Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat

2012 ◽  
Vol 302 (2) ◽  
pp. E254-E264 ◽  
Author(s):  
Viviane Delghingaro-Augusto ◽  
Simon Décary ◽  
Marie-Line Peyot ◽  
Martin G. Latour ◽  
Julien Lamontagne ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cell Function ◽  
Acid Oxidation ◽  
Oral Glucose ◽  
Β Cell ◽  
Voluntary Running ◽  
Zdf Rats

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

2004 ◽  
Vol 287 (3) ◽  
pp. E390-E404 ◽  
Author(s):  
Laura E. Parton ◽  
Frédérique Diraison ◽  
Suzanne E. Neill ◽  
Sujoy K. Ghosh ◽  
Mark A. Rubino ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pancreatic Islet ◽  
Target Genes ◽  
Cell Function ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Β Cell ◽  
The Impact

Peroxisome proliferator-activated receptor-γ (PPARγ) serves as a target for the thiazolidinedione class of antidiabetic drugs and is an important regulator of adipose tissue differentiation. By contrast, the principal target genes for PPARγ in the pancreatic islet and the impact of their induction on insulin secretion are largely undefined. Here, we show that mRNAs encoding both isoforms of rodent PPARγ, γ1 and γ2, are expressed in primary rat islets and are upregulated by overexpresssion of the lipogenic transcription factor sterol response element-binding protein 1c. Unexpectedly, however, oligonucleotide microarray analysis demonstrates that graded activation of PPARγ achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPARγ1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPARγ1 reduces islet triglyceride levels and enhances the oxidation of exogenous palmitate while decreasing glucose oxidation, cellular ATP content, and glucose-, but not depolarization-stimulated, insulin secretion. We conclude that, in the context of the pancreatic islet, the principal response to PPARγ expression and activation is the activation of genes involved in the disposal, rather than the synthesis, of fatty acids. Although fatty acid oxidation may have beneficial effects on β-cell function in the longer term by countering β-cell “lipotoxicity,” the acute response to this metabolic shift is a marked inhibition of insulin secretion.

scholarly journals Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion

2002 ◽  
Vol 364 (1) ◽  
pp. 219-226 ◽  
Author(s):  
Blanca RUBÍ ◽  
Peter A. ANTINOZZI ◽  
Laura HERRERO ◽  
Hisamitsu ISHIHARA ◽  
Guillermina ASINS ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Β Cells ◽  
Β Cell ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Lipid metabolism in the β-cell is critical for the regulation of insulin secretion. Pancreatic β-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured β-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5mM glucose (1.7-fold) and 15mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15mM glucose or 30mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15mM glucose (−40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the β-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in β-cells exposed to fatty acids.

Interactions between effects of adrenalectomy and diet on insulin secretion in fa/fa Zucker rats

2001 ◽  
Vol 79 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Molly T Kibenge ◽  
Catherine B Chan
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Weight Gain ◽  
Cell Function ◽  
Cafeteria Diet ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Oral Glucose

Our objective was to determine if a cafeteria-type diet with increased fat content would block the decrease in insulin secretion induced by adrenalectomy in obese rats. Five week old Zucker (fa/fa) rats were adrenalectomized. One week later, half of the adrenalectomized groups, and age-matched, sham-operated animals were given a diet of 16% fat and 44% carbohydrate. Control animals were maintained on standard rat chow (4.6% fat and 49% carbohydrate). After 4 weeks on the diets, in vivo measurements included caloric intake, weight gain, plasma corticosterone, triglyceride, free fatty acids, and oral glucose tolerance tests. In vitro measurements included glucose-stimulated insulin secretion, glucose phosphorylating activity, islet triglyceride content, and fatty acid oxidizing activity of cultured islets. Generally, the cafeteria diet did not block the effects of adrenalectomy on in vitro insulin secretion parameters, even though in sham-operated animals weight gain and insulin resistance was induced by the diet in vivo. Adrenalectomy and the diet exerted independent effects on glucose phosphorylation and fatty acid oxidation in islets. In conclusion, adrenalectomy decreased the elevated insulin secretion in fa/fa rats. The failure of a cafeteria diet enriched in fat to block the adrenalectomy-mediated changes in B-cell function indicates the importance of glucocorticoids and centrally-mediated effects on insulin secretion and other metabolic parameters.Key words: obesity, insulin secretion, islets of Langerhans, adrenalectomy, high fat diet.

