Beta-cell Proliferation Research Articles

2030-P: BS-016, a Novel Oleanolic Acid Derivative, Exerts Antidiabetic and Anti-Obesity Effects in Preclinical Studies

There is an urgent need for innovative treatment targeting multiple pathways of type 2 diabetes such as weight loss, insulin sensitization and beta cell proliferation. Natural products have been shown to have the potential to treat diabetes. Here we develop a novel compound from oleanolic acid with improved bioavailability and efficacy. BS-016 reduces blood glucose and induces a sustained weight loss in DIO mice, producing 15% weight loss in combination study. In db/db diabetic mice, BS-016 lowers plasma glucose and improves glucose homeostasis. In vitro studies show BS-016 promotes insulin sensitivity by activating PPAR gamma and increases energy expenditure. Taken together, these results indicate BS-016 is a promising agent for treating diabetes and obesity. Disclosure Y. Du: None.

38-OR: Beta-Arrestin-1 Regulates Pancreatic Beta-Cell Function and Plays a Key Role in Maintaining Whole Body Glucose Homeostasis

Beta-arrestin-1 and -2 (barr1 and barr2, respectively) are major GPCR-associated signaling molecules that are widely expressed throughout the body. Studies with whole body barr1 and barr2 KO mice have shown that beta-arrestins play important roles in key metabolic functions. In this study, we inactivated the barr1 gene in a conditional fashion specifically in beta-cells of adult mice (beta-barr1-KO mice). In vivo studies showed that beta-barr1-KO mice exhibited a pronounced impairment in glucose tolerance and glucose-stimulated insulin secretion (GSIS), when mice were maintained on high-fat diet (HFD). Studies with isolated perifused pancreatic islets prepared from HFD beta-barr1-KO mice confirmed that barr1 deletion in beta-cells led to a significant decrease in GSIS. Interestingly, HFD beta-barr1-KO mice displayed pronounced reductions in beta-cell mass and the rate of beta-cell proliferation, suggesting that barr1 is required for the expansion of beta-cell mass that occurs during HFD feeding. To test whether enhanced barr1 signaling in beta-cells might ameliorate the metabolic deficits associated with the consumption of a HFD, we also generated transgenic mice over-expressing barr1 in beta-cells (RIPII-barr1 mice). These transgenic mice displayed metabolic phenotypes that were opposite to those observed with the beta-barr1-KO mice, including improved glucose tolerance and GSIS in vivo as well as increased beta-cell mass. This is the first study demonstrating that barr1 is critical for the proper function of pancreatic beta-cells and for maintaining whole body glucose homeostasis. Identification of the cellular mechanisms through which barr1 signaling promotes beta-cell function and proliferation may lead to the development of novel drugs useful for the treatment of type 2 diabetes. Disclosure L.F. Barella: None. M. Rossi: None. S. Pydi: None. S. Jain: None. L. Zhu: None. W. Chen: None. J. Wess: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

2190-P: Sex-Based Differences in Nr4a1 Beta-Cell Activity

The orphan nuclear hormone receptor Nr4a1 plays a critical role in maintaining and expanding functional beta cell mass. Overexpression of Nr4a1 is sufficient to induce beta cell proliferation in primary beta cells by upregulating cell cycle progression, while maintaining glucose-stimulated insulin secretion. Full body deletion of Nr4a1 results in decreased beta cell mass, while resulting in modified fuel utilization in liver and muscle. Knock down of Nr4a1 decreases glycolytic and TCA cycle gene expression, impairs mitochondrial respiration, decreases cellular ATP levels, and ultimately decreases glucose-stimulated insulin secretion. While Nr4a1 is currently considered an orphaned nuclear hormone receptor, recent findings suggest that unsaturated fatty acids may function as a ligand, and that exposure to these fatty acid’s changes Nr4a1 affinity for promoters of genes involved in fuel utilization. To determine the effect of Nr4a1 presence of absence in the beta cell, and the effect of fatty acid exposure, we developed a beta cell specific, inducible, Nr4a1 knock out mouse. Male and female mice, deficient for Nr4a1 beginning at 3 months of age, were fed a normal chow or high fat diet for an additional four months. Here we present data demonstrating a sex specific difference in phenotype. Male mice demonstrated improved glucose tolerance at four months of feeding, while female mice demonstrated impaired glucose tolerance as early as one month of feeding. Here we present data regarding differences in beta cell mass, glucose stimulated insulin secretion, as well as Nr4a1 DNA binding from in islets from male and female mice exposed to unsaturated and saturated fatty acids. These data begin to demonstrate the role of Nr4a1 in controlling gene expression as a function of nutrient exposure, as well as sex-based differences in Nr4a1 activity. Disclosure J.S. Tessem: None. J. Herring: None. C.J. Smith: None. M.C. Austin: None. A.G. Wynn: None. Funding American Diabetes Association (1-17-IBS-101 to J.S.T.)

