Preliminary characterization of calcium binding in islet-cell plasma membranes

Naber, Stephen P.; McDonald, Jay M.; Jarett, Leonard; McDaniel, Michael L.; Ludvigsen, Carl; Lacy, Paul E.

doi:10.1007/bf00281823

Cited by 71 publications

(33 citation statements)

References 32 publications

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“…For GSIS assays in islets, pancreatic islets were harvested from male SpragueDawley rats weighing ϳ250 g, as described previously (30,31). Islets were transduced with either Ad-siControl or Ad-siACC1 for 48 h at 4 ϫ 10 7 plaque-forming units/islet.…”

Section: Methodsmentioning

confidence: 99%

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Ronnebaum

Joseph

Ilkayeva

et al. 2008

Journal of Biological Chemistry

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Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60 -80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to ␤-cells suppressed [ 14 C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

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Section: Methodsmentioning

confidence: 99%

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Ronnebaum

Joseph

Ilkayeva

et al. 2008

Journal of Biological Chemistry

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“…Pancreatic islets were isolated according to the method of Naber et al (10) with some modifications and were maintained in suspension culture in 60-mm Petri dishes at 37ЊC in a humidified atmosphere of 5% CO 2 and 95% air (11). The culture medium consisted of RPMI 1640 medium supplemented with 8.0 mM glucose, 10% fetal bovine serum, 200 units͞ml penicillin, 0.2 mg͞ml streptomycin, and 2% BSA, fraction V (Miles) either with or without 1 mM long chain fatty acid mixture (oleate-to-palmitate, 2:1; sodium salt; Sigma).…”

Section: Methodsmentioning

confidence: 99%

Direct antidiabetic effect of leptin through triglyceride depletion of tissues

Shimabukuro

Kanemaru

Chen

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

602

474

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Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was Ϸ20 times normal, and esterification capacity was increased 3-to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an ''indirect pathway'' of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.

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“…Skeletal muscles, liver and epididymal fat were dissected and placed immediately in liquid nitrogen. Pancreatic islets were isolated according to the method of Naber and co-workers [33].…”

Section: Methodsmentioning

confidence: 99%

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetesprone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

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Preliminary characterization of calcium binding in islet-cell plasma membranes

Cited by 71 publications

References 32 publications

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Direct antidiabetic effect of leptin through triglyceride depletion of tissues

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

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