The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo

Aims/hypothesis

Regulation of insulin secretion along the secretory pathway is incompletely understood. We addressed the expression of SIL1, a nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 kD (GRP78), in pancreatic beta cells and investigated whether or not SIL1 is involved in beta cell function.

Methods

SIL1 expression was analysed by immunoblotting and immunofluorescence. Metabolic and islet variables, including glucose tolerance, beta cell mass, insulin secretion, islet ultrastructure, insulin content and levels of ER stress marker proteins, were addressed in Sil1 knockout (Sil1 ^?/?) mice. Insulin, proinsulin and C-peptide release was addressed in Sil1 ^?/? islets, and SIL1 overexpression or knockdown was explored in MIN6 cells in vitro. Models of type 1 diabetes and insulin resistance were induced in Sil1 ^?/? mice by administration of streptozotocin (STZ) and a high-fat diet (HFD), respectively.

Results

We show that SIL1 is expressed in pancreatic beta cells and is required for islet insulin content, islet sizing, glucose tolerance and glucose-stimulated insulin secretion in vivo. Levels of pancreatic ER stress markers are increased in Sil1 ^?/? mice, and Sil1 ^?/? beta cell ER is ultrastructurally compromised. Isolated Sil1 ^?/? islets show lower proinsulin and insulin content and impaired glucose-stimulated insulin secretion. Modulation of SIL1 protein levels in MIN6 cells correlates with changes in insulin content and secreted insulin. Furthermore, Sil1 ^?/? mice are more susceptible to STZ-induced type 1 diabetes with increased apoptosis. Upon HFD feeding, Sil1 ^?/? mice show markedly lower insulin secretion and exacerbated glucose intolerance compared with control mice. Surprisingly, however, HFD-fed Sil1 ^?/? mice display pronounced islet hyperplasia with low amounts of insulin in total pancreas.

Conclusions/interpretation

These results reveal a novel role for the nucleotide exchange factor SIL1 in pancreatic beta cell function under physiological and disease conditions such as diabetes and the metabolic syndrome.     

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Aims/hypothesis

Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas.

Methods

Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.

Results

Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca²⁺ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, in βSOCS2 mice proinsulin maturation is impaired, leading to an altered structure of insulin secretory granules and augmented levels of proinsulin. The latter is likely to be due to decreased production of prohormone convertase 1 (PC1/3), which plays a key role in proinsulin cleavage.

Conclusions/Interpretations

SOCS2 was shown to be a potent regulator of proinsulin processing and insulin secretion in beta cells. While its constitutive production is insufficient to induce overt diabetes in this mouse model, it causes glucose intolerance. Thus, increased SOCS2 production could be an important event predisposing to beta cell failure.     

β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice

Aims/hypothesis

Beta cell failure due to progressive secretory dysfunction and limited expansion of beta cell mass is a key feature of type 2 diabetes. Beta cell function and mass are controlled by glucose and hormones/neurotransmitters that activate G protein-coupled receptors or receptor tyrosine kinases. We have investigated the role of β-arrestin (ARRB)2, a scaffold protein known to modulate such receptor signalling, in the modulation of beta cell function and mass, with a specific interest in glucagon-like peptide-1 (GLP-1), muscarinic and insulin receptors.

Methods

β-arrestin2-knockout mice and their wild-type littermates were fed a normal or a high-fat diet (HFD). Glucose tolerance, insulin sensitivity and insulin secretion were assessed in vivo. Beta cell mass was evaluated in pancreatic sections. Free cytosolic [Ca²⁺] and insulin secretion were determined using perifused islets. The insulin signalling pathway was evaluated by western blotting.

Results

Arrb2-knockout mice exhibited impaired glucose tolerance and insulin secretion in vivo, but normal insulin sensitivity compared with wild type. Surprisingly, the absence of ARRB2 did not affect glucose-stimulated insulin secretion or GLP-1- and acetylcholine-mediated amplifications from perifused islets, but it decreased the islet insulin content and beta cell mass. Additionally, there was no compensatory beta cell mass expansion through proliferation in response to the HFD. Furthermore, Arrb2 deletion altered the islet insulin signalling pathway.

Conclusions/interpretation

ARRB2 is unlikely to be involved in the regulation of insulin secretion, but it is required for beta cell mass plasticity. Additionally, we provide new insights into the mechanisms involved in insulin signalling in beta cells.     

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Aims/hypothesis

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is regulated by paracrine factors, the identity and mechanisms of action of which are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis.

Methods

We examined glucose homeostatic responses in mice lacking activin B and in pancreatic islets derived from these mutants. We compared the ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and beta cells.

Results

Mice lacking activin B displayed elevated serum insulin levels and GSIS. Injection of a soluble activin B antagonist phenocopied these changes in wild-type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS, which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild-type islets, while activin A displayed the opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta cells, while Smad2 showed a preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets.

Conclusions/interpretation

These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta cells, and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.     

Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets

Aims/hypothesis

Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)–ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS.

Methods

Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels.

Results

We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph–ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice.

Conclusions/interpretation

We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance.     

Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet

Aims/hypothesis

Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.

Methods

Male and female littermate Tlr2 ^+/+ and Tlr2 ^?/? mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production.

Results

While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2 ^?/? mice were protected from the adverse effects of HFD compared with Tlr2 ^+/+ littermate controls. Female Tlr2 ^?/? mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2 ^?/? mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2 ^?/? mice did not increase IL-1β expression in response to a NEFA mixture, whereas Tlr2 ^+/+ control tissues did.

Conclusion/interpretation

These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.     

Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin

Aims/hypothesis

The small G-protein ras-related C3 botulinum toxin substrate 1 (RAC1) plays various roles in mammalian cells, such as in the regulation of cytoskeletal organisation, cell adhesion, migration and morphological changes. The present study examines the effects of RAC1 ablation on pancreatic beta cell function.

Methods

Isolated islets from pancreatic beta cell-specific Rac1-knockout (betaRac1 ^?/?) mice and RAC1 knockdown INS-1 insulinoma cells treated with small interfering RNA were used to investigate insulin secretion and cytoskeletal organisation in pancreatic beta cells.

Results

BetaRac1 ^?/? mice showed decreased glucose-stimulated insulin secretion, while there were no apparent differences in islet morphology. Isolated islets from the mice had blunted insulin secretion in response to high glucose levels. In RAC1 knockdown INS-1 cells, insulin secretion was also decreased in response to high glucose levels, consistent with the phenotype of betaRac1 ^?/? mice. Even under high glucose levels, RAC1 knockdown INS-1 cells remained intact with F-actin, which inhibits the recruitment of the insulin granules, resulting in an inhibition of insulin secretion.

Conclusions/interpretation

In RAC1-deficient pancreatic beta cells, F-actin acts as a barrier for insulin granules and reduces glucose-stimulated insulin secretion.     

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

Aims/hypothesis

MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesity-associated type 2 diabetes and to assess their potential contribution to the development of the disease.

Methods

MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells.

Results

MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation.

Conclusions/interpretation

We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs.     

Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model

Aims/hypothesis

Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old).

Methods

After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated.

Results

Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice.

Conclusions/interpretation

In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.     

Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice

Aims/hypothesis

Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis.

Methods

First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg?kg^?1?day^?1, i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425.

Results

In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle.

Conclusions/interpretation

Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.     

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice

Aims/hypothesis

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the Alb-Cre promoter to drive Ptp1b deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulin-resistant adult mice.

Methods

Inducible Ptp1b liver-specific knockout mice were generated using SA-Cre-ER ^T2 mice crossed with Ptp1b floxed (Ptp1b ^fl/fl) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liver-specific deletion of Ptp1b (SA-Ptp1b ^?/? mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined.

Results

Despite no significant change in body weight relative to HFD-fed Ptp1b ^fl/fl control mice, HFD-fed SA-Ptp1b ^?/? mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH₂-terminal kinase 2 phosphorylation, and decreased expression of Pepck.

Conclusions/interpretation

Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects.     

Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis

Background and aim

Impaired fatty liver regeneration has already been reported in many genetic modification models. However, in diet-induced simple hepatic steatosis, which showed similar phenotype with clinical pathology, whether liver regeneration is impaired or not remains unclear. In this study, we evaluated liver regeneration in mice with diet-induced simple hepatic steatosis, and focused on excess lipid accumulation occurring during liver regeneration.

Methods

Mice were fed high fat diet (HFD) or control diet for 9–10 weeks. We analyzed intrahepatic lipid accumulation, DNA replication, and various signaling pathways including cell proliferation and ER stress during liver regeneration after partial hepatectomy. In addition, some of mice were pretreated with tauroursodeoxycholic acid (TUDCA), a chemical chaperone which alleviates ER stress, and then we estimated TUDCA effects on liver regeneration.

Results

The peak of hepatocyte BrdU incorporation, the expression of proliferation cell nuclear antigen (PCNA) protein, and the expressions of cell cycle-related genes were observed in delayed time in HFD mice. The expression of phosphorylated Erk1/2 was also delayed in HFD mice. The amounts of liver triglyceride were at least twofold higher in HFD mice at each time point. Intrahepatic palmitic acid was increased especially in HFD mice. ER stress induced during liver regeneration was significantly higher in HFD mice. In HFD mice, pretreatment with TUDCA reduced ER stress and resulted in improvement of delayed liver regeneration.

Conclusion

In simple hepatic steatosis, lipid overloading occurring during liver regeneration might be caused ER stress and results in delayed hepatocyte DNA replication.     

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Aims/hypothesis

Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development.

Methods

The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 ^?/?) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes.

Results

CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 ^?/? mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion.

Conclusions/interpretation

The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes.     

Glucagon regulates orexin A secretion in humans and rodents

Aims/hypothesis

Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro.

Methods

In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic–euglycaemic clamp experiments, and insulin–hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic–euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets.

Results

Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody.

Conclusions/interpretation

Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism.     

SMAD2 disruption in mouse pancreatic beta cells leads to islet hyperplasia and impaired insulin secretion due to the attenuation of ATP-sensitive K+ channel activity

Aims/hypothesis

The TGF-β superfamily of ligands provides important signals for the development of pancreas islets. However, it is not yet known whether the TGF-β family signalling pathway is required for essential islet functions in the adult pancreas.

Methods

To identify distinct roles for the downstream components of the canonical TGF-β signalling pathway, a Cre-loxP system was used to disrupt SMAD2, an intracellular transducer of TGF-β signals, in pancreatic beta cells (i.e. Smad2β knockout [KO] mice). The activity of ATP-sensitive K⁺ channels (K_ATP channels) was recorded in mutant beta cells using patch-clamp techniques.

Results

The Smad2βKO mice exhibited defective insulin secretion in response to glucose and overt diabetes. Interestingly, disruption of SMAD2 in beta cells was associated with a striking islet hyperplasia and increased pancreatic insulin content, together with defective glucose-responsive insulin secretion. The activity of K_ATP channels was decreased in mutant beta cells.

Conclusions/interpretation

These results suggest that in the adult pancreas, TGF-β signalling through SMAD2 is crucial for not only the determination of beta cell mass but also the maintenance of defining features of mature pancreatic beta cells, and that this involves modulation of K_ATP channel activity.