Time-dependent effects of endogenous hyperglucagonemia on glucose homeostasis and hepatic glucagon action
Camila Lubaczeuski, Nadejda Bozadjieva-Kramer, Ruy A. Louzada, George K. Gittes, Gil Leibowitz, Ernesto Bernal-Mizrachi
Camila Lubaczeuski, Nadejda Bozadjieva-Kramer, Ruy A. Louzada, George K. Gittes, Gil Leibowitz, Ernesto Bernal-Mizrachi
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Research Article Endocrinology Metabolism

Time-dependent effects of endogenous hyperglucagonemia on glucose homeostasis and hepatic glucagon action

Abstract

Elevation of glucagon levels and increase in α cell proliferation is associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications for understanding abnormal responses to hypoglycemia in patients with diabetes and provide novel avenues for diabetes management. Using mice with inducible induction of Rheb1 in α cells (αRhebTg mice), we showed that short-term activation of mTORC1 signaling is sufficient to induce hyperglucagonemia through increased glucagon secretion. Hyperglucagonemia in αRhebTg mice was also associated with an increase in α cell size and mass expansion. This model allowed us to identify the effects of chronic and short-term hyperglucagonemia on glucose homeostasis by regulating glucagon signaling in the liver. Short-term hyperglucagonemia impaired glucose tolerance, which was reversible over time. Liver glucagon resistance in αRhebTg mice was associated with reduced expression of the glucagon receptor and genes involved in gluconeogenesis, amino acid metabolism, and urea production. However, only genes regulating gluconeogenesis returned to baseline upon improvement of glycemia. Overall, these studies demonstrate that hyperglucagonemia exerts a biphasic response on glucose metabolism: Short-term hyperglucagonemia lead to glucose intolerance, whereas chronic exposure to glucagon reduced hepatic glucagon action and improved glucose tolerance

Authors

Camila Lubaczeuski, Nadejda Bozadjieva-Kramer, Ruy A. Louzada, George K. Gittes, Gil Leibowitz, Ernesto Bernal-Mizrachi

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Figure 3

Postnatal induction of hyperglucagonemia results in transient fasting hyperglycemia and glucose intolerance.

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Postnatal induction of hyperglucagonemia results in transient fasting hy...
(A) Control and RhebTg mice were exposed to Dox diet during pregnancy, lactation, and weaning. After 1 month of age, control and αRhebTg mice were placed on regular chow to induce Rheb overexpression. (B) Body weight before removing Dox (day 0) and after 3, 10, and 60 days of switching to control chow (n = 11 controls and n = 14 αRhebTg). (C) Fasting (12 hours) glucose (n = 5–10 controls and n = 5–10 αRhebTg) and (D) fasting (12 hours) glucagon levels before removing Dox and switching to control chow (day 0) (n = 6–17 controls and n = 7–22 αRhebTg). (E) Fasting (12 hours) insulin levels after removing Dox (day 10 and day 60) in control (n = 3–4) and αRhebTg (n = 4–6) mice. (F) i.p. glucose tolerance test (2 g/kg.bw) (n = 9 controls and n = 8 αRhebTg) after 6-hour fast. (G) Blood glucose response during ITT (0.75 units/kg.bw) and (H) AUC calculated for the ITT normalized by the baseline (n = 6–8 controls and n = 14–11 αRhebTg). (I) Glucagon response before (4-hour fast) and after 30 minutes of insulin injection (0.75 units/kg.bw) performed 3 days after removing Dox diet (n = 5–6 controls and n= 9 αRhebTg). (J) Glucose tolerance test (2 g/kg.bw) (n = 7–9 controls and n = 13 αRhebTg) after 6-hour fast. (K) Blood glucose response to ITT (0.75 units/kg.bw) and (L) AUC calculated for the ITT normalized by the baseline (n = 5 controls and n = 13 αRhebTg). (M) Glucagon response before (4-hour fast) and after 30 minutes of insulin injection (0.75 units/kg.bw) performed 10 days after in control chow diet (n = 4–5 controls and n = 9–14 αRhebTg). (N) Glucose tolerance test (2 g/kg.bw) performed 60 days after removing Dox diet (n = 4 controls and n = 7 αRhebTg) after 6-hour fast. (O) Blood glucose response to ITT (0.75 units/kg.bw) and (P) AUC calculated for the ITT normalized by the baseline (n = 6–9 controls and n = 11 αRhebTg). (Q) Glucagon response before (4-hour fast) and after 30 minutes of insulin injection (0.75 units/kg.bw) performed 60 days after removing Dox diet (n = 4–5 controls and n = 11–12 αRhebTg). Data for B, F, G, J, K, N, and O are shown as the mean ± SEM. *P < 0.05 (2-way ANOVA with Šidák’s post test), and for C, D, E, H, I, L, M, P, and Q, data are shown as the mean ± SEM. *P < 0.05 (Student’s 2-tailed t test).