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 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.

Pregnancy restores insulin secretion from pancreatic islets in cafeteria diet-induced obese rats

2010 ◽  
Vol 298 (2) ◽  
pp. R320-R328 ◽  
Author(s):  
E. C. Vanzela ◽  
R. A. Ribeiro ◽  
C. A. Machado de Oliveira ◽  
F. B. Rodrigues ◽  
M. L. Bonfleur ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Oxidation ◽  
Cafeteria Diet ◽  
Mrna Levels ◽  
Diet Induced Obesity ◽  
Obese Rats ◽  
Intracellular Ca ◽  
Depolarizing Agents

Insulin resistance during pregnancy is counteracted by enhanced insulin secretion. This condition is aggravated by obesity, which increases the risk of gestational diabetes. Therefore, pancreatic islet functionality was investigated in control nonpregnant (C) and pregnant (CP), and cafeteria diet-fed nonpregnant (Caf), and pregnant (CafP) obese rats. Isolated islets were used for measurements of insulin secretion (RIA), NAD(P)H production (MTS), glucose oxidation (14CO2 production), intracellular Ca2+ levels (fura-2 AM), and gene expression (real-time PCR). Impaired glucose tolerance was clearly established in Caf and CafP rats at the 14th wk on a diet. Insulin secretion induced by direct depolarizing agents such as KCl and tolbutamide and increasing concentrations of glucose was significantly reduced in Caf, compared with C islets. This reduction was not observed in islets from CP and CafP rats. Accordingly, the glucose oxidation and production of reduced equivalents were increased in CafP islets. The glucose-induced Ca2+ increase was significantly lower in Caf and higher in CafP, compared with all other groups. CP and CafP islets demonstrated an increased Ca2+ oscillation frequency, compared with both C and Caf islets, and the amplitude of oscillations was augmented in CafP, compared with Caf islets. In addition, Cavα1.2 and SERCA2a mRNA levels were reduced in Caf islets. Cavα1.2, but not SERCA2a, mRNA was normalized in CafP islets. In conclusion, cafeteria diet-induced obesity impairs insulin secretion. This alteration is related to the impairment of Ca2+ handling in pancreatic islets, in especial Ca2+ influx, a defect that is reversed during pregnancy allowing normalization of insulin secretion.

scholarly journals Somatostatin Receptor Subtype-2-Deficient Mice with Diet-Induced Obesity Have Hyperglycemia, Nonfasting Hyperglucagonemia, and Decreased Hepatic Glycogen Deposition

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3887-3899 ◽  
Author(s):  
Vandana Singh ◽  
Carsten Grötzinger ◽  
Krzysztof W. Nowak ◽  
Sylvia Zacharias ◽  
Eva Göncz ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Hepatic Glycogen ◽  
Receptor Subtype ◽  
Isolated Pancreatic Islets ◽  
Diet Induced Obesity ◽  
Hepatic Glucose ◽  
Somatostatin Receptor Subtype 2 ◽  
Deficient Mice

Hypersecretion of glucagon contributes to abnormally increased hepatic glucose output in type 2 diabetes. Somatostatin (SST) inhibits murine glucagon secretion from isolated pancreatic islets via somatostatin receptor subtype-2 (sst2). Here, we characterize the role of sst2 in controlling glucose homeostasis in mice with diet-induced obesity. Sst2-deficient (sst2−/−) and control mice were fed high-fat diet for 14 wk, and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid contents were quantified enzymatically and visualized histomorphologically. Enzymes regulating glycogen and lipid synthesis and breakdown were measured by real-time PCR and/or Western blot. Gluconeogenesis and glycogenolysis were determined from isolated primary hepatocytes and glucagon or insulin secretion from isolated pancreatic islets. Nonfasting glucose, glucagon, and fasting nonesterified fatty acids of sst2−/− mice were increased. Inhibition of glucagon secretion from sst2-deficient pancreatic islets by glucose or somatostatin was impaired. Insulin less potently reduced blood glucose concentration in sst2-deficient mice as compared with wild-type mice. Sst2-deficient mice had decreased nonfasting hepatic glycogen and lipid content. The activity/expression of enzymes controlling hepatic glycogen synthesis of sst2−/− mice was decreased, whereas enzymes facilitating glycogenolysis and lipolysis were increased. Somatostatin and an sst2-selective agonist decreased glucagon-induced glycogenolysis, without influencing de novo glucose production using cultured primary hepatocytes. This study demonstrates that ablation of sst2 leads to hyperglucagonemia. Increased glucagon concentration is associated with impaired glucose control in sst2−/− mice, resulting from decreased hepatic glucose storage, increased glycogen breakdown, and reduced lipid accumulation. Sst2 may constitute a therapeutic target to lower hyperglucagonemia in type 2 diabetes.

scholarly journals The possible mechanisms by which phanoside stimulates insulin secretion from rat islets

2007 ◽  
Vol 192 (2) ◽  
pp. 389-394 ◽  
Author(s):  
Nguyen Khanh Hoa ◽  
Åke Norberg ◽  
Rannar Sillard ◽  
Dao Van Phan ◽  
Nguyen Duy Thuan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
B Cells ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Pertussis Toxin ◽  
Insulin Response ◽  
Gk Rat ◽  
Isolated Pancreatic Islets ◽  
Gk Rats ◽  
Rat Islets

We recently showed that phanoside, a gypenoside isolated from the plant Gynostemma pentaphyllum, stimulates insulin secretion from rat pancreatic islets. To study the mechanisms by which phanoside stimulates insulin secretion. Isolated pancreatic islets of normal Wistar (W) rats and spontaneously diabetic Goto-Kakizaki (GK) rats were batch incubated or perifused. At both 3.3 and 16.7 mM glucose, phanoside stimulated insulin secretion several fold in both W and diabetic GK rat islets. In perifusion of W islets, phanoside (75 and 150 μM) dose dependently increased insulin secretion that returned to basal levels when phanoside was omitted. When W rat islets were incubated at 3.3 mM glucose with 150 μM phanoside and 0.25 mM diazoxide to keep K-ATP channels open, insulin secretion was similar to that in islets incubated in 150 μM phanoside alone. At 16.7 mM glucose, phanoside-stimulated insulin secretion was reduced in the presence of 0.25 mM diazoxide (P<0.01). In W islets depolarized by 50 mM KCl and with diazoxide, phanoside stimulated insulin release twofold at 3.3 mM glucose but did not further increase the release at 16.7 mM glucose. When using nimodipine to block L-type Ca2+ channels in B-cells, phanoside-induced insulin secretion was unaffected at 3.3 mM glucose but decreased at 16.7 mM glucose (P<0.01). Pretreatment of islets with pertussis toxin to inhibit exocytotic Ge-protein did not affect insulin response to 150 μM phanoside. Phanoside stimulated insulin secretion from Wand GK rat islets. This effect seems to be exerted distal to K-ATP channels and L-type Ca2+ channels, which is on the exocytotic machinery of the B-cells.

Increased L-CPT-1 activity and altered gene expression in pancreatic islets of malnourished adult rats: a possible relationship between elevated free fatty acid levels and impaired insulin secretion

2008 ◽  
Vol 19 (2) ◽  
pp. 85-90 ◽  
Author(s):  
Marise Auxiliadora de Barros Reis ◽  
Vanessa Cristina Arantes ◽  
Daniel Andrade Cunha ◽  
Márcia Queiroz Latorraca ◽  
Marcos Hikari Toyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Pancreatic Islets ◽  
Adult Rats ◽  
Altered Gene Expression ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin ◽  
Altered Gene

Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats

2013 ◽  
Vol 430 (2) ◽  
pp. 676-682 ◽  
Author(s):  
Miho Tsuchiya ◽  
Yasuko Manabe ◽  
Kenichiro Yamada ◽  
Yasuro Furuichi ◽  
Masahiro Hosaka ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Diabetic Rats ◽  
Insulin Content ◽  
Chronic Exercise

Tetracaine stimulates insulin secretion through the mobilization of Ca2+ from thapsigargin- and IP3-insensitive Ca2+ reservoir in pancreatic β-cells

2000 ◽  
Vol 78 (6) ◽  
pp. 462-468 ◽  
Author(s):  
José Roberto Bosqueiro ◽  
Everardo Magalhães Carneiro ◽  
Silvana Bordin ◽  
Antonio Carlos Boschero
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Isolated Islets ◽  
Inositol Triphosphate ◽  
Free Medium ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Isolated Pancreatic Islets ◽  
High Concentrations

The effect of tetracaine on 45Ca efflux, cytoplasmic Ca2+ concentration [Ca2+]i, and insulin secretion in isolated pancreatic islets and β-cells was studied. In the absence of external Ca2+, tetracaine (0.1-2.0 mM) increased the 45Ca efflux from isolated islets in a dose-dependant manner. Tetracaine did not affect the increase in 45Ca efflux caused by 50 mM K+ or by the association of carbachol (0.2 mM) and 50 mM K+. Tetracaine permanently increased the [Ca2+]i in isolated β-cells in Ca2+-free medium enriched with 2.8 mM glucose and 25 µM D-600 (methoxiverapamil). This effect was also observed in the presence of 10 mM caffeine or 1 µM thapsigargin. In the presence of 16.7 mM glucose, tetracaine transiently increased the insulin secretion from islets perfused in the absence and presence of external Ca2+. These data indicate that tetracaine mobilises Ca2+ from a thapsigargin-insensitive store and stimulates insulin secretion in the absence of extracellular Ca2+. The increase in 45Ca efflux caused by high concentrations of K+ and by carbachol indicates that tetracaine did not interfere with a cation or inositol triphosphate sensitive Ca2+ pool in β-cells.

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.

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