Nutritionally Induced Insulin Resistance and Receptor Defect Leading to β‐Cell Failure in Animal Models

Abstract

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."

Hyperinsulinism in mice with heterozygous loss of KATP channels

“…Beta cell hyperexcitability and secretory phenotype: an 'inverse-U' model We have thus further proposed [18], and the data here support, an inverse-U model [40] for the general beta cell response to hyperexcitability generated by alterations of K + (or other) conductances (Fig. 7).…”

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

“…An increase in beta cell death, probably mediated by GLT, has been observed in several animal models, as well as in patients with type 2 diabetes [1][2][3][4][5][6][7][8][9][10][11][12][13][14]23]. This study is the first to demonstrate a direct protective effect of the lactogenic hormones, PRL and PL, on beta cell survival against GLT-induced cell death in both rodent and human beta cells.…”

“…It occurs when islet beta cells are unable to secrete adequate insulin to meet the extra demands of the body, mainly because of enhanced beta cell dysfunction and reduced beta cell mass. The reduction in functional pancreatic beta cell mass results partly from increased beta cell apoptosis [1][2][3][4], observed in several animal models of type 2 diabetes, such as ob/ob and db/db mice on a C57BL/KS background, transgenic rodents overexpressing human islet amyloid polypeptide, Zucker diabetic fatty rats, and Psammomys obesus [5][6][7][8][9]. Increased beta cell death is also observed in pancreatic sections from patients with type 2 diabetes relative to normal non-diabetic individuals [10,11].…”

Evidence for a major gene affecting the transition from normoglycaemia to hyperglycaemia in Psammomys obesus

“…Psammomys Single gene causing type-2 diabetes in Psammomys obesus J Hillel et al was demonstrated to have a low density of insulin receptors in muscle and liver (Kanety et al, 1994), low GLUT4 protein (Shafrir et al, 1999b) and low PTPase activites (Meyerovitch et al, 2002). These attributes of a desert-adjusted animal limit its capacity to cope with nutritional surplus.…”