Nutritionally induced insulin resistance and receptor defect leading to beta-cell failure in animal models.
Animals with genetically or nutritionally induced insulin resistance and Type 2 diabetes comprise two groups: those with resilient beta-cells, e.g., ob/ob mice or fa/fa rats, capable of longstanding compensatory insulin hypersecretion and those with labile beta-cells in which the secretion pressure leads to beta-cell degranulation and apoptosis, e.g., db/db mice and Psammomys gerbils (sand rats). Psammomys features low insulin receptor density; on a relatively high energy diet it becomes hyperinsulinemic and hyperglycemic. In hyperinsulinemic clamp the hepatic glucose production is only partially suppressed by insulin, even in the normoglycemic state. The capacity of insulin to activate muscle and liver receptor tyrosine kinase is nearly abolished. GLUT4 content and mRNA are markedly reduced. Hyperinsulinemia was also demonstrated to inhibit insulin signaling and glucose transport in several other species. Among the factors affecting the insulin signaling pathway, phosphorylation of serine/threonine appears to be the prominent cause of receptor malfunction as inferred from the finding of overexpression of PKC epsilon isoforms in the muscle and liver of Psammomys. The insulin resistance syndrome progressing in animals with labile beta-cells to overt diabetes and beta-cell failure is a "thrifty gene" characteristic. This is probably also true for human populations emerging from food scarcity into nutritional affluence, inappropriate for their metabolic capacity. Thus, the nutritionally induced hyperinsulinemia, associated with PKC epsilon activation may be looked upon from the molecular point of view as "PKC epsilon overexpression syndrome."
Shafrir
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Department of Biochemistry, Hadassah University Hospital, Jerusalem, Israel. shafrir@md2.huji.ac.il
Ziv
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Mosthaf
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D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects* / Q000378:metabolism; D005849:Gerbillinae; D051275:Glucose Transporter Type 4; D000882:Haplorhini; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D006946:Hyperinsulinism / Q000209:etiology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C