scholarly journals Insulin Secretion Is Increased in Pancreatic Islets of Neuropeptide Y-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5716-5723 ◽  
Author(s):  
Yumi Imai ◽  
Hiral R. Patel ◽  
Evan J. Hawkins ◽  
Nicolai M. Doliba ◽  
Franz M. Matschinsky ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Neuropeptide Y ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Basal Insulin ◽  
High Fat ◽  
Y1 Receptor ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion ◽  
Deficient Mice

Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y1 receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y1 receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y1 receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis

2006 ◽  
Vol 291 (5) ◽  
pp. E982-E994 ◽  
Author(s):  
Laura E. Parton ◽  
Patrick J. McMillen ◽  
Yingnian Shen ◽  
Elizabeth Docherty ◽  
Erin Sharpe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Basal Insulin ◽  
Regulatory Element ◽  
Dominant Negative ◽  
Gene Profiling ◽  
Rat Islets ◽  
Zdf Rat ◽  
Element Binding Protein ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control ( fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected ( Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca2+ channel subunit α1D, CPT2, SUR2, rab9, syt13), or inhibited ( syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1α (HNF1α), HNF3β/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

scholarly journals SUN-658 CHL1 Increases Insulin Secretion&Negatively Regulates the Poliferation of Pancreatic β Cell

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Tao Yang ◽  
Qi Fu ◽  
Hemin Jiang
Keyword(s):  
Cell Cycle ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Nod Mice ◽  
Pancreatic Β Cell ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Min6 Cells

Abstract CHL1 Increases Insulin Secretion & Negatively Regulates The Poliferation Of Pancreatic β Cell Objective: CHL1 belongs to neural recognition molecules of the immunoglobulin superfamily, is mainly expressed in the nervous system. CHL1 is involved in neuronal migration, axonal growth, and dendritic projection. RNA sequencing of single human islet cells confirmed that CHL1 had an expression difference in β cells of type 2 diabetes and healthy controls. However, whether CHL1 gene regulates islet function remained to be explored. Methods: PCR and Western Blot were applied to investigate the tissue distribution of CHL1 in wild-type C57BL/6J mice. The islet expression of CHL1 gene was observed in pancreatic islets of NOD mice and high-fat-diet C57BL/6J mice of different ages. MIN6 cells with siRNA to silence CHL1 or with lentivirus to overexpress CHL1 were constructed. Effects of the gene on proliferation, apoptosis, cell cycle and insulin secretion were determined by using CCK8, EdU, TUNEL, AV/PI, GSIS, electron microscopy and flow cytometry. Results: CHL1 was localized on the cell membrane and expressed in the nervous system, islet of pancreas and gastrointestinal tract. CHL1 was hypoexpressed in the pancreatic islets of obese mice, hyperexpressed in the pancreatic islets of NOD mice and in vitro after treated with cytokines. After silencing CHL1 in MIN6 cells, insulin secretion decreased in 20 mM glucose with down-regulation of INS1, SLC2A2 gene, and transmission electron microscope showed the number of insulin secretary granules <50nm from the cell membrane was significantly reduced. Silencing of CHL1 in MIN6 cells induced cell proliferation, reduced apoptosis rate, prolonged the S phase of cell cycle and shortened the G1 phase with downregulated expression of p21, p53 and up-regulated expression of cyclin D1, opposite results were found in CHL1 over-expressing MIN6 cells. Proliferation induced by silencing of CHL1 was inhibited by ERK inhibitor (PD98059), which indicates that ERK pathway is essential for signaling by these molecules in pancreatic β cell. Conclusion: The expression of CHL1 gene was significantly decreased in the pancreatic islets of obese mice induced by high-fat diet. The low expression of CHL1 gene promotes the proliferation of MIN6 cells through the ERK pathway and affect cell cycle through the p53 pathway. This may be one of the mechanisms that pancreatic β cells compensatory hyperplasia in the stage of obesity-induced pre-diabetes.

scholarly journals The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic β-cell identity and function

2020 ◽  
Author(s):  
Livia Lopez-Noriega ◽  
Rebecca Callingham ◽  
Aida Martinez-Sánchez ◽  
Grazia Pizza ◽  
Nejc Haberman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
High Glucose ◽  
High Fat Diet ◽  
High Fat ◽  
Β Cell ◽  
And Function

AbstractLong non-coding RNAs (lncRNAs) are emerging as crucial regulators of β-cell development and function. Consequently, the mis-expression of members of this group may contribute to the risk of type 2 diabetes (T2D). Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in β-cell function. The transcription factor Pax6 is required for the development of pancreatic islets and maintenance of a fully differentiated β-cell phenotype. Pax6os1/PAX6-AS1 expression was increased in pancreatic islets and β-cell lines at high glucose concentrations, in islets from mice fed a high fat diet, and in those from patients with type 2 diabetes. Silencing or deletion of Pax6os1/PAX6-AS1 in MIN6 cells and EndoC-βH1cells, respectively, upregulated β-cell signature genes, including insulin. Moreover, shRNA-mediated silencing of PAX6-AS1 in human islets not only increased insulin mRNA, but also enhanced glucose-stimulated insulin secretion and calcium dynamics. In contrast, inactivation of Pax6os1 in mice was largely without effect on glucose homeostasis, though female Pax6os1 null mice on high fat diet (HFD) showed a tendency towards enhanced glucose clearance. Together, our results suggest that increased expression of PAX6-AS1 at high glucose levels may contribute to β-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting PAX6-AS1 may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in type 2 diabetes.

High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice

2013 ◽  
Vol 304 (10) ◽  
pp. E1053-E1063 ◽  
Author(s):  
Johanna L. Barclay ◽  
Anton Shostak ◽  
Alexei Leliavski ◽  
Anthony H. Tsang ◽  
Olaf Jöhren ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Genetic Manipulation ◽  
Metabolic Effects ◽  
Lipid Uptake ◽  
High Fat ◽  
Obesity And Diabetes ◽  
Deficient Mice

Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes ( Per1–3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and - 2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2−/− mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2−/− mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.

scholarly journals γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1242-1250 ◽  
Author(s):  
Chisayo Kozuka ◽  
Sumito Sunagawa ◽  
Rei Ueda ◽  
Moritake Higa ◽  
Hideaki Tanaka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
High Fat Diet ◽  
Diabetic Mice ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Abstract Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

Relationship between insulin secretion, insulin content and dry weight of single rat pancreatic islets

1980 ◽  
Vol 94 (3) ◽  
pp. 365-370
Author(s):  
G. H. J. Wolters ◽  
W. Konijnendijk
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Outer Surface ◽  
Basal Insulin ◽  
Dry Weight ◽  
Insulin Content ◽  
Curvilinear Relationship ◽  
Rat Pancreatic Islets ◽  
Basal Insulin Secretion

Abstract. Single islets were incubated at glucose 5 mm for 60 min and subsequently at glucose 15 mm for 30 min. The insulin content of the incubated islets was proportional to the dry weight of the islets. The insulin secretion (Y) demonstrated a curvilinear relationship with the dry weight (X) of the islets, which could be described by the function Y = aX⅔ (a being a constant). On basis of this function it can be calculated that the insulin secretion of a particular islet is proportional to its outer surface. The consequence of this is that small sized islets secrete relatively much more insulin than large islets. Islets isolated with either purified or crude collagenase gave the same results except that a higher basal insulin secretion was observed with crude collagenase.

scholarly journals DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet

FEBS Open Bio ◽  
2014 ◽  
Vol 4 (1) ◽  
pp. 141-146 ◽  
Author(s):  
Katherine Veras ◽  
Felipe Natali Almeida ◽  
Renato Tadeu Nachbar ◽  
Daniel Simões de Jesus ◽  
João Paulo Camporez ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
High Fat Diet ◽  
Ovariectomized Rats ◽  
High Fat ◽  
Glucose Stimulated Insulin Secretion
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