Myotubes from severely obese type 2 diabetic subjects accumulate less lipids and show higher lipolytic rate than myotubes from severely obese non-diabetic subjects.

Siril S Bakke,Rune Sandbu,Marianne O Ludahl,Lisbeth Damlien,Vigdis Aas,Yuan Z Feng,Camilla Stensrud,Brita Marie Solheim,G Hege Thoresen,Eili T Kase,Cedric Moro,Jøran Hjelmesæth,Arild C Rustan,Natasa Nikolić

doi:10.1371/journal.pone.0119556

Abstract

About 80% of patients with type 2 diabetes are classified as overweight. However, only about 1/3 of severely obese subjects have type 2 diabetes. This indicates that several severely obese individuals may possess certain characteristics that protect them against type 2 diabetes. We therefore hypothesized that this apparent paradox could be related to fundamental differences in skeletal muscle lipid handling. Energy metabolism and metabolic flexibility were examined in human myotubes derived from severely obese subjects without (BMI 44±7 kg/m2) and with type 2 diabetes (BMI 43±6 kg/m2). Lower insulin sensitivity was observed in myotubes from severely obese subjects with type 2 diabetes. Lipolysis rate was higher, and oleic acid accumulation, triacylglycerol content, and fatty acid adaptability were lower in myotubes from severely obese subjects with type 2 diabetes compared to severely obese non-diabetic subjects. There were no differences in lipid distribution and mRNA and protein expression of the lipases HSL and ATGL, the lipase cofactor CGI-58, or the lipid droplet proteins PLIN2 and PLIN3. Glucose and oleic acid oxidation were also similar in cells from the two groups. In conclusion, myotubes established from severely obese donors with established type 2 diabetes had lower ability for lipid accumulation and higher lipolysis rate than myotubes from severely obese donors without diabetes. This indicates that a difference in intramyocellular lipid turnover might be fundamental in evolving type 2 diabetes.

Highlights

Overweight and obesity are strongly associated with insulin resistance and type 2 diabetes, and the majority of subjects with type 2 diabetes are classified as overweight or obese [1]
Studies performed on cultured skeletal muscle cells from severely obese subjects are few [9,10,11,12,13], but the main findings from these studies are that myotubes from the severely obese subjects have a reduced complete fatty acid oxidation compared to cells from lean subjects [10, 11, 13], in addition to a reduced mitochondrial content [11]
Obese without type 2 diabetes and severely obese with type 2 diabetes differed in fasting plasma glucose and in HbA1c

Summary

Introduction

Overweight and obesity are strongly associated with insulin resistance and type 2 diabetes, and the majority of subjects with type 2 diabetes are classified as overweight or obese [1]. Metabolic flexibility is defined as the muscle’s ability to change between predominantly fatty acid oxidation in the fasting state and carbohydrate oxidation in the fed state (reviewed in [3]) This flexibility is reduced in insulin resistance and type 2 diabetes in vivo [4]. Other studies on myotubes from obese subjects with diabetes (BMI30 kg/m2) have shown reduced lipid oxidation associated with obesity and type 2 diabetes [14,15,16]. Athletes that are highly insulin sensitive have a higher content of lipid in skeletal muscle than both overweight sedentary and overweight type 2 diabetic individuals [27] Based on these findings, new theories have emerged that focus on abnormal lipid storage or TAG lipolysis rather than lipid storage per se (reviewed in [25])

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