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Human Ī²-Cell Proliferation and Intracellular Signaling: Driving in the Dark Without a Road Map
A major goal in diabetes research is to find ways to enhance the mass and function of insulin secreting Ī²-cells in the endocrine pancreas to prevent and/or delay the onset or even reverse overt diabetes. In this Perspectives in Diabetes article, we highlight the contrast between the relatively large body of information that is available in regard to signaling pathways, proteins, and mechanisms that together provide a road map for efforts to regenerate Ī²-cells in rodents versus the scant information in human Ī²-cells. To reverse the state of ignorance regarding human Ī²-cell signaling, we suggest a series of questions for consideration by the scientific community to construct a human Ī²-cell proliferation road map. The hope is that the knowledge from the new studies will allow the community to move faster towards developing therapeutic approaches to enhance human Ī²-cell mass in the long-term goal of preventing and/or curing type 1 and type 2 diabetes
Transient early food restriction leads to hypothalamic changes in the longālived crowded litter female mice
Transient nutrient restriction in the 3Ā weeks between birth and weaning (producing ācrowded litterā or CL mice) leads to a significant increase in lifespan and is associated with permanent changes in energy homeostasis, leptin, and insulin sensitivity. Here, we show this brief period of early food restriction leads to permanent modulation of the arcuate nucleus of the hypothalamus (ARH), markedly increasing formation of both orexigenic agoutiārelated peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the paraventricular nucleus of the hypothalamus (PVH). An additional 4Ā weeks of caloric restriction, after weaning, does not further intensify the formation of AgRP and POMC projections. Acute leptin stimulation of 12āmonthāold mice leads to a stronger increase in the levels of hypothalamic pStat3 and cFos activity in CL mice than in controls, suggesting that preweaning food restriction leads to longālasting enhancement of leptin signaling. In contrast, FoxO1 nuclear exclusion in response to insulin is equivalent in young adult CL and control mice, suggesting that hypothalamic insulin signaling is not modulated by the crowded litter intervention. Markers of hypothalamic reactive gliosis associated with aging, such as Iba1āpositive microglia and GFAPāpositive astrocytes, are significantly reduced in CL mice as compared to controls at 12 and 22Ā months of age. Lastly, ageāassociated overproduction of TNFāĪ± in microglial cells is reduced in CL mice than in ageāmatched controls. Together, these results suggest that transient early life nutrient deprivation leads to longāterm hypothalamic changes which may contribute to the longevity of CL mice.e12379Transient nutrient restriction in the 3Ā weeks between birth and weaning (producing ācrowded litterā or CL mice) leads to longāterm hypothalamic changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111266/1/phy212379.pd
Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet Ī² cells
MTORC1 signaling and regulation of pancreatic Ī²-cell mass
The capacity of Ī² cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of Ī² cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for Ī²-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of Ī²-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in Ī² cells. This review will discuss recent advances in the understanding of how this pathway regulates Ī²-cell mass and present data on the role of TSC1 in modulation of Ī²-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic Ī² cells results in improved glucose tolerance, hyperinsulinemia and expansion of Ī²-cell mass that persists with aging
Decreased IRS Signaling Impairs Ī²-Cell Cycle Progression and Survival in Transgenic Mice Overexpressing S6K in Ī²-Cells
Transgenic Overexpression of Active Calcineurin in Ī²-Cells Results in Decreased Ī²-Cell Mass and Hyperglycemia
BACKGROUND:Glucose modulates beta-cell mass and function through an initial depolarization and Ca(2+) influx, which then triggers a number of growth regulating signaling pathways. One of the most important downstream effectors in Ca(2+) signaling is the calcium/Calmodulin activated serine threonine phosphatase, calcineurin. Recent evidence suggests that calcineurin/NFAT is essential for beta-cell proliferation, and that in its absence loss of beta-cells results in diabetes. We hypothesized that in contrast, activation of calcineurin might result in expansion of beta-cell mass and resistance to diabetes. METHODOLOGY/PRINCIPAL FINDINGS:To determine the role of activation of calcineurin signaling in the regulation of pancreatic beta-cell mass and proliferation, we created mice that expressed a constitutively active form of calcineurin under the insulin gene promoter (caCn(RIP)). To our surprise, these mice exhibited glucose intolerance. In vitro studies demonstrated that while the second phase of Insulin secretion is enhanced, the overall insulin secretory response was conserved. Islet morphometric studies demonstrated decreased beta-cell mass suggesting that this was a major component responsible for altered Insulin secretion and glucose intolerance in caCn(RIP) mice. The reduced beta-cell mass was accompanied by decreased proliferation and enhanced apoptosis. CONCLUSIONS:Our studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineurin activity may contribute, along with other genetic and environmental factors, to beta-cell dysfunction and diabetes
Loss of mTORC1 signalling impairs Ī²-cell homeostasis and insulin processing
Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that Ī²-cell-specific loss of mTORC1 causes diabetes and Ī²-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (Ī²raKO) and inducible (MIP-Ī²raKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates Ī²-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates Ī²-cell proliferation. Restoration of both pathways partially recovers Ī²-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in Ī²-cells and identify downstream pathways driving Ī²-cell mass, function and insulin processing
Genetic Deficiency of Glycogen Synthase Kinase-3Ī² Corrects Diabetes in Mouse Models of Insulin Resistance
Despite treatment with agents that enhance Ī²-cell function and insulin action, reduction in Ī²-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3Ī² (Gsk-3Ī²). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3Ī² to regulation of Ī²-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/ā) exhibit insulin resistance and a doubling of Ī²-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3Ī² (Gsk-3Ī²+/ā) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced Ī²-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2ā/ā), like the Ir+/ā mice, are insulin resistant, but develop profound Ī²-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3Ī² activity associated with a marked reduction of Ī²-cell proliferation and increased apoptosis. Irs2ā/ā mice crossed with Gsk-3Ī²+/ā mice preserved Ī²-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2ā/ā mice had increased cyclin-dependent kinase inhibitor p27kip1 that was limiting for Ī²-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of Ī²-cell mass in Gsk-3Ī²+/āIrs2ā/ā mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus Ī²-cellāspecific effects of reduction of Gsk3Ī² activity on preservation of Ī²-cell mass, mice homozygous for a floxed Gsk-3Ī² allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce Ī²-cellāspecific knockout of Gsk-3Ī² (Ī²Gsk-3Ī²ā/ā). Like Gsk-3Ī²+/ā mice, Ī²Gsk-3Ī²ā/ā mice also prevented the diabetes of the Irs2ā/ā mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within Ī²-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of Ī²-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve Ī²-cells and prevent diabetes onset
Loss of mTORC1 signaling alters pancreatic Ī± cell mass and impairs glucagon secretion
Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic Ī± cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of Ī± cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in Ī± cells (Ī±RaptorKO), we showed that mTORC1 signaling is dispensable for Ī± cell development, but essential for Ī± cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in Ī±RaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In Ī±RaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for Ī± cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling Ī± cell-mass maintenance
S6K1 controls pancreatic Ī² cell size independently of intrauterine growth restriction
Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of Ī² cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased Ī² cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic Ī² cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore Ī² cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic Ī² cell lesion. Consistent with this hypothesis, reexpression of S6K1 in Ī² cells of S6K1-/- mice restored embryonic Ī² cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic Ī² cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced Ī² cell growth and eventual development of T2DM later in life
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