Hepatic sensitivity to insulin: effects of sulfonylurea drugs

Insulin regulation of hepatic glucose production (HGP) is altered in non-insulin-dependent diabetes mellitus (NIDDM), resulting in increased glucose output by the liver; this contributes to the elevation in plasma glucose concentration observed both in the basal state and postprandially. Therefore, restoration of normal insulin action in the liver must be a goal of hypoglycemic therapy. Sulfonylureas have been widely used for treatment of NIDDM over the past 30 years. In addition to their stimulatory effect on insulin secretion, these compounds seem to possess extrapancreatic effects. Early in vitro studies showed that addition of sulfonylureas to the perfusion medium of liver preparations could exert a significant suppressive effect on HGP. Subsequent experience suggested that these compounds could act at the level of the insulin receptor as well as at various postreceptor sites. These studies showed that sulfonylureas may inhibit glycogenolysis and gluconeogenesis while stimulating glycogen synthesis. Results obtained in vivo in NIDDM patients are in agreement with the in vitro studies. Long-term treatment with sulfonylureas is associated with a decline in fasting plasma glucose concentration and a parallel reduction in HGP. Nevertheless, the direct effect of sulfonylurea administration on the liver remains unclear, since the reduction in HGP that occurs during sulfonylurea treatment may be secondary to an overall improvement in insulin secretion. It is also of interest that in insulin-dependent diabetic patients, sulfonylurea administration in combination with insulin injections is not followed by a significant change in HGP. Possible effects of sulfonylureas on glucagon secretion and on the metabolism of free fatty acids (FFAS) may also contribute to improved sensitivity of the liver to the suppressive action of insulin, since these agents appear to reduce plasma glucagon and FFA concentrations. Thus, present data support an extrapancreatic action of sulfonylureas on the liver. However, it does appear that a certain degree of residual insulin secretion is required for sulfonylurea agents to elicit their hepatic effect.
Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by abnormally high fasting blood glucose levels. It appears to be caused, in part, by decreased insulin sensitivity in the liver, which leads to increased glucose production, and by decreased insulin sensitivity in various tissues, which leads to reduced glucose uptake. Studies have shown that fasting blood glucose levels and glucose production by the liver are closely related. Treatments that could increase the liver's sensitivity to insulin during fasting could be very beneficial in controlling glucose levels. This review examined data concerning the effects of sulfonylurea agents on insulin-mediated glucose metabolism in the liver. Early studies on animal models showed that these drugs could suppress glucose production by the liver, and further animal studies revealed the possible mechanisms by which this might occur. Some studies found that sulfonylureas inhibit the breakdown of liver glycogen (storage form of glucose) and stimulate the liver to produce glycogen. Other studies showed that these drugs inhibit liver gluconeogenesis (producing glucose from fat and protein sources) and act on the insulin receptors on liver cells. Research has also been performed with patients who have NIDDM. Initial studies showed that sulfonylureas are useful in lowering blood glucose levels, but the mechanism by which they work was not clear and remains so. Further studies in patients found that these drugs decreased glucose production in the liver, but it is not clear if this is a direct result of the drug's effects on the liver or if it is an indirect result of increased insulin secretion. More recent research has indicated that both direct and indirect mechanisms are involved in suppressing liver glucose production. They suggest that although a certain amount of insulin secretion is required for sulfonylurea agents to be effective in reducing glucose production, the diminished production can not solely be explained by the increase in insulin. Further studies should clarify the effects these drugs have on the liver. (Consumer Summary produced by Reliance Medical Information, Inc.)