scholarly journals Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

2011 ◽  
Vol 300 (2) ◽  
pp. E410-E421 ◽  
Author(s):  
A. D. Dobrian ◽  
Q. Ma ◽  
J. W. Lindsay ◽  
K. A. Leone ◽  
K. Ma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Pancreatic Islets ◽  
Pancreatic Islet ◽  
Cell Function ◽  
Fasting Blood Glucose ◽  
Stromal Vascular Fraction ◽  
Metabolic Dysfunction ◽  
Reduced Body ◽  
Β Cell Function

Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin ( P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction ( P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice

2005 ◽  
Vol 288 (3) ◽  
pp. E510-E518 ◽  
Author(s):  
Fumiko Kawasaki ◽  
Masafumi Matsuda ◽  
Yukiko Kanda ◽  
Hiroshi Inoue ◽  
Kohei Kaku
Keyword(s):  
Pancreatic Islets ◽  
Cell Function ◽  
Early Stage ◽  
Cell Damage ◽  
Fasting Blood Glucose ◽  
Diabetic Animal ◽  
Β Cell ◽  
Islet Mass ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

To evaluate preventive effects of pioglitazone on pancreatic β-cell damage in C57BL/KsJ db/ db mice, an obese diabetic animal model, the pancreatic islets were compared morphologically between pioglitazone-treated (100 mg/kg daily po) and untreated db/db mice ( n = 7 for each) after a 12-wk intervention (6–18 wk of age). The fasting blood glucose level was significantly improved by the treatment with pioglitazone (260 ± 12 vs. 554 ± 62 mg/dl, P < 0.05). The islet mass in the pancreas was significantly greater in pioglitazone-treated mice than in untreated mice (10.2 ± 1.1 vs. 4.6 ± 0.2 mg, P < 0.01). Subsequently, biochemical and physiological analyses of the β-cell function were employed using pioglitazone-treated and untreated db/db mice ( n = 6 for each) and pioglitazone-treated and untreated db/+ mice ( n = 6 for each). After 2 wk of treatment (10–12 wk of age), the plasma levels of triglyceride and free fatty acid were significantly decreased, whereas the plasma adiponectin level increased significantly compared with the untreated group (65.2 ± 18.0 vs. 18.3 ± 1.3 μg/ml, P < 0.05). Pioglitazone significantly reduced the triglyceride content in the islets (43.3 ± 3.6 vs. 65.6 ± 7.6 ng/islet, P < 0.05) with improved glucose-stimulated insulin secretion. Pioglitazone showed no significant effects on the biochemical and physiological parameters in db/+ mice. The present study first demonstrated that pioglitazone prevents β-cell damage in an early stage of the disease progression in db/db mice morphologically and physiologically. Our results suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the pancreatic islets.

scholarly journals Higher Ratio of Abdominal Subcutaneous to Visceral Adipose Tissue Related with Preservation of Islet β-Cell Function in Healthy Individuals

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Juan Liu ◽  
Jianbin Liu ◽  
Hai Li ◽  
Liehua Liu ◽  
Jing Zheng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Protective Factor ◽  
Cell Function ◽  
Late Phase ◽  
Metabolic Dysfunction ◽  
Healthy Group ◽  
Matsuda Index ◽  
Β Cell Function ◽  
Visceral Adipose

Objective. To investigate the relationship between abdominal adipose tissue distribution, β-cell function, and insulin sensitivity (IS) in a Chinese population. Methods. One hundred and eighty-eight healthy subjects (healthy group), 239 with normal glucose, and 1~4 abnormal metabolic traits (metabolic dysfunction group, MD group) and 125 with hyperglycemia (hyperglycemia group) were studied. HOMA-IR, HOMA-B, Matsuda index, early- (I0–30/G0–30) and late-phase (I30–120/G30–120) insulin responses and the corresponding disposition indexes (DI) were calculated. The area of abdominal subcutaneous adipose tissue (ASAT) and visceral adipose tissue (VAT) was measured and the ratio of ASAT to VAT (SVR) was calculated. Results. SVR was correlated positively with Matsuda index in healthy, MD, and hyperglycemia groups, and inversely with HOMA-IR. SVR positively related with both early- and late-phase DI in the healthy group only. In the healthy group, the hyperbolas of I0–30/G0–30 and I30–120/G30–120 versus Matsuda index in the highest quarter of SVR were significantly right shifted compared to those in the lowest (both P<0.05). Conclusions. In healthy adults, higher SVR was a protective factor for β-cell function and IS, while in those with glucometabolic abnormality, higher SVR contributed to a relative better IS, indicating SVR is possible to be an early predicator of type 2 diabetes development.

scholarly journals The role of gut microbiota and amino metabolism in the effects of improvement of islet β-cell function after modified jejunoileal bypass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cai Tan ◽  
Zhihua Zheng ◽  
Xiaogang Wan ◽  
Jiaqing Cao ◽  
Ran Wei ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Cell Function ◽  
Body Weight Gain ◽  
Fasting Blood Glucose ◽  
Jejunoileal Bypass ◽  
Β Cell ◽  
Β Cell Function ◽  
Branched Chain

AbstractThe change in gut microbiota is an important mechanism of the amelioration of type 2 diabetes mellitus (T2DM) after bariatric surgery. Here, we observe that the modified jejunoileal bypass effectively decreases body weight gain, fasting blood glucose, and lipids level in serum; additionally, islet β-cell function, glucose tolerance, and insulin resistance were markedly ameliorated. The hypoglycemic effect and the improvement in islet β-cell function depend on the changes in gut microbiota structure. modified jejunoileal bypass increases the abundance of gut Escherichia coli and Ruminococcus gnavus and the levels of serum glycine, histidine, and glutamine in T2DM rats; and decreases the abundance of Prevotella copri and the levels of serum branched chain amino acids, which are significantly related to the improvement of islet β-cell function in T2DM rats. Our results suggest that amino acid metabolism may contribute to the islet β-cell function in T2DM rats after modified jejunoileal bypass and that improving gut microbiota composition is a potential therapeutic strategy for T2DM.

scholarly journals Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 444-452 ◽  
Author(s):  
Kyuho Kim ◽  
Chang-Myung Oh ◽  
Mica Ohara-Imaizumi ◽  
Sangkyu Park ◽  
Jun Namkung ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Β Cell ◽  
Pancreas Perfusion ◽  
Insulin Resistant ◽  
Β Cell Function ◽  
Resistant State ◽  
Insulin Resistant State

The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b−/− (Htr2b βKO), Htr3a−/− (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)−/− (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.

scholarly journals VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Frank Chenfei Ning ◽  
Nina Jensen ◽  
Jiarui Mi ◽  
William Lindström ◽  
Mirela Balan ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Lipid Accumulation ◽  
Cell Function ◽  
Lipid Uptake ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Β Cell Function ◽  
Triglyceride Content

AbstractType 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.

scholarly journals Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health

2016 ◽  
Vol 311 (1) ◽  
pp. R79-R88 ◽  
Author(s):  
Lorna M. Dickson ◽  
Shriya Gandhi ◽  
Brian T. Layden ◽  
Ronald N. Cohen ◽  
Barton Wicksteed
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Cell Function ◽  
Uncoupling Protein ◽  
Metabolic Health ◽  
Regulatory Subunit ◽  
Increase Energy Expenditure ◽  
Brown Adipose ◽  
Β Cell Function ◽  
Pka Regulatory Subunit

Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health.

scholarly journals Polysaccharides fromEnteromorpha proliferaImprove Glucose Metabolism in Diabetic Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Wenting Lin ◽  
Wenxiang Wang ◽  
Dongdong Liao ◽  
Damiao Chen ◽  
Pingping Zhu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Mrna Expression ◽  
Glucose Transporter ◽  
Fasting Blood Glucose ◽  
Diabetic Rats ◽  
High Dose ◽  
Sensitivity Index ◽  
Serum Samples ◽  
Glut 4

This study investigated the effects of polysaccharides fromEnteromorpha prolifera(PEP) on glucose metabolism in a rat model of diabetes mellitus (DM). PEP (0, 150, 300, and 600 mg/kg) was administered intragastrically to rats for four weeks. After treatment, fasting blood glucose (FBG) and insulin (INS) levels were measured, and the insulin sensitivity index (ISI) was calculated. The morphopathological changes in the pancreas were observed. Serum samples were collected to measure the oxidant-antioxidant status. The mRNA expression levels of glucokinase (GCK) and insulin receptor (InsR) in liver tissue and glucose transporter type 4 (GLUT-4) and adiponectin (APN) in adipose tissue were determined. Compared with the model group, the FBG and INS levels were lower, the ISI was higher, and the number of isletβ-cells was significantly increased in all the PEP groups. In the medium- and high-dose PEP groups, MDA levels decreased, and the enzymatic activities of SOD and GSH-Px increased. The mRNA expression of InsR and GCK increased in all the PEP groups; APN mRNA expression increased in the high-dose PEP group, and GLUT-4 mRNA expression increased in adipose tissue. These findings suggest that PEP is a potential therapeutic agent that can be utilized to treat DM.

