Abstract
BackgroundAnimal and cell culture data suggest a critical role for Munc18c and Syntaxin 4 proteins in insulin mediated glucose transport in skeletal muscle, but no studies have been published in humans.MethodsWe investigated the effect of a 12 vs. 48 hr fast on insulin action and skeletal muscle Munc18c and Syntaxin 4 protein in lean and obese subjects. Healthy lean (n = 14; age = 28.0 +/- 1.4 yr; BMI = 22.8 +/- 0.42 kg/m2) and obese subjects (n = 11; age = 34.6 +/- 2.3 yr; BMI = 36.1 +/- 1.5 kg/m2) were studied twice following a 12 and 48 hr fast. Skeletal muscle biopsies were obtained before a 3 hr 40 mU/m2/min hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose infusion.ResultsGlucose rate of disappearance (Rd) during the clamp was lower in obese vs. lean subjects after the 12 hr fast (obese: 6.25 +/- 0.67 vs. lean: 9.42 +/- 1.1 mg/kgFFM/min, p = 0.007), and decreased significantly in both groups after the 48 hr fast (obese 3.49 +/- 0.31 vs. lean: 3.91 +/- 0.42 mg/kgFFM/min, p = 0.002). Munc18c content was not significantly different between lean and obese subjects after the 12 hour fast, and decreased after the 48 hr fast in both groups (p = 0.013). Syntaxin 4 content was not altered by obesity or fasting duration. There was a strong positive relationship between plasma glucose concentration and Munc18c content in lean and obese subjects during both 12 and 48 hr fasts (R2 = 0.447, p = 0.0015). Significant negative relationships were also found between Munc18c and FFA (p = 0.041), beta-hydroxybutyrate (p = 0.039), and skeletal muscle AKT content (p = 0.035) in lean and obese subjects.ConclusionThese data indicate Munc18c and Syntaxin 4 are present in human skeletal muscle. Munc18c content was not significantly different between lean and obese subjects, and is therefore unlikely to explain obesity-induced insulin resistance. Munc18c content decreased after prolonged fasting in lean and obese subjects concurrently with reduced insulin action. These data suggest changes in Munc18c content in skeletal muscle are associated with short-term changes in insulin action in humans.
Highlights
Introduction humansDefects in skeletal muscle insulin signaling haveInsulin resistance is commonly observed in obese been extensively studied, and much is known aboutNutrition & Metabolism 2008, 5:21 http://www.nutritionandmetabolism.com/content/5/1/21 obesity and Type 2 diabetes which can help explain insulin resistance in these populations
This study was designed to determine if Munc18c and Syntaxin 4 are present in human skeletal muscle
Insulin stimulated glucose rate of disappearance (Rd) was significantly greater in lean compared to obese subjects after the 12 hour fast (Table 1)
Summary
Introduction humansDefects in skeletal muscle insulin signaling haveInsulin resistance is commonly observed in obese been extensively studied, and much is known about (page number not for citation purposes)Nutrition & Metabolism 2008, 5:21 http://www.nutritionandmetabolism.com/content/5/1/21 obesity and Type 2 diabetes which can help explain insulin resistance in these populations. Insulin resistance is commonly observed in obese been extensively studied, and much is known about (page number not for citation purposes). The role of alterations in GLUT4 vesicle tethering, docking, and fusion to the plasma membrane in causing insulin resistance is not clear. Vesicle associated membrane protein 2 (VAMP2) is a v-SNARE interacting with Syntaxin 4 in the docking step of GLUT4 translocation. Insulin binding to the sarcolemma may remove inhibition of Munc18c either through dissociation or repositioning [5], promoting Syntaxin 4 and VAMP2 interaction, allowing GLUT4 vesicle fusion to the plasma membrane [6]. Animal and cell culture data suggest a critical role for Munc18c and Syntaxin 4 proteins in insulin mediated glucose transport in skeletal muscle, but no studies have been published in humans
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