Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

Jakob G. Knudsen; Alexander Hamilton; Reshma Ramracheya; Andrei I. Tarasov; Melissa Brereton; Elizabeth Haythorne; Margarita V. Chibalina; Peter Spégel; Hindrik Mulder; Quan Zhang; Frances M. Ashcroft; Julie Adam; Patrik Rorsman

doi:10.1016/j.cmet.2018.10.003

Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

Jakob G. Knudsen, Alexander Hamilton, Reshma Ramracheya, Andrei I. Tarasov, Melissa Brereton, Elizabeth Haythorne, Margarita V. Chibalina, Peter Spégel, Hindrik Mulder, Quan Zhang, Frances M. Ashcroft, Julie Adam, Patrik Rorsman

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Abstract

Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.

Original language	English
Journal	Cell Metabolism
Volume	29
Issue number	2
Pages (from-to)	430-442, e1-e4
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2018.10.003
Publication status	Published - 5 Feb 2019
Externally published	Yes

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Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP ProductionFinal published version, 7.01 MBLicence: CC BY

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Knudsen, J. G., Hamilton, A., Ramracheya, R., Tarasov, A. I., Brereton, M., Haythorne, E., Chibalina, M. V., Spégel, P., Mulder, H., Zhang, Q., Ashcroft, F. M., Adam, J., & Rorsman, P. (2019). Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production. Cell Metabolism, 29(2), 430-442, e1-e4. https://doi.org/10.1016/j.cmet.2018.10.003

Knudsen, JG, Hamilton, A, Ramracheya, R, Tarasov, AI, Brereton, M, Haythorne, E, Chibalina, MV, Spégel, P, Mulder, H, Zhang, Q, Ashcroft, FM, Adam, J & Rorsman, P 2019, 'Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production', Cell Metabolism, vol. 29, no. 2, pp. 430-442, e1-e4. https://doi.org/10.1016/j.cmet.2018.10.003

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title = "Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production",

abstract = "Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.",

author = "Knudsen, {Jakob G.} and Alexander Hamilton and Reshma Ramracheya and Tarasov, {Andrei I.} and Melissa Brereton and Elizabeth Haythorne and Chibalina, {Margarita V.} and Peter Sp{\'e}gel and Hindrik Mulder and Quan Zhang and Ashcroft, {Frances M.} and Julie Adam and Patrik Rorsman",

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T1 - Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

AU - Knudsen, Jakob G.

AU - Hamilton, Alexander

AU - Ramracheya, Reshma

AU - Tarasov, Andrei I.

AU - Brereton, Melissa

AU - Haythorne, Elizabeth

AU - Chibalina, Margarita V.

AU - Spégel, Peter

AU - Mulder, Hindrik

AU - Zhang, Quan

AU - Ashcroft, Frances M.

AU - Adam, Julie

AU - Rorsman, Patrik

PY - 2019/2/5

Y1 - 2019/2/5

N2 - Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.

AB - Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.

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DO - 10.1016/j.cmet.2018.10.003

M3 - Journal article

C2 - 30415925

SN - 1550-4131

VL - 29

SP - 430-442, e1-e4

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

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