Glucose intolerance in monosodium glutamate obesity is linked to hyperglucagonemia and insulin resistance in α cells

• Published in: Journal of cellular physiology 2019-05, Vol.234 (5), p.7019-7031
• Main Authors: Araujo, Thiago R., da Silva, Joel A., Vettorazzi, Jean F., Freitas, Israelle N., Lubaczeuski, Camila, Magalhães, Emily A., Silva, Juliana N., Ribeiro, Elane S., Boschero, Antonio C., Carneiro, Everardo M., Bonfleur, Maria L., Ribeiro, Rosane Aparecida
• Format: Article
• Language: English
• Subjects: Adipose Tissue, White - metabolism; Animals; Biomarkers - blood; Blood glucose; Blood Glucose - metabolism; Body weight; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; Glucagon; Glucagon - blood; glucagon secretion; Glucagon-Secreting Cells - metabolism; Glucose; Glucose Intolerance - blood; Glucose Intolerance - chemically induced; Glucose Intolerance - physiopathology; Glucose tolerance; hepatic glucose output; Immunoreactivity; Insulin; Insulin - blood; Insulin Resistance; Intolerance; Kinases; Lipase; lipolysis; Liver - metabolism; Male; Mice; Monosodium glutamate; Mouse devices; Obesity; Obesity - blood; Obesity - chemically induced; Obesity - physiopathology; Phosphoenolpyruvate Carboxykinase (ATP) - metabolism; Phosphorylation; Protein kinase A; Proteins; Rapamycin; Sodium Glutamate; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27455

Obesity predisposes to glucose intolerance and type 2 diabetes (T2D). This disease is often characterized by insulin resistance, changes in insulin clearance, and β‐cell dysfunction. However, studies indicate that, for T2D development, disruptions in glucagon physiology also occur. Herein, we investigated the involvement of glucagon in impaired glycemia control in monosodium glutamate (MSG)‐obese mice. Male Swiss mice were subcutaneously injected daily, during the first 5 days after birth, with MSG (4 mg/g body weight [BW]) or saline (1.25 mg/g BW). At 90 days of age, MSG‐obese mice were hyperglycemic, hyperinsulinemic, and hyperglucagonemic and had lost the capacity to increase their insulin/glucagon ratio when transitioning from the fasting to fed state, exacerbating hepatic glucose output. Furthermore, hepatic protein expressions of phosphorylated (p)‐protein kinase A (PKA) and cAMP response element‐binding protein (pCREB), and of phosphoenolpyruvate carboxykinase (PEPCK) enzyme were higher in fed MSG, before and after glucagon stimulation. Increased pPKA and phosphorylated hormone‐sensitive lipase content were also observed in white fat of MSG. MSG islets hypersecreted glucagon in response to 11.1 and 0.5 mmol/L glucose, a phenomenon that persisted in the presence of insulin. Additionally, MSG α cells were hypertrophic displaying increased α‐cell mass and immunoreactivity to phosphorylated mammalian target of rapamycin (pmTOR) protein. Therefore, severe glucose intolerance in MSG‐obese mice was associated with increased hepatic glucose output, in association with hyperglucagonemia, caused by the refractory actions of glucose and insulin in α cells and via an effect that may be due to enhanced mTOR activation. Neonatal treatment with monosodium glutamate (MSG) induces obesity and impaired body glucose control at adulthood in mice. We demonstrated that pancreatic α cells of MSG mice did not suppress glucagon release in response to increased glucose and insulin levels, leading to hyperglucagonemia and the loss of capacity to enhance insulin/glucagon ratio in the fed state. Hyperglucagonemia in turn exacerbates hepatic glucose production, impairing glucose clearance, and homeostasis in MSG mice. Since increased phosphorylated mammalian target of rapamycin (pmTOR) immunoreactivity was detected in MSG α cells, this protein may account for the α‐cell dysfunction, hypertrophy and enlarged mass. Therefore, these data indicate that both β and α cells must be con