Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat

MacDonald, Malcolm J.; Efendic, S.; Ostenson, C. G.

doi:10.2337/diabetes.45.7.886

Cited by 42 publications

(55 citation statements)

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“…This result strongly suggests that decreased mGPDH activity is not a primary defect causing impaired glucose-stimulated insulin secretion in GK rats. Consistent with this, it was recently reported that the decreased enzyme activity returned to normal after insulin treatment of GK rats, suggesting that decreased mGPDH activity in GK rat islets is secondary to a diabetic phenomenon [16].…”

Section: Discussionsupporting

confidence: 68%

“…These observations are in contrast to those in previous reports in which enzyme activity and the mGPDH protein level decreased to 30±40 % of those in control Wistar rats [11,16]. This may be due to differences in genetic or environmental conditions (e. g. colony, age, food, etc.).…”

Section: Discussioncontrasting

confidence: 56%

“…The protein concentration was determined by Lowry's method, and aliquots containing 100 mg protein were used for the enzyme assay. We measured the activity of mGPDH enzyme using a previously described colourimetric assay [16]. Islet extracts containing 40 mg protein were incubated in 200 ml of 50 mmol/l BICINE buffer (Sigma, St. Louis, Mo.…”

Section: Methodsmentioning

confidence: 99%

“…These lines of evidence suggest that decreased mGPDH activity and the resultant decrease in glycerol phosphate shuttle activity may be responsible, at least in part, for the impaired insulin secretion in both the animal models and human NIDDM. Recently, it was reported that insulin treatment of GK rats normalized islet mGPDH activity [16], suggesting that decreased mGPDH enzyme activity in GK rats is secondary to a diabetic syndrome, rather than the primary genetic defect. However, the insulin secretory response after the enzyme activity had returned to normal was not examined in that study and it is still not known whether this decreased enzyme activity is responsible, to some extent, for the altered insulin secretion.…”

Section: : 649±653]mentioning

confidence: 99%

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Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets

et al. 1998

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In the GK (Goto-Kakizaki) rat, a spontaneous diabetic rodent model produced by repeated selective breeding of the Wistar rat, the insulin secretory response to glucose is selectively impaired [1,2] as in human non-insulin-dependent diabetes mellitus (NIDDM) patients [3]. Because the defect is specific for glucose-stimulated insulin secretion, the metabolic glucose signal appears to be impaired [4,5]. Glucose must enter beta cells and be metabolized via glycolytic and mitochondrial oxidative pathways in order to stimulate insulin release. The resulting changes in the intracellular ATP/ADP ratio close the ATP dependent potassium channel (K-ATP), leading to membrane depolarization, Ca 2+ entry and insulin exocytosis. In GK rats, it was suggested that the step responsible for the metabolic dysfunction of beta cells is located within the glycolytic pathway before Diabetologia (1998) Summary Glucose-stimulated insulin secretion is impaired in GK (Goto-Kakizaki) rats, perhaps because of abnormalities in glucose metabolism in pancreatic islet beta cells. The glycerol phosphate shuttle plays a major role in glucose metabolism by reoxidizing cytosolic NADH generated by glycolysis. In the pancreatic islets of GK rats, the activity of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase (mGPDH), the key enzyme of the glycerol phosphate shuttle, is decreased and this abnormality may be responsible, at least in part, for impaired glucose-stimulated insulin secretion. To investigate this possibility, we overexpressed mGPDH in islets isolated from GK rats via recombinant adenovirus-mediated gene transduction, and examined glucose-stimulated insulin secretion. In islets isolated from diabetic GK rats at 8 to 10 weeks of age, glucose-stimulated insulin secretion was severely impaired, and mGPDH activity was decreased to 79 % of that in non-diabetic Wistar rats. When mGPDH was overexpressed in islets from GK rats, enzyme activity and protein content increased 2-and 6-fold, respectively. Basal (3 mmol/l glucose) and glucose-stimulated (20 mmol/l) insulin secretion from the Adex1CAlacZ-infected GK rat islets were, respectively, 4.4 ± 0.7 and 8.1 ± 0.7 ng × islet 1 × 30 min 1 , and those from mGPDH-overexpressed GK rat islets 4.7 ± 0.3 and 9.1 ± 0.8 ng × islet 1 × 30 min 1 , in contrast to those from the Adex1-CAlacZ-infected non-diabetic Wistar rat islets (4.7 ± 1.6 and 47.6 ± 11.9 ng × islet 1 × 30 min 1 ). Thus, glucose-stimulated insulin secretion is severely impaired in GK rats even in the stage when mGPDH activity is modestly decreased, and at this stage, overexpression of mGPDH cannot restore glucose-stimulated insulin secretion. We conclude that decreased mGPDH activity in GK rat islets is not the defect primarily responsible for impaired glucose-stimulated insulin secretion. [Diabetologia (1998) 41: 649±653]