332-LB: Mir-132 Controls Pancreatic Beta-Cell Proliferation and Survival through the Pten/Akt/Foxo3 Signaling

Aim and Hypothesis: microRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. We aimed to identify miRNAs and their downstream targets involved in regeneration of islet beta cells following partial pancreatectomy (pP) in mice. Methods: RNA from laser capture microdissected islets of pP and sham-operated mice were profiled with microarrays to identify miRNAs implicated in control of beta cell regeneration. Altered expression of selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA and protein expression levels and signaling upon miR-132 knockdown and overexpression in mouse MIN6 cells and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pP miR-132-/-and control mice. Results: pP significantly increased the number of BrdU+/insulin+ positive islet cells. Microarray profiling revealed 14 miRNAs, including miR-132, to be significantly upregulated in LCM islets of partially pancreatectomized mice and confirmed by RT-PCR. Downregulation of miR-132 in MIN6 cells reduced proliferation while enhancing the levels of pro-apoptotic cleaved caspase-9. Microarray profiling, RT-PCR and immunoblotting revealed downregulated expression of Pten, with concomitant increased levels of pro-proliferative factors as well as inactivation of pro-apoptotic Foxo3. Overexpression of miR-132 in human insulinoma cells EndoC-βH1 validated the findings. In vivo regeneration of beta cells was reduced in pP miR-132-/- mice compared to control mice. Conclusions: Our study provides compelling evidence for miR-132 being critical for regeneration of mouse islet beta cells in vivo through downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell regeneration. Disclosure S. Kersting: None. H. Mziaut: None. Funding German Center for Diabetes Research (to S.K.)

2193-P: SREBP1c-PAX4 Axis Mediates Pancreatic Beta-Cell Compensatory Responses upon Metabolic Stress

Sterol responsive element-binding protein 1c (SREBP1c) is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic beta cells are largely unknown. In this study, we demonstrate that SREBP1c regulates beta cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic beta cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated beta cell proliferation through its novel target gene, PAX4. Compared to SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, beta cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating beta cell compensatory responses in obesity. Disclosure J. Kim: None. Funding Korean National Research Foundation (2011-0018312)

237-LB: Identification of Small Molecules That Increase Beta-Cell Mass in Hyperinsulinemic Zebrafish Alström Syndrome Model

Alström syndrome is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration, and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early onset type 2 diabetes mellitus (T2DM). We previously published data supporting the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes. Both adult and larval alms1-/- animals exhibit reduced insulin+ areas alongside defective peripheral glucose uptake and concomitant hyperinsulinemia in larval alms1-/- animals. Gene expression changes in beta-cells isolated from alms1-/- mutants revealed changes consistent with insulin hyperproduction, insulin hypersecretion and glucose sensing failure. Therefore, we used this model, in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM, in a high-throughput screen to examine small molecule compounds effecting pancreatic mass in vivo. The external development, simple growing conditions, and large number of progeny in the zebrafish allow for rapid screening with parallel elimination of lethal compounds. We examined the Microsource Spectrum Collection 2000, a library of 2,560 compounds, for those which increase beta-cell mass in wildtype, alms1-/- animals or both. These identified compounds are indicated in future studies for beta-cell proliferation pathways, T2DM diabetes-specific interactions, and potential targets for future therapeutic development. Disclosure J. Dunleavey: None. D.A. Annis: None. T.L. Hostelley: None. N.A. Zaghloul: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

327-LB: Transgenic Overexpression of MicroRNA-30d Impairs Glucose Homeostasis by Regulating Beta-Cell Proliferation and Dedifferentiation

