Med Clin N Am 88 (2004) 787–835
Pathogenesis of type 2 diabetes mellitus
Ralph A. DeFronzo, MD
Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
Normal glucose homeostasis A discussion of the pathogenesis of type 2 diabetes mellitus must start with a review of mechanisms involved in the maintenance of normal glucose homeostasisin the basal or postabsorptive state (10–12 h overnight fast) and following ingestion of a typical mixed meal [1–9]. In the postabsorptive state the majority of total body glucose disposal takes place in insulinindependent tissues. Thus, approximately 50% of all glucose use occurs in the brain, which is insulin-independent and becomes saturated at a plasma glucose concentration of approximately40 mg/dL . Another 25% of glucose disposal occurs in the splanchnic area (liver plus gastrointestinal tissues), which is also insulin-independent. The remaining 25% of glucose use in the postabsorptive state takes place in insulin-dependent tissues, primarily muscle, and to a lesser extent adipose tissue. Basal glucose use, approximately 2.0 mg/kg/min, is precisely matched by the rate ofendogenous glucose production (Fig. 1). Approximately 85% of endogenous glucose production is derived from the liver, and the remaining 15% is produced by the kidney. Glycogenolysis and gluconeogenesis contribute equally to the basal rate of hepatic glucose production. Following glucose ingestion, the increase in plasma glucose concentration stimulates insulin release, and the combination ofhyperinsulinemia and hyperglycemia (1) stimulates glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues and (2) suppresses endogenous (primarily hepatic) glucose production (Box 1) [1–9]. The majority ($80%–85%) of glucose uptake by peripheral tissues occur in muscle, with a small amount ($4%–5%) metabolized by adipocytes. Although fat tissue is responsible for only a smallamount of total body glucose disposal, it plays a very important role in the maintenance of total body glucose homeostasis by regulating the release of free fatty acids (FFA) from stored triglycerides (see discussion below) and through the production of adipocytokines that inﬂuence insulin sensitivity in muscle and liver
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.doi:10.1016/j.mcna.2004.04.013
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
Fig. 1. Postabsorptive state. Glucose production and glucose use in the normal human in the postabsorptive state. (From DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes 1997;5:117–9; with permission.)
[11–14]. Insulin isa potent antilipolytic hormone, and even small increments in the plasma insulin concentration markedly inhibit lipolysis, leading to a decline in the plasma level of free fatty acid . The decline in plasma FFA concentration augments muscle glucose uptake and contributes to the inhibition of hepatic glucose production. Thus, changes in the plasma FFA concentration in response to increasedplasma levels of insulin and glucose play an important role in the maintenance of normal glucose homeostasis [11–14]. Glucagon also plays a central role in the regulation of glucose homeostasis [9,15]. Under postabsorptive conditions, approximately half of total hepatic glucose output is dependent on the maintenance of normal basal glucagon levels, and inhibition of basal glucagon secretion withsomatostatin causes a reduction in hepatic glucose production and plasma
Box 1. Factors responsible for the maintenance of normal glucose tolerance in healthy subjects A. Insulin secretion B. Tissue glucose uptake 1. Peripheral (primarily muscle) 2. Splanchnic (liver plus gut) C. Suppression of HGP 1. Decreased FFA 2. Decreased glucagons D. Route of glucose administration
R.A. DeFronzo / Med...
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