Short summary

Type 2 diabetes are characterized by insulin resistance in skeletal muscle. This is associated with increased risk of heart disease, and it represents a major challenge in treating type 2 diabetes. No specific treatment of insulin resistance is currently available, except from increased physical activity and weight-loss. 

The purpose of our project is to investigate the effect of insulin and exercise on insulin sensitivity, use of glucose and fat, enzymes mediating insulin action, function and content of mito-chondria and storage of fat in skeletal muscles.

Rationale

BACKGROUND: 

Insulin resistance (IR) plays a major role for the increased risk of cardiovascular disease (CVD) in obesity and type 2 diabetes (T2D). Targeted treatment of IR in affected tissues is, however, almost non-existing, except for weight-loss and physical activity. The central hypothesis of this proposal is that abnormalities in glucose and lipid metabolism as well as defects in molecular processes regulated by insulin and exercise can explain the link between IR, mitochondrial dysfunction and lipid accumulation observed in skeletal muscle in obesity and T2D. Focusing on these metabolic and molecular abnormalities, the major goal of our project is to discover novel targets for the treatment of IR and mimicking exercise, which can be used in the prevention and treatment of T2D and CVD.

HYPOTHESIS:

Compared to matched controls, we hypothesize that individuals with obesity and T2D are characterized by abnormalities in the fasting, resting state and/or an impaired effect of insulin, acute exercise and/or exercise training on: 

a) insulin secretion, insulin sensitivity and substrate metabolism 

b) distal components and modulaters of insulin signaling in muscle 

c) markers of mitochondrial dynamics and mitophagy in muscle and fat 

d) regulators of lipid droplet function and interaction with mitochondria in muscle and fat 

e) transcriptional and signalling networks regulating muscle metabolism 

f) phosphorylation and acetylation of metabolic and signaling enzymes in muscle and fat 

g) regulators of adipose tissue expandability in fat 

h) metabolomic signature in plasma 

AIM:

In this proposal, we plan a series of studies, in which we combine state-of-the-art metabolic characterization and novel exercise interventions with detailed investigations of blood samples, skeletal muscle and fat biopsies with the aim to identify defects in the above-mentioned novel regulatory systems and examine their potential relation to known abnormalities in insulin signaling, glucose and lipid metabolism and mitochondrial function in obesity and T2D. Further mechanistic insight will be obtained by further characterization of such defects in cultured myotubes and adipocytes as well as mice models in close collaboration with our research partners. We ultimately expect that this will help us to identify novel targets for treatment of IR and mimicking exercise, which are currently missing in the treatment and prevention of T2D and CVD. 

Description of the cohort

Study Cohort: 15 overweight/obese men with T2D (age 40-65 and BMI 28-35) will be matched to 15 obese and 15 lean (BMI 20-25) glucose tolerant healthy men according to gender, age and level of physical activity. 

Inclusion criteria: GAD65 antibody negative men with T2D (duration 6 months to 10 years) without diabetic complications, and treated with either diet alone or diet in combination with either metformin, oral DPP-4 inhibitors or sulphonylureas. Patients should be able and willing to discontinue all drugs for 1 weeks prior to the studies. Obese and lean controls should be healthy, glucose tolerant and drug naive. Obese and lean controls should have no family history of diabetes.

Exclusion criteria: Any unknown disease or need for medication that occurs after inclusion. Abnormal ECG, screening blood tests and/or severe hypertension. Impaired glucose tolerance in non-diabetic subjects

Data and biological material

We collect biological materials in the form of: blood and biospies from muscle- and adipose tissue. 

Collaborating researchers and departments

Department of Sports Science and Clinical Biomechanics, University of Southern Denmark

• Professor Niels Ørtenblad, PhD 

• Professor Nils Færgeman, PhD 
• Professor Martin Røssel Larsen, PhD