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Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of βand α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes. Diabetes 2014;63:994-1007 | DOI: 10.2337/db13-1013, Insulin resistance, along with β-cell inadequacy, represent the key features in the pathogenesis of type 2 diabetes, and that both are essential for the full manifestation of the disease is [...]

Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substratelphosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cθ (PKCθ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-cell replication. This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes. Diabetes 2014; 63:819-831 | DOI: 10.2337/db13-1146, Induction of proliferation in human β-cells is a major goal of current research in both types 1 and 2 diabetes. Over the last 20 years, dramatic progress has occurred in [...]

Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MS-based measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes. Diabetes 2014;63:259-269 | DOI: 10.2337/db13-1012, Studies of patients with maturity-onset diabetes of the young (MODY) have provided important insight into disease mechanisms of pancreatic β-cell failure and diabetes development and also contributed to novel treatment [...]

Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic [CD4.sup.+] and [CD8.sup.+] T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic [CD4.sup.+] and [CD8.sup.+] T cells with [NOD.RAG1.sup.-/-] islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes. Diabetes 2014;63:188-202 | DOI: 10.2337/db13-0204, Type 1 diabetes (T1D) is a chronic T-cell-mediated autoimmune disease characterized by selective destruction of β-cells, resulting in hyperglycemia (1). A major limitation to successful therapy has been a lack [...]

Patients with type 2 diabetes (T2D) often exhibit hyperglucagonemia despite hyperglycemia, implicating defective α-cell function. Although endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in α-cell biology remains unclear. X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), and its deficiency in β-cells has been reported to impair insulin secretion, leading to glucose intolerance. To evaluate the role of XBP1 in α-cells, we created complementary in vivo (α-cell-specific XBP1 knockout [αXBPKO] mice) and in vitro (stable XBP1 knockdown α-cell line [αXBPKD]) models. The αXBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. αXBPKD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun N[H.sub.2]-terminal kinase. Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) (p[Y.sup.896]) and phosphorylation of Akt while enhancing serine phosphorylation (p[S.sup.307]) of IRS1. Consequently, the αXBPKD cells exhibited blunted suppression of glucagon secretion after insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion., In addition to the defects in β-cell secretory function and reduced β-cell mass, patients with type 2 diabetes (T2D) frequently manifest hyperglucagonemia that contributes to uncontrolled hyperglycemia (1-3). Although it [...]

A major goal in diabetes research is to find ways to enhance the mass and function of insulin secreting β-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 β-cells in rodents versus the scant information in human β-cells. To reverse the state of ignorance regarding human β-cell signaling, we suggest a series of questions for consideration by the scientific community to construct a human β-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 β-cell mass in the long-term goal of preventing and/or curing type 1 and type 2 diabetes. Diabetes 61:2205-2213, 2012, THE CHALLENGE OF INDUCING HUMAN β-CELL REPLICATION A principal goal of the National Institutes of Health/ National Institute of Diabetes and Digestive and Kidney Diseases, Juvenile Diabetes Research Foundation, American [...]

Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologlcally from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications. Diabetes 61:301-309, 2012, Type 2 diabetes (T2D) is characterized both by impaired insulin sensitivity and impaired insulin secretion. Multiple lines of evidence support the hypothesis that the pancreatic β-cell is an insulin-responsive tissue, [...]

OBJECTIVE--Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes, p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. RESEARCH DESIGN AND METHODS--We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation. RESULTS--Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from -14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. CONCLUSIONS--These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes., The maintenance of adult β-cell mass is critical for the appropriate regulation of glucose homeostasis in both humans and rodents. β-Cell replication is generally accepted as essential for β-cell expansion [...]

