of diabetic vasculopathy.

Drug-induced reversal of early diabetic microangiopathy.

We performed three oral glucose-tolerance tests and three muscle biopsies over a period of approximately three years in 41 asymptomatic patients with chemical diabetes. At base line, 13 (32 per cent) had an increased capillary basement-membrane width in muscle. Twenty-three patients received glipizide, a new oral hypoglycemic compound, and 18 received placebo. In the patients receiving placebo the mean width of the muscle capillary basement membrane increased from 135.9 +/- 9.0 nm (S.E.M.) to 169.3 +/- 9.5 nm (P = 0.01), but in those receiving glipizide the value decreased to a level no different from that in subjects without diabetes: from 152.9 +/- 2.9 to 127.5 +/- 5.1 nm (P = 0.01). These findings suggest that microangiopathy, as indicated by an increased capillary basement-membrane width in muscle, may be present in a considerable number of patients with asymptomatic diabetes and that the changes can be reversed by early drug treatment.