MicroRNAs (miRNAs) are small non-coding RNAs that bind to target mRNAs and inhibit the translation in mammals. Abnormal miRNA functions are closely associated with pancreatic beta-cell loss and dysfunction in type 2 diabetes. Downregulation of miR-30d has been observed in the islets of diabetic mice. To investigate the in vivo function of miR-30d in pancreatic beta cells, we generated the transgenic mice that overexpressed miR-30d specifically in the pancreatic beta cells. Compared to wild type mice, the transgenic mice that overexpressed miR-30d resulted in hyperglycemia and glucose intolerance with reduced beta-cell mass and insulin production following high fat diet treatment. Strikingly, loss of beta-cell mass was partially due to beta-cell dedifferentiation to glucagon-producing alpha-cells, resulted in increased plasma glucagon level. The transcriptomic analysis combined with bioinformatic analysis of islets isolated from transgenic verses control mice identified connective tissue growth factor (CTGF) and Cyclin E2 as miR-30d potential targets. Moreover, several β-cell disallowed genes (e.g., MCT4/SLC16A3, LDHA) were observed upregulated in transgenic mice, which have been reported as positive markers of dedifferentiated human β-cells from type 2 diabetic patients. Taken together, miR-30d plays an essential role in maintaining mature beta-cell identity. Disclosure X. Tang: None. Funding National Institutes of Health

A Novel Dual-Function GLP-1 Analogue Prevents Type 1 Diabetes Onset in NOD Mice by Controlling the Balance of Treg/Th17 and Th2/Th1

Background: Type 1 diabetes is a polygenic disease that is influenced by environmental factors. A cure is not available, and patients depend on lifelong insulin injections. There is no clinical drug that can both promote the proliferation of islet beta cells and eliminate the immune attack of autoreactive T cells on beta cells. This study aimed to design a new bifunctional fusion polypeptide that is expected to have a good effect on type 1 diabetes. Methods: Our previous studies found that VP peptide, an immunomodulatory peptide that can eliminate inflammatory microenvironment, and EGLP-1, a structural analogue of GLP-1 that has the effect of protection of the pancreatic beta cells. So, we combined VP peptide and EGLP-1 to form a novel bifunctional peptide P30, hoping that VP may be an appropriate target as an immuno-modulatory arm, while GLP-1 analog may be suitable as a beta cell protective arm in combination therapy for T1D. The protective effect of each group on islets was determined by H&E and immunofluorescence, and the proportion of Treg/Th17 and Th2/Th1 cells were detected by flow cytometry. Findings: Our data demonstrate that P30 treatment significantly reduced the morbidity and mortality in NOD mice and alleviated pancreatitis symptoms. In addition, P30 has the function of enhancing immunoregulation involving increasing the ratio of Treg/Th17 cells and Th2/Th1 cells. Interpretation: These findings indicate that P30 represents a very promising strategy for prevention type 1 diabetes in mouse models of NOD. Funding: National Natural Science Foundation of China (Grant No. 81570696 and No. 31270985); Qing Lan Project; Program for Jiangsu Province Innovative Research Team; the Fundamental Research Funds for the Central Universities (2016ZPY010, 2632017PY06). Declaration of Interest: The authors declare that there is no duality of interest associated with this manuscript. Ethical Approval: All studies were approved by the Institutional Animal Care and Use Committee of China Pharmaceutical University (Nanjing, China).

Naringin Ameliorates Streptozotocin-Induced Diabetes through Forkhead Box M1-Mediated Beta Cell Proliferation

Background: Adult pancreatic beta cells, though quiescent, can proliferate in response to physiological need. This inherent character is used in exploring the possibilities of expanding the beta cell mass in the treatment of diabetes. Forkhead box M1 (FoxM1) transcription factor is an important regulator in the proliferation and survival of adult beta cell mass. Naringin, a flavanone glycoside, is reported to have antidiabetic activity and exhibited an increase in insulin levels in diabetic animals. Objectives: The present study tried to evaluate the role of naringin in the regulation of FoxM1 in the pancreas of diabetic rats and to reascertain its antilipidemic and antioxidant properties. Methods: Diabetes was induced in male rats using streptozotocin and treated with naringin (100 mg/kg) orally for 4 and 8 weeks. Serum biochemical parameters, insulin, gene and protein expression of FoxM1, and antioxidant markers in rat pancreas were analyzed. Results: Naringin administration reduced the blood sugar, urea, creatinine, and cholesterol values and improved the pancreatic antioxidant status in diabetic rats. Naringin-treated diabetic rats showed a significant increase in mRNA and protein expression of FoxM1 compared to the diabetic control rats, indicating regeneration of cells. It also increased the insulin immunopositive cells, indicating functional beta cells. Conclusion: Naringin was found to upregulate the FoxM1 transcription factor in diabetic animals, which influenced the proliferation and functional status of beta cells.