OBJECTIVE--Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in Insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action. RESEARCH DESIGN AND METHODS--We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KC1. We evaluated human and mouse islets, several β-cell lines, and CB1R-null ([CB1R.sup.-/-]) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. RESULTS--ECs are generated within β-cells, which also express CB1Rs that are hilly functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased p-cell proliferation and mass, coupled with enhanced IR signaling in p-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on β-cells in a G[α.sub.1]-dependent manner. CONCLUSIONS--These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes., Insulin is the prime mediator of glucose homeostasis. A paucity (as occurs in type 1 diabetes) or surplus (due to excessive exogenous insulin administration or insulin-secreting tumors) of insulin causes [...]

OBJECTIVE--A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory β-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of β-cell mass in two different models of insulin resistance. RESEARCH DESIGN AND METHODS--We created compound knockouts by crossing mice deficient in cyclin D2 (D2KO) with either the insulin receptor substrate 1 knockout (IRS1KO) mice or the insulin receptor liver-specific knockout mice (LIRKO), neither of which develops overt diabetes on its own because of robust compensatory β-cell hyperplasia. We phenotyped the double knockouts and used RT-qPCR and immunohistochemistry to examine β-cell mass. RESULTS--Both compound knockouts, D2KO/LIRKO and D2KO/IRS1KO, exhibited insulin resistance and hyperinsulinemia and an absence of compensatory p-cell hyperplasia. However, the diabetic D2KO/LIRKO group rapidly succumbed early compared with a relatively normal lifespan in the glucose-intolerant D2KO/IRSIKO mice. CONCLUSIONS--This study provides direct genetic evidence that cyclin D2 is essential for the expansion of β-cell mass in response to a spectrum of insulin resistance and points to the cell-cycle protein as a potential therapeutic target that can be harnessed for preventing and curing type 2 diabetes. Diabetes 59:987-996, 2010, The maintenance of an adequate and functional pancreatic B-cell mass dictates the body's ability to compensate for insulin resistance. Recent studies in autopsy samples from humans reported expansion of β-cell [...]

OBJECTIVE--Leptin acts via its receptor (LepRb) to signal the status of body energy stores. Leptin binding to LepRb initiates signaling by activating the associated Janus kinase 2 (Jak2) tyrosine kinase, which promotes the phosphorylation of tyrosine residues on the intracellular tail of LepRb. Two previously examined LepRb phosphorylation sites mediate several, but not all, aspects of leptin action, leading us to hypothesize that Jak2 signaling might contribute to leptin action independently of LepRb phosphorylation sites. We therefore determined the potential role in leptin action for signals that are activated by Jak2 independently of LepRb phosphorylation (Jak2-autonomous signals). RESEARCH DESIGN AND METHODS--We inserted sequences encoding a truncated LepRb mutant ([LepRbΔ65c], which activates Jak2 normally, but is devoid of other LepRb intracellular sequences) into the mouse Lepr locus. We examined the leptin-regulated physiology of the resulting Δ/Δmice relative to LepRb-deficient db/db animals. RESULTS--The Δ/Δ animals were similar to db/db animals in terms of energy homeostasis, neuroendocrine and immune function, and regulation of the hypothalamic arcuate nucleus, but demonstrated modest improvements in glucose homeostasis. CONCLUSIONS--The ability of Jak2-autonomous LepRb signals to modulate glucose homeostasis in Δ/Δanimals suggests a role for these signals in leptin action. Because Jak2-autonomous LepRb signals fail to mediate most leptin action, however, signals from other LepRb intracellular sequences predominate., Adipose tissue produces the hormone, leptin, in proportion to fat stores to communicate the status of long-term energy reserves to the brain and other organ systems (1-4). In addition to [...]

OBJECTIVE--Phogrin and IA-2, autoantigens in insulin-dependent diabetes, have been shown to be involved in insulin secretion in pancreatic β-cells; however, implications at a molecular level are confusing from experiment to experiment. We analyzed biological functions of phogrin in β-cells by an RNA interference technique. RESEARCH DESIGN AND METHODS--Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured p-cell lines and mouse islets. Both glucose-stimulated insulin secretion and cell proliferation rate were determined in the phogrin-knockdown cells. Furthermore, protein expression was profiled in these cells. To see the binding partner of phogrin in β-cells, coimmunoprecipitation analysis was carried out. RESULTS--Adenoviral expression of shPhogrin efficiently decreased its endogenous expression in pancreatic β-cells. Silencing of phogrin in β-cells abrogated the glucose-mediated mitogenic effect, which was accompanied by a reduction in the level of insulin receptor substrate 2 (IRS2) protein, without any changes in insulin secretion. Phogrin formed a complex with insulin receptor at the plasma membrane, and their interaction was promoted by high-gincose stimulation that in turn led to stabilization of IRS2 protein. Corroboratively, phogrin knockdown had no additional effect on the proliferation of p-cell line derived from the insulin receptor-knockout mouse. CONCLUSIONS--Phogrin is involved in p-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor. We propose that phogrin and IA-2 function as an essential regulator of autocrine insulin action in pancreatic β-cells., Glucose is a principle regulator pancreatic B-cell survival and growth as well as insulin secretion (1). It is a potent mitogen on pancreatic B-cells and regulates islet β-cells mass through [...]

OBJECTIVE--Calcium-permeable cation channel TRPV2 is expressed in pancreatic β-cells. We investigated regulation and function of TRPV2 in β-cells. RESEARCH DESIGN AND METHODS--Translocation of TRPV2 was assessed in MIN6 cells and cultured mouse β-cells by transfecting TRPV2 fused to green fluorescent protein or TRPV2 containing c-Myc tag in the extracellular domain. Calcium entry was assessed by monitoring fura-2 fluorescence. RESULTS--In MIN6 cells, TRPV2 was observed mainly in cytoplasm in an unstimulated condition. Addition of exogenous insulin induced translocation and insertion of TRPV2 to the plasma membrane. Consistent with these observations, insulin increased calcium entry, which was inhibited by tranilast, an inhibitor of TRPV2, or by knockdown of TRPV2 using shRNA. A high concentration of glucose also induced translocation of TRPV2, which was blocked by nefedipine, diazoxide, and somatostatin, agents blocking glucose-induced insulin secretion. Knockdown of the insulin receptor attenuated insulin-induced translocation of TRPV2. Similarly, the effect of insulin on TRPV2 translocation was not observed in a β-cell line derived from islets obtained from a β-cell-specific insulin receptor knockout mouse. Knockdown of TRPV2 or addition of tranilast significantly inhibited insulin secretion induced by a high concentration of glucose. Likewise, cell growth induced by serum and glucose was inhibited by tranilast or by knockdown of TRPV2. Finally, insulin-induced translocation of TRPV2 was observed in cultured mouse β-cells, and knockdown of TRPV2 reduced insulin secretion induced by glucose. CONCLUSIONS--TRPV2 is regulated by insulin and is involved in the autocrine action of this hormone on β-cells., Insulin elicits pleiotropic actions in a variety of target cells and plays a pivotal role in regulating nutrient metabolism. Recent studies have revealed that the insulin signal is necessary to [...]

OBJECTIVE--Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (L-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene ([Cc1.sup.-/-]). RESEARCH DESIGN AND METHODS--Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the [Cc1.sup.-/-] and wild-type [Cc1.sup.+/+] groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels. RESULTS--Like L-SACC1, [Cc1.sup.-/-] mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5-6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred [Cc1.sup.-/-] mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic β-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in [Cc1.sup.-/-] mice (inbred and outbred strains). CONCLUSIONS--Intact insulin secretion in response to glucose and impairment of insulin clearance in L-SACC1 and [Cc1.sup.-/-] mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver., In response to physiological stimuli, insulin is secreted from pancreatic β-cells into the portal circulation in a pulsatile manner. Through its first passage, ~50% of the secreted insulin is cleared [...]

Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal β-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57B1/6 or 129Sv genetic background showed a significant reduction in β-cell mass and complemented our earlier observation of increased β-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent β-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4α, and HNF1α. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of β-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis., Several neuropeptides that act in the central nervous system to regulate feeding behavior and energy homeostasis are also expressed in the enteric system as part of a potential hypothalamic-pancreatic axis [...]

Mice with deletion of insulin receptor substrate (IRS)-1 (IRS-1 knockout [KO] mice) show mild insulin resistance and defective glucose-stimulated insulin secretion and reduced insulin synthesis. To further define the role of IRS-1 in islet function, we examined the insulin secretory defect in the knockouts using freshly isolated islets and primary β-cells. IRS-1 KO β-cells exhibited a significantly shorter increase in intracellular free [Ca.sup.2+] concentration ([[Ca.sup.2+].sub.i]) than controls when briefly stimulated with glucose or glyceraldehyde and when L-arginine was used to potentiate the stimulatory effect of glucose. These changes were paralleled by a lower number of exocytotic events in the KO β-cells in response to the same secretagogues, indicating reduced insulin secretion. Furthermore, the normal oscillations in intracellular [Ca.sup.2+] and [O.sub.2] consumption after glucose stimulation were dampened in freshly isolated KO islets. Semiquantitative RT-PCR showed a dramatically reduced islet expression of sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase (SERCA)-2b and -3 in the mutants. These data provide evidence that IRS-1 modulation of insulin secretion is associated with [Ca.sup.2+] signaling and expression of SERCA-2b and -3 genes in pancreatic islets and provides a direct link between insulin resistance and defective insulin secretion., The insulin/IGF-1 receptor signaling pathway plays a significant role in the regulation of both insulin secretion and synthesis (1-5). We and other laboratories have shown that the insulin receptor substrate [...]

Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in insulin action and insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the insulin receptor and insulin receptor substrate-1 on three genetic backgrounds (C57BL/6 [B6], 129Sv, and DBA). Although DH mice on all backgrounds showed insulin resistance, their phenotypes were dramatically different. B6 DH mice exhibited marked hyperinsulinemia and massive islet hyperplasia and developed early hyperglycemia, with 85% overtly diabetic by 6 months. By contrast, 129Sv DH mice showed mild hyperinsulinemia and minimal islet hyperplasia, and, Several common human disorders, including obesity, diabetes, hyperlipidemia, atherosclerosis, and hypertension, have complex patterns of inheritance with superimposed effects created by diet, level of exercise, and other environmental factors (1-3). [...]

Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 129S6 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyperglycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes. Diabetes 52: 1535-1543, 2003, Type 2 diabetes is a multifactorial disorder in which ~50-70% of cases can be attributed to genetic factors (1), with the rest being due to environmental factors (such as diet [...]

L-783,281, an antidiabetic fungal metabolite that has previously been shown to activate insulin signaling in CHO cells, was tested for its effect on intracellular [Ca.sup.2+] ([[[Ca.sup.2+]].sub.i]) and insulin secretion in [...]

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific [...]

Type 2 diabetes is characterized by insulin resistance and impaired [Beta]-cell secretion. Although genetic defects likely contribute to the common form of type 2 diabetes, the genes potentially predisposing to [...]

To define the role of the liver in whole body glucose homeostasis, we generated mice with a liver-specific knockout of the insulin receptor (IR) gene using the Cre-loxP system. Mice [...]

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We recently showed that tissue-specific disruption of the insulin receptor (IR) in pancreatic [...]

Mice heterozygous for the insulin receptor and insulin receptor substrate-1 (IR/IRS-1) manifest marked insulin resistance and islet hyperplasia and 50% develop diabetes by 4-6 months of age. By contrast, mice [...]

The epidemic type 2 diabetes and the ever of increasing economic burden on society is a constant reminder of the continuing need for better therapeutic approaches to delay and/or prevent [...]