Clinical trial NCT04177303: Incretin Hormones in Type 1 Diabetes Mellitus;Effect of Metformin Treatment
Official title: Gut-derived Incretin Hormones in the Pathophysiology of Type 1 Diabetes Mellitus; Effect of Metformin Treatment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Keywords: Metformin
Incretin hormones
Inflammation
Microbiome
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2019-11-26
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pilot, mechanistic, phase 3, randomized, placebo-controlled, parallel designed, double-blinded clinical trial
Primary purpose: TREATMENT

Brief summary: Investigators aim is to conduct an RCT to study the effect of adjunct metformin treatment to insulin monotherapy in patients with type 1 diabetes, targeting the intestinal incretin secretion. The patients will be randomly allocated to metformin or placebo treatment for 4 months

Detailed description: Compared to the large armamentarium of antidiabetic agents for Type 2 Diabetes Mellitus (T2DM), the insulinocentric therapeutic approach in Type 1 Diabetes Mellitus (T1DM) has distracted the scientific perspective from the rise of novel therapies. Insulin monotherapy has long overshadowed the overall hormonal dysregulation that demarcates T1DM . In specific, the significance of the gut-derived incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide), which are implicated with glucose metabolism via the gut-pancreatic axis, has been merely addressed.

Investigators' goal in the current protocol is to delineate the glucoregulatory role of incretin hormones in T1DM and the therapeutic advantages of adjunct metformin treatment over insulin monotherapy. In the absence of such knowledge, the development of effective strategies to improve metabolic homeostasis and ameliorate complications in T1DM patients will remain problematic. The central hypothesis of the study is that metformin, as an incretin-secretagogue, will enhance postprandial incretin secretion in T1DM patients, which will be reflected in reduced glucagon secretion and improvement in glycemic volatility. Mechanistic insight will be provided through changes in specific amino acids and metabolites patterns, chronic inflammation and the microbiome composition.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* T1DM (Diagnosis of diabetes before the age of 35 years and insulin use within 1 year of diagnosis)
* Treatment with multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII)

Exclusion Criteria:

* Any cardiovascular disease within the last 3 months
* NYHA stage 3 or 4 heart failure
* Uncontrolled angina
* Liver failure \[AST\>135 IU/L or ALT\>129IU/L (3 x the upper normal limit)\] • Kidney failure or GFR\<60 ml/min/1.73m2
* Gastrointestinal disease or gastroparesis
* Prior diagnosis of cancer within 2 years
* Other medication that affect glucose metabolism within the last 3 months (metformin, SGLT2, GLP-1 analogues, amylin analogues, systemic glucocorticosteroids)
* Untreated or uncontrolled thyroid disease
* Pregnancy or breastfeeding
* Alcohol consumption \> 2-drinks per day or other substance abuse

Primary outcomes:
measure: Change in GLP-1 (glucagon like peptide) and GIP (gastric inhibitory peptide) postprandial secretion
timeFrame: 4 months
Secondary outcomes:
measure: Change in glycemic variability pre- and post- treatment
timeFrame: 4 months
measure: Metabolomic profile of each treatment group
timeFrame: 4 months
measure: Change in inflammatory state
timeFrame: 4 months
measure: Change in endothelial dysfunction
timeFrame: 4 months
measure: Change in cytokine production
timeFrame: 4 months
measure: Change in matrix metalloproteinase-9 (MMP-9) levels
timeFrame: 4 months
measure: Change in chemokine production
timeFrame: 4 months
measure: Change in gene expression
timeFrame: 4 months
measure: Change in gut microbiome analysis
timeFrame: 4 months
Other outcomes:
Locations:
city: Thessaloníki
country: Greece
facility: Diabetes Center, 1st Internal Medicine Department, AHEPA University General Hospital of Thessaloniki
state: Thessaloniki
Study officials:
affiliation: 1st Internal Medicine Department, AHEPA University Hospital
name: Kotsa Kalliopi, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: