The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

Silvestre, Marta P.; Vlaskovsky, P.; McMahon, Chris; Tay, Audrey; Poppitt, Sally D.

doi:10.1111/obr.12631

Cited by 13 publications

(7 citation statements)

References 74 publications

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“…Additionally, the FMO3 is suppressed by insulin, and also increased by glucagon37 which is secreted from pancreatic α-cells to promote the elevation of blood glucose 39. Both the suppression of glucagon and insulin resistance are in parallel with weight loss and act together to improve the glucose homeostasis following a weight-loss diet intervention 40. These previous studies support our observation that the association of TMAO with insulin sensitivity might be partially affected by adiposity.…”

Section: Discussionsupporting

confidence: 87%

Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial

Heianza

Sun

et al. 2018

Gut

136

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ObjectiveAlterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention.DesignWe included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated.ResultsGreater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids.ConclusionOur findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism.Trial registration numberNCT00072995.

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Section: Discussionsupporting

confidence: 87%

Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial

Heianza

Sun

et al. 2018

Gut

136

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“…Kramer et al hypothesized that cross‐reactivity of the glucagon assays with other PGDPs, especially oxyntomodulin, may have contributed to the difference in results 18 . In the current study, we used a state‐of‐the‐art, novel, well‐validated glucagon assay that did not cross‐react with oxyntomodulin, and showed a non‐differential decrease in glucagon concentrations during the MMTT after weight loss in both the placebo and actively treated groups, which is consistent with a previous weight‐loss trial 19 and a recent meta‐analysis showing a decrease in fasting glucagon after weight loss 20 . We also showed that MPGF is regulated in a manner similar to glucagon in humans.…”

Section: Discussionsupporting

confidence: 84%

“…Our study highlights that the changes in glucagon and MPGF may predominately occur through weight loss. Weight loss has pleiotropic effects and may alter alpha cell secretory products via improvements in insulin sensitivity and reduction in insulin concentration 19,20 or additional hormones. Decrease in glucagon concentration has also been suggested to be a defence mechanism to increase hunger during energy restriction 20 .…”

Section: Discussionmentioning

confidence: 99%

Effect of the glucagon‐like peptide‐1 analogue liraglutide versus placebo treatment on circulating proglucagon‐derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial

Kim

Nachmanoff

Stefanakis

et al. 2020

Diabetes Obesity Metabolism

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Aim To examine how circulating glucagon‐like peptide‐1 (GLP‐1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon‐derived peptides (PGDPs), including endogenous GLP‐1, glucagon‐like peptide‐2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. Materials and Methods Adults who were overweight/obese (body mass index 27‐40 kg/m2) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP‐1 agonist [GLP‐1A]) and endogenous (GLP‐1E) GLP‐1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady‐state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area‐under‐the‐curve (AUC) was calculated for ISR, glucose and levels of PGDPs. Results Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean −3.6%, 95% CI [−5.2% to −2.1%]), SSPG (−32% [−43% to −22%]) and glucose AUC (−7.0% [−11.5% to −2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP‐1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = −0.54) and SSPG (r = −0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP‐1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP‐1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP‐1 receptor agonists to decrease their endogenous production in contrast to weight loss‐dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. Conclusions Circulating GLP‐1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

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“…Furthermore, fasting plasma glucagon decreases in obese subjects after weight loss. Both bariatric surgery and dietary intervention result in comparable reduction in fasting plasma glucagon level [91].…”

Section: Excessive Glucagon Secretion Is Present In Subjects With Impmentioning

confidence: 97%

Metabolic effects of glucagon in humans

Adeva‐Andany¹,

Funcasta-Calderón²,

Fernández‐Fernández³

et al. 2019

Journal of Clinical & Translational Endocrinology

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Diabetes is a common metabolic disorder that involves glucose, amino acids, and fatty acids. Either insulin deficiency or insulin resistance may cause diabetes. Insulin deficiency causes type 1 diabetes and diabetes associated with total pancreatectomy. Glucagon produces insulin resistance. Glucagon-induced insulin resistance promotes type 2 diabetes and diabetes associated with glucagonoma. Further, glucagon-induced insulin resistance aggravates the metabolic consequences of the insulin-deficient state. A major metabolic effect of insulin is the accumulation of glucose as glycogen in the liver. Glucagon opposes hepatic insulin action and enhances the rate of gluconeogenesis, increasing hepatic glucose output. In order to support gluconeogenesis, glucagon promotes skeletal muscle wasting to supply amino acids as gluconeogenic precursors. Glucagon promotes hepatic fatty acid oxidation to supply energy required to sustain gluconeogenesis. Hepatic fatty acid oxidation generates β-hydroxybutyrate and acetoacetate (ketogenesis). Prospective studies reveal that elevated glucagon secretion at baseline occurs in healthy subjects who develop impaired glucose tolerance at follow-up compared with subjects who maintain normal glucose tolerance, suggesting a relationship between elevated glucagon secretion and development of impaired glucose tolerance. Prospective studies have identified animal protein consumption as an independent risk factor for type 2 diabetes and cardiovascular disease. Animal protein intake activates glucagon secretion inducing sustained elevations in plasma glucagon. Glucagon is a major hormone that causes insulin resistance. Insulin resistance is an established cardiovascular risk factor additionally to its pathogenic role in diabetes. Glucagon may be a potential link between animal protein intake and the risk of developing type 2 diabetes and cardiovascular disease.

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The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

Cited by 13 publications

References 74 publications

Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial

Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial

Effect of the glucagon‐like peptide‐1 analogue liraglutide versus placebo treatment on circulating proglucagon‐derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial

Metabolic effects of glucagon in humans

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