Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function

Abstract

Insulin-like growth factor 2 (IGF2), produced and secreted by adult b-cells, functions as an autocrine activator of the b-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in b-cell and whole-body physiology is not known. Here, we studied mice with b-cell-specific inactivation of Igf2 (bIGF2KO mice) and assessed b-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female bIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female bIGF2KO mice displayed lower GSIS compared with control mice, but reduced b-cell mass was observed only in female bIGF2KO mice. During pregnancy, there was no increase in b-cell proliferation and mass in bIGF2KO mice. Finally, b-cell mass expansion in response to acute induction of insulin resistance was lower in bIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult b-cell mass and function to preserve in vivo GSIS in aging and to adapt b-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.Glucose homeostasis depends on the balance between insulin secretion by pancreatic b-cells and insulin action on peripheral tissues (1). In response to the development of insulin resistance in muscle, liver, and fat, pancreatic b-cells increase their insulin secretion capacity in order to maintain normoglycemia. This compensatory response depends not only on an enhanced secretion capacity of individual b-cells but also, at least in rodents, on an increase in their number (2). In adult life, this plasticity is essential to maintain normoglycemia in insulin resistance conditions associated with obesity, pregnancy, and aging (3-5). Failure of this b-cell compensatory response leads to the onset of type 2 diabetes.The mechanisms by which insulin resistance in peripheral tissues induces compensatory insulin secretion capacity are incompletely understood. Their identification is, however, of highest interest for the development of novel therapies for diabetes. Evidence suggests that both circulating and nervous signals are involved. Glucose was one of the first signals identified to induce b-cell proliferation (6-8) through a signaling pathway that requires glucose metabolism, insulin secretion, and activation of the insulin receptor (IR)/Akt pathway (9,10). Incompletely characterized soluble factors, distinct from glucose, are produced by insulinresistant hepatocytes to increase b-cell mass (11,12), whereas bile acids can increase b-cell secretion capacity, independent of a change in b-cell number (13). Nerve connections between the liver and the islets can also potently stimulate b-cell proliferation (14).Increased b-cell proliferation and secretion capacity is a hallmark of pregnancy both in rodents and humans (3,15). This adaptive response i...

MesenchymalIgf2is a major paracrine regulator of pancreatic growth and function

“…Beta-cell mass is unaffected by beta-cell specific Igf2 deletion at 42 weeks in chow fed animals (Hammerle et al , unpublished). These results are largely similar to those recently reported in 24-26 weeks old beta-cell specific Igf2 knockout mice fed with normal chow diet 18 .…”

“…Very little is known about the main sites of Igf2 expression and imprinting during pancreas development. Moreover, most mouse transgenic studies conducted so far have been directed to the beta-cells, in which Igf2 is overexpressed 16,17 or knocked-out 18 , or focused on mice that overexpress Igf2 19,20 or lack Igf1 and Igf2 constitutively 21 .…”

A CCR2+ myeloid cell niche required for pancreatic β cell growth

“…Thus, myeloid cell-derived IGF signaling may act as a mitogen and be most critically needed early after birth, at the peak of tissue growth, whereas it may be compensated for by other adaptive signals later in life. In addition, other cellular sources of IGF2, e.g., autocrine β cellderived IGF2, were reportedly involved in regulating β cell adaptation to increased metabolic demand in adulthood (63). Whether epithelial-and myeloid-derived IGF2 enable distinct cell-context-specific mechanisms of cell proliferation remains to be determined.…”

Insulin-Like Growth Factors and Metabolic Syndrome in Obese Children

“…IGF-II is involved in the regulation of β-cells, albeit that its effects are unclear. In animal models, autocrine IGF-II regulates β-cell mass and function, and is relevant for β-cell adaptation to metabolic stress and insulin resistance [17]. By contrast, transgenic mice overexpressing IGF-II in β-cells developed insulin resistance [18] and increased IGF-II levels in pancreatic islets predisposed diabetes.…”