Cholesterol Regulates Glucose-stimulated Insulin Secretion through Phosphatidylinositol 4,5-Bisphosphate

Hao, Mingming; Bogan, Jonathan

doi:10.1074/jbc.m109.038034

Cited by 55 publications

(42 citation statements)

References 75 publications

(53 reference statements)

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“…There is evidence that an increase in the cholesterol content of pancreatic ␤-islet cells decreases insulin secretion. 17 However, given that statin treatment will, if anything, decrease cellular cholesterol levels, this is an unlikely explanation for the observed increase in new-onset diabetes mellitus. It is possible that statins decrease insulin sensitivity in the liver or muscle, although there is no direct experimental evidence to support this.…”

Section: Discussionmentioning

confidence: 99%

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

et al. 2011

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Background-High-density lipoproteins have antidiabetic properties in vitro. Furthermore, elevated high-density lipoprotein levels accompanying a genetic deficiency of cholesteryl ester transfer protein are associated with decreased levels of plasma glucose. We now investigate effects on glucose homeostasis of inhibiting cholesteryl ester transfer protein with torcetrapib. Methods and Results-A post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was conducted to investigate effects of the cholesteryl ester transfer protein inhibitor torcetrapib on glycemic control in the 6661 diabetic patients in the trial. At baseline, there were no differences between the 2 treatment arms with respect to plasma glucose, insulin, hemoglobin A 1c , or the homeostasis model assessment of insulin resistance. After 3 months, the diabetic subjects taking the combination of torcetrapib plus atorvastatin had plasma glucose levels 0.34 mmol/L lower (PϽ0.0001) and insulin levels 11.7 U/mL lower (PϽ0.0001) than in those receiving atorvastatin alone. Homeostasis model assessment of insulin resistance values decreased from 49.1 to 47.3 (PϽ0.0001) in the torcetrapib/atorvastatin arm compared with an increase in homeostasis model assessment of insulin resistance in the atorvastatin arm. At the 6-month time point, the mean hemoglobin A 1c level in the atorvastatin arm was 7.29% compared with 7.06% in the torcetrapib/atorvastatin arm (PϽ0.0001). These effects of torcetrapib remained apparent for up to 12 months. Torcetrapib also lowered both glucose and insulin levels in the participants without diabetes mellitus, although the effects were not as great as in those with diabetes mellitus. Conclusions-Treatment with torcetrapib improves glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus. It remains to be determined whether this effect is the consequence of raising high-density lipoprotein.at Clinical Trial Registration-http:www.clinicaltrials.gov. Unique identifier: NCT00134264. (Circulation. 2011;124:555-562.)

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Section: Discussionmentioning

confidence: 99%

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

et al. 2011

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“…Basolateral membrane cholesterol extraction with M-β-CD also reduced the Na + /K + pump activity in A6 renal epithelia [50] . In addition, some reports showed that cholesterol depletion suppressed insulin secretion [51][52][53] , and decreased cholesterol levels in the pancreas may contribute to the severity of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

Wang

Liu

et al. 2012

Acta Pharmacol Sin

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Aim: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Methods: Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. Results: In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Conclusion: Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.

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“…These data suggest that although antibodies significantly reduced the mobilization of Cy3-actin to the vertex, the population of actin that reached the vertex was able to continue to polymerize in the presence of JP. Many studies have shown that actin polymerization can be regulated by cholesterol and the phosphoinositide PtdIns(4,5)P 2 (Hao and Bogan, 2009;Kwik et al, 2003;Rozelle et al, 2000). However, most of the evidence has been collected at the plasma membrane, and it is unclear whether lipids control actin dynamics on lysosomal organelles.…”

Section: Snares and Hops Regulate Actin Enrichmentmentioning

confidence: 99%

SNAREs, HOPS, and regulatory lipids control the dynamics of vacuolar actin during homotypic fusion

Karunakaran

Sasser

Rajalekshmi

et al. 2012

Journal of Cell Science

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SummaryHomotypic vacuole fusion requires SNAREs, the Rab Ypt7p, the tethering complex HOPS, regulatory lipids and actin. In Saccharomyces cerevisiae, actin functions at two stages of vacuole fusion. Pre-existing actin filaments are depolymerized to allow docking and assembly of the vertex ring (a microdomain enriched in proteins and lipids that mediate fusion). Actin is then polymerized late in the pathway to aid fusion. Here, we report that the fusion machinery regulates the accumulation of actin at the vertex ring. Using Cy3-labeled yeast actin to track its dynamics, we found that its vertex enrichment was abolished when actin monomers were stabilized by latrunculin-B, independent of the extent of incorporation. By contrast, stabilization of filamentous actin with jasplakinolide markedly augmented actin vertex enrichment. Importantly, agents that inhibit SNAREs, Ypt7p and HOPS inhibited the vertex enrichment of actin, demonstrating that the cytoskeleton and the fusion machinery are interdependently regulated. Actin mobilization was also inhibited by ligating ergosterol and PtdIns(3)P, whereas the ligation or modification of PtdIns(4,5)P 2 augmented the vertex enrichment of actin. The proteins and lipids that regulated actin mobilization to the vertex did not affect the total incorporation of Cy3-actin, indicating that actin mobilization and polymerization activities can be dissociated during membrane fusion.

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Cholesterol Regulates Glucose-stimulated Insulin Secretion through Phosphatidylinositol 4,5-Bisphosphate

Cited by 55 publications

References 75 publications

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

SNAREs, HOPS, and regulatory lipids control the dynamics of vacuolar actin during homotypic fusion

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Cholesterol Regulates Glucose-stimulated Insulin Secretion through Phosphatidylinositol 4,5-Bisphosphate

Cited by 55 publications

References 75 publications

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A 1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A 1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

SNAREs, HOPS, and regulatory lipids control the dynamics of vacuolar actin during homotypic fusion

Contact Info

Product

Resources

About

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A _1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial