Type 2 diabetes often presents on a background genetic predisposition and is characterized by insulin resistance and relative insulin deficiency. Insulin resistance is aggravated by aging, physical inactivity, and overweight (body mass index [BMI] 25-29.9 kg/m²) or obesity (BMI >30 kg/m²). Among obese patients, weight loss often reduces the degree of insulin resistance and may delay diabetes onset or ameliorate diabetes severity and thereby reduce risk of long-term complications. Insulin resistance affects primarily the liver, muscle, and adipocytes, and it is characterized by complex derangements in cellular receptors, intracellular glucose kinase function, and other intracellular metabolic processes. The complexity and variety of these intracellular derangements suggest that what is now classified as type 2 diabetes may be in fact a larger group of conditions that await future definition.
In type 2 diabetes, insufficient levels of insulin fail to meet the elevated demand caused by an increased insulin resistance. Adaptive changes in beta-cell mass and beta-cell function typically allow the regulation of insulin demand during insulin resistance. If functional beta-cell compensation becomes insufficient, a cycle of incomplete glucose clearance and subsequent elevated blood glucose contributes to further deterioration of beta-cell mass and function. The increased beta-cell workload results in functional exhaustion, possible dedifferentiation, and, finally, beta-cell death. Beta-cell function is estimated to be decreased by about 50% to 80% at the time of diagnosis of type 2 diabetes, and protection and recovery of beta-cell function should be a main treatment and prevention target.
The precise mechanism by which the diabetic metabolic state leads to microvascular and macrovascular complications is only partly understood but likely involves both uncontrolled blood pressure (BP) and uncontrolled glucose, increasing the risk of microvascular complications such as retinopathy and nephropathy. Mechanisms may involve defects in aldose reductase and other metabolic pathways, damage to tissues from accumulation of advanced glycosylation end products, and other mechanisms. With respect to macrovascular complications, high BP and glucose raise risk, but so do lipid abnormalities and tobacco use. One unifying theory postulates the existence of a metabolic syndrome that includes diabetes mellitus, hypertension, dyslipidemias, and obesity, and predisposes to coronary heart disease, stroke, and peripheral artery disease. However, this theory is not universally accepted as more clinically useful than assessing individual cardiovascular risk factors.
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