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