Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance

Abstract

Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory ␤-cell growth, we examined two models of insulin resistance. In the first model, we used liverspecific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in ␤-cell mass. LIRKO mice, also lacking functional insulin receptors in ␤-cells (␤IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to ␤IRKO and ␤-cell-specific IGF1 receptor knockout (␤IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, ␤IRKO, but not ␤IG-FRKO, mice exhibited poor islet growth consistent with insulinstimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance.␤-cell growth ͉ compensatory hyperplasia ͉ ␤-cell apoptosis I nsulin resistance is a common feature of type 2 diabetes, obesity, and hyperlipidemias (1). In patients with type 2 diabetes and mouse models of diabetes and obesity, the ␤-cells compensate for the insulin resistance by increasing their mass (2, 3). One of these models, the liver-specific insulin receptor knockout (LIRKO) mouse, manifests severe insulin resistance and glucose intolerance, but the mutants do not become overtly diabetic due, in part, to a significant increase in ␤-cell mass (4). Although lineage tracing experiments in normal mice and studies in cyclin D2 knockouts indicate that ␤-cell replication is a major mechanism for regeneration of adult ␤-cells (5, 42), the signals that induce ␤-cell replication are not fully defined.Insulin and IGFI and the proteins in their signaling pathways regulate cell growth and function (6), but their specificity in modulating ␤-cell proliferation is not fully explored. Thus, ␤-cellspecific insulin receptor (␤IRKO) (7), IGF1 receptor knockout (␤IGFRKO) (8, 9), or double mutants (10) surprisingly exhibited normal growth and development of ␤-cells consistent with data from global knockouts of insulin receptor or IGF1 receptor genes (11). Mice with global knockout of IRS1 (12, 13) or IRS2 genes (12, 14) also do not manifest defects in the development of islet cells, whereas overexpression of Akt in ␤-cells promotes an increase in cell size (15). Together these studies indicate that insulin/IGF1 signaling is not critical for early development and growth of ␤-cells.Our follow-up studies showed that ␤IRKO, but not ␤IGFRKO, mice developed an age-dependent decrease in ␤-cell mass and a susceptibility to develop overt diabetes (7,16,17). F...

Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats

“…The insulin and insulin-like growth factor signaling pathways play an important role in the control of β-cell growth and of insulin biosynthesis and secretion (22)(23)(24). Analysis of the initial components of the insulin signaling pathway revealed an increase in the expression of IR-β in LP islets compared to NP islets (Figure 2A).…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…Beta cell insulin resistance impairs trophic, proliferative and survival signals, e.g. the phosphatidylinositol-3 kinasephosphokinase B pathway, and promotes early beta cell failure in an animal model [65]. Increased beta cell secretory activity sensitises beta cells to the pro-apoptotic action of inflammatory mediators, mainly when increasing substrate metabolism [66], but these effects are difficult to isolate from the effects of substrate-induced islet innate immunity [67].…”

Oscillatory control of insulin secretion

“…In addition to its endocrine effects leading to glucose uptake in muscle and adipose tissue and glycogen storage in liver, insulin has autocrine effects on β-cells, regulating gene transcription (Leibiger et al, 1998;Xu and Rothenberg, 1998;Wu et al, 1999;da Silva Xavier et al, 2000), proliferation (Withers et al, 1998;Kulkarni et al, 1999a;Okada et al, 2007), glucose metabolism (Borelli et al, 2004;Nunemaker et al, 2004), insulin biosynthesis and secretion (reviewed in (Rutter, 1999) and (Leibiger et al, 2002). β-cells thus express insulin receptors (Verspohl and Ammon, 1980;Patel et al, 1982) as well as downstream adapter and signalling proteins, like insulin receptor substrate proteins IRS-1, -2, -3, -4, PI3-kinase and protein kinase B/Akt (Rothenberg et al, 1995;Velloso et al, 1995;Harbeck et al, 1996;Holst et al, 1998;Withers et al, 1998;Kulkarni et al, 1999b;Muller et al, 2006).…”

“…Since insulin has been suggested to be an important stimulus for β-cell proliferation in states of insulin resistance (Okada et al, 2007), loss of pulsatile insulin secretion in prediabetic and diabetic states (Lang et al, 1981;O'Rahilly et al, 1988) may not only be envisioned to contribute to insulin resistance in the extrapancreatic target tissues, but also to impair the compensatory expansion of the β-cell mass.…”