Novel pharmaceutical approaches to regulate glucose homeostasis

Abstract: The Western sedentary life-style and calorie excess is causing an increased incidence of obesity and type 2 diabetes. When untreated, these diseases are associated with heart- and vascular disease, stroke, cancer, neuropathic pain, renal failure and infertility. The expected lifespan of type 2 diabetic patents is reduced by ~5-10 years compared to the healthy population. Presently there are several available therapies to treat type 2 diabetic patients, but no drug can normalise the high blood glucose level characteristic of the disease. There is a need to further understand the underlying mechanisms of the type 2 diabetes and to bring more efficient drugs to the patients. Decreasing calorie intake and increasing physical exercise are valuable tools for the treatment of type 2 diabetes. Unfortunately, life-style is a challenge to change and many patients are not able to perform physical activity. The enzyme AMP-activated protein kinase (AMPK) is activated by both fasting and muscle contraction. We have sought to illuminate the impact of chronic activation with a chemically synthesised AMPK-activator, 5-aminoimidazole-4-carboxy-amide-1-beta-ribofuranoside (AICAR), in rodent models of type 2 diabetes (study I and II). Type 2 diabetes is associated with increased glucocorticoid levels, which concomitantly lead to a decrease in adiponectin levels. Cortisone is transformed to its active form cortisol, via 11hydroxysteroid dehydrogenase (HSD) type 1. In study III, we sought to ascertain if inhibition of 11betaHSD1, with a new adipose-tissue-specific inhibitor, BVT116429, affects the concentration of circulating adiponectin with accompanying amelioration of glucose homeostasis in diabetic mice. The ob/ob, KKAy and KKAy-CETP mice, were used to study the pharmacodynamic parameters and biomarkers of AMPK activation and 11betaHSD1 inhibition. The three animal models feature severe obesity, hyperinsulinaemia and hyperglycaemia. Activation of AMPK via AICAR-treatment and inhibition of 11betaHSD1 with BVT116429 resulted in improved glucose homeostasis. Clinical chemistry parameters were improved, including decreased plasma glucose. The underlying mechanisms for the improvements in glucose homeostasis were studied. Acute AMPK activation normalised insulin-stimulated glucose uptake, which is in accordance with an observed two-fold increase in protein expression of GLUT-4, hexokinase II, and myocyte enhancer factor 2. Inhibition of 11HSD1 with BVT116429 increased the concentration of adiponectin both in vivo and in vitro. Pharmacodynamic studies were performed in well-validated models of type 2 diabetes, which increases the chance of succeeding in future clinical trails. This may increase the opportunity to help people with type 2 diabetes to live a longer and healthier life. Drug discovery involves a complex series of steps, where the potential drug must pass several phases to reach the market and the patient. The chemical substances used in these studies were subjected to early drug discovery and analysis. The observed effects of these chemicals provide evidence for the usefulness of targeting AMPK and 11betaHSD1 in vivo for the treatment of metabolic disturbances in type 2 diabetes and obesity.