The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes.

Endoplasmic reticulum (ER) stress in beta cells induces a signaling network called the unfolded protein response (UPR), which plays a dual role in diabetes. A key regulator of ER-stress and UPR, the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis to compensatory pancreatic beta cell proliferation in diabetes has not been studied. Here, we detected significantly lower levels of ORMDL3 mRNA in leukocytes of peripheral blood specimens from type 1 diabetes (T1D) children, compared to normal children. Moreover, these ORMDL3 levels in T1D children exhibited further decreases upon follow-up. ORMDL3 levels in islets from NOD mice, a mouse model for T1D in humans, showed a mild increase before diabetes onset, but a gradual decrease subsequently. In high glucose culture, beta cell proliferation, but not apoptosis, was increased by overexpression of ORMDL3 levels, likely mediated by its downstream factor ATF6. Mechanistically, ORMDL3 transcriptionally activated ATF6, which was confirmed in a promoter reporter assay. Together, our data suggest that ORMDL3 may increase beta cell proliferation through ATF6 as an early compensatory change in response to diabetes.

Bromodomain inhibition instructs macrophages to promote beta cell proliferation and suppress autoimmune diabetes

Abstract A hallmark of autoimmune type 1 diabetes (T1D) is the decline of beta cell mass. Any regimen to promote beta cell expansion will have a great therapeutic promise. We have previously demonstrated that an epigenetic inhibitor targeting BET proteins (I-BET) promotes beta cell proliferation in an animal model of T1D. However, the underlying mechanisms remains unknown. Using both gain-of and loss-of function assays, we demonstrate that macrophages play an indispensable role in I-BET-elicited beta cell proliferation. In vivo ablation of macrophages significantly abolishes, while the supplementation of I-BET preconditioned macrophages enhances, I-BET induced beta cell proliferation. On a molecular level, elevated production of platelet-derived growth factor (PDGF) in I-BET treated macrophages mobilizes PDGFR signaling in beta cells. In summary, these findings reveal a novel strategy to expand beta cells by harnessing macrophages.

Estradiol 17-β Induces Pancreatic Beta-Cell Proliferation through Distinct Estrogen Receptors in a Glucose Dependent Manner

Background: Estradiol 17-beta (E2) enhances the function and survival of pancreatic beta-cells but its clinical use has been questioned due to concerns regarding oncogenic potential and feminizing effects in males. The G-protein coupled estrogen receptor (GPER), expressed in pancreatic islets, exhibits estrogenic beta-cell protective effects, without the feminizing effects of the nuclear ERs. Here, we examine the outcome of selective activation of the three estrogen receptors ERα, ERβ and GPER on replication, in human pancreatic islets and the INS1-E rodent β-cell line, under hyperglycemic conditions such as occur in diabetes mellitus. Methods: Pancreatic islets from nine human donors and INS1-E cells were grown at glucose concentrations of 11mM and 25mM and examined for DNA synthesis using 3[H]-thymidine incorporation, after 24 hour treatment with E2 and specific agonists for ERα, ERβ and GPER (PPT 10nM, DPN 10nM and G1 100nM, respectively). Expression of the three ERs was examined by qRT-PCR. Results: In human islets, under glucose 11mM, agonists to ERα and GPER induced a significant ~2 folds increase in 3[H]-thymidine incorporation (p

Nuclear receptor TLX regulates islet beta cell proliferation via E2F6

Both type 1 and type 2 diabetes are associated with loss of functional beta cell mass, and strategies to restore beta cells are urgently needed. We reported previously that overexpression of the nuclear receptor TLX induces beta cell proliferation, but the underlying molecular mechanism has not been defined. Here, we identified direct targets of TLX in beta cells at the genome-wide level by ChIP-Seq. These targets include a cadre of regulators that are known to be critical for proliferation. Among these ChIP targets, E2F6 was tightly associated with the cell cycle modules, and thus, we further analyzed E2F6 expression and function in beta cells. We showed that E2F6 is strongly downregulated by TLX, and its expression inhibits beta cell proliferation. Moreover, coexpression of E2F6 with TLX partially abrogated the proliferative effects of TLX. These results strongly suggest that TLX acts through E2F6 to regulate beta cell proliferation. Together, the results of this study reveal a direct interaction between TLX and E2F6 and suggest new targets for the expansion of functional beta cell mass.

