The Effects of GLP-1 in Maturity-Onset Diabetes of The Young (MODY)

The purpose of this study is to evaluate the treatment potential of GLP-1-analogues in patients with Maturity Onset Diabetes of the Young (MODY) compared to common treatment.

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes responsible for approximately 1-2% of all cases of diabetes. The disease is clinically defined by: 1) autosomal dominant inheritance (diabetes for at least two consecutive generations), 2) non-insulin dependent diabetes at onset (or measurable serum C-peptide three years after onset), and 3) diagnosis in a young age (at least one family member with onset before the age of 25 years). Clinically, MODY-patients resemble patients with type 2 diabetes (T2DM) more than patients with type 1 diabetes mellitus (T1DM). MODY is genetically heterogeneous, with known mutations in eight different genes and mutations in either of these genes leads to specific forms of MODY. Based on a national epidemiological survey, we know that in Denmark, approximately 50% of patients who are diagnosed with MODY have mutations in the hepatocyte nuclear factor (HNF) 4 alpha (HNF4A) (MODY1), glucokinase (GCK) (MODY2), or HNF1A (MODY3) genes.

MODY3 is the most common form of MODY in Denmark (approximately 60% of all patients with MODY). Patients with MODY3 are often diagnosed around puberty, more than 50% of mutation carriers will develop diabetes before the age of 25, and the lifetime risk of developing diabetes is higher than 95%. The typical course of disease is characterised by a rapid progression from impaired glucose tolerance to diabetes. After the diagnosis of diabetes, the glucose tolerance is further impaired due to a continuous loss of beta cell function. MODY3 often develops abruptly with classic hyperglycaemic symptoms such as polyuria and polydipsia, which is why this form of diabetes is often misclassified as T1DM. Patients with MODY3 have the same risk of developing microvascular and macrovascular late diabetic complications as patients with T2DM, and, strict glycaemic control combined with proper screening for diabetic late complications is crucial for a good prognosis.

About half of MODY3 patients are treated with diet or oral antidiabetic agents, the latter mostly in the form of sulphonylureas (SU), which, if possible is preferred to insulin injections. Due to a high sensitivity to SU combined with normal or even increased insulin sensitivity (MODY3 patients are more insulin sensitive than age- and body mass index (BMI)-matched patients with T2DM), this treatment is often associated with hypoglycaemia even when rather low doses of SU are used. Although SU treatment offhand seems to constitute a logical choice of treatment in MODY, due to beta cell dysfunction, the risk of hypoglycaemia is a clinical drawback due to potential suboptimal glycaemic control and decreased patient compliance. In a recent study, in which patients with MODY3 were exposed to physical activity (light cycling for 30 minutes approximately 2 hours after meal ingestion), hypoglycaemia was observed in 40% of subjects treated with short-acting SU (glibenclamide) with one patient experiencing hypoglycaemia for 12 hours.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which is secreted from endocrine L cells of the small intestine in response to nutrients in the gut lumen. GLP-1 conveys an insulinotropic effect through GLP-1 receptors (GLP-1R) on pancreatic beta cells thereby decreasing plasma glucose (PG). Moreover, GLP-1 inhibits the secretion of glucagon from pancreatic alpha cells, which further contributes to lowering of the PG levels. Both of these effects are strictly glucose-dependent (more pronounced at higher PG levels) and the effects cease as PG levels reaches values below 4-5 mM. Therefore, the hormones keep PG at normal levels without increasing the risk of hypoglycaemia. In addition, GLP-1 inhibits gastrointestinal motility including gastric emptying and leads to a centrally-mediated inhibition of appetite resulting in reduced food intake. Thus, GLP-1 is essential for glycaemic control. The GLP-1R agonist, liraglutide (Victoza®), has 97% homology to the naturally occurring GLP-1 hormone, but has a longer half-life (11-15 hours).

Since the effects of the incretin hormones are strictly glucose-dependent, treatment with GLP-1R agonists is rarely associated with hypoglycaemia. Thus, the current study aims to elucidate whether liraglutide (Victoza®) could be a safe and efficacious new treatment modality for patients with MODY.

Eligibility Criteria:
Inclusion Criteria:

* Caucasian above 18 years of age
* Well characterised MODY3
* Body mass index (BMI) \> 19 kg/m2
* Normal haemoglobin (males \> 8.2 mM, females \> 7.2 mM)
* Normal blood pressure (\< 160/100 mmHg)
* Informed consent
* Capability to perform a light cycling test (heart rate 100-120 beats per minute during 30 minutes)
* Females: use of anticonception (IUC or hormonal)

Exclusion Criteria:

* Heart failure: New York Heart Association class III-IV
* Uraemia, end-stage renal disease, or any other cause of impaired renal function with s-creatinine \> 130 µM and/or albuminuria
* Liver disease (alanine amino transferase (ALAT) and/or aspartate amino transferase (ASAT) \> 2 × upper normal serum levels)
* Anaemia
* Acute or chronic pancreatitis
* Stroma or thyroid cancer
* Pregnancy or breast feeding
* Inability to complete the study
* Treatment naïve patients with HbA1c \< 7.0 %
* Treatment with medicine that can not be paused for 12 hours
* Known allergic reaction to study medication
* Intention to become pregnant
* Unwillingness to complete the protocol