Abstract and Introduction
Insulin resistance often is the primary metabolic abnormality leading to the development of type 2 diabetes. Type 2 diabetes can be viewed as the consequence of a series of pathophysiologic changes, each of which makes the patient vulnerable to subsequent disruption of normal glucose homeostasis. In most individuals, insulin resistance is the first of a sequence of abnormalities leading to the development of type 2 diabetes. Insulin resistance is compensated by increased insulin secretion (hyperinsulinemia), which allows glucose metabolism to remain normal. The beta cells in genetically susceptible individuals become impaired, leading to delayed and insufficient insulin secretion. Due to decreasing beta-cell function, the individual with insulin resistance first develops postprandial hyperglycemia and subsequently develops fasting hyperglycemia. Chronic hyperglycemia contributes to a further suppression of pancreatic beta-cell insulin secretion and worsens insulin resistance. These 3 components (insulin resistance, insulin deficiency, and glucose toxicity) are the targets of our therapeutic interventions. The distinction between insulin-sensitive and insulin-resistant type 2 diabetes is important when considering treatment. A drug that treats insulin resistance may be the drug of choice for an insulin-resistant patient, but should not be prescribed for a patient with insulin-sensitive diabetes.
In the United States, nearly 30 million individuals have some form of glucose intolerance or diabetes (type 1 or, much more commonly, type 2). Further breakdown of these numbers reveals critical facts for primary care providers: there are 10.3 million individuals diagnosed with diabetes, 5.3 million who have undiagnosed diabetes, and 13.4 million who have impaired glucose tolerance without frank diabetes, including those with the insulin resistance syndrome.[1,2] Those who are insulin resistant are at high risk for the development of common metabolic disorders -- for example, non-insulin dependent diabetes, obesity, dyslipidemia, and hypertension -- that can lead to early cardiovascular disease with its resultant morbidity and mortality. Understanding the pathophysiology of insulin resistance is vital in primary care.
The pathogenesis of type 2 diabetes ordinarily involves the development of insulin resistance associated with compensatory hyperinsulinemia, followed by progressive beta-cell impairment that results in decreasing insulin secretion and hyperglycemia. Hyperglycemia itself causes additional inhibition of insulin secretion and more insulin resistance (glucose toxicity), which further accentuates the hyperglycemia. Thus, the development of type 2 diabetes is usually characterized by 2 abnormalities: impaired insulin action and deficient insulin secretion. Both impairments are made worse by hyperglycemia. Normal beta cells can compensate for insulin resistance. Type 2 diabetes, therefore, cannot occur in the absence of beta-cell abnormalities.
This article reviews the mechanisms of normal glucose homeostasis and the pathogenesis of insulin resistance and hyperglycemia. Because "type 2 diabetes" is a general term for several related diseases characterized by impaired glucose tolerance, the various manifestations of type 2 diabetes are also briefly reviewed.
© 2000 Cliggott Publishing, Division of CMP Healthcare Media
Cite this: Pathogenesis of Type 2 Diabetes - Medscape - May 01, 2000.