Metabolism
Abstract
The molecular link between obesity and β cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas β cells and parts of the brain — including the hypothalamus —increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional β cells expressing Irs2 repopulated the pancreas, restoring sufficient β cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult β cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.
Authors
Xueying Lin, Akiko Taguchi, Sunmin Park, Jake A. Kushner, Fan Li, Yedan Li, Morris F. White
Abstract
We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory β cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in β cells and the hypothalamus, we generated β cell–specific Irs2 KO and hypothalamus-specific Irs2 knockdown (βHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of βHT-IRS2 mice was indistinguishable from that of control mice. The βHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the βHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the βHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. β Cell mass and β cell proliferation in the βHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the βHT-IRS2 mice. We conclude that, in β cells and the hypothalamus, Irs2 is crucially involved in the regulation of β cell mass and leptin sensitivity.
Authors
Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Wataru Yano, Ryo Suzuki, Kohjiro Ueki, Iseki Takamoto, Hidemi Satoh, Toshiyuki Maki, Tetsuya Kubota, Masao Moroi, Miki Okada-Iwabu, Osamu Ezaki, Ryozo Nagai, Yoichi Ueta, Takashi Kadowaki, Tetsuo Noda
Abstract
The insulin and IGF signaling pathways are critical for development and maintenance of pancreatic β cell mass and function. The serine-threonine kinase Akt is one of several mediators regulated by these pathways. We have studied the role of Akt in pancreatic β cell physiology by generating transgenic mice expressing a kinase-dead mutant of this enzyme in β cells. Reduction of Akt activity in transgenic animals resulted in impaired glucose tolerance due to defective insulin secretion. The mechanisms involved in dysregulation of secretion in these mice lie at the level of insulin exocytosis and are not the result of abnormalities in glucose signaling or function of voltage-gated Ca2+ channels. Therefore, transgenic mice showed increased susceptibility to developing glucose intolerance and diabetes following fat feeding. These observations suggest that Akt plays a novel and important role in the regulation of distal components of the secretory pathway and that this enzyme represents a therapeutic target for improvement of β cell function in diabetes.
Authors
Ernesto Bernal-Mizrachi, Szabolcs Fatrai, James D. Johnson, Mitsuru Ohsugi, Kenichi Otani, Zhiqiang Han, Kenneth S. Polonsky, M. Alan Permutt
Abstract
The endocrine pancreas undergoes major remodeling during neonatal development when replication of differentiated β cells is the major mechanism by which β cell mass is regulated. The molecular mechanisms that govern the replication of terminally differentiated β cells are unclear. We show that during neonatal development, cyclin D2 expression in the endocrine pancreas coincides with the replication of endocrine cells and a massive increase in islet mass. Using cyclin D2–/– mice, we demonstrate that cyclin D2 is required for the replication of endocrine cells but is expendable for exocrine and ductal cell replication. As a result, 14-day-old cyclin D2–/– mice display dramatically smaller islets and a 4-fold reduction in β cell mass in comparison to their WT littermates. Consistent with these morphological findings, the cyclin D2–/– mice are glucose intolerant. These results suggest that cyclin D2 plays a key role in regulating the transition of β cells from quiescence to replication and may provide a target for the development of therapeutic strategies to induce expansion and/or regeneration of β cells.
Authors
Senta Georgia, Anil Bhushan
Abstract
The autoimmune disease type 1 diabetes in humans and NOD mice is determined by multiple genetic factors, among the strongest of which is the inheritance of diabetes-permissive MHC class II alleles associated with susceptibility to disease. Here we examined whether expression of MHC class II alleles associated with resistance to disease could be used to prevent the occurrence of diabetes. Expression of diabetes-resistant MHC class II I-Aβ chain molecules in NOD mice following retroviral transduction of autologous bone marrow hematopoietic stem cells prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from the development of insulitis and diabetes. These data suggest that type 1 diabetes could be prevented in individuals expressing MHC alleles associated with susceptibility to disease by restoration of protective MHC class II expression through genetic engineering of hematopoietic stem cells.
Authors
Chaorui Tian, Jessamyn Bagley, Nathalie Cretin, Nilufer Seth, Kai W. Wucherpfennig, John Iacomini
Abstract
The ABC transporters ABCG5 and ABCG8 limit absorption and promote excretion of dietary plant sterols. It is not known why plant sterols are so assiduously excluded from the body. Here we show that accumulation of plant sterols in mice lacking ABCG5 and ABCG8 (G5G8–/– mice) profoundly perturbs cholesterol homeostasis in the adrenal gland. The adrenal glands of the G5G8–/– mice were grossly abnormal in appearance (brown, not white) due to a 91% reduction in cholesterol content. Despite the very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Moreover, levels of ABCA1, which mediates sterol efflux, were increased 10-fold in the G5G8–/– adrenals. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. To determine which plant sterol(s) caused the metabolic changes, we examined the effects of individual plant sterols on cholesterol metabolism in cultured adrenal cells. Addition of stigmasterol, but not sitosterol, inhibited SREBP-2 processing and reduced cholesterol synthesis. Stigmasterol also activated the liver X receptor in a cell-based reporter assay. These data indicate that selected dietary plant sterols disrupt cholesterol homeostasis by affecting two critical regulatory pathways of lipid metabolism.
