A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing’s Syndrome

Summers, Scott A.; Nelson, Don H.

doi:10.2337/diabetes.54.3.591

Cited by 164 publications

(126 citation statements)

References 203 publications

(147 reference statements)

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“…4 C and D). Ceramides have also been suggested to be mediators of insulin resistance (29,30). In contrast to the observed difference in diacylglycerol, there was no difference in ceramide content of Recent studies have suggested that circulating adipocytokines can modulate insulin sensitivity and fat content of liver and muscle (31)(32)(33)(34).…”

Section: Decreased Novel Pkc Membrane Translocation and Increased Akt2mentioning

confidence: 42%

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Choi¹,

Savage²,

Abu-Elheiga

et al. 2007

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

280

232

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Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2 ؊/؊ and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulinstimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2 ؊/؊ and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2 ؊/؊ mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2 ؊/؊ mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKC activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2 ؊/؊ mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. diet-induced obesity prevention ͉ intracellular diacylglycerol ͉ increased fat oxidation ͉ insulin resistance prevention

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Section: Decreased Novel Pkc Membrane Translocation and Increased Akt2mentioning

confidence: 42%

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Choi¹,

Savage²,

Abu-Elheiga

et al. 2007

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

280

232

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“…Although the signaling mechanisms of PDX-1 regulation by glucose are still debated, involvement of the phosphatidylinositol 3-kinase pathway has been suggested (27,(31)(32)(33)43). Because ceramide has been shown to interfere with this pathway, particularly at the level of protein kinase B in all cell types tested thus far (44), it is tempting to speculate that ceramide might dampen a stimulatory signal from glucose to PDX-1 via the phosphatidylinositol 3-kinase pathway. Alternatively, ceramide may activate c-Jun NH 2 -terminal kinase in beta cells as it does in other cells (45,46).…”

Section: Discussionmentioning

confidence: 99%

Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of Langerhans

Hagman

Hays

Parazzoli

et al. 2005

Journal of Biological Chemistry

187

176

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Abnormalities in lipid metabolism have been proposed as contributing factors to both defective insulin secretion from the pancreatic beta cell and peripheral insulin resistance in type 2 diabetes. Previously, we have shown that prolonged exposure of isolated rat islets of Langerhans to excessive fatty acid levels impairs insulin gene transcription. This study was designed to assess whether palmitate alters the expression and binding activity of the key regulatory factors pancreas-duodenum homeobox-1 (PDX-1), MafA, and Beta2, which respectively bind to the A3, C1, and E1 elements in the proximal region of the insulin promoter. Nuclear extracts of isolated rat islets cultured with 0.5 mM palmitate exhibited reduced binding activity to the A3 and C1 elements but not the E1 element. Palmitate did not affect the overall expression of PDX-1 but reduced its nuclear localization. In contrast, palmitate blocked the stimulation of MafA mRNA and protein expression by glucose. Combined adenovirus-mediated overexpression of PDX-1 and MafA in islets completely prevented the inhibition of insulin gene expression by palmitate. These results demonstrate that prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of PDX-1 and cellular expression of MafA.The prevalence of diabetes mellitus is increasing dramatically in Western countries, in part because of the increase in obesity. Type 2 diabetes mellitus, the most frequent form of the disease, is characterized by defective insulin secretion from the pancreatic beta cells and peripheral insulin resistance. According to the lipotoxicity hypothesis, abnormalities in lipid metabolism contribute to both defects (1) and in particular to the inexorable decline of beta cell function observed during the course of the disease (2). However, the mechanisms of lipotoxicity in the beta cell remain largely unknown.In vitro, prolonged exposure to excessive concentrations of fatty acids inhibits glucose-stimulated insulin secretion (3-7) and insulin gene expression (8 -11). Previous studies in our laboratory have shown that deleterious effects of fatty acids appear mediated by distinct mechanisms; whereas inhibition of insulin secretion is observed after culture with palmitate, oleate, and other fatty acids (7), insulin gene expression is only affected by palmitate and is mediated via de novo synthesis of ceramide (11). In isolated rat islets, we have shown that palmitate markedly blunts the activation by glucose of an insulin promoter reporter construct, indicating a transcriptional mode of action (11). However, the mechanisms by which palmitate affects the insulin promoter are unknown.Both beta cell-specific expression and metabolic regulation of the insulin gene are conferred by a highly conserved region lying ϳ340 bp upstream of the transcription initiation site that constitutes the promoter/enhancer region (12-14). The main glucose-responsive elements on the insulin promoter are the highly conserved A3 (15), C1 (16), and E1 (16) sites,...

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“…1 [6][7][8]. Ceramide, a second messenger in this pathway, is generated during the hydrolysis of plasma membrane sphingomyelin by the enzyme neutral sphingomyelinase or the hydrolysis of lysosomal and endosomal sphingomyelin by acid sphingomyelinase [9].…”

Section: Introductionmentioning

confidence: 99%

Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes

et al. 2007

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Aims/hypothesis Intramyocellular lipids, including ceramide, a second messenger in the sphingomyelin signalling pathway, might contribute to the development of insulin resistance. The aim of our study was to assess parameters of the skeletal muscle sphingomyelin signalling pathway in men at risk of developing type 2 diabetes. Methods We studied 12 lean (BMI<25 kg/m 2 ) men without a family history of diabetes (control group), 12 lean male offspring of type 2 diabetic patients, and 21 men with overweight or obesity comprising 12 with NGT (obese-NGT) and nine with IGT (obese-IGT). A euglycaemic-hyperinsulinaemic clamp and a biopsy of vastus lateralis muscle were performed. Ceramide, sphingomyelin, sphinganine and sphingosine levels and sphingomyelinase and ceramidase activities were measured in muscle. Muscle diacylglycerol and triacylglycerol levels were estimated in a subgroup of 27 men (comprising men from all the above groups). Results Compared with the control group, the lean offspring of diabetic patients and the men with overweight or obesity showed lower insulin sensitivity (all p<0.005) and a greater muscle ceramide level (all p<0.01). The obese-IGT group had lower insulin sensitivity (p=0.0018) and higher muscle ceramide (p=0.0022) than the obese-NGT group. There was lower muscle sphingosine level and alkaline ceramidase activity in offspring of diabetic patients (p=0.038 and p=0.031, respectively) and higher sphinganine level in the obese-NGT (p=0.049) and obese-IGT (p=0.002) groups than in the control group. Muscle sphingomyelin was lower (p=0.0028) and neutral sphingomyelinase activity was higher (p=0.00079) in the obese-IGT than in the obese-NGT group. Muscle ceramide was related to insulin sensitivity independently of other muscle lipid fractions. Conclusions/interpretations Ceramide accumulates in muscle of men at risk of developing type 2 diabetes.

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A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing’s Syndrome

Cited by 164 publications

References 203 publications

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of Langerhans

Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes

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