The Nature Of Insulin Resistance

It is undoubtedly the case that insulin resistance can result from many, many primary defects. Elucidation of insulin receptor action, signal transduction, intra- a

& u cellular mediators, and the molecular genetics determining each is the focus of a prodigious and vigorous area of research. In this overview, only a few aspects can be mentioned.

The specific derangement(s) responsible for insulin resistance in most patients with type 2 diabetes has not been identified. Key factors implicated, however, are docking proteins that interact with the insulin receptor [insulin receptor substrate-1 and -2 (IRS-1 and IRS-2)] that facilitate assembly of complexes of intracellular proteins that initiate signaling through multiple pathways, one of which is mitogenic and one of which gives rise to many of the metabolic actions of insulin. Roles of IRS-1 and IRS-2 appear to be tissue-specific as judged from experiments in knockout mice. These proteins are involved in actions of insulin in adipose tissue, liver, and skeletal muscle among other tissues. IRS-2 has been implicated in growth, development, and function of pancreatic beta cells.

Defects in insulin receptors and glucose transport effector systems have been implicated in syndromes of insulin resistance that are either genetic or secondary to obesity, pregnancy, endocrinopathies, cirrhosis, pancreatic carcinoma, and hepatitis C among other conditions. Cytokines such as tumor necrosis factor-alpha (TNF-a) mediate insulin resistance in general and in adipose tissue particularly. The role of transcription factors in mediating actions of insulin, particularly the peroxisome proliferator-activated receptors (PPAR), is suggested by the beneficial effects on insulin resistance induced by PPAR ligands such as the glita-zones. A particularly intriguing potential cause of insulin resistance in women with the polycystic ovarian syndrome is abnormal serine kinase activity resulting in serine phosphorylation as opposed as tyrosine phosphorylation of the insulin receptor with consequent lack of autophosphorylation and functional impairment.

Syndromes of insulin resistance are usually readily detectable based on clinical observation and knowledge of their manifestations. Definitive demonstration of insulin resistance requires sophisticated laboratory testing. The eugly-cemic insulin clamp procedure is the ''gold standard'' in a research environment. More universally available procedures such as determination of fasting insulin concentrations in blood in patients not receiving exogenous insulin may be useful, as may the homeostasis model assessment (HOMA) that requires only simultaneous determination of fasting glucose and fasting insulin concentrations. With one iteration of this approach, the concentration of insulin in blood in |U/mL multi- -o plied by the concentration of glucose in blood in mg/dL is divided by 22.5 to |

provide an index. Results have been correlated with those obtained with sophisti- £

cated procedures such as the frequently sampled intravenous glucose tolerance test/minimal model and the insulin tolerance test and found to be robust. In all of these procedures, measurements of insulin concentrations must be performed by laboratories with rigorously standardized reagents and procedures to acquire valid results.

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