Circulating lipids are lowered but pancreatic islet lipid metabolism and insulin secretion are unaltered in exercise-trained female rats

2007 ◽  
Vol 32 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Julien Lamontagne ◽  
Pellegrino Masiello ◽  
Mariannick Marcil ◽  
Viviane Delghingaro-Augusto ◽  
Yan Burelle ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acids ◽  
Fatty Acid Oxidation ◽  
Female Rats ◽  
Acid Oxidation ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

Deteriorating islet β-cell function is key in the progression of an impaired glucose tolerance state to overt type 2 diabetes (T2D), a transition that can be delayed by exercise. We have previously shown that trained rats are protected from heart ischemia–reperfusion injury in correlation with an increase in cardiac tissue fatty-acid oxidation. This trained metabolic phenotype, if induced in the islet, could also prevent β-cell failure in the pathogenesis of T2D. To assess the effect of training on islet lipid metabolism and insulin secretion, female Sprague–Dawley rats were exercised on a treadmill for 90 min/d, 4 d/week, for 10 weeks. Islet fatty-acid oxidation, the expression of key lipid metabolism genes, and glucose-stimulated insulin secretion were determined in freshly isolated islets from trained and sedentary control rats after a 48 h rest period from the last exercise. Although this moderate training reduced plasma glycerol, free fatty acids, and triglyceride levels by about 40%, consistent with reduced lipolysis from adipose tissue, it did not alter islet fatty-acid oxidation, nor the islet expression of key transcription factors and enzymes of lipid metabolism. The training also had no effect on glucose-stimulated insulin secretion or its amplification by free fatty acids. In summary, chronic exercise training did not cause an intrinsic change in islet lipid metabolism. Training did, however, substantially reduce the exposure of islets to exogenous lipid, thereby providing a potential mechanism by which exercise can prevent islet β-cell failure leading to T2D.

scholarly journals Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor α Transcriptional Up-Regulation of Fatty Acid Oxidation

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 375-382 ◽  
Author(s):  
Sandrine Gremlich ◽  
Christopher Nolan ◽  
Raphaël Roduit ◽  
Rémy Burcelin ◽  
Marie-Line Peyot ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pancreatic Islet ◽  
Cellular Response ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-α (PPARα)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARα null (PPARαKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARα expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARα expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARαKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARα null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARα, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARα, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

scholarly journals Vigorous Physical Activity may be Important for the Insulin Sensitivity in Immigrants From the Middle East and Native Swedes

2015 ◽  
Vol 12 (2) ◽  
pp. 273-281 ◽  
Author(s):  
Daniel Arvidsson ◽  
Ulf Lindblad ◽  
Jan Sundquist ◽  
Kristina Sundquist ◽  
Leif Groop ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Sensitivity ◽  
Sedentary Time ◽  
Cell Function ◽  
Vigorous Physical Activity ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Β Cell ◽  
Β Cell Function ◽  
Activity Measures

Purpose:To compare physical activity measures and their associations with insulin sensitivity, β-cell function and body mass index (BMI) between Iraqi immigrants and native Swedes.Methods:A cross-sectional study of 493 Iraqis (58% men) and 469 Swedes (54% men) aged 30 to 75 years living in the city of Malmö, Sweden. Accelerometry was used for physical activity measures (sedentary time, breaks in sedentary time, moderate and vigorous physical activity, total counts). Insulin sensitivity index and oral disposal index were determined from an oral glucose tolerance test and BMI by body weight and height.Results:Iraqi men were less physically active than Swedish men, while the physical activity was more similar in the women. BMI was a strong predictor of insulin sensitivity and β-cell function and frequently associated with the physical activity measures. BMI modified the associations of insulin sensitivity and β-cell function with the physical activity measures to such extent that only VPA and total counts show direct associations with insulin sensitivity in addition to the indirect associations via BMI. Iraqi women demonstrated weaker associations compared with Swedish women.Conclusions:Physical activity and performed at vigorous intensity may be important mainly for the insulin sensitivity in Iraqi immigrants and native Swedes.

Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance

2006 ◽  
Vol 291 (6) ◽  
pp. E1144-E1150 ◽  
Author(s):  
Elza Muscelli ◽  
Andrea Mari ◽  
Andrea Natali ◽  
Brenno D. Astiarraga ◽  
Stefania Camastra ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

The mechanisms by which the enteroinsular axis influences β-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate β-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m2 (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The β-cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, β-cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min−1·m−2·mM−1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of β-cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of β-cell function, particularly β-cell glucose sensitivity. In IGT, β-cell function is inherently impaired, whereas the incretin effect is only partially affected.

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