Hyperinsulinemia in hypertension: increased secretion, reduced clearance or both?

Peripheral hyperinsulinism is said to be associated and perhaps implicated in the pathogenesis of hypertension. There is however some inconsistency in the evidence of the relationship between insulin and blood pressure. We prospectively investigated glucose metabolism, insulin and C-peptide values and serum lipids in a large sample of hypertensive as compared with age and body habitus-matched normotensive subjects. As a group, the 145 hypertensives (blood pressure: 160/99 +/- 8.5/6.5 mmHg, mean +/- SD) had significantly elevated fasting plasma insulin (p < 0.02), total and LDL-cholesterol (p < 0.01) than 132 normotensive control subjects. The fasting HbA1c (glycated hemoglobin A1c)/insulin ratio, an estimate of insulin sensitivity, was significantly lower (5.15 +/- 1.45) in the hypertensives than normotensives (5.8 +/- 1.5, p < 0.001). Hypertensives had normal fasting C-peptide levels and lower C-peptide/insulin molar ratios, indicating low hepatic insulin extraction. There was no correlation between mean blood pressure (1/3 systolic + 2/3 diastolic) and fasting serum C-peptide (p = 0.14), insulin (p = 0.11), HbA1c/insulin ratio (p = 0.6), C-peptide/insulin ratio (p = 0.22) and HbA1c (p = 0.19), even after adjusting for age, BMI and family history of diabetes. The differences between hypertensives and normotensives persisted after dividing the subjects according to the presence/absence of either obesity or impaired glucose tolerance, but the significance was lost due to the smaller samples of the subgroups. The obese hypertensives with impaired glucose tolerance had the lowest values of insulin sensitivity and clearance in the fasting state.(ABSTRACT TRUNCATED AT 250 WORDS)

Is a family history of diabetes associated with an increased level of cardiovascular risk factors? Studies in healthy people and in subjects with different degree of glucose intolerance.

In order to evaluate whether the presence of a positive family history of diabetes (PFH) may have a negative impact on both glucose metabolism and cardiovascular risk factors, we studied parameters of carbohydrate metabolism (fasting and 2h-plasma glucose, HbA1c) and beta-cell function (fasting insulin and C-peptide), as well as the levels of some established cardiovascular risk factors (total cholesterol and triglycerides, HDL-cholesterol, blood pressure) in 729 subjects who were seen within the frame of a Regional Health Program in Taranto, South Italy. According to the NDDG criteria, 147 men and 235 women had normal glucose tolerance, 54 men and 66 women non-diagnostic OGTT, 65 men and 79 women impaired glucose tolerance, and 45 men and 58 women newly-diagnosed Type 2 diabetes. There was a continuous increase of PFH across the categories of glucose intolerance (p < 0.001). Subjects with PFH were younger (4 years on the average) than subjects without PFH. After adjustment for age, there was no difference in the clinical and metabolic parameters considered across the categories of glucose tolerance between subjects with or without PFH. Only in OGTT-diagnosed diabetics, was the presence of PFH associated with significantly greater levels of total cholesterol and 2h-plasma glucose, as well as a trend for triglycerides and HbA1c to be higher. There was a continuous increase in fasting glucose, HbA1c, insulin and C-peptide across the categories; however, the C-peptide/insulin molar ratio was lowest in OGTT-diagnosed diabetics. There was a graded and significant increase in the levels of cardiovascular risk factors across the categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors.

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose -4.1 mmol.l-1; glycosylated haemoglobin A1 decrease -1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These positive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile < 10 mmol.l-1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile > 10 mmol.l-1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (-21.6 U/day). Metformin was well tolerated by all diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

The combined insulin and sulfonylurea therapy in diabetes of elderly people.

The usefulness and safety of the combined insulin-sulfonylurea (gliclazide) therapy were investigated in 70 elderly diabetic patients poorly controlled by insulin alone. More than half (45 diabetics, 64% of total) ameliorated significantly their metabolic control after six months of the combined treatment: not only the glycemic profile and glycated hemoglobin Alc were significantly decreased, but the daily insulin dose was reduced by approx. 35% (p < 0.01). These positive results in terms of improved glycemic control as well as reduction of daily insulin needs were still present after a mean period of follow-up of 5 years. The good percentage of positive results, the small incidence of hypoglycemic episodes and the consistent reduction of peripheral hyperinsulinism make this intervention (insulin-gliclazide) a safe strategy that can be adopted in a population of elderly diabetics, poorly controlled on insulin alone.

Impaired insulin secretion in human diabetes mellitus. Effect of pharmacological activation of gamma-aminobutyric acid system.

To evaluate whether the gamma-aminobutyric acid (GABA)ergic system plays a role in the defective insulin secretion in human diabetes mellitus, 15 non-insulin-dependent diabetics with fasting hyperglycemia above 140 mg/dl were submitted to two consecutive i.v. glucose tolerance tests (IVGTT) (0.33 g/kg b.w.), in basal conditions and after pharmacologic activation of the GABA system with baclofen and sodium valproate. Baclofen, a synthetic analogue, was given to 8 diabetics in two divided doses of 10 mg each 8h and 1h before the post-treatment test; sodium valproate, a drug that increases endogenous GABA activity, was given orally (800 mg) 60 min before the performance of the post-treatment IVGTT. Neither treatment brought about significant changes in insulin, C-peptide, glucagon or growth hormone responses to i.v. glucose nor did they significantly change glucose disappearance rates. These results seem to indicate that GABA does not play a major role in the pathogenesis of defective insulin secretion in non-insulin-dependent diabetes mellitus.