Metformin treatment and gastrointestinal symptoms in youth: Findings from a large tertiary care referral center.

OBJECTIVES: Metformin is the only oral therapy for youth with type 2 diabetes, but up to 50% require additional agents within 2 years of diagnosis. Extended-release (XR) metformin formulations may improve adherence and tolerability-important mediators of treatment response-but data in youth is lacking. To evaluate rates of gastrointestinal (GI) symptoms in patients treated with metformin (SR and XR) and the change in GI symptoms after changes in metformin therapy. RESEARCH DESIGN AND METHODS: Retrospective chart review of youth with Type 2 or prediabetes seen in a multidisciplinary clinic during 2016-2019. RESULTS: Of 488 eligible patients, 41.4% and 21.1% were taking metformin SR and XR respectively, with most (58%, n = 178/305) taking a total daily dose of ≥1500 mg/day. Those not on metformin tended to be younger, leaner, and had lower HbA1cs than those taking metformin, p < 0.05. Thirty percentage of patients described GI symptoms, most commonly, abdominal pain and diarrhea. There was no difference in GI symptoms in those on SR versus XR (18.3% vs. 14.6%, p = 0.41). Among patients who initiated metformin, rates of GI symptoms increased (13%-33%, p = 0.001, n = 99), while rates tended to decrease when metformin was discontinued (28%-12%, p = 0.076, n = 50). Rates of GI symptoms were unchanged among those that switched from SR to XR metformin (17% vs. 14%, p = 0.6, n = 58). CONCLUSIONS: GI symptoms are common in youth with type 2 diabetes taking metformin XR and SR. Adjuncts to mitigate GI symptoms in youth on metformin therapy are needed to improve quality of life and medication adherence.

Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance.

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are "by products" of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = -0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = -0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT:02960659.

Measuring Insulin Resistance in Humans.

BACKGROUND: Insulin resistance is a pathophysiological condition associated with diabetes and cardiometabolic diseases that is characterized by a diminished tissue response to insulin action. Our understanding of this complex phenomenon and its role in the pathogenesis of cardiometabolic diseases is rooted in the discovery of insulin, its isolation and purification, and the challenges encountered with its therapeutic use. SUMMARY: In this historical perspective, we explore the evolution of the term "insulin resistance" and demonstrate how advances in insulin and glucose analytics contributed to the recognition and validation of this metabolic entity. We identify primary discoveries which were pivotal in expanding our knowledge of insulin resistance, the challenges in measurement and interpretation, contemporary techniques, and areas of future exploration. Key Message: Measurements of insulin resistance are important tools for defining and treating cardiometabolic diseases. Accurate quantification of this pathophysiological entity requires careful consideration of the assumptions and pitfalls of the methodological techniques and the historical and clinical context when interpreting and applying the results.