Interleukin-6 regulates pancreatic α-cell mass expansion

Abstract

Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced ␤-cell function and mass, an increased proportion of ␣-cells relative to ␤-cells, and ␣-cell dysfunction. Here we show that the ␣ cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the ␣-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates ␣-cell proliferation, prevents apoptosis due to metabolic stress, and regulates ␣-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased ␣-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of ␣-cell mass display decreased fasting glucagon levels. However, despite these ␣-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic ␣-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional ␤-cell compensation to increased metabolic demand.alpha-cell mass ͉ beta-cell function ͉ high-fat diet ͉ pancreatic islet

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…Indeed, a direct action on β-cell function is improbable because the Glp2r mRNA transcripts have not been detected in pancreatic islets, but only in mouse whole pancreas (Bahrami et al 2010) or rat and human pancreatic α-cells (de Heer et al 2007). Despite exogenous GLP2 increases glucagon secretion (Meier et al 2006, de Heer et al 2007, elimination of GLP2R signalling in genetically obese mice leads to increased glucagon secretion and α-cell mass, which has been interpreted as due to increased proinflammatory signals (Bahrami et al 2010), for example interleukin-6, in turn, involved in α-cell mass expansion (Ellingsgaard et al 2008). Unluckily, glucagon levels were not measured in HFD-fed mice after GLP2 (3-33) or Gly 2 -GLP2 chronic treatment.…”

Myokines in insulin resistance and type 2 diabetes

“…Recent data from Ellingsgaard et al have shown that IL-6 increases proliferation of both alpha and beta cells and prevents apoptosis of alpha cells owing to metabolic stress (Table 1) [51]. Moreover, IL-6 promotes glucagon-like peptide-1 (GLP-1) secretion and production in intestinal L cells and pancreatic alpha cells, thereby leading to improved beta cell insulin secretion and glucose tolerance [52].…”

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Excessive nutrient intake, such as high-protein [87] or high-fat diets [88], has also been described as modulating beta and alpha cell morphology. Increased levels of IL-6 in type 2…”

“…Highest rate of beta cell proliferation [21,22] Increased insulin secretion, which is, in part, due to transient insulin resistance [44,45] Doubling of beta cell mass by 5 years of age [22] Several-fold increase in beta cell mass from birth to adulthood [50,51] Increase in beta cells per islet and in islet size [51,52] Evidence of beta cell neogenesis and a regenerative response in diabetes [53] Mature beta cells are sensitive to perturbations in cell cycle control [60] Pro-survival effects of lactogen hormones on beta cells [99,100] but not alpha cells [102] Cytoprotective effect of GLP-1 on beta cells [104] GIP stimulates glucagon secretion [113], while GLP-1 inhibits secretion [112] Increase in beta cell mass reported in obesity [119] Reduction in beta cell mass and relative increase in alpha cell mass in diabetes [74] Decline in beta cell function; decline in beta cell replication Beta cell mass remains relatively constant in healthy humans [121] No major alterations in beta cell size [120] Beta cell apoptosis is low and remains constant throughout life [21] In diabetes: Mitochondrial dysfunction, oxidative stress, ER stress and accumulation of intermediate-sized amyloid particles [127] Neonatal age Puberty Adolescence Adulthood Old age diabetes coupled with high expression of IL-6 receptors on alpha cells suggest that this cytokine could contribute to the increased alpha cell mass observed in diabetes [88]. This notion is supported by fasting hypoglucagonaemia and an inability of mice lacking IL-6 to increase their alpha cell mass.…”