Regulation Of Β-cell Function Research Articles

Loss of B cell regulatory function is associated with delayed healing in patients with tibia fracture.

The process of bone regeneration after fracture is a complex and well-orchestrated process usually requiring 3-12 weeks. A subset of patients, however, exhibit delayed healing time and even incomplete restoration of the normal bone structure. Although the precise mechanism is unknown, studies have shown that smurf1 may play a role during the process. Here, we sought to determine the involvement of the immune system in impaired bone healing. We found that immediately after fracture, the B-cell composition was shifted toward increased frequency of plasmablasts and decreased frequency of naïve B cells, reflecting higher inflammatory status. The percentage of CD19(+) CD24(+) CD38(+) regulatory B cells was also upregulated in response to bone fracture. The production of IL-10, a pivotal cytokine in regulatory B-cell function, was upregulated in all patients. Interestingly, the increase in IL-10 production was only sustained throughout the healing course in normal healing patients but not in delayed healing patients. Rather, delayed healing patients downregulated B-cell IL-10 secretion early and had reduced level of regulatory B-cell activity. Together, these data revealed a role of regulatory B cells in the endogenous bone regeneration process and an alternation in B-cell-mediated regulation in delayed healing patients.

Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls β, α, and δ-cell masses in genetic obese mice.

Taurine (Tau) regulates β-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in β-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and β-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating β-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.

Activation of Melatonin Signaling Promotes β-Cell Survival and Function.

Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.

The ezrin-radixin-moesin family of proteins in the regulation of B-cell immune response.

Dynamic reorganization of the cortical cytoskeleton is essential for numerous cellular processes, including B- and T-cell activation and migration. The ezrin-radixin-moesin (ERM) family of proteins plays structural and regulatory roles in the rearrangement of plasma membrane flexibility and protrusions through its members' reversible interaction with cortical actin filaments and the plasma membrane. Recent studies demonstrated that ERM proteins not only are involved in cytoskeletal organization but also offer a platform for the transmission of signals in response to a variety of extracellular stimuli through their ability to cross-link transmembrane receptors with downstream signaling components. In this review, we summarize present knowledge relating to ERMs and recent progress made toward elucidating a novel role for them in the regulation of B-cell function in health and disease.

Beyond the Protein-Coding Sequence: Noncoding RNAs in the Pathogenesis of Type 2 Diabetes

Diabetes mellitus results from a deficiency or failure to maintain normal glucose homeostasis. The most common form of the disease is type 2 diabetes (T2D), a progressive metabolic disorder characterized by elevated glucose levels that develops in response to either multi-organ insulin resistance or insufficient insulin secretion from pancreatic β-cells. Although the etiology of T2D is complex, many factors are known to contribute to defects of glucose homeostasis, including obesity, unhealthy lifestyle choices, genetic susceptibility, and environmental exposures. In addition to these factors, noncoding RNAs (ncRNAs) have been recently implicated in the pathogenesis of T2D, playing roles in several of the pathophysiological mechanisms underlying the disease, particularly in insulin-sensitive tissues such as pancreatic β-cells, liver, muscle, and adipose tissue. A growing number of publications demonstrate that polymorphisms in ncRNAs or their target genes may represent a new class of genetic variation contributing to the development of T2D. This review summarizes both the current state of knowledge of ncRNAs, specifically microRNAs (miRNAs), involved in the regulation of β-cell function, insulin sensitivity, and insulin action in peripheral organs. The role of genetic variation in miRNAs or miRNA binding sites in the pathogenesis of T2D is also discussed. While far less is known about the impact of long ncRNAs (lncRNAs) in the development of T2D, emerging evidence suggests that these molecules may be able to contribute to β-cell dysfunction in response to hyperglycemia. This article provides an overview of the studies conducted to date in this field, focusing on lncRNAs that are dysregulated in human pancreatic islets.

Apoptotic cells ameliorate chronic intestinal inflammation by enhancing regulatory B-cell function.

Apoptosis is a programmed physiological death of unwanted cells, and handling of apoptotic cells (ACs) is thought to have profound effects on immune-mediated disorders. However, there is scant information regarding the role of ACs in intestinal inflammation, in which immune homeostasis is a major concern. To investigate this, we injected ACs into a severe combined immunodeficiency adoptive transfer model of chronic colitis in the presence and absence of cotransferred whole B or regulatory B cell (Breg)-depleted B cells. We also injected syngeneic ACs into AKR/N mice as a control and into milk fat globule-epidermal growth factor 8 knockout mice deficient of phagocytic function. Chronic colitis severity was significantly reduced in the AC as opposed to the phosphate-buffered saline group with cotransferred whole B cells. The AC-mediated effect was lost in the absence of B cells or presence of Breg-depleted B cells. In addition, ACs induced splenic B cells to secrete significantly increased levels of interleukin 10 in AKR/N mice but not milk fat globule-epidermal growth factor 8 knockout mice. Apoptotic leukocytes were induced by reactive oxygen species during granulocyte/monocyte apheresis therapy in rabbits and H2O2-induced apoptotic neutrophils ameliorated mice colitis. Our results indicate that ACs are protective only in the presence of B cells and phagocytosis of ACs induced interleukin 10 producing Bregs. Thus, the ameliorative effect seen in this study might have been exerted by AC-induced Bregs through increased production of the immunosuppressive cytokine interleukin 10, whereas an AC-mediated effect may contribute to the anti-inflammatory effect of granulocyte/monocyte apheresis as a novel therapeutic mechanism for inflammatory bowel disease.

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Both type 1 and type 2 diabetes are associated with insufficient functional β-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of β-cell function. Previously, deletion of HIF-1α or HIF-1β in pancreatic β-cells, as well as constitutive activation of the HIF pathway in β-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2α overexpression in pancreatic β-cells in vivo. We overexpressed HIF-2α in pancreatic β-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2α overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or β-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2α in the pancreatic β-cells does not play a significant role in β-cell function and glucose homeostasis.

Glucagon-like peptide-1 stimulates type 3 iodothyronine deiodinase expression in a mouse insulinoma cell line

AimsThe pathophysiological roles of thyroid hormones in glucose metabolism remain uncertain. Type 3 iodothyronine deiodinase (D3) converts thyroxine (T4) and 3,5,3′-triiodothyronine (T3) to 3,3′,5′-triiodothyronine (rT3) and 3,3′-diiodothyronine (T2), respectively, inactivating thyroid hormones in a cell-specific fashion. In the present study, we identified D3 expression in MIN6 cells derived from a mouse insulinoma cell line and examined the mechanisms regulating D3 expression in these cells. Main methodsWe characterized D3 activity using HPLC analysis, and examined the effect of GLP-1 or exendin-4 on D3 expression and cAMP accumulation in MIN6 cells. We also measured insulin secretion from MIN6 cells exposed to GLP-1 and T3. Key findingsWe identified enzyme activity that catalyzes the conversion of T3 to T2 in MIN6 cells, which showed characteristics compatible with those for D3. D3 mRNA was identified in these cells using RT-PCR analysis. Forskolin rapidly stimulated D3 mRNA and D3 activity. Glucagon-like peptide-1 (GLP-1) increased D3 expression in a dose-dependent manner, and this effect was inhibited by the protein kinase A (PKA) inhibitor H-89. Exendin-4, a GLP-1 receptor agonist, also stimulated D3 expression in MIN6 cells. These results suggest that a cAMP-PKA-mediated pathway participates in GLP-1-stimulated D3 expression in MIN6 cells. Furthermore, GLP-1 stimulated insulin secretion was suppressed by the addition of T3 in MIN6 cells. SignificanceOur findings indicate that GLP-1 regulates intracellular T3 concentration in pancreatic β cells via a cAMP-PKA-D3-mediated pathway that may also regulate β-cell function.

