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CONTEXT: Abnormal brain glucose metabolism may cause cognitive disease in type 2 diabetes, yet the relation between insulin resistance and brain glucose metabolism has not been systematically described. OBJECTIVE: We evaluated the impact of metabolic condition (fasting vs insulin stimulation, e.g., from hyperinsulinemic clamp) on the association between insulin resistance of different etiologies and brain glucose metabolism. DATA SOURCES: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception until February 2022. STUDY SELECTION: Of 656 unique records, we deemed thirty-one eligible. Criteria were studies assessing brain glucose metabolism (uptake or metabolic rate) by 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography ([18F]-FDG-PET) in individuals characterized by measures of or clinical proxies for insulin resistance (e.g., type 2 diabetes and obesity). DATA EXTRACTION: Two independent investigators extracted data and assessed study quality. DATA SYNTHESIS: We applied random-effects models to pool Hedge's g standardized mean differences. Insulin resistance was associated with decreased brain glucose metabolism during fasting (-0.47SD, 95%CI: -0.73 to -0.22, p<0.001, I2=71%) and increased metabolism during insulin stimulation (1.44SD, 95%CI: 0.79 to 2.09, p=0.002, I2=43%). Contrary to type 2 diabetes and other insulin resistance-related conditions, obesity was not associated with brain hypometabolism in fasting states (0.29SD, 95%CI: -0.81 to 1.39). CONCLUSIONS: Metabolic conditions modify associations between insulin resistance and brain glucose metabolism, i.e. most individuals with insulin resistance display hypometabolism during fasting and hypermetabolism during insulin stimulation.
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Increased plasma levels of glucagon (hyperglucagonaemia) promote diabetes development but is also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance towards amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, consisting of two study days: a glucagon injection and measurements of plasma amino acids, and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The delta-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (p=0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (p<0.0001), but not T1D (p>0.99). In contrast, glucagon-induced glucose increments were similar in controls and MASLD (p=0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.
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Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2â¯mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.
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Hormônio Adrenocorticotrópico , Glucagon , Glicopeptídeos , Humanos , Glicopeptídeos/metabolismo , Glucagon/metabolismo , Glucagon/sangue , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Masculino , Adulto , Feminino , Hipófise/metabolismo , Hipófise/efeitos dos fármacos , Hidrocortisona/sangue , Receptores de Glucagon/metabolismo , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/sangue , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases. METHODS: We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model. RESULTS: FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver. CONCLUSION: The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.
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Fatores de Crescimento de Fibroblastos , Glucagon , Fator 15 de Diferenciação de Crescimento , Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/sangue , Glucagon/sangue , Glucagon/metabolismo , Animais , Humanos , Camundongos , Masculino , Feminino , Adulto , Insulina/farmacologia , Insulina/sangue , Insulina/metabolismo , Pessoa de Meia-Idade , Fígado/metabolismo , Fígado/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/sangue , Obesidade/metabolismo , Camundongos Endogâmicos C57BL , Fígado Gorduroso/metabolismo , Sobrepeso/metabolismoRESUMO
BACKGROUND: Plasma concentrations of glucagon, GLP-1 and GIP are reported in numerous clinical trials as outcome measures but preanalytical guidelines are lacking. We addressed the impact of commonly used blood containers in metabolic research on measurements of glucagon, GLP-1 and GIP in humans. METHODS: Seventeen overweight individuals were subjected to an overnight fast followed by an intravenous infusion of amino acids to stimulate hormonal secretion. Blood was sampled into five containers: EDTA-coated tubes supplemented with DMSO (control), a neprilysin inhibitor, aprotinin (a kallikrein inhibitor) or a DPP-4 inhibitor, and P800 tubes. Plasma was kept on ice before and after centrifugation and stored at -80 Celsius until batch analysis using validated sandwich ELISAs or radioimmunoassays (RIA). RESULTS: Measures of fasting plasma glucagon did not depend on sampling containers, whether measured by ELISA or RIA. Amino acid-induced hyperglucagonemia was numerically higher when blood was collected into P800 tubes or tubes with aprotinin. The use of p800 tubes resulted in higher concentrations of GLP-1 by RIA compared to control tubes but not for measurements with sandwich ELISA. Plasma concentrations of GIP measured by ELISA were higher in control tubes and negatively affected by P800 and the addition of aprotinin. CONCLUSIONS: The choice of blood containers impacts on measurements of plasma concentrations of glucagon, GLP-1 and GIP, and based on this study, we recommend using EDTA-coated tubes without protease inhibitors or P800 tubes for measurements of glucagon, GLP-1 and GIP in clinical trials.
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Peptídeo 1 Semelhante ao Glucagon , Glucagon , Humanos , Glucagon/metabolismo , Aprotinina , Ácido Edético , Polipeptídeo Inibidor Gástrico/metabolismo , Glicemia/análise , Insulina , Fragmentos de PeptídeosRESUMO
Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
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A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥ 25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.
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Glucagon , Hepatopatia Gordurosa não Alcoólica , Humanos , Glucagon/metabolismo , Estudos Transversais , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , AminoácidosRESUMO
Glucagon is a key regulator of metabolism and is used in the diagnostic of neuroendocrine tumors. Accurate measurement of glucagon requires both extreme sensitivity and specificity since several peptides are derived from the same proglucagon precursor encoding part of the glucagon sequence and given that glucagon circulates in picomolar concentrations. A sandwich ELISA was recently developed and extensively evaluated; however, this method may not be accurate when measuring glucagon in patients with an enhanced production of proglucagon-derived peptides as seen after Roux-en-Y gastric bypass (RYGB). To overcome this, a modified version of the ELISA was developed. In this study, we evaluate an unmodified and a modified version of the ELISA in healthy individuals, individuals with obesity, and finally in two cohorts of patients following RYGB surgery using different nutrient stimuli to assess glucagon dynamics. Finally, in vitro spike-in recoveries using native glucagon and proglucagon-derived peptides were performed in buffer and in plasma. Our data support that both versions of the ELISA accurately capture endogenous and exogenous glucagon in healthy individuals and in individuals with obesity. However, the unmodified version of the assay may overestimate glucagon levels in patients following RYGB in line with minimal but consistent cross-reactivity to oxyntomodulin and glicentin that both are 50-fold increased after RYGB. Importantly, we did not find any changes between the two protocols at fasted conditions and therefore diagnostics of glucagonomas is not affected by the choice of assay procedure nor the surgical history of the patient (RYGB).