Glucose clamp studies were performed to see if glucose utilization increased during extended periods of moderate hyperinsulinemia (80–100 μu/ml). Modifications of the standard euglycemic clamp were performed, and the amount of glucose metabolized (M) and the metabolic clearance rate (MCR) of glucose were calculated for each 10-min interval during the study. In seven subjects, the clamp was performed for 180 min, with the glucose infusion rate fixed from 120 to 180 min at the rate necessary to maintain basal plasma glucose concentration from 80 to 120 min. Under these conditions, mean plasma glucose concentration fell 18% during the last 60 min of the study, indicating increased glucose utilization. Twenty-four subjects, nonobese and obese normals and type II diabetics, had 3-h clamp studies performed. We documented an average increase of M by 21% and MCR by 28% in the third hour as compared with the second hour. Five-hour clamp studies in nine subjects and 8-h studies in two subjects indicated a continued rise in glucose MCR, until a plateau was reached at 4–6 h after initiation of hyperinsulinemia (mean = 88 μU/ml). This plateau was approximately 85% above the MCR of the last 30 min of a standard glucose clamp. Measurement of glucose turnover with 3H-3-glucose suggested that increasing suppression of hepatic glucose production was not responsible for the increases in glucose utilization noted. Insulin binding to erythrocytes was determined in 13 subjects before and after 180 min of hyperinsulinemia, and showed decreased total specific insulin binding. In a two-component high- and low-affinity model of insulin binding, the observed decrease in total insulin binding was primarily caused by a decrease in the high-affinity receptor component. These results suggested that glucose utilization continuously increased during a 5-h period of constant hyperinsulinemia, and this was due possibly to enhanced insulin sensitivity. This change took place in spite of a concomitant decrease in number of insulin receptors.

The effect of glipizide treatment on diabetic control and on in vivo insulin secretion and action was studied in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were examined before and after a minimum of 3 mo treatment. Mean (+/- SEM) fasting plasma glucose level fell from 264 +/- 12 mg/dl to 172 +/- 10 mg/dl (P < 0.001) after glipizide treatment, and this was associated with a fall in total plasma glucose response to a test meal of approximately 35%. Mean (+/- SEM) fasting plasma insulin levels increased slightly from 15 +/- 2 micronU/ml following sulfonylurea treatment, and the total plasma insulin response to the test meal increased by 63%. However, there was no correlation (r = - 0.20) between the increase in plasma insulin response and the fall in plasma glucose levels that occurred as the result of sulfonylurea therapy. Glipizide treatment also led to enhanced in vivo insulin action, whether measured by the insulin clamp technique (P < 0.001) or the insulin suppression test (P< 0.02). Furthermore, in this instance there was a significant correlation (r - 0.69, P < 0.001) between the enhanced insulin action and the improvement on diabetes control. Thus, chronic therapy with glipizide, a new sulfonylurea agent, led to increased in vivo insulin secretion and insulin action. These results lend direct support to the assumption that sulfonylurea compounds have a substantial extrapancreatic effect on glucose homeostasis, and suggest that this effect contributes to the therapeutic efficacy of these drugs.

Diabetic nephropathy (DNP) is associated with increased cardiovascular mortality. This may be contributed to by associated cardiovascular autonomic dysfunction (CAD). The aim of this study was to investigate the prevalence of CAD in patients with insulin-dependent diabetes mellitus (IDDM) at different stages of DNP. We studied patients with incipient DNP (group 1, n = 10), overt DNP (group 2, n = 20), renal insufficiency (group 3, n = 27), and end-stage renal failure (group 4, n = 12) and compared them with 30 IDDM patients without clinical signs of DNP (group 5) and with 17 nondiabetic controls (group 6). All groups were matched for age and diabetic groups were matched for duration of diabetes. Assessments of CAD included beat-to-beat variation during forced respiration, heart-rate response to standing, heart-rate response to Valsalva maneuver, basal heart rate, and blood pressure response to standing. Clinical evaluation included assessment of the history and an examination for peripheral polyneuropathy. We found mean impairment of heart-rate variation during respiration, in response to Valsalva maneuver, and in heart-rate response to standing in all diabetic groups compared with nondiabetic controls (P less than .01). Heart-rate responses differed significantly between patients with renal insufficiency (groups 3 and 4) and with other patient groups (group 5; P less than .01). CAD was shown to be more prevalent in patients with DNP, more so as DNP progresses. To some extent, it is already present in the early stages of DNP. CAD may be a contributory factor for increased cardiovascular mortality in patients with DNP.(ABSTRACT TRUNCATED AT 250 WORDS)

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