Human adipose tissue–derived mesenchymal stromal cells promote B-cell motility and chemoattraction

Background aimsMesenchymal stromal cells hold special interest for cell-based therapy because of their tissue-regenerative and immunosuppressive abilities. B-cell involvement in chronic inflammatory and autoimmune pathologies makes them a desirable target for cell-based therapy. Mesenchymal stromal cells are able to regulate B-cell function; although the mechanisms are little known, they imply cell-to-cell contact. MethodsWe studied the ability of human adipose tissue–derived mesenchymal stromal cells (ASCs) to attract B cells. ResultsWe show that ASCs promote B-cell migration through the secretion of chemotactic factors. Inflammatory/innate signals do not modify ASC capacity to mediate B-cell motility and chemotaxis. Analysis of a panel of B cell–related chemokines showed that none of them appeared to be responsible for B-cell motility. Other ASC-secreted factors able to promote cell motility and chemotaxis, such as the cytokine interleukin-8 and prostaglandin E2, did not appear to be implicated. ConclusionsWe propose that ASC promotion of B-cell migration by undefined secreted factors is crucial for ASC regulation of B-cell responses.

CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse β-cells

ObjectiveGlucagon-like peptide-1 (GLP-1) plays a major role in pancreatic β-cell function and survival by increasing cytoplasmic cAMP levels, which are thought to affect transcription through activation of the basic leucine zipper (bZIP) transcription factor CREB. Here, we test CREB function in the adult β-cell through inducible gene deletion.MethodsWe employed cell type-specific and inducible gene ablation to determine CREB function in pancreatic β-cells in mice.ResultsBy ablating CREB acutely in mature β-cells in tamoxifen-treated CrebloxP/loxP;Pdx1-CreERT2 mice, we show that CREB has little impact on β-cell turnover, in contrast to what had been postulated previously. Rather, CREB is required for GLP-1 to elicit its full effects on stimulating glucose-induced insulin secretion and protection from cytokine-induced apoptosis. Mechanistically, we find that CREB regulates expression of the pro-apoptotic gene p21 (Cdkn1a) in β-cells, thus demonstrating that CREB is essential to mediating this critical aspect of GLP-1 receptor signaling.ConclusionsIn sum, our studies using conditional gene deletion put into question current notions about the importance of CREB in regulating β-cell function and mass. However, we reveal an important role for CREB in the β-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes.

Deletion of ARNT (Aryl hydrocarbon receptor nuclear translocator) in β-cells causes islet transplant failure with impaired β-cell function.

BackgroundReplacing β-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of β-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates β-cell function, and potentially survival. Lack of ARNT impairs the ability of β-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown.AimTo investigate the effect of β-cell deletion of ARNT on graft outcomes.MethodsIslets were isolated from donor mice which had β-cell specific ARNT-deletion (β-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) ½ of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas.ResultsIn the supra-physiological-mass model (3∶1), both groups achieved reasonable glycaemia, with slightly higher levels in β-ARNT-recipients. In adequate-mass model (1∶1), β-ARNT recipients had poor glucose control versus floxed-control recipients and versus the β-ARNT donors. In the low-β-cell-mass model (½:1) β-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or β-cell mass between groups indicating that the defect was not due to early altered β-cell survival.ConclusionOutcomes for islet transplants lacking β-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1∶1 transplant model, there was no difference in β-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1α have increased apoptosis and decreased islet volume. ARNT also partners HIF-2α and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2α and AhR in transplant outcomes is needed.