The direct effect of lobeglitazone, a new thiazolidinedione, on pancreatic beta cells: A comparison with other thiazolidinediones

AimsThe direct effects of thiazolidinediones (TZDs) on pancreatic beta cells have been controversial. The aim of this study was to find out whether a novel TZD, lobeglitazone, has beneficial effects on pancreatic beta cells and db/db mice compared to those of other TZDs. MethodsINS-1 cells were incubated at a high-glucose concentration with various concentrations of troglitazone, rosiglitazone, pioglitazone, and lobeglitazone. Apoptosis and proliferation of beta cells, markers for ER stress and glucose-stimulated insulin secretion (GSIS) were assessed. In addition, C57BL/6 db/db mice were treated with pioglitazone or lobeglitazone for 4 weeks, and metabolic parameters and the configuration of pancreatic islets were also examined. ResultsLobeglitazone and other TZDs decreased INS-1 cell apoptosis in high-glucose conditions. Lobeglitazone and other TZDs significantly decreased hyperglycemia-induced increases in ER stress markers and increased GSIS. Metabolic parameters showed greater improvement in db/db mice treated with pioglitazone and lobeglitazone than in control mice. Islet size, cell proliferation, and beta cell mass were increased, and collagen surrounding the islets was decreased in treated mice. ConclusionsLobeglitazone showed beneficial effects on beta cell survival and function against hyperglycemia. The prosurvival and profunction effects of lobeglitazone were comparable to those of other TZDs.

Sfrp5 increases glucose-stimulated insulin secretion in the rat pancreatic beta cell line INS-1E.

Previous studies reported that secreted frizzled-related protein-5 (Sfrp5) decreases beta cell proliferation and increases fasting insulin levels, but studies on direct effects of Sfrp5 on insulin secretion and its underlying mechanisms are missing. This study examined effects of Sfrp5 on (i) beta cell viability and proliferation, (ii) basal and glucose-stimulated insulin secretion and (iii) canonical and non-canonical Wnt signalling pathways. We incubated rat INS-1E cells with 0.1, 1 or 5 μg/ml recombinant Sfrp5 for 24h. We measured basal and glucose-stimulated insulin secretion at glucose concentrations of 2.5 and 20 mmol/l. Phosphorylated and total protein content as well as mRNA levels of markers of cell proliferation, canonical and non-canonical Wnt signalling pathways were examined using Western blotting and real-time PCR. Differences between treatments were analysed by repeated measurement one-way ANOVA or Friedman’s test followed by correction for multiple testing using the Benjamini-Hochberg procedure. At 5 μg/ml, Sfrp5 reduced mRNA levels of cyclin-B1 by 25% (p<0.05). At 1 and 5 μg/ml, Sfrp5 increased glucose-stimulated insulin secretion by 24% and by 34% (both p<0.05), respectively, but had no impact on basal insulin secretion. Sfrp5 reduced the phosphorylation of the splicing forms p46 and p54 of JNK by 39% (p<0.01) and 49% (p<0.05), respectively. In conclusion, Sfrp5 reduced markers of cell proliferation, but increased in parallel dose-dependently glucose-stimulated insulin secretion in INS-1E cells. This effect is likely mediated by reduced JNK activity, an important component of the non-canonical Wnt signalling pathway.

Cellular proliferation in mouse and human pancreatic islets is regulated by serpin B13 inhibition and downstream targeting of E-cadherin by cathepsin L.