Authors
Chendong Yang, Liqing Yu, Weiping Li, Fang Xu, Jonathan C. Cohen, Helen H. Hobbs
Abstract
Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C–θ (PKC-θ), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-θ are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-θ KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40–50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate–1 (IRS-1) and IRS-1–associated PI3K activity. In contrast, PKC-θ inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-θ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-θ is a potential therapeutic target for the treatment of type 2 diabetes.
Authors
Jason K. Kim, Jonathan J. Fillmore, Mary Jean Sunshine, Bjoern Albrecht, Takamasa Higashimori, Dong-Wook Kim, Zhen-Xiang Liu, Timothy J. Soos, Gary W. Cline, William R. O’Brien, Dan R. Littman, Gerald I. Shulman
Abstract
Inadequate compensatory β cell hyperplasia in insulin-resistant states triggers the development of overt diabetes. The mechanisms that underlie this crucial adaptive response are not fully defined. Here we show that the compensatory islet-growth response to insulin resistance in 2 models — insulin receptor (IR)/IR substrate–1 (IRS-1) double heterozygous mice and liver-specific IR KO (LIRKO) mice — is severely restricted by PDX-1 heterozygosity. Six-month-old IR/IRS-1 and LIRKO mice both showed up to a 10-fold increase in β cell mass, which involved epithelial-to-mesenchymal transition. In both models, superimposition of PDX-1 haploinsufficiency upon the background of insulin resistance completely abrogated the adaptive islet hyperplastic response, and instead the β cells showed apoptosis resulting in premature death of the mice. This study shows that, in postdevelopmental states of β cell growth, PDX-1 is a critical regulator of β cell replication and is required for the compensatory response to insulin resistance.
Authors
Rohit N. Kulkarni, Ulupi S. Jhala, Jonathon N. Winnay, Stan Krajewski, Marc Montminy, C. Ronald Kahn
Abstract
Diabetes in humans accelerates cardiovascular disease caused by atherosclerosis. The relative contributions of hyperglycemia and dyslipidemia to atherosclerosis in patients with diabetes are not clear, largely because there is a lack of suitable animal models. We therefore have developed a transgenic mouse model that closely mimics atherosclerosis in humans with type 1 diabetes by breeding low-density lipoprotein receptor–deficient mice with transgenic mice in which type 1 diabetes can be induced at will. These mice express a viral protein under control of the insulin promoter and, when infected by the virus, develop an autoimmune attack on the insulin-producing β cells and subsequently develop type 1 diabetes. When these mice are fed a cholesterol-free diet, diabetes, in the absence of associated lipid abnormalities, causes both accelerated lesion initiation and increased arterial macrophage accumulation. When diabetic mice are fed cholesterol-rich diets, on the other hand, they develop severe hypertriglyceridemia and advanced lesions, characterized by extensive intralesional hemorrhage. This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis. Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.
Authors
Catherine B. Renard, Farah Kramer, Fredrik Johansson, Najib Lamharzi, Lisa R. Tannock, Matthias G. von Herrath, Alan Chait, Karin E. Bornfeldt
Abstract
The regulation of insulin secretion by pancreatic β cells is perturbed in several diseases, including adult-onset (type 2) diabetes and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The first mouse model for PHHI has a conditional deletion of the gene encoding the winged-helix transcription factor Foxa2 (Forkhead box a2, formerly Hepatocyte nuclear factor 3β) in pancreatic β cells. Using isolated islets, we found that Foxa2 deficiency resulted in excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. Most PHHI cases are associated with mutations in SUR1 (Sulfonylurea receptor 1) or KIR6.2 (Inward rectifier K+ channel member 6.2), which encode the subunits of the ATP-sensitive K+ channel, and RNA in situ hybridization of mutant mouse islets revealed that expression of both genes is Foxa2 dependent. We utilized expression profiling to identify additional targets of Foxa2. Strikingly, one of these genes, Hadhsc, encodes short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, deficiency of which has been shown to cause PHHI in humans. Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets. Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion.
Authors
Kristen A. Lantz, Marko Z. Vatamaniuk, John E. Brestelli, Joshua R. Friedman, Franz M. Matschinsky, Klaus H. Kaestner
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)