Tolbutamide does not alter insulin requirement in Type 1 (insulin-dependent) diabetes

Abstract

We examined whether tolbutamide has any acute or short-term effects on insulin action in Type 1 (insulin-dependent) diabetes. A euglycaemic glucose clamp was performed in seven Type 1 diabetic patients without clinical insulin resistance by infusing glucose at a constant rate of 0.01 mmol X kg-1 X min-1 for 3h together with a simultaneous insulin infusion using an 'artificial pancreas'. The insulin infusion rate required to maintain blood glucose at 6.7 mmol/l at a set low glucose infusion rate provides an index of insulin action in vivo. The euglycaemic clamp was performed on 3 separate days in the same patient: (1) in the basal state; (2) during simultaneous intravenous tolbutamide infusion of 0.5 g/h, and (3) after treatment with 2.5 g tolbutamide/day for 6 days in addition to insulin. The insulin infusion rate needed to maintain the set blood glucose level did not differ significantly between the three experimental conditions (1.2 +/- 0.2 versus 1.3 +/- 0.3 versus 1.2 +/- 0.3 U/h). Plasma glucagon, growth hormone, non-esterified fatty acid and glycerol levels did not differ between control or sulphonylurea treatment studies. The results suggest that tolbutamide does not exert any acute or short-term effects on insulin action in vivo in Type 1 diabetes. Our results do not provide support for the idea that this agent is a clinically useful adjunct to insulin in such patients.

Increasing the Decrement in Insulin Secretion Improves Glucagon Responses to Hypoglycemia in Advanced Type 2 Diabetes

“…Tolbutamide has been found to increase glucagon secretion in isolated rat ␣-cells (16) and in insulin-deficient type 1 diabetes in some (17) but not all (18) studies, and in the present studies in patients with advanced type 2 diabetes, plasma glucagon tended to be greater during the infusion of tolbutamide than during the infusion of saline. It may therefore be argued that the increased glucagon responses following tolbutamide may be explained by ongoing stimulation of glucagon secretion or simply greater plasma glucagon levels immediately before inducing hypoglycemia.…”

Clinical Pharmacology of Sulfonylureas

“…Given the extreme sensitivity of liver for small changes in the insulin concentration, it is quite possible that small changes in portal insulin concentrations have been overlooked. (4) There have also been difficulties in confirming initial reports of increased insulin binding during sulfonylurea therapy (GRUNBERGER et al 1982;RATZMANN et al 1984;DOLAIS-KITABGI et al 1983). (5) Finally, and probably most important, chronic hyperglycemia can cause both peripheral and hepatic insulin resistance, which can be attenuated by improved glucose control independently of the mode of treatment (YKI-JÄRVINEN 1990;ROSSETTI et al 1987).…”

“…(1) Sulfonylureas do not reduce plasma glucose in pancreatectomized animals or in patients with type 1 diabetes (MIRSKY et al 1956;HOUSSAY and PENHOS 1956;GRUNBERGER et al 1982;RATZMANN et al 1984), or in NIDDM patients made insulinopenic with somatostatin (WIDEN 1993). (2) Early studies examining the extrapancreatic effects of sulfonylureas did not appreciate the problem with restudying patients at identical plasma glucose levels.…”

Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control

“…Based on results obtained in insulin-dependent diabetic patients where sulphonylurea have failed to lower blood glucose [41,42] it has been argued that any change in tissue insulin sensitivity during longterm sulphonylurea treatment may be due to improved metabolic control induced by the pancreatic effects of the drugs. Other investigators [43] have, however, reported that after 6 weeks of glyburide administration, total whole body glucose uptake improved in healthy control subjects despite unchanged fasting levels of serum insulin and plasma glucose.…”