Pathogenesis of type 2 diabetes with emphasis on the mechanism of insulin resistance

Type 2 diabetes is characterized by chronic hyperglycemia and develops slowly through stages of early impairments of glucose metabolism. The disease is often associated with obesity, physical inactivity, decreased insulin sensitivity and impaired insulin responsiveness. An increase in the muscle concentration of malonyl CoA, an inhibitor of fatty-acid oxidation, has been observed in association with insulin resistance and type 2 diabetes.

The thesis aimed to evaluate the influence of sex and diabetes heredity on the prevalence and pathogenesis of early abnormalities of glucose metabolism, as well as the impact of exercise training on phenotype characteristics and insulin sensitivity in people with or without mild type 2 diabetes. The impact of exercise training on cellular and molecular mechanisms regulating insulin sensitivity in muscle was also investigated.

The subject-material comprised of approximately 8,000 men and women, with or without family history of type 2 diabetes (FHD). They participated in the Stockholm Diabetes Prevention Program (SDPP). The participants were categorized according to an oral glucose tolerance test (OGTT) and the homeostasis model assessment (HOMA) was used to determine insulin sensitivity and beta cell function. Thirteen men with type 2 diabetes and 17 sex, age-, and body mass index-matched control subjects were evaluated to compare phenotype characteristics, insulin sensitivity and malonyl CoA levels in biopsies from the vastus lateralis muscle. Furthermore, eleven healthy middle-aged controls and twelve patients with type 2 diabetes were investigated before and after a 12-week training program to explore molecular mechanisms mediating training improved insulin sensitivity.

Prevalence of early abnormalities of glucose metabolism was two to three times higher in subjects with FHD and two to three times higher in men compared to women. In these subjects both waist circumference and systolic blood pressure were increased and insulin sensitivity and beta cell function were decreased. Subjects with impaired fasting glucose (IFG) had more pronounced impairment of beta cell function and insulin sensitivity than subjects with impaired glucose tolerance (IGT).

Patients with type 2 diabetes had significantly lower physical fitness (V02max) and higher truncal fat mass compared to healthy controls. The plasma concentration of free fatty acids and the rate of fatty acid oxidation during the hyperinsulinemic euglycemic clamp, were higher in the diabetic subjects than in the controls. During the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in patients. Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the patients with type 2 diabetes.

Long-term exercise training decreased intra-abdominal fat mass and improved V02max in both controls and patients. Subjects with type 2 diabetes improved insulin sensitivity by 77%, when measured by hyperinsulinemic euglycemic clamp, whereas no significant change was seen in the controls. Furthermore, after training the basal concentration of malonyl CoA in muscle was significantly decreased in both groups.

This was accompanied by increased activity of malonyl CoA decarboxylase (MCD). In patients, the basal diacylglycerol (DAG) levels decreased after training whereas MCD mRNA and abundance of peroxisomal-proliferator-activated receptor (PPAR) γ co-activator 1 α (PGC-1α) increased in controls. No changes in the phosphorylation of AMP-activated protein kinase (AMPK) or acetyl CoA carboxylase (ACC) were seen. In conclusion, type 2 diabetes heredity and male sex increased the prevalence of early abnormalities of glucose homeostasis. Insulin sensitivity is decreased in mild type 2 diabetes which closely correlates with an increase in truncal fat mass, decrease in physical fitness and unexpectedly high levels of malonyl CoA in muscle.

We propose that high levels of muscle malonyl CoA, in combination with decreased suppression of plasma FFA, constitute a crucial mechanism behind insulin resistance in type 2 diabetes. Physical training markedly improved insulin sensitivity and decreased intra-abdominal fat area in patients with type 2 diabetes. This study demonstrates for the first time in man that physical training increased activity of MCD in muscle. We believe that the latter mechanism significantly accounts for the decrease of muscle malonyl CoA and DAG, resulting in improved insulin sensitivity.

List of scientific papers

I. Kuhl J, Hilding A, Ostenson CG, Grill V, Efendic S, Bavenholm P (2005). Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity. Diabetologia. 48(1): 35-40.
https://pubmed.ncbi.nlm.nih.gov/15619073

II. Bavenholm PN, Kuhl J, Pigon J, Saha AK, Ruderman NB, Efendic S (2003). Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation. J Clin Endocrinol Metab. 88(1): 82-7.
https://pubmed.ncbi.nlm.nih.gov/12519834

III. Kuhl JE, Ruderman NB, Musi N, Goodyear LJ, Patti ME, Crunkhorn S, Dronamraju D, Thorell A, Nygren J, Ljungkvist O, Degerblad M, Stahle A, Brismar TB, Andersen KL, Saha AK, Efendic S, Bavenholm PN (2006). Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle. Am J Physiol Endocrinol Metab. 290(6): E1296-303.
https://pubmed.ncbi.nlm.nih.gov/16434556

IV. Kuhl J, Ruderman N, Musi N, Goodyear L, Patti ME, Thorell A, Nygren J, Ljungkvist O, Degerblad M, Stahle A, Brismar T, Saha A, Efendic S, Bavenholm P (2006). Effects of Exercise Training on Phenotype Characteristics, Insulin Sensitivity and Malonyl CoA Regulation in Subjects with Type 2 Diabetes. [Manuscript]