Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia

Junker, Anders E; Gluud, Lise Lotte; Holst, Jens J.; Knop, Filip K.; Vilsbøll, Tina

doi:10.1111/joim.12462

Cited by 68 publications

(61 citation statements)

References 51 publications

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“…Despite reduced L-cell density, enteroendocrine function seemed to be preserved through higher intracellular GLP-1 content. Recent papers showed that during OGTT in various types of metabolic diseases, GLP-1 release is delayed along with prolongation of the postprandial hyperglycaemia [24], [25], [26]. In our study, GLP-1 secretion was measured belatedly, 30 min after GLP-1 secretagogue administration.…”

Section: Discussionmentioning

confidence: 63%

Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Schmitt

Aranias

Viel

et al. 2017

Molecular Metabolism

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ObjectiveIntestinal glucose absorption is orchestrated by specialized glucose transporters such as SGLT1 and GLUT2. However, the role of GLUT2 in the regulation of glucose absorption remains to be fully elucidated.MethodsWe wanted to evaluate the role of GLUT2 on glucose absorption and glucose homeostasis after intestinal-specific deletion of GLUT2 in mice (GLUT2ΔIEC mice).ResultsAs anticipated, intestinal GLUT2 deletion provoked glucose malabsorption as visualized by the delay in the distribution of oral sugar in tissues. Consequences of intestinal GLUT2 deletion in GLUT2ΔIEC mice were limiting body weight gain despite normal food intake, improving glucose tolerance, and increasing ketone body production. These features were reminiscent of calorie restriction. Other adaptations to intestinal GLUT2 deletion were reduced microvillus length and altered gut microbiota composition, which was associated with improved inflammatory status. Moreover, a reduced density of glucagon-like peptide-1 (GLP-1) positive cells was compensated by increased GLP-1 content per L-cell, suggesting a preserved enteroendocrine function in GLUT2ΔIEC mice.ConclusionsIntestinal GLUT2 modulates glucose absorption and constitutes a control step for the distribution of dietary sugar to tissues. Consequently, metabolic and gut homeostasis are improved in the absence of functional GLUT2 in the intestine, thus mimicking calorie restriction.

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Section: Discussionmentioning

confidence: 63%

Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Schmitt

Aranias

Viel

et al. 2017

Molecular Metabolism

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“…Consistent with this proposed feedback loop, individuals with glucagon-producing tumours have decreased levels of plasma amino acids [11,31], and, conversely, individuals with glucagon receptor mutations [10,32,33] and mice with glucagon receptor deficiency [30,34] exhibit increased levels of plasma amino acids. Hyperglucagonaemia has also been reported in individuals with fatty liver disease independent of their glycaemic status [35], and this has recently been linked to an increased plasma pool of amino acids including alanine, but excluding the BCAAs isoleucine, leucine and valine [36].…”

Section: Discussionmentioning

confidence: 99%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

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Aims/hypothesis The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon. Methods To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance. Results Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. Conclusions/interpretation This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

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“…The impact of glucagon on NAFLD has not been elucidated. Junker and colleagues [109] have shown that patients with NAFLD have fasting hyperglucagonemia, independent of their glucose tolerance status. According to the authors, this finding suggests that NAFLD might be involved in the generation of hyperglucagonemia in T2D, which is supported by several animal studies [110].…”

Section: Pancreatic Hormones and Nafldmentioning

confidence: 99%

Pathophysiology of Non Alcoholic Fatty Liver Disease

Petta

Gastaldelli

Rebelos

et al. 2016

IJMS

144

105

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The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.

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Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia

Abstract: Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Cited by 68 publications

References 51 publications

Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Pathophysiology of Non Alcoholic Fatty Liver Disease

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