Metformin is the only approved oral agent for youth with type 2 diabetes (T2D), but its mechanism of action remains controversial. Recent data suggests a primary role for the entero-insular instead of the gluconeogenic pathway, but there is no data in youth, in whom metformin efficacy is ∼50%. Our objectives were to: (1) compare incretin concentrations, glucagon-like 1 peptide (GLP-1) and gastric inhibitory polypeptide (GIP) in 12 youth with T2D not on metformin to 10 healthy age and BMI-matched controls, and (2) determine the change in incretins and gluconeogenesis (GNG) after 3 months of metformin in 8 youth with T2D. Intact GLP-1 and total GIP were measured at 0 and 2-hour during a 75g OGTT and basal GNG (2H20) and glucose production (6,62H2glucose) measured after an overnight fast. Compared to controls, youth with T2D before metformin had higher HbA1c and glucose levels and lower fasting and 2-hour GLP-1 (P<0.05 Table). After metformin, HbA1c decreased and fasting GLP-1 increased but there was no change in BMI, GNG or glucose production (P>0.1 Table). Post-metformin GLP-1 was comparable to levels in controls (P>0.1). There was no difference in GIP between youth with and without T2D and no change with metformin. Overall, improved glycemic control with short-term metformin in youth was associated with increased GLP-1 concentrations independent of changes in BMI and GNG supporting an entero-insular mechanistic pathway.

Disclosure

C.K. Cravalho: None. A.G. Meyers: None. L. Mabundo: None. A.B. Courville: None. S. Bernstein: None. Y. Dai: None. M. Walter: None. S. Chacko: None. M.W. Haymond: Advisory Panel; Self; Daiichi Sankyo Company, Limited, Zealand Pharma A/S. Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca. S.T. Chung: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases

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