Identifying The Responsible Cellular Event

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The cellular abnormality accounting for clinical insulin resistance could theoretically involve any one of the multiple steps of the insulin signaling cascade as described above. Alterations in insulin production, insulin binding, or intracellu-lar signaling each have the potential to induce an insulin-resistant state. For example, an abnormal beta-cell product resulting from a mutation in the gene coding for the insulin molecule (i.e., mutant insulin syndromes) may be associated with impaired insulin action (6). These conditions may arise secondary to single amino acid substitutions in regions of the molecule that interact with the insulin receptor with reduced affinity and ultimately result in an impaired biological action (6). An example of an acquired defect associated with insulin resistance is the development and presence of ''anti-insulin antibodies.'' In this state, antibodies directed against the insulin molecule can complex with insulin and reduce the amount available to target insulin receptors (6). Fortunately, due to the common use of recombinant human insulin in clinical practice, high titers of insulin antibodies are now rare. The conditions outlined above may be referred to as pre-receptor causes of insulin resistance, since these defects occur prior to or at the binding of insulin to the receptor. The insulin resistance most commonly observed clinically is referred to as a postreceptor defect, referring to alterations in the insulin signaling cascade following insulin receptor activation.

Insulin resistance is also frequently observed in clinical conditions associated with overproduction of counter-regulatory hormones such as cortisol, epi- | nephrine, and growth hormone (6). Specifically, acromegaly, Cushing's syn- £ drome, and pheochromocytoma, on clinical grounds, are associated with attenuated insulin action and may present with impaired carbohydrate metabolism. A number of other human diseases and conditions characterized by insulin M resistance have been described, as recently reviewed by Hunter and Garvey; these J are listed in Table 1 (6).

Table 1 Human Diseases and Conditions Characterized by Insulin Resistance

Insulin resistance may be primary

Insulin resistance may be secondary Insulin resistance associated with genetic syndromes

Type 2 diabetes mellitus

Insulin resistance syndrome (syndrome X)

Gestational diabetes mellitus Type A severe insulin resistance Lipoatrophic diabetes Leprechaunism

Rabson-Mendenhall syndrome Hypertension

Atherosclerotic cardiovascular disease

Obesity

Type 1 diabetes mellitus

Type B severe insulin resistance

Hyperlipidemias

Pregnancy

Acute illness and stress

Cushing's disease and syndrome

Pheochromocytoma

Acromegaly

Hyperthyroidism

Liver cirrhosis

Renal failure

Progeroid syndromes (e.g., Werner's syndrome) Cytogenetic disorders (Down's, Turner's, and

Klinefelter's) Ataxia telangiectasia Muscular dystrophies Friedreich's ataxia Alstrom syndrome Laurence-Moon-Biedl syndrome Pseudo-Refsum's syndrome Other rare hereditary neuromuscular disorders

Source: From Ref. 6.

Copyright © Marcel Dekker, Inc. All rights reserved.

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