Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported on plant mixture extract comprising of Nigella sativa, Myrrh, Gum Olibanum, Gum Asafoetida and Aloe to have a blood glucose lowering effect. The present study with streptozotocin diabetic rats is focussed on the mechanism of action, specifically on a) hepatic gluconeogenesis b) activity of key gluconeogenic enzymes, pyruvate carboxylase (PC) and phosphoenol-pyruvate carboxykinase (PEPCK). Similar studies using a biguanide, phenformin, have been conducted to compare the mode of action of these two compounds. The blood glucose levels (mean +/- SEM) before and after treatment with the plants extract were (16.7 +/- 1.7 mmol/L and 8.5 +/- 1.3 mmol/L) and with phenformin (15.1 +/- 1.3 mmol/L and 10.7 +/- 1.5 mmol/L). The rate of gluconeogenesis in isolated hepatocytes as well as activity of PC and PEPCK in liver homogenates is significantly lowered following treatment with the plants extract. Although phenformin also lowers blood glucose, it does not affect hepatic gluconeogenesis under stated experimental conditions. It is concluded that the anti-diabetic action of the plants extract may, at least partly, be mediated through decreased hepatic gluconeogenesis. The extract may prove to be a useful therapeutic agent in the treatment of non-insulin dependent diabetes mellitus (NIDDM).
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PMID:The effect of a plants mixture extract on liver gluconeogenesis in streptozotocin induced diabetic rats. 184 51

The enzyme activity of the mitochondrial glycerol phosphate dehydrogenase (mGPD) in the pancreatic islet has been reported to be less than one-half of normal in the Goto-Kakizaki (GK) rat, a genetic model of NIDDM. In the current study, mGPD enzyme activity and the amount of mGPD protein, as judged by Western analysis, were 35-40% of normal in the islets of these animals. With the exception of pyruvate carboxylase, the activities of other enzymes were not abnormal. The assayable activity and amount of pyruvate carboxylase protein were decreased approximately 50% in the islets of the GK rats. Because mGPD, which is the key enzyme of the glycerol phosphate shuttle, and pyruvate carboxylase, which is the key component of the pyruvate malate shuttle, have been proposed to be essential for stimulus-secretion coupling in the pancreatic beta-cell, an important question is whether the decreases in these enzymes have a causal role in the hyperglycemia or whether the diabetic syndrome caused the decreases. To attempt to differentiate between these two possibilities, GK rats were treated with insulin to normalize their blood sugars. The activities of both mGPD and pyruvate carboxylase were also normalized by insulin treatment. An incidental discovery of this study was the identification of a high level of propionyl-CoA carboxylase activity and a lesser amount of methylcrotonyl-CoA carboxylase activity in pancreatic islets. These enzymes were normal in the islets of the GK rats. This is the first report on the presence of these two carboxylases in the islet and of low pyruvate carboxylase activity in the islet in NIDDM. We conclude that the decreased mGPD and pyruvate carboxylase in the pancreatic islet of the GK rat result from the diabetic syndrome.
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PMID:Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat. 866 38

The mechanism of increased hepatic glucose production in obese non-insulin-dependent diabetic (NIDDM) patients is unknown. The New Zealand Obese (NZO) mouse, a polygenic model of obesity and NIDDM shows increased hepatic glucose production. To determine the mechanism of this phenomenon, we measured gluconeogenesis from U-14C-glycerol and U-14C-alanine and relevant gluconeogenic enzymes. Gluconeogenesis from glycerol (0.07 +/- 0.01 vs 0.21 +/- 0.02 micromol.min-1.body mass index (BMI)-1, p < 0.005) and alanine (0.57 +/- 0.07 vs 0.99 +/- 0.07 micromol.min-1.BMI-1, p < 0.005) was elevated in control mice NZO vs as was glycerol turnover (0.25 +/- 0.02 vs 0.63 +/- 0.09 micromol.min-1.BMI-1, p < 0.05). Fructose 1,6-bisphosphatase activity (44.2 +/- 1.9 vs 55.7 +/- 4.1 nmol.min-1.mg protein-1, p < 0.05) and protein levels (6.9 +/- 1.1 vs 16.7 +/- 2.3 arbitrary units, p < 0.01) were increased in NZO mouse livers, as was the activity of pyruvate carboxylase (0.12 +/- 0.01 vs 0.17 +/- 0.02 nmol.min-1.mg protein-1, p < 0.05). To ascertain whether elevated lipid supply is responsible for these biochemical changes in NZO mice, we fed lean control mice a 60% fat diet for 2 weeks. Fat-fed mice were hyperinsulinaemic (76.37 +/- 4.06 vs 98.00 +/- 7.07 pmol/l, p = 0.05) and had elevated plasma non-esterified fatty acid levels (0.44 +/- 0.05 vs 0.59 +/- 0.03 mmol/l, p = 0.05). Fructose 1,6-bisphosphatase activity (43.86 +/- 2.54 vs 52.93 +/- 3.09 nmol.min-1.mg protein-1, p = 0.05) and protein levels (33.03 +/- 0.96 vs 40.04 +/- 1.26 arbitrary units, p = 0.005) and pyruvate carboxylase activity (0.10 +/- 0.003 vs 0.14 +/- 0.01 nmol.min-1.mg protein-1, p < 0.05) were elevated in fat-fed mice. We conclude that in NZO mice increased hepatic glucose production is due to elevated lipolysis resulting from obesity.
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PMID:The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus. 878 11

