Impact of SGLT2 on Glucosuria in HNF1A-MODY

Study Overview
=================
Brief Summary
-----------------
Maturity onset diabetes of the young (MODY) is a subtype of diabetes which is caused by mutations in specific genes leading to diabetes. The most common cause of MODY is due to mutations in the gene hepatocyte nuclear factor 1 alpha (HNF1A) and is consequently named HNF1A-MODY (or MODY3). HNF1A-MODY is associated with urinary excretion of glucose at lower blood glucose levels compared to other types of diabetes. Normally, glucose is reabsorbed by sodium-glucose cotransporter 2 (SGLT2), but SGLT2 is downregulated due to the mutation in HNF1A. Investigators aim to evaluate the impact of the decreased expression of SGLT2 on glucosuria in patients with HNF1A-MODY compared to patients with type 2 diabetes (T2D) using a single dose of an SGLT2 inhibitor during a glucose clamp experiment.

Detailed Description
-----------------
Participants: Patients with HNF1A-MODY (n=12) and patients with T2D (n=12)

Official Title
-----------------
Impact of SGLT2 on Glucosuria in HNF1A-MODY

Conditions
-----------------
Maturity-Onset Diabetes of the Young, Type 3, Type 2 Diabetes

Intervention / Treatment
-----------------
* Other: Hyperglycaemic clamp
* Drug: Placebo
* Drug: Empagliflozin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years HNF1A-MODY verified by genetic testing (only patients with HNF1A-MODY) Type 2 diabetes diagnosis according to World Health Organization (only patients with type 2 diabetes) Treatment with diet and/or a glucose-lowering drug (only patients with HNF1A-MODY) Normal haemoglobin (males 8.3-10.5 mmol/l, females 7.3-9.5 mmol/l) Informed consent Exclusion Criteria: Nephropathy (estimated GFR <60 ml/min/1.73m2 and/or albuminuria) Known significant liver disease and/or plasma alanine aminotransferase (ALT) and/or plasma aspartate aminotransferase (AST) above 2 × normal values) Pregnancy or breastfeeding Treatment with SGLT2 inhibitor Fasting plasma glucose > 10 mmol/l Family history of HNF1A-MODY (only patients with type 2 diabetes)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HNF1A-MODY - SGLT2 inhibition<br>3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp) | Other: Hyperglycaemic clamp<br>* Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour)<br>Drug: Empagliflozin<br>* Single-dose, 25 mg, two hours before clamp<br>|
| Placebo Comparator: HNF1A-MODY - Placebo<br>3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin) | Other: Hyperglycaemic clamp<br>* Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour)<br>Drug: Placebo<br>* Placebo comparator to empagliflozin<br>|
| Active Comparator: Type 2 Diabetes - SGLT2 inhibition<br>3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp) | Other: Hyperglycaemic clamp<br>* Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour)<br>Drug: Empagliflozin<br>* Single-dose, 25 mg, two hours before clamp<br>|
| Placebo Comparator: Type 2 Diabetes - Placebo<br>3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin) | Other: Hyperglycaemic clamp<br>* Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour)<br>Drug: Placebo<br>* Placebo comparator to empagliflozin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary glucose excretion |  | Assesed during 3 hour hyperglycaemic clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary glucose excretion adjusted for glomerular filtration rate (GFR) | GFR: 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) plasma clearance | Assesed during 3 hour hyperglycaemic clamp | 
| Infused amount of glucose |  | Assesed during 3 hour hyperglycaemic clamp | 
| Urine volume |  | Assesed during 3 hour hyperglycaemic clamp | 
| Glucose tissue disposal | difference between infused and excreted glucose | Assesed during 3 hour hyperglycaemic clamp | 
| Urinary creatinine clearance | Urinary creatinine clearance calculated by plasma creatinine concentration and urinary creatinine excretion | Assesed during 3 hour hyperglycaemic clamp | 
| Concentration of plasma c-peptide | Summarized as area under the curve (AUC) | Assesed during 3 hour hyperglycaemic clamp | 
| Concentration of plasma glucagon | Summarized as AUC | Assesed during 3 hour hyperglycaemic clamp | 
| Renal threshold of glucose excretion | Estimated using plasma glucose concentrations, urinary glucose excretion and GFR | Assesed during 3 hour hyperglycaemic clamp | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sodium-Glucose Transporter 2, Sodium-Glucose Transporter 2 Inhibitors, Glycosuria