Incretin hormones and maturity onset diabetes of the young--pathophysiological implications and anti-diabetic treatment potential.

Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride in 16 patients with HNF1A-diabetes. At baseline and at the end of each treatment period a standardised meal test followed by a light bicycling test was performed. The results of the studies showed that patients with HNF1A-diabetes were less glucose tolerant than patients with GCK-diabetes, but both groups were more glucose intolerant than CTRLs. In spite of glucose intolerance patients with GCK-diabetes showed normal incretin effect, whereas patients with HNF1A-diabetes showed an impaired incretin effect. Patients with HNF1A-diabetes were also characterised by an inappropriate insulin response. Normal insulin sensitivity was found in both groups of diabetes patients. In the prospective intervention trial a glucose lowering effect on fasting plasma glucose (FPG) was demonstrated with both treatments without significant difference between the treatments. The postprandial plasma glucose responses were also lower with both glimepiride and liraglutide compared to baseline without significant difference between treatments. In spite of these findings glimepiride seems to have superior glucose lowering effects according to both FPG and postprandial glucose responses. Hypoglycaemic events (plasma glucose ≤ 3.9 mM) occurred 18 times during glimepiride treatment and once during liraglutide treatment. No differences between treatments were demonstrated according to insulin and glucagon responses and gastric emptying, and counter-regulatory responses were preserved during both treatments. No effect of either treatment was seen on fructosamine or HbA1c. In conclusion, patients with GCK-diabetes show normal incretin and glucagon physiology, thus resembling healthy individuals, in spite of fasting hyperglycaemia and subtle glucose intolerance. In contrast, patients with HNF1A-diabetes exhibited noticeable glucose intolerance, beta cell dysfunction, impaired incretin effect, and inappropriate glucagon response to oral stimuli, hence resembling patients with type 2 diabetes. However, normal responses of incretin hormones and normal insulin sensitivity were found in patients with HNF1A-diabetes. Six weeks of treatment with glimepiride or liraglutide demonstrated glucose lowering effects. This effect was greater with glimepiride, although insignificant, but at the expense of a higher risk of hypoglycaemia (predominantly mild). GLP-1RAs may have a place in treatment of patients with HNF1A-diabetes, especially when hypoglycaemia is a problem. Future studies are required to clarify this.