If Metformin Inhibited the Mitochondrial Glycerol Phosphate Dehydrogenase It Might Not Benefit Diabetes

Mitochondrial glycerol phosphate dehydrogenase (mGPD) is the rate-limiting enzyme of the glycerol phosphate redox shuttle. It was recently claimed that metformin, a first line drug used for the treatment of type 2 diabetes, inhibits liver mGPD 30-50% suppressing gluconeogenesis through a redox mechanism. Various factors cast doubt on this idea. Total body100% knockout of mGPD in mice has adverse effects in several tissues where mGPD is high, but has little or no effect in liver where mGPD is the lowest of ten tissues. Metformin has beneficial effects in humans in tissues with high levels of mGPD such as pancreatic beta cells where mGPD is much higher than in liver. Insulin secretion in mGPD knockout mouse beta cells is normal because, like liver, beta cells possess the malate aspartate redox shuttle that’s redox action is redundant to the glycerol phosphate shuttle. For these and other reasons we used four different enzyme assays to reassess whether metformin inhibited mGPD. Metformin did not inhibit mGPD in homogenates or mitochondria from insulin cells or liver cells. If metformin actually inhibited mGPD, adverse effects in tissues where the level of mGPD is much higher than in liver could prevent metformin’s use as a diabetes medicine.

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Metformin’s Therapeutic Action in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase

10.2337/figshare.14394359.v1 ◽

2021 ◽

Author(s):

Michael J. MacDonald ◽

Israr-ul H. Ansari ◽

Melissa J. Longacre ◽

Scott W. Stoker

Keyword(s):

Adverse Effects ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Glycerol Phosphate ◽

Beneficial Effects ◽

Insulin Cells ◽

Cast Doubt ◽

Redox Shuttle ◽

Treatment Of Diabetes ◽

Glycerol Phosphate Dehydrogenase

Mitochondrial glycerol phosphate dehydrogenase (mGPD) is the rate-limiting enzyme of the glycerol phosphate redox shuttle. It was recently claimed that metformin, a first line drug used for the treatment of type 2 diabetes, inhibits liver mGPD 30-50% suppressing gluconeogenesis through a redox mechanism. Various factors cast doubt on this idea. Total body100% knockout of mGPD in mice has adverse effects in several tissues where mGPD is high, but has little or no effect in liver where mGPD is the lowest of ten tissues. Metformin has beneficial effects in humans in tissues with high levels of mGPD such as pancreatic beta cells where mGPD is much higher than in liver. Insulin secretion in mGPD knockout mouse beta cells is normal because, like liver, beta cells possess the malate aspartate redox shuttle that’s redox action is redundant to the glycerol phosphate shuttle. For these and other reasons we used four different enzyme assays to reassess whether metformin inhibited mGPD. Metformin did not inhibit mGPD in homogenates or mitochondria from insulin cells or liver cells. If metformin actually inhibited mGPD, adverse effects in tissues where the level of mGPD is much higher than in liver could prevent metformin’s use as a diabetes medicine.

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Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

Neuroendocrinology ◽

10.1159/000492387 ◽

2018 ◽

Vol 107 (4) ◽

pp. 324-339 ◽

Cited By ~ 5

Author(s):

Suvi T. Ruohonen ◽

Laura Valve ◽

Katja Tuomainen ◽

Liisa Ailanen ◽

Matias Röyttä ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Energy Expenditure ◽

Visceral Fat ◽

Diet Induced Obesity ◽

Running Wheel Exercise ◽

Total Body ◽

High Caloric Diet ◽

White Fat

The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A–/– mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A–/– mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A–/– mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A–/– mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A–/– mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.

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Metformin’s Therapeutic Action in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase

10.2337/figshare.14394359.v2 ◽

2021 ◽

Author(s):

Michael J. MacDonald ◽

Israr-ul H. Ansari ◽

Melissa J. Longacre ◽

Scott W. Stoker

Keyword(s):

Adverse Effects ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Glycerol Phosphate ◽

Beneficial Effects ◽

Insulin Cells ◽

Cast Doubt ◽

Redox Shuttle ◽

Treatment Of Diabetes ◽

Glycerol Phosphate Dehydrogenase

Mitochondrial glycerol phosphate dehydrogenase (mGPD) is the rate-limiting enzyme of the glycerol phosphate redox shuttle. It was recently claimed that metformin, a first line drug used for the treatment of type 2 diabetes, inhibits liver mGPD 30-50% suppressing gluconeogenesis through a redox mechanism. Various factors cast doubt on this idea. Total body100% knockout of mGPD in mice has adverse effects in several tissues where mGPD is high, but has little or no effect in liver where mGPD is the lowest of ten tissues. Metformin has beneficial effects in humans in tissues with high levels of mGPD such as pancreatic beta cells where mGPD is much higher than in liver. Insulin secretion in mGPD knockout mouse beta cells is normal because, like liver, beta cells possess the malate aspartate redox shuttle that’s redox action is redundant to the glycerol phosphate shuttle. For these and other reasons we used four different enzyme assays to reassess whether metformin inhibited mGPD. Metformin did not inhibit mGPD in homogenates or mitochondria from insulin cells or liver cells. If metformin actually inhibited mGPD, adverse effects in tissues where the level of mGPD is much higher than in liver could prevent metformin’s use as a diabetes medicine.

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α-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00573.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. E218-E224 ◽

Cited By ~ 49

Author(s):

Mary E. Rabaglia ◽

Mark P. Gray-Keller ◽

Brian L. Frey ◽

Michael R. Shortreed ◽

Lloyd M. Smith ◽

...

Keyword(s):

Insulin Secretion ◽

Mouse Strains ◽

Stimulate Insulin Secretion ◽

Insulin Resistant ◽

Severe Diabetes ◽

Patients At Risk ◽

Mouse Islets ◽

Branched Chain ◽

Rate Limiting

Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin ob mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, α-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, α-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of α-ketoglutarate is a requisite step in the response of mouse islets to KIC. α-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that α-ketoglutarate may directly stimulate insulin secretion and that increased formation of α-ketoglutarate leads to hyperinsulinemia.

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