Dataset Information

Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.

ABSTRACT: The therapeutic mechanism of metformin action remains incompletely understood. Whether metformin inhibits glucagon-stimulated endogenous glucose production (EGP), as in preclinical studies, is unclear in humans. To test this hypothesis, we studied nine prediabetic individuals using a randomized, placebo-controlled, double-blinded, crossover study design. Metformin increased glucose tolerance, insulin sensitivity, and plasma glucagon. Metformin did not alter average basal EGP, although individual variability in EGP correlated with plasma glucagon. Metformin increased basal EGP in individuals with severe hyperglucagonemia (>150 pg/ml). Decreased fasting glucose after metformin treatment appears to increase glucagon to stimulate EGP and prevent further declines in glucose. Similarly, intravenous glucagon infusion elevated plasma glucagon (>150 pg/ml) and stimulated a greater increase in EGP during metformin therapy. Metformin also counteracted the protein-catabolic effect of glucagon. Collectively, these data indicate that metformin does not inhibit glucagon-stimulated EGP, but hyperglucagonemia may decrease the ability of the metformin to lower EGP in prediabetic individuals.

SUBMITTER: Konopka AR

PROVIDER: S-EPMC4871720 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.

Konopka Adam R AR Esponda Raul Ruiz RR Robinson Matthew M MM Johnson Matthew L ML Carter Rickey E RE Schiavon Michele M Cobelli Claudio C Wondisford Fredric E FE Lanza Ian R IR Nair K Sreekumaran KS

Cell reports 20160505 7

The therapeutic mechanism of metformin action remains incompletely understood. Whether metformin inhibits glucagon-stimulated endogenous glucose production (EGP), as in preclinical studies, is unclear in humans. To test this hypothesis, we studied nine prediabetic individuals using a randomized, placebo-controlled, double-blinded, crossover study design. Metformin increased glucose tolerance, insulin sensitivity, and plasma glucagon. Metformin did not alter average basal EGP, although individual ...[more]

PMID: 27160898

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Project description:The goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic β-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic β-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic β-cell function. Patients in the LM group had a reduction in weight (-1.7 ± 0.6, p < 0.05) and body mass index (BMI, -0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (-4425 ± 871 vs -1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic β-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic β-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic β-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461.

Dataset Information

Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.

Publications

Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.

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