Selected Metabolic Aspects Of Diabetesg

A lay person would describe diabetes as too much sugar in the blood. So would J

most medical students and physicians. However, hyperglycemia is simply the tip of the iceberg, albeit one of profound pathogenetic impact. Type 2 diabetes is, in fact, a syndrome in which resistance to insulin in peripheral tissues is present for years, if not decades, before hyperglycemia becomes evident. As compensatory pancreatic secretory mechanisms in response to the insulin resistance begin to fail, relative and

u subsequently absolute insulin deficiency occurs resulting in clinical hyperglycemia. Consequently, the signs and symptoms of polyuria and polydipsia become apparent associated with elevated HbAlc and exacerbation of hyperlipidemia.

Many of the metabolic derangements typical of diabetes can be understood in terms of a few seminal actions of insulin. The dependence of acetyl CoA carboxylase activity on insulin in the liver results, in the case of insulin resistance, in failure of production of malonyl CoA, the first intermediate in fatty acid synthesis. Accordingly, fatty acid synthesis declines in the liver, in turn causing an increase in hepatic gluconeogenesis and hepatic glucose output. The reduction in malonyl CoA concentrations in hepatocytes reduces the inhibition of an enzyme pivotal in fatty acid synthesis, carnitine palmitoyl CoA transferase (CPT-1). Insulin itself inhibits this enzyme and, accordingly, in states of insulin resistance, CPT-1 activity increases markedly. The result is increased FFA oxidation. In the extreme case, when FFA oxidation is excessive and disproportional to FFA synthesis, 2-carbon fragments (acetyl CoA) are formed in abundance and give rise to ketone bodies and potentially ketoacidosis. The latter does not occur generally in type 2 diabetic subjects unless markedly diminished insulin secretory capacity has occurred.

Acetyl CoA is an allosteric inhibitor of pyruvate dehydrogenase. Thus, glucose oxidation diminishes when FFA oxidation is excessive. The decreased glucose oxidation leads to accumulation of citrate, an inhibitor of a rate-limiting enzyme in the glycolytic pathway, fructose 1, 6, phosphatase. Glucose-6-phos-phate concentrations consequently increase. This, in turn, diminishes the uptake of glucose contributing to hyperglycemia as does the decreased glycogen synthe-tase activity in skeletal muscle and decreased glucose transport in the same tissue.

A second key fundamental action of insulin is augmentation of lipoprotein lipase activity. Accordingly, in states of insulin resistance the diminished activity of this enzyme potentiates accumulation of triglycerides, elevation of VLDL in blood, and the hypertriglyceridemia typical of type 2 diabetes.

Beta-cell exhaustion is known to be potentiated by hyperglycemia. Thus, a vicious circle occurs when insulin resistance is followed by a failure of compensatory mechanisms and consequently hyperglycemia. The high blood glucose concentrations exacerbate beta-cell dysfunction and accelerate the evolution of metabolic consequences of type 2 diabetes. The inhibition of insulin secretion induced by hyperglycemia is referred to as ''glucose toxicity'' and can be re- -o versed by effective treatment that leads to glycemic control.

In the postabsorptive state, patients with insulin resistance are less able to accumulate precursors of triglycerides in adipose tissue such as 3-carbon frag- g1

ments to which fatty acids can be esterified. The result is elaboration of FFA from adipose tissue contributing to the dyslipidemia.

Insulin mediates the uptake in skeletal muscle of glucose through glucose transporter-mediated functions and activation of enzymes such as hexokinase. In a

& u states of insulin resistance, uptake is diminished with consequent exacerbation of hyperglycemia. The major physiological abnormality in whole-body insulin-mediated glucose disposal is a reduction in nonoxidative disposal reflective of an impairment in the muscle glycogen synthesis pathway associated with insulin resistance.

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