News & Research

    University of Pittsburgh, Pittsburgh, Pennsylvania

Mechanisms of mitochondria impairment in obesity and type 2 diabetes

General Research Subject: Type 2 Diabetes

Focus: Integrated Physiology\Muscle, Integrated Physiology\Insulin Resistance, Obesity

Type of Grant: Clinical Translational Research

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

Type 2 diabetes mellitus (T2DM) and obesity are major public health concerns that are increasing in prevalence across all ages and ethnic groups. There is intense public health interest in the developing interventions for T2DM and its complications. Currently intensive glucose-lowering interventions are considered as a valuable tool for treatment of T2DM complications. Skeletal muscles are most important tissue in glucose utilization. Processing of glucose in skeletal muscle depends on the proper function of mitochondria. We have previously revealed functional abnormalities in skeletal muscle mitochondria that are associated with obesity and Type 2 Diabetes.

We hypothesize that mitochondrial dysfunction in the combination with excessive energy intake creates an abnormal metabolite profile in the cytoplasm and that the products of incomplete oxidation of glucose and fat are responsible for reduced insulin-dependent transport glucose into skeletal muscle. We will test this hypothesis using inter-disciplinary clinical investigation -- combining advanced highly sensitive methods for enzyme profiling of skeletal muscle mitochondria and mass spectroscopy for tissue metabolite profiling in lean, obese and T2DM individuals. We hypothesize that coordinated analysis of mitochondria enzyme profile and metabolite profile in skeletal muscle will help to understand the mechanism of mitochondria dysfunction and it will help to encircle a potential set of metabolites responsible for the disruption of glucose transport in obesity and type 2 diabetes. We believe that the understanding the mechanisms of the mitochondrial defect in skeletal muscle and the developing an appropriate corrective intervention is vital for treatment of type 2 diabetes.

Reseacher Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes? 

The goal of our inter-disciplinary clinical project is to elucidate the molecular mechanisms that lead to development of skeletal muscle insulin resistance and mitochondria dysfunction in obesity and type 2 diabetes. Skeletal muscle insulin resistance is characterized by reduced glucose utilization in skeletal muscle during insulin stimulation. Skeletal muscle insulin resistance is linked to hyperglycemia that is a major cause of diabetic complications. Oxidation of glucose in skeletal muscle is critical for maintenance of normal level of glucose in blood. Mitochondria play central role in the oxidative processing of glucose and fatty acids that provide ATP and building blocks for cell metabolism. Glucose oxidation in skeletal muscle depends on proper function of mitochondria. Our previous data show that skeletal muscle insulin resistance in obesity or type 2 diabetes linked to internal mitochondrial defect that includes reduced activity of electron transport chain and disbalance between electron transport chain, TCA cycle and  -oxidation pathway.

We hypothesize that mitochondrial defect in combination with excessive fat supply can lead to accumulation of toxic products of incomplete oxidation of fat and glucose in muscle tissue. The accumulation of toxic by-products of metabolism can cause insulin resistance. We will test this hypothesis using advanced highly sensitive methods for enzyme profiling of skeletal muscle mitochondria, and mass spectroscopy for tissue metabolite profiling in biopsies obtained from lean, obese, and type 2 diabetes individuals. We hypothesize that coordinated analysis of mitochondria enzyme profile and metabolite profile in skeletal muscle of lean and obese individuals will help to understand the mechanism of mitochondria dysfunction, and will help to encircle a potential set of metabolites responsible for development of insulin resistance. The comparison of obese and type 2 diabetes individuals can reveal the specific effects of type 2 diabetes on mitochondria function and metabolic profile. Using our advanced techniques, we expect to obtain data that will provide rationale for interventions that can normalize metabolite profile, or improve the mitochondria function or both in skeletal muscle in obesity and type 2 diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

Hyperglycemia is a major cause of diabetic complications. Currently intensive glucose-lowering interventions are considered as a valuable tool for treatment of type 2 diabetes complications. Skeletal muscle is a most important tissue in maintaining of normal glucose level in the blood.  Processing of glucose in skeletal muscle depends on the proper function of mitochondria. Our previous data show that skeletal muscle mitochondria in obesity and type 2 diabetes are deficient in ability to oxidize NADH, the process that leads to synthesis of muscle ATP.

We believe that the correction of mitochondrial dysfunction in skeletal muscle is an important step in the application of intensive glucose control. Also, our proposed study considers the mitochondrial dysfunction as a prime factor contributing to the pathogenesis of insulin resistance. We hypothesize that mitochondrial dysfunction in the combination with excessive energy intake creates an abnormal metabolite profile in the cytoplasm and that profile is responsible for forming a nutrient signals that induces insulin resistance. We expect to obtain data that will provide rationale for interventions that can normalize metabolite profile, or improve the mitochondria function or both in skeletal muscle in obesity and type 2 diabetes.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

We developed several advanced techniques for analysis of mitochondria function and content and proximal metabolic pathways that allow to significantly reduce the content of tissue required for analysis (from 2-3 g to 30-50 mg of human skeletal muscle biopsy). We developed a unique non-destructive procedure for analysis of activity of mitochondrial electron transport chain in skeletal muscle. Standard technique provides only ~50% extraction of mitochondria from skeletal muscle. Our previously developed procedure allows the assessment of mitochondria function in human skeletal muscle without necessity of mitochondria isolation. We also developed a technique that allows to accurately estimate content of mitochondria in human tissue. This technique is based on the quantifying the tissue cardiolipin, a specific lipid marker of inner mitochondrial membrane. This award is great opportunity to apply these advanced techniques for research in type 2 diabetes mellitus and obesity that are major public health concerns.

In what direction do you see the future of diabetes research going? 

Elucidating of mechanisms of development of insulin resistance in obesity will be a major challenge. Another most important direction in diabetes research is the understanding of mechanisms that provide maintaining of  -cells mass and  -cells proper function in human pancreas.