scholarly journals High β-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice

2009 ◽  
Vol 296 (6) ◽  
pp. E1251-E1261 ◽  
Author(s):  
Elodie Masson ◽  
Shlomit Koren ◽  
Fathima Razik ◽  
Howard Goldberg ◽  
Edwin P. Kwan ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Insulin Content ◽  
Β Cell ◽  
Interacting Protein ◽  
Isolated Pancreatic Islets ◽  
Thioredoxin Interacting Protein ◽  
Deficient Mice

Thioredoxin-interacting protein (TxNIP) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets, and recent studies suggest that TxNIP is a proapoptotic factor in β-cells that may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic β-cell mass and/or insulin secretion. TxNIP-deficient (Hcb-19/TxNIP−/−) mice had lower baseline glycemia, higher circulating insulin concentrations, and higher total pancreatic insulin content and β-cell mass than control mice (C3H). Hcb-19/TxNIP−/− did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although β-cell mass remained higher in Hcb-19/TxNIP−/− mice compared with C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1β, interferon-γ, and tumor necrosis factor-α. Furthermore, when corrected for insulin content, isolated pancreatic islets from TxNIP−/− mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of β-cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be because of an increase in β-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced β-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.

Abstract 63: ACE2 Deficiency Reduces Insulin Content of Isolated Pancreatic Islets and Plasma Insulin Concentrations Post-Glucose Challenge in Obese C57BL/6 Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Robin C Shoemaker ◽  
Lisa A Cassis
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Plasma Insulin ◽  
Insulin Content ◽  
Isolated Pancreatic Islets ◽  
Diet Induced Obesity ◽  
Glucose Challenge ◽  
Ace2 Gene ◽  
Deficient Mice

Objective: Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Angiotensin converting enzyme 2 (ACE2) negatively regulates the RAS by catabolizing angiotensin II (AngII). Preliminary data indicate that ACE2 deficient mice display impairments in glucose homeostasis at 8 weeks of age. We tested the hypothesis that ACE2 deficiency promotes the development of glucose intolerance and β-cell dysfunction in mice with diet-induced obesity. Methods and Results: Male Ace2 +/y or -/y mice were fed a low fat (LF, 10% kcal as fat) or high fat (HF, 60% kcal as fat) diet for 5 or 17 weeks. After 5 weeks, plasma insulin concentrations (0, 30 min) following a glucose challenge were significantly greater in HF versus ( vs) LF-fed mice. However, glucose-stimulated increases in plasma insulin concentrations were decreased in HF-fed ACE2 deficient mice compared to controls (2.96 ± 0.18 vs 4.44 ± 0.40 ng/ul, respectively; P<0.01). Surprisingly, isolated pancreatic islets from HF-fed mice of either genotype released similar concentrations of insulin in response to glucose. However, mRNA abundance of insulin was significantly reduced in islets from HF-fed Ace2 -/y compared to +/y mice (1.76 ± 0.17 vs 2.54 ± 0.18 insulin/18S ratio; P<0.05). After 17 weeks, the plasma insulin response to glucose was further reduced in the HF-fed ACE2 deficient mice compared to controls (8.07 ± 0.98 vs 13.90 ± 1.10 ng/ul; P<0.01). Further, LF-fed ACE2 deficient mice also displayed reductions in plasma glucose-stimulated insulin concentrations (1.92 ± 0.98 vs 3.09 ± 0.98 ng/ul; P<0.01). Islets from HF-fed wild type mice displayed reduced ACE2 gene expression compared to LF (0.069 ± 0.009 vs 0.169 ± 0.01, ACE2/18S ratio; P<0.001) and AngII totally suppressed islet glucose-stimulated insulin secretion compared to vehicle (-0.16 ± 0.18 vs 0.9 ± 0.26, fold change over basal; P<0.05). Conclusions: These results demonstrate that ACE2 deficiency promotes the development of T2D by regulating islet insulin content. Moreover, diet-induced obesity reduces islet ACE2 gene expression with augmented AngII-induced impairment of insulin secretion.

scholarly journals Cytokine-mediated β-cell damage in PARP-1-deficient islets

2012 ◽  
Vol 303 (2) ◽  
pp. E172-E179 ◽  
Author(s):  
Teresa Andreone ◽  
Gordon P. Meares ◽  
Katherine J. Hughes ◽  
Polly A. Hansen ◽  
John A. Corbett
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Cell Death ◽  
Insulin Secretion ◽  
Cell Damage ◽  
Β Cell ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Parp 1 ◽  
Deficient Mice

Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from β-nicotinamide adenine dinucleotide (NAD+). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated β-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.

scholarly journals Erratum to: “Dehydroepiandrosterone increases β-cell mass and improves the glucose-induced insulin secretion by pancreatic islets from aged rats” [FEBS Lett. 580 (2006) 285-290]

FEBS Letters ◽  
2006 ◽  
Vol 580 (5) ◽  
pp. 1528-1528
Author(s):  
Mayrin C. Medina ◽  
Lílian C. Souza ◽  
Luciana C. Caperuto ◽  
Gabriel F. Anhê ◽  
Angélica M. Amanso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Aged Rats ◽  
Β Cell

scholarly journals Dehydroepiandrosterone increases β-cell mass and improves the glucose-induced insulin secretion by pancreatic islets from aged rats