We previously reported that exposure to antibodies neutralising serpin B13, a protease inhibitor expressed in exocrine pancreatic ducts, promotes beta cell proliferation, underscoring the importance of a functional relationship between exocrine and endocrine pancreas. The aim of the present study was to identify the molecular events that link inhibition of serpin B13 to islet cell proliferation. We used an in vitro culture system consisting of isolated pancreatic islets, an extract of pancreatic ductal epithelium and a monoclonal antibody (mAb) to serpin B13 or IgG isotype control. In vivo studies involved treatment of mice with these mAbs. The catalytic activity of cathepsin L (CatL), a cysteine protease target of serpin B13, was augmented in the pancreas of mice injected with serpin B13 mAb. Furthermore, the addition of serpin B13 mAb to the islets, together with the pancreatic ductal epithelium lysate, caused CatL-dependent cleavage of E-cadherin and concomitant upregulation of REG genes, ultimately leading to beta cell proliferation. Direct blockade of E-cadherin with mAb also markedly enhanced REG gene induction, while chemical inhibition of β-catenin, a binding target of E-cadherin, prevented the serpin B13 mAb-induced upregulation of REG genes. Our work implicates the CatL-E-cadherin-REG pathway in the regulation of islet cell proliferation in response to signals generated in exocrine pancreatic tissue and demonstrates that protease activity may promote adaptive changes in the islets. Microarray data that support the findings of this study have been deposited in Gene Expression Omnibus (GEO) with the accession no. GSE125151.

Relationship between serum osteocalcin/undercarboxylated osteocalcin and type 2 diabetes: a systematic review/meta-analysis study protocol

IntroductionThe global burden of type 2 diabetes (T2DM) is steadily increasing. Experimental studies have demonstrated that a novel hormone secreted by bone cells, osteocalcin (OC), can stimulate beta-cell proliferation and...

Glucocorticoids and checkpoint tyrosine kinase inhibitors stimulate rat pancreatic beta cell proliferation differentially.

Cell therapy for diabetes could benefit from the identification of small-molecule compounds that increase the number of functional pancreatic beta cells. Using a newly developed screening assay, we previously identified glucocorticoids as potent stimulators of human and rat beta cell proliferation. We now compare the stimulatory action of these steroid hormones to a selection of checkpoint tyrosine kinase inhibitors that were also found to activate the cell cycle-in beta cells and analyzed their respective effects on DNA-synthesis, beta cell numbers and expression of cell cycle regulators. Our data using glucocorticoids in combination with a receptor antagonist, mifepristone, show that 48h exposure is sufficient to allow beta cells to pass the cell cycle restriction point and to become committed to cell division regardless of sustained glucocorticoid-signaling. To reach the end-point of mitosis another 40h is required. Within 14 days glucocorticoids stimulate up to 75% of the cells to undergo mitosis, which indicates that these steroid hormones act as proliferation competence-inducing factors. In contrast, by correlating thymidine-analogue incorporation to changes in absolute cell numbers, we show that the checkpoint kinase inhibitors, as compared to glucocorticoids, stimulate DNA-synthesis only during a short time-window in a minority of cells, insufficient to give a measurable increase of beta cell numbers. Glucocorticoids, but not the kinase inhibitors, were also found to induce changes in the expression of checkpoint regulators. Our data, using checkpoint kinase-specific inhibitors further point to a role for Chk1 and Cdk1 in G1/S transition and progression of beta cells through the cell cycle upon stimulation with glucocorticoids.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.

GLP-1 mediated improvement of the glucose tolerance in the T2DM GK rat model after massive jejunal resection

ObjectiveThe aim of this study was to clarify the role of the middle gut in the entero-pancreatic axis modification that leads to glucose improvement in the Goto-Kakizaki (GK) rat as a non-obese T2DM model. BackgroundBariatric surgery is considered an assured solution for type 2 Diabetes (T2DM). Enterohormones such as ghrelin, gastric inhibitory polypeptide and mainly glucagon-like peptide-1 (GLP-1) were recognized as key players in the physiophathological mechanisms associated with entero-pancreatic axis regulation and glucose tolerance improvement. However, the influence of anatomical arrangements post-bariatric surgery on this axis is still debatable. MethodTo this purpose, 50% of small intestine resections were performed on GK rats (n = 6), preserving the proximal half of the jejunum and the ileum (IR50). Phenotypic and functional changes, such as performance in oral glucose tolerance tests, ileal release of GLP-1, beta-cell sensitivity to GLP-1, beta-cell mass, and turnover were characterized in IR50 and the surgical control group (Sham). ResultsThe glucose tolerance was improved and ileal release of GLP-1 was enhanced four weeks after IR50 versus the control group rats. Beta-cell mass, beta-cell proliferation, and beta-cell sensitivity to GLP-1 were also increased in the pancreas of IR50 versus the control group rats. Conclusionthe jejunal exclusion increases beta-cell-mass and improves glucose tolerance by increasing in GLP-1 expression and number of receptors via the entero-pancreatic axis.