The etiology, natural history, and relationship of
insulin resistance to
type 2 diabetes mellitus and the effects of
insulin-sensitizing agents are described.
Insulin resistance results from a combination of genetic and environmental factors and contributes to
type 2 diabetes mellitus,
dyslipidemia,
hypertension, central (
abdominal) obesity, and
cardiovascular disease.
Insulin resistance does not necessarily progress to
impaired glucose tolerance or diabetes because insulin secretion by normal pancreatic beta cells can increase to compensate for reduced physiological activity. Diabetes may develop in
insulin-resistant persons with inherited secretory and
glucose-sensing defects in beta cells. The pathogenesis of diabetes appears to involve a progressive decrease in beta-cell mass, potentially triggered by abnormalities in
adipocytokine release from intraabdominal fat cells.
Metformin and the
thiazolidinediones are used to treat
insulin resistance, but their actions differ.
Metformin reduces
free-fatty-acid efflux from fat cells, thereby suppressing hepatic
glucose production, and indirectly improves peripheral
insulin sensitivity and endothelial function.
Thiazolidinediones improve peripheral
insulin sensitivity by reducing circulating
free fatty acids but also by suppressing
adipocytokines, which increase
insulin resistance.
Thiazolidinediones also improve endothelial function and may prevent or delay the onset of diabetes.
Insulin is intrinsically antiatherogenic but may mediate
arterial inflammation in
insulin-resistant patients. Unlike
metformin, the
thiazolidinediones suppress this inflammatory pathway and may indirectly help preserve beta-cell function.
Insulin resistance, resulting from a combination of genetic and environmental factors, plays a central role in
type 2 diabetes mellitus. Diabetes may develop in
insulin-resistant persons with inherited secretory and
glucose-sensing defects in beta cells.
Metformin and
thiazolidinediones are
insulin-sensitizing agents with different mechanisms of action and effects in patients with
type 2 diabetes mellitus.