FEBS Letters ◽  
2005 ◽  
Vol 580 (1) ◽  
pp. 285-290 ◽  
Author(s):  
Mayrin C. Medina ◽  
Lílian C. Souza ◽  
Luciana C. Caperuto ◽  
Gabriel F. Anhê ◽  
Angélica M. Amanso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Aged Rats ◽  
Β Cell

scholarly journals Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep

2013 ◽  
Vol 304 (4) ◽  
pp. E352-E362 ◽  
Author(s):  
Monika M. Gadhia ◽  
Anne M. Maliszewski ◽  
Meghan C. O'Meara ◽  
Stephanie R. Thorn ◽  
Jinny R. Lavezzi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Cell Mass ◽  
Late Gestation ◽  
Insulin Content ◽  
Acid Mixture ◽  
Β Cell ◽  
Fetal Sheep ◽  
Glucose Stimulated Insulin Secretion

Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10–14 days during late gestation to target a 25–50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group ( P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) ( P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group ( P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell.

scholarly journals Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

2009 ◽  
Vol 297 (3) ◽  
pp. E695-E707 ◽  
Author(s):  
Richard W. Gelling ◽  
Patricia M. Vuguin ◽  
Xiu Quan Du ◽  
Lingguang Cui ◽  
John Rømer ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Insulin Content ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucagon Receptor ◽  
Pancreatic Insulin ◽  
Pancreatic Insulin Content

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

scholarly journals Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

2014 ◽  
Vol 306 (1) ◽  
pp. E58-E64 ◽  
Author(s):  
Xiaochuan Chen ◽  
Alice S. Green ◽  
Antoni R. Macko ◽  
Dustin T. Yates ◽  
Amy C. Kelly ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Chronic Exposure ◽  
Uncoupling Protein ◽  
Adrenergic Blockade ◽  
Protein Subunit ◽  
Β Cell ◽  
Fetal Sheep ◽  
Isolated Pancreatic Islets ◽  
Glucose Stimulated Insulin Secretion

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater ( P < 0.05) plasma NE concentrations and exhibited hyperglycemia ( P < 0.01) and hypoinsulinemia ( P < 0.01) compared with controls. GSIS during the NE infusion was also reduced ( P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater ( P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower ( P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets.

scholarly journals β Cell GHS-R Regulates Insulin Secretion and Sensitivity

2021 ◽  
Vol 22 (8) ◽  
pp. 3950
Author(s):  
Geetali Pradhan ◽  
Chia-Shan Wu ◽  
Daniel Villarreal ◽  
Jong Han Lee ◽  
Hye Won Han ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
Fluorescent Protein ◽  
Therapeutic Potential ◽  
Fasting Blood Glucose ◽  
Β Cell ◽  
Growth Hormone Secretagogue ◽  
Isolated Pancreatic Islets

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

scholarly journals Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome

2012 ◽  
Vol 16 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Christine M. Oslowski ◽  
Takashi Hara ◽  
Bryan O'Sullivan-Murphy ◽  
Kohsuke Kanekura ◽  
Simin Lu ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Β Cell ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

scholarly journals Participation of Akt, Menin, and p21 in Pregnancy-Induced β-Cell Proliferation

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 847-855 ◽  
Author(s):  
Elizabeth Hughes ◽  
Carol Huang
Keyword(s):  
Cell Proliferation ◽  
Pancreatic Islets ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Signaling Molecules ◽  
Β Cell ◽  
Inhibitory Protein ◽  
Isolated Pancreatic Islets ◽  
Expression Levels ◽  
Relative Contribution

β-Cell mass increases during pregnancy to accommodate for insulin resistance. This increase is mainly due to β-cell proliferation, a process that requires intact prolactin receptor (Prlr) signaling. Signaling molecules that are known to regulate β-cell proliferation include Jak2, Akt, the tumor suppressor menin, and cell cycle proteins. Whether these pathways are involved in prolactin-mediated β-cell proliferation is unknown. Using the heterozygous prolactin receptor-null (Prlr+/−) mice, we isolated pancreatic islets from both Prlr+/+ and Prlr+/− mice on d 0 and 15 of pregnancy and examined the expression levels of these signaling molecules. In the wild-type mice (Prlr+/+), both phospho-Jak2 and phospho-Akt expression in pancreatic islets increased during pregnancy, which were attenuated in the pregnant Prlr+/− mice. During pregnancy, menin expression was reduced by 50 and 20% in the Prlr+/+ and the Prlr+/− mice, respectively, and the pregnant Prlr+/− mice had higher islet p18 levels than the Prlr+/+ mice. Interestingly, between d 0 and 15 of pregnancy, expression of cyclin inhibitory protein p21cip was increased in the Prlr+/+ mice, but this increase was blunted in the Prlr+/− mice. Lastly, we did not find any difference in the expression levels of cyclins D1, D2, and inhibitory kinases between the pregnant Prlr+/+ and Prlr+/− mice. Therefore, we conclude that during pregnancy, placental hormones act through the prolactin receptor to increase β-cell mass by up regulating β-cell proliferation by engaging Jak2, Akt, menin/p18, and p21. Future studies will determine the relative contribution of these molecules in maintaining normal glucose homeostasis during pregnancy.

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