GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent

Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans

The molecular transducers of benefits from different exercise modalities remain incompletely defined. Here we report that 12\ua0weeks of high-intensity aerobic interval (HIIT), resistance (RT), and combined exercise training enhanced insulin sensitivity and lean mass, but only HIIT and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration. HIIT revealed a more robust increase in\ua0gene transcripts than other exercise modalities, particularly in older adults, although little overlap with corresponding individual protein abundance was noted. HIIT reversed many age-related differences in the proteome, particularly of mitochondrial proteins in concert with increased mitochondrial protein synthesis. Both RT and HIIT enhanced proteins involved in translational machinery irrespective of age. Only small changes of methylation of DNA promoter regions were observed. We provide evidence for predominant exercise regulation at the translational level, enhancing translational capacity and proteome abundance to explain phenotypic gains in muscle mitochondrial function and hypertrophy in all ages

Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes

Summary: 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. : Using a randomized, double-blinded, placebo-controlled, crossover study design in prediabetic individuals, Konopka et al. show that metformin improves fasting and postprandial glycemia without inhibiting glucagon-stimulated glucose production as reported in preclinical studies. During metformin therapy, increased glucagon and glucogenic precursors may maintain glucose production to prevent hypoglycemia

Erratum: Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes (Cell Reports (2016) 15(7) (1394–1400) (S2211124716304375) (10.1016/j.celrep.2016.04.024))

(Cell Reports 15, 1394–1400; May 17, 2016) In the originally published version of this article, the labels “Placebo” and “Metformin” were mistakenly switched in Table S2, which displayed plasma concentrations of amino acids. We have corrected this error as well as the following additional errors, which we would like to bring to the attention of the readers: 1. The third bullet point within the Highlights now reads “…metformin increases glucogenic amino acids …” rather than “… metformin decreases glucogenic amino acids …”2. The last sentence of the In Brief blurb now reads “… increased glucagon and glucogenic precursors” rather than “increased glucagon and decreased glucogenic precursors” (the word “decreased” was removed).3. In paragraph 6, line 21 of page 1396, the text now reads “.. including decreased metabolites of the urea pathway …” rather than “including elevated metabolites of the urea pathway”4. In paragraph 6, line 26 of page 1396, the text now reads “.. revealed an increase in glucogenic AAs” rather than “.. revealed a decline in glucogenic AAs”Although amino acid metabolites are not the primary outcome of the work described in this paper and these errors do not alter the main conclusions outlined therein, the authors regret the errors

Predictors of whole-body insulin sensitivity across ages and adiposity in adult humans

Context: Numerous factors are purported to influence insulin sensitivity incluDing age, adiposity, mitochondrial function, and physical fitness. Univariate associations cannot address the complexity of insulin resistance or the interrelationship among potential determinants. Objective: The objective of the study was to identify significant independent predictors of insulin sensitivity across a range of age and adiposity in humans. Design, Setting, and Participants: Peripheral and hepatic insulin sensitivity were measured by two stage hyperinsulinemic-euglycemic clamps in 116 men and women (aged 19-78 y). Insulin-stimulated glucose disposal, the suppression of endogenous glucose production during hyperinsulinemia, and homeostatic model assessment of insulin resistance were tested for associations with 11 potential predictors. Abdominal subcutaneous fat, visceral fat (AFVISC), intrahepatic lipid, and intramyocellular lipid (IMCL) were quantified by magnetic resonance imaging and spectroscopy. Skeletal muscle mitochondrial respiratory capacity (state 3), coupling efficiency, and reactive oxygen species production were evaluated from muscle biopsies. Aerobic fitness was measured from whole-body maximum oxygen uptake (VO2 peak), and metabolic flexibility was determined using indirect calorimetry. Results: Multiple regression analysis revealed that AFVISC (P .0001) and intrahepatic lipid (P < .002)wereindependent negative predictors of peripheral insulin sensitivity, whereasVO2peak(P .0007) and IMCL (P.023) were positive predictors. Mitochondrial capacity and efficiency were not independent determinants of peripheral insulin sensitivity. The suppression of endogenous glucose production during hyperinsulinemia model of hepatic insulin sensitivity revealed percentage fat (P.0001) andAFVISC (P.001) as significant negative predictors. Modeling homeostatic model assessment of insulin resistance identified AFVISC (P .0001), VO2 peak (P < .001), and IMCL (P < .01) as independent predictors. Conclusion: The reduction in insulin sensitivity observed with aging is driven primarily by agerelated changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age

GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent

GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk1,2. Over 60% of this effect is attributable to metformin’s ability to lower body weight in a sustained manner3. The molecular mechanisms through which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent