Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4379-4393. https://doi.org/10.1172/JCI90004.
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Research Article Endocrinology Metabolism

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Abstract

Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell–mass maintenance.

Authors

Nadejda Bozadjieva, Manuel Blandino-Rosano, Jennifer Chase, Xiao-Qing Dai, Kelsey Cummings, Jennifer Gimeno, Danielle Dean, Alvin C. Powers, George K. Gittes, Markus A. Rüegg, Michael N. Hall, Patrick E. MacDonald, Ernesto Bernal-Mizrachi

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Figure 6

mTORC1 regulates glucagon secretion by alterations in KATP channel expression and activity.

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mTORC1 regulates glucagon secretion by alterations in KATP channel expre...
Glucagon response from isolated islets to (A) KCl (30 mM) (n = 8 mice) and (B) arginine (ARG, 20 mM) (n = 8 mice) under low-glucose (LG, 1 mM) Krebs buffer. Glucagon response in isolated islets to increasing concentrations of (C) tolbutamide (0–100 μM) under low-glucose conditions (n = 3–4 mice), (D) diazoxide (0–100 μM) under high-glucose (6 mM) conditions (n = 5–8 mice), and (E) diazoxide (0–100 μM) under low-glucose conditions (n = 7–11 mice). (F) KATP channel activity during washout of intracellular ATP and (G) current amplitude quantification at 180 seconds in α cells from control and αRaptorHET mice (n = 30–41 cells from 3–4 mice). (H) RNA expression of SUR1 and Kir6.2 in FACS-enriched α cell population from control and αRaptorHET mice (n = 6). (I) Single-cell analysis of SUR1 expression frequency in α cells from 1-month-old control and αRaptorKO mice (n = 20–21 cells from 3–4 mice). (J) RNA expression (n = 7–8) and (K) protein levels of SUR1 and KIR6.2 from αTC-1 cells treated with vehicle or rapamycin (30 nM) for 48 hours (n = 7). All secretion assays (A–E) represent results from 2–3 independent experiments. Data are presented as fold change and shown as means ± SEM. *P ≤ 0.05 (Student’s 2-tailed t test).