Chapter Ten - The Calcium-Sensing Receptor and β-Cell Function

In addition to its central role controlling systemic calcium homeostasis, the extracellular calcium-sensing receptor (CaSR) can be found on multiple cell types not associated with controlling plasma calcium. The endocrine pancreas is one such tissue, and it is apparent that the receptor plays an important role in regulating β-cell function. During exocytosis, divalent cations are coreleased with insulin and their concentration within the restricted intercellular compartments of the pancreatic islet increases sufficiently to activate the CaSR on neighboring cells. Acute and chronic activation of the receptor has multiple effects on the β-cell, from increasing cadherin-based cell-cell adhesion to directly altering the expression and function of various potassium and voltage-dependent calcium channels. The promiscuous activation of multiple binding partners improves cell adhesion, cell coupling, and cell-to-cell communication within the islet and is the basis for the effect of the CaSR on β-cell function and improved glucose responsiveness.

Regulation of β-cell function by RNA-binding proteins

β-cells of the pancreatic islets are highly specialized and high-throughput units for the production of insulin, the key hormone for maintenance of glucose homeostasis. Elevation of extracellular glucose and/or GLP-1 levels triggers a rapid upregulation of insulin biosynthesis through the activation of post-transcriptional mechanisms. RNA-binding proteins are emerging as key factors in the regulation of these mechanisms as well as in other aspects of β-cell function and glucose homeostasis at large, and thus may be implicated in the pathogenesis of diabetes. Here we review current research in the field, with a major emphasis on RNA-binding proteins that control biosynthesis of insulin and other components of the insulin secretory granules by modulating the stability and translation of their mRNAs.

Microphthalmia Transcription Factor Regulates Pancreatic β-Cell Function

Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell–specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function.

Identification of a pathway by which glucose regulates β-catenin signalling via the cAMP/protein kinase A pathway in β-cell models

Pancreatic β-cells are highly responsive to changes in glucose, but the mechanisms involved are only partially understood. There is increasing evidence that the β-catenin signalling pathway plays an important role in regulating β-cell function, but the mechanisms regulating β-catenin signalling in these cells is not well understood. In the present study we show that β-catenin levels and downstream signalling are regulated by changes in glucose levels in INS-1E and β-TC6-F7 β-cell models. We found a glucose-dependent increase in levels of β-catenin in the cytoplasm and nucleus of INS-1E cells. Expression of cyclin D1 also increased with glucose and required the presence of β-catenin. This was associated with an increase in phosphorylation of β-catenin on Ser552, which is known to stabilize the molecule and increase its transcriptional activity. In a search for possible signalling intermediates we found forskolin and cell-permeable cAMP analogues recapitulated the glucose effects, suggesting a role for cAMP and PKA (cAMP-dependent protein kinase/protein kinase A) downstream of glucose. Furthermore, glucose caused sustained increases in cAMP. Two different inhibitors of adenylate cyclase and PKA signalling blocked the effects of glucose, whereas siRNA (small interfering RNA) knockdown of PKA blocked the effects of glucose on β-catenin signalling. Finally, reducing β-catenin levels with either siRNA or pyrvinium impaired glucose- and KCl-stimulated insulin secretion. Taken together the results of the present study define a pathway by which changes in glucose levels can regulate β-catenin using a mechanism which involves cAMP production and the activation of PKA. This identifies a pathway that may be important in glucose-dependent regulation of gene expression and insulin secretion in β-cells.

Taurine supplementation improves liver glucose control in normal protein and malnourished mice fed a high‐fat diet

Poor nutrition during the perinatal period is associated with an increased risk for metabolic syndrome in adulthood. Taurine (TAU) regulates β-cell function and glucose homeo-stasis. Here, we assessed the effects of TAU supplementation upon adiposity and glucose control in malnourished mice fed a high-fat diet (HFD). Weaned male C57BL/6J mice were fed a control (14% protein - C) or a protein-restricted (6% protein - R) diet for 6 weeks. Afterwards, mice received or not an HFD for 8 weeks (CH and RH). Half of the HFDmice were supplemented with 5% TAU after weaning (CHT and RHT). Protein restriction led to typical malnutrition features. HFD increased body weight, adiposity, and led to hyperleptinemia, hyperphagia, glucose intolerance, and higher liver glucose output in RH and CH groups. Fasted R mice showed higher plasma adiponectin levels and increased phosphorylation of the AMP-activated protein kinase (p-AMPK) in the liver. These parameters were reduced in RH mice and increased p-AMPK persisted in RHT. TAU prevented obesity and improved glucose tolerance only in CHT, but liver glucose control was ameliorated in both supplemented groups. Better CHT liver glucose control was linked to increased Akt (thymoma viral proto-oncogene/protein kinase B) phosphorylation. Malnourished mice fed an HFD developed obesity, glucose intolerance, and increased liver glucose output. TAU preserved only normal liver glucose control in RHT mice, an effect associated with increased liver p-AMPK content.

Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

The calcium-regulated transcription coactivator, Ca(2)(+)-responsive transactivator (CREST) was expressed in pancreatic β-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto-Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of β-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of β-cell function, we established a stable β-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in β-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to β-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in β-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in β-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.

Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice

Tim-1, a type I transmembrane glycoprotein, consists of an IgV domain and a mucin domain. The IgV domain is essential for binding Tim-1 to its ligands, but little is known about the role of the mucin domain, even though genetic association of TIM-1 with atopy/asthma has been linked to the length of mucin domain. We generated a Tim-1-mutant mouse (Tim-1(Δmucin)) in which the mucin domain was deleted genetically. The mutant mice showed a profound defect in IL-10 production from regulatory B cells (Bregs). Associated with the loss of IL-10 production in B cells, older Tim-1(Δmucin) mice developed spontaneous autoimmunity associated with hyperactive T cells, with increased production of IFN-γ and elevated serum levels of Ig and autoantibodies. However, Tim-1(Δmucin) mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice on a C57BL/6 background. Tim-1(Δmucin)lpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance.

Vitamin D and Diabetes

There is no doubt that vitamin D deficiency is the cause of several metabolic bone diseases, but vitamin D status is also linked to many major human diseases including immune disorders. Mounting data strengthen the link between vitamin D and diabetes, in particular T1D and T2D. Despite some inconsistencies between studies that associate serum 25(OH)D levels with the risk of developing T1D or T2D, there seems to be an overall trend for an inverse correlation between levels of 25(OH)D and both disorders. There is also compelling evidence that 1,25(OH)2D regulates b-cell function by different mechanisms, such as influencing insulin secretion by regulating intracellular levels of Ca2+, increasing β-cell resistance to apoptosis, and perhaps also increasing β-cell replication. The capacity of vitamin D, more specifically 1,25(OH)2D, to modulate immune responses is of particular interest for both the therapy and prevention of diabetes. In the case of T1D, vitamin D supplementation in prediabetic individuals could help prevent or reduce the initiation of autoimmune processes possibly by regulating thymic selection of the T-cell repertoire, decreasing the numbers of autoreactive T cells, and inducing Treg cells. Although immune modulation is generally discussed for the treatment of T1D, it is also relevant for T2D. Indeed, recent studies have shown that T2D patients have increased systemic inflammation and that this state can induce β-cell dysfunction and death. Supplementation trials with regular vitamin D for the protection against the development of T1D and T2D have generated some contradictory data, but many weaknesses can be identified in these trials as most were underpowered or open-labeled. However, the overwhelming strength of preclinical data and of the observational studies make vitamin D or its analogues strong candidates for the prevention or treatment of diabetes or its complications. However, proof of causality needs well-designed clinical trials and if positive, adequate dosing, regimen, and compound studies are needed to define the contribution of vitamin D status and therapy in the global diabetes problem. There are many confounding factors that need to be taken into consideration when translating successful vitamin D therapies in animal models into humans, for example, gender, age, lifestyle, and genetic background. To come to solid conclusions on the potential of vitamin D or its analogues in the prevention of or therapy for all forms of diabetes, it is clear that large prospective trials with carefully selected populations and end points will be needed, but should also receive high priority.

Insulin Augmentation of Glucose-Stimulated Insulin Secretion Is Impaired in Insulin-Resistant Humans

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 immunologically 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.