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Section: Discussionsupporting

confidence: 68%

Section: Discussioncontrasting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: : 649±653]mentioning

confidence: 99%

See 2 more Smart Citations

Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets

et al. 1998

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“…This peculiar biochemical organization (high mGPDH/lactate dehydrogenase ratio) is thought to be important for optimal coupling of glucose metabolism by the ␤ cell and insulin secretion. Observations of a decreased activity of mGPDH in islets from type 2 diabetic patients and several animal models of the disease (11) have lent support to this concept, although recent studies have challenged the hypothesis (39,40).…”

Section: Discussionmentioning

confidence: 95%

The Oscillatory Behavior of Pancreatic Islets from Mice with Mitochondrial Glycerol-3-phosphate Dehydrogenase Knockout

Ravier¹,

Eto²,

Jonkers³

et al. 2000

Journal of Biological Chemistry

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] i on the exocytotic process (6 -8). Both pathways require glucose metabolism and appear to depend on a rise in the ATP/ADP ratio (9).Glucose metabolism in ␤ cells essentially occurs through aerobic glycolysis (10 -12). An increase in the glucose concentration is followed by an acceleration of glycolysis and an even greater stimulation of mitochondrial oxidative events, in which Ca 2ϩ may play an important role. Thus, the elevation of [Ca 2ϩ ] i is paralleled by an increase in mitochondrial Ca 2ϩ (13) that may then activate the three Ca 2ϩ -sensitive intramitochondrial dehydrogenases and promote ATP synthesis (14). Another feature of the ␤ cell metabolic organization is a low activity of lactate dehydrogenase (12,15). Cytosolic NADH formed during glycolysis is re-oxidized (and ATP synthesis concomitantly stimulated) by transfer of the reducing equivalents into mitochondria through the glycerol phosphate shuttle and the malate-aspartate shuttle (16, 17). The rate-limiting enzyme of the former shuttle, mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is located on the outer face of the mitochondrial membrane and can be activated by increases in cytosolic [Ca 2ϩ ] i (18,19). The importance of the NADH shuttles for glucose-induced insulin secretion (20) has received strong support from a recent study using islets from mice with a targeted disruption of mGPDH (21).Many ␤ cell responses to glucose are oscillatory. Oscillations of the membrane potential drive oscillations of [Ca 2ϩ ] i , leading to oscillations of insulin secretion that can be amplified by metabolic oscillations (4,(22)(23)(24)(25)(26). It is still unclear whether oscillations of glucose metabolism are intrinsic and initiate the whole chain of other pulsatile events or are entrained by the oscillations of [Ca 2ϩ ] i (27). The Ca 2ϩ sensitivity of mGPDH makes the enzyme a possible key site of the interplay between glucose metabolism and [Ca 2ϩ ] i oscillations. Thus, imposed oscillations of free Ca 2ϩ in islet mitochondrial extracts induced oscillations of mGPDH activity (28). If the hypothesis is correct, the oscillatory behavior of stimulus secretion coupling should be perturbed by mGPDH defects. The present study addressed this question with islets isolated from mGPDH knock-out (mG-PDH Ϫ/Ϫ ) mice (21). We compared the oscillations of ␤ cell

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Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

Pei

Guo

Peng

et al. 2022

Medicinal Research Reviews

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The key proteins involved in transcriptional regulation play convergent roles in cellular homeostasis, and their dysfunction mediates aberrant gene expressions that underline the hallmarks of tumorigenesis. As tumor progression is dependent on such abnormal regulation of transcription, it is important to discover novel chemical entities as antitumor drugs that target key tumor‐associated proteins involved in transcriptional regulation. Despite most key proteins (especially transcription factors) involved in transcriptional regulation are historically recognized as undruggable targets, multiple targeting approaches at diverse levels of transcriptional regulation, such as epigenetic intervention, inhibition of DNA‐binding of transcriptional factors, and inhibition of the protein–protein interactions (PPIs), have been established in preclinically or clinically studies. In addition, several new approaches have recently been described, such as targeting proteasomal degradation and eliciting synthetic lethality. This review will emphasize on accentuating these developing therapeutic approaches and provide a thorough conspectus of the drug development to target key proteins involved in transcriptional regulation and their impact on future oncotherapy.

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Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat

Cited by 42 publications

References 0 publications

Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets

Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets

The Oscillatory Behavior of Pancreatic Islets from Mice with Mitochondrial Glycerol-3-phosphate Dehydrogenase Knockout

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

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