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Obesity and type 2 diabetes are complex metabolic disorders linked to insulin resistance in skeletal muscle. Weight loss, a fundamental treatment for these conditions, has been shown to improve insulin responses in skeletal muscle but the underlying mechanisms are not clearly understood. Previous studies suggest the accumulation of bioactive molecules such as diacylglycerols (DAGs) and ceramides in skeletal muscle may play a role. In the journal Diabetes, Dr. Max C. Petersen and colleagues recently reported the results of their investigation on the impact of weight loss on skeletal muscle bioactive lipids in patients with obesity and type 2 diabetes.¹

 鈥淭he purpose of the current study was to test the hypothesis that the improvement in skeletal muscle insulin sensitivity induced by marked weight loss in people with obesity and [type 2 diabetes] is associated with decreases in muscle sarcolemmal sn-1,2-DAG, sarcolemmal C18:0 ceramide, and mitochondrial C18:0 ceramide contents,鈥� Dr. Petersen and coauthors stated in the article. 

Study design, participant demographics

The study participants included 6 male and 8 female adults with obesity (body weight = 125 卤 20kg; BMI = 43.1 卤 5.6kg/m2) and type 2 diabetes (fasting glucose = 117 卤 20mg/dL) who underwent a 16-week weight loss intervention (Roux-en-Y gastric bypass surgery (n = 9) or low-calorie diet (n = 5)) and achieved at least 15% reduction in weight that was sustained for 3 weeks before post-intervention studies were conducted. Of the 14 participants, 6 were taking insulin before the study began and 3 remained on the medication up to the time of the post-intervention visit. Before the study began, 10 participants were taking a statin and they continued to take this medication throughout the study. 

Obesity, insulin resistance, and ceramides

Changes in body weight, skeletal muscle insulin sensitivity and lipid profiles were measured before and after the intervention. The average duration between the start of the intervention and the assessments after weight loss was 17 卤 4 weeks. Participants achieved a substantial weight loss of 18.6 卤 2.1% (range 16.0% to 24.4%) of their initial body weight, which significantly improved insulin sensitivity. This led to a decrease in HbA1c, fasting plasma glucose and the need for diabetes medication by the end of the study. 

Weight loss did not impact total ceramide content but the investigators observed changes in specific subtypes of muscle ceramide. Total C18:0, C22:0, and C24:0 ceramides decreased by 20% and total C24:1 ceramides increased by 45%. Further, changes in ceramides were observed in multiple fractions of skeletal muscle. 

• C24:1 ceramide levels increased by 50% (P < 0.0001) in the sarcolemmal compartment. 
• Within the mitochondria-endoplasmic reticulum fraction, C18:0, C22:0, and C24:0 ceramides decreased by 20% (all P < 0.005), while C24:1 ceramide levels increased by 40% (P < 0.0001). 
• In the cytosolic compartment, C24:1 ceramide content also increased by 50% (P = 0.015).

Weight loss did not have any impact on the content of total or individual diacylglycerols in subcellular fractions. 

Clinical implications

In the context of obesity and type 2 diabetes, mitochondrial and endoplasmic reticulum stress have been linked to the development of insulin resistance as excessive ceramide accumulation can disrupt their function. The findings of this study suggest that weight loss may alleviate mitochondrial and endoplasmic reticulum stress by reducing ceramide levels, thereby promoting insulin sensitivity. 

鈥淭hese results demonstrate that a decrease in mitochondrial-ER saturated ceramides, including C18:0, are associated with weight loss鈥搃nduced improvements in skeletal muscle insulin sensitivity, but suggest changes in sarcolemmal sn-1,2-DAGs and ceramides are not responsible for the doubling of skeletal muscle insulin sensitivity induced by marked weight loss (decrease in mean BMI from 43.1 kg/m2 to 35.0 kg/m2) in people with obesity and T2D,鈥� Dr. Petersen and coauthors wrote. 

The study demonstrates that weight loss remains a critical component of the management of obesity and type 2 diabetes. Pharmacological interventions that target ceramide metabolism may offer additional therapeutic benefits for these individuals but future research should further explore this option.

Study limitations, future directions

Although the researchers provide important evidence supporting the role of ceramides and DAGs in weight-loss induced benefits in people with obesity and type 2 diabetes, they also noted several limitations of the study.

• The limited sample size and thus reduced the statistical power to detect smaller changes in muscle bioactive lipid content.
• Insufficient muscle tissue prevented the analysis of key metabolic pathways regulated by diacylglycerides and ceramides.
• Challenges in separating mitochondrial and ER compartments might have obscured differences in lipid content.
• The study did not control for potential changes in physical activity levels after intervention, which could influence muscle lipids and insulin sensitivity.
• The absence of a weight-stable control group made it difficult to assess the impact of study participation on the results.
• Participants still had obesity and elevated HbA1c levels, indicating that metabolic dysfunction was not completely resolved by weight loss and improved insulin sensitivity. 

In summary, this study adds important evidence to the understanding of the mechanisms underlying the beneficial effects of weight loss on insulin sensitivity. Elucidating the role of muscle ceramide levels may be a critical step for the development of targeted therapies for the treatment of obesity and type 2 diabetes.

Published: December 27, 2024