Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing.

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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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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Glycerol Phosphate Dehydrogenase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase: Activities in Oligodendrocytes, Neurons, Astrocytes, and Myelin Isolated from Developing Rat Brains

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1982.tb08637.x ◽

1982 ◽

Vol 38 (2) ◽

pp. 360-367 ◽

Cited By ~ 38

Author(s):

Wendy Cammer ◽

D. Stephen Snyder ◽

Thomas R. Zimmerman ◽

Muhammad Farooq ◽

William T. Norton

Keyword(s):

Lactate Dehydrogenase ◽

Glycerol Phosphate ◽

Glucose 6 Phosphate Dehydrogenase ◽

Developing Rat ◽

Glycerol Phosphate Dehydrogenase

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Beta Cell Autophagy in the Pathogenesis of Type 1 Diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00151.2021 ◽

2021 ◽

Author(s):

Charanya Muralidharan ◽

Amelia K Linnemann

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Potential Role ◽

Cell Dysfunction ◽

Unconventional Secretion ◽

Insulin Dependent

Type 1 diabetes is an insulin-dependent, autoimmune disease where the pancreatic beta cells are destroyed resulting in hyperglycemia. This multi-factorial disease involves multiple environmental and genetic factors, and has no clear etiology. Accumulating evidence suggests that early signaling defects within the beta cells may promote a change in the local immune mileu, contributing to autoimmunity. Therefore, many studies have been focused on intrinsic beta cell mechanisms that aid in restoration of cellular homeostasis under environmental conditions that cause dysfunction. One of these intrinsic mechanisms to promote homeostasis is autophagy, defects in which are clearly linked with beta cell dysfunction in the context of type 2 diabetes. Recent studies have now also pointed towards beta cell autophagy defects in the context of type 1 diabetes. In this perspectives review, we will discuss the evidence supporting a role for beta cell autophagy in the pathogenesis of type 1 diabetes, including a potential role for unconventional secretion of autophagosomes/lysosomes in the changing dialogue between the beta cell and immune cells.

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Pathways of reducing equivalents in hepatocytes from rats. Estimation of cytosolic fluxes by means of 3H-labelled substrates for either A- or B-specific dehydrogenases

Biochemical Journal ◽

10.1042/bj2430625 ◽

1987 ◽

Vol 243 (3) ◽

pp. 625-630 ◽

Cited By ~ 3

Author(s):

C Vind ◽

A Hunding ◽

N Grunnet

Keyword(s):

Experimental Data ◽

Lactate Dehydrogenase ◽

Alcohol Dehydrogenase ◽

Least Squares ◽

Oxidation Rate ◽

Isolated Hepatocytes ◽

Glycerol Phosphate ◽

Hydrogen Atoms ◽

Best Fit ◽

Glycerol Phosphate Dehydrogenase

The metabolism of [2-3H]lactate and [2-3H]glycerol was studied in isolated hepatocytes from fed rats. In order to estimate the rate of equilibrium between the 4A and 4B hydrogen atoms of NADH, we compared the flow of 3H from [2-3H]lactate and [2-3H]glycerol, the oxidations of which are catalysed by A- and B-type dehydrogenases, respectively. Hepatocytes were incubated with lactate, glycerol and ethanol and tracer amounts of [2-3H]lactate or [2-3H]glycerol and the labelling rates of lactate, ethanol, glucose and glycerol phosphate were determined. The data were used to calculate the oxidation rate of NADH catalysed by lactate dehydrogenase, alcohol dehydrogenase, triosephosphate dehydrogenase and glycerol phosphate dehydrogenase. The rates were calculated by obtaining the best fit of a model to the experimental data by using a least-squares procedure. The results support our model and suggest that the fluxes through various dehydrogenases are sufficient to equilibrate the 4A and 4B hydrogen atoms of cytosolic NADH. The validity of the metabolic models used was evaluated by comparison of rates of NADH oxidation catalysed by cytosolic dehydrogenases as calculated by two different models.

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