scholarly journals Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets

2019 ◽  
Vol 5 (3) ◽  
Author(s):  
Ge Li ◽  
Tihomira D Petkova ◽  
Eleonora Laritsky ◽  
Noah Kessler ◽  
Maria S Baker ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Control Male ◽  
Small Litter ◽  
Endoplasmic Reticulum Calcium ◽  
Expression Of Genes ◽  
Β Cell Function

Abstract Pancreatic islets of type 2 diabetes patients have altered DNA methylation, contributing to islet dysfunction and the onset of type 2 diabetes. The cause of these epigenetic alterations is largely unknown. We set out to test whether (i) islet DNA methylation would change with aging and (ii) early postnatal overnutrition would persistently alter DNA methylation. We performed genome-scale DNA methylation profiling in islets from postnatally over-nourished (suckled in a small litter) and control male mice at both postnatal day 21 and postnatal day 180. DNA methylation differences were validated using quantitative bisulfite pyrosequencing, and associations with expression were assessed by RT-PCR. We discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging (R2 = 0.33, P < 0.0001). These methylation differences were inversely correlated with mRNA expression of genes relevant to β cell function [including Rab3b (Ras-related protein Rab-3B), Cacnb3 (voltage-dependent L-type calcium channel subunit 3), Atp2a3 (sarcoplasmic/endoplasmic reticulum calcium ATPase 3) and Ins2 (insulin 2)]. Relative to control, small litter islets showed DNA methylation differences directly after weaning and in adulthood, but few of these were present at both ages. Surprisingly, we found substantial overlap of methylated loci caused by aging and small litter feeding, suggesting that the age-associated gain of DNA methylation happened much earlier in small litter islets than control islets. Our results provide the novel insights that aging-associated DNA methylation increases reflect an epigenetic drift toward the exocrine pancreas epigenome, and that early postnatal overnutrition may accelerate this process.

scholarly journals Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1β

2007 ◽  
Vol 192 (2) ◽  
pp. 381-387 ◽  
Author(s):  
Andreas Börjesson ◽  
Carina Carlsson
Keyword(s):  
Pancreatic Islets ◽  
Cell Function ◽  
Culture Media ◽  
Mrna Level ◽  
Interleukin 1Β ◽  
Mrna Levels ◽  
Rat Pancreatic Islets ◽  
Significant Prolongation ◽  
Β Cell Function

In order to elucidate a possible relationship between β-cell function and conversion of proinsulin to insulin, isolated rat pancreatic islets were maintained in tissue culture for 1 week at various glucose concentrations (5.6–56 mM). Studies were also conducted on islets cultured for 48 h with interleukin-1β (IL-1β). By pulse-chase labelling and immunoprecipitation, the relative contents of newly synthesized proinsulin and insulin were determined. ELISA was used to analyse insulin and proinsulin content in medium and within islets. Using real-time PCR, the mRNA levels of proinsulin converting enzymes (PC1 and PC2) were studied. Islets cultured at 56 mM glucose had an increased proportion of newly synthesized proinsulin when compared with islets cultured at 5.6 mM glucose after a 90-min chase periods, however, no difference was observed after culture at 11 and 28 mM glucose. ELISA measurements revealed that culture at increased glucose concentrations as well as islet exposure to IL-1β increased proinsulin accumulation in the culture media. The mRNA expression of PC1 was increased after culture at 11 and 28 mM glucose. Treatment for 48 h with IL-1β increased the proportion of proinsulin both at 45 and 90 min when compared with control islets. These islets also displayed a decreased mRNA level of PC1 as well as PC2. Calculations of the half-time for proinsulin demonstrated a significant prolongation after treatment with IL-1β. We conclude that a sustained functional stimulation by glucose of islets is coupled to a decreased conversion of proinsulin which is also true for islets treated with IL-1β. This may contribute to the elevated levels of proinsulin found both at the onset of type 1 diabetes as well as in type 2 diabetes.

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