Assessment and Treatment of Impaired Insulin-Secretion and Action in Type 2 Diabetes
Type 2 diabetes (T2D) is a disease characterised by varying degrees of defect in insulin secretion and insulin sensitivity and associated with increased morbidity and mortality. Optimal glycaemic control reduces the progression of diabetic complications. Over time, there is a steady deterioration of glycaemic control that raises the need for effective therapy targeted at the underlying defects in order to achieve treatment goals. The methods available for assessment of insulin secretion and insulin sensitivity have not been suitable for use in clinical practice. The introduction of thiazolidinediones (TZDs) targeting the insulin resistance component of T2D has been promising but accompanied with some adverse effects, mainly fluid retention and heart failure. In this thesis, a simple method for independent measurement of β-cell function and insulin sensitivity at the same time (combined glucagon-insulin tolerance test, GITT) has been developed (Paper I). We also evaluated the effect of a TZD (pioglitazone) and a long-acting insulin (glargine) as add-on in the treatment of patients with T2D, not achieving glycaemic goals when treated with classic anti-diabetic agents on glycaemic control, insulin sensitivity, β-cell function and markers of increased cardiovascular load (Papers II &IV). We also investigated the effect of pioglitazone on eye protrusion (Paper III).
GITT showed good reproducibility and the index of insulin sensitivity derived from the GITT showed good correlation with the M-value from the euglycaemic clamp. The test also showed good discriminating capacity between individuals with varying degrees of glucose tolerance (Paper I). Both pioglitazone and insulin glargine were effective in reducing HbA1c levels in combination with other oral glucose lowering agents but pioglitazone caused fluid retention and increased levels of natriuretic peptides suggesting increased cardiac load (Papers II & IV). While pioglitazone improved insulin sensitivity and lipids, insulin glargine resulted in improved β-cell function (Paper IV). Pioglitazone also caused an increase in eye protrusion in a subgroup of patients, probably by causing an increase in retrobulbar adipogenesis (Paper III). Taken together, these results can hopefully help clinicians in the choice of novel add-on treatment and in monitoring of untoward side effects. GITT seems to be a promising tool for assessing insulin secretion and action in clinical practice.