The enzyme activities of mitochondrial glycerol phosphate dehydrogenase (mGPD) (EC 1.1.99.5) and pyruvate carboxylase (PC) (EC 6.4.1.1) have been reported to be low in the pancreatic islet of several rodent models of NIDDM. The present study was undertaken to discern whether mGPD is abnormal in the Zucker diabetic fatty (ZDF) rat (ZDF/Gmi-fa/fa), an animal model of NIDDM in which insulin secretion is unable to counteract the insulin resistance associated with the obesity that characterizes this model. Experiments were performed in prediabetic 6-week-old ZDF rats in comparison with 12-week-old overtly hyperglycemic animals and, as controls, Zucker lean (ZL) rats (ZDF/Gmi-+/fa or -+/+) and Wistar rats (+/+) of the same ages. The enzyme activity of mGPD was 32 and 18% of normal in islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001 by analysis of variance). The activity of PC, which like mGPD is relatively abundant in the pancreatic islet, was 17 and 10% of normal in the islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001). The activity of mGPD was normal in islets from ZL rats. However, PC activity was slightly lower in islets of 6- (51% of normal, P = 0.007) and 12-week-old (67% of normal, P = 0.01) ZL rats. The amounts of mGPD protein, as judged from Western analysis, and of PC protein, as judged from probing transblots with streptavidin that binds to biotin-containing enzymes, roughly correlated with the enzyme activities. This indicates that the decreased enzyme activities are caused by the decreased net synthesis of these enzymes rather than by the decreased activity of a normal amount of enzyme. The enzyme activity of succinate dehydrogenase, a control for mGPD, was normal in the ZL and ZDF rats. An incidental finding of the current study was the discovery of beta-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in the islet. Levels of these enzymes were also normal. Although reductions in mGPD and PC may contribute to the abnormal insulin secretion present in overt diabetes, they are modest compared with the severe reductions seen in inherited inborn errors of metabolism. Because of this and because more than a single enzyme is affected and the enzymes in the islet are diminished in more than one rodent model of NIDDM, these reductions are unlikely to represent the primary genetic defect in the ZDF rat. Since ZDF rats are euglycemic at 6 weeks of age and ZL animals are euglycemic throughout life and since these animals demonstrate low enzyme activities, this evidence suggests that it is not hyperglycemia but rather some other component of the diabetic syndrome that is responsible for the reductions in these enzymes.
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PMID:Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats. 886 70

To test whether gluconeogenesis is increased in non-insulin-dependent diabetic (NIDDM) patients we infused (post-absorptive state) healthy subjects and NIDDM patients with [6,6-2H2]glucose (150 min) and [3-13C]lactate (6 h). Liver glutamine was sampled with phenylacetate and its labelling pattern determined (mass spectrometry) after purification of the glutamine moiety of urinary phenylacetylglutamine. After correction for 13CO2 re-incorporation (control test with NaH13CO3 infusion) this pattern was used to calculate the dilution factor (F) in the hepatic oxaloacetate pool and fluxes through liver Krebs cycle. NIDDM patients had increased lactate turnover rates (16.18+/-0.92 vs 12.14+/-0.60 micromol x kg(-1) x min(-1), p < 0.01) and a moderate rise in glucose production (EGP) (15.39+/-0.87 vs 12.52+/-0.28 micromol x kg(-1) x min(-1) , p = 0.047). Uncorrected contributions of gluconeogenesis to EGP were 31+/-3 % (control subjects) and 17+/-2 % (NIDDM patients). F was comparable (1.34+/-0.02 and 1.39 0.09, respectively) and the corrected percent and absolute contributions of gluconeogenesis were not increased in NIDDM (25+/-3 % and 3.8+/-O.5 micromol x kg(1) x min[-1]) compared to control subjects (41+/-3 % and 5.1+/-0.4 micromol x kg(-1) x min(-1]). The calculated pyruvate carboxylase over pyruvate dehydrogenase activity ratio was comparable (12.1+/-2.6 vs 11.2+/-1.4). Lastly hepatic fatty oxidation, as estimated by the model, was not increased in NIDDM (1.8+/-0.4 vs 1.6+/-0.1 micromol x kg(-1) x min[-1]). In conclusion, in the patients studied we found no evidence of increased hepatic fatty oxidation, or, despite the increased lactate turnover rate, an increased gluconeogenesis.
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PMID:Non-invasive tracing of liver intermediary metabolism in normal subjects and in moderately hyperglycaemic NIDDM subjects. Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM. 949 56

Chronic lipid exposure is implicated in beta-cell dysfunction in type 2 diabetes. We therefore used oligonucleotide arrays to define global alterations in gene expression in MIN6 cells after 48-h pretreatment with oleate or palmitate. Altogether, 126 genes were altered > or =1.9-fold by palmitate, 62 by oleate, and 46 by both lipids. Importantly, nine of the palmitate-regulated genes are known to be correspondingly changed in models of type 2 diabetes. A tendency toward beta-cell de-differentiation was also apparent with palmitate: pyruvate carboxylase and mitochondrial glycerol 3-phosphate dehydrogenase were downregulated, whereas lactate dehydrogenase and fructose 1,6-bisphosphatases were induced. Increases in the latter (also seen with oleate), along with glucosamine-phosphate N-acetyl transferase, imply upregulation of the hexosamine biosynthesis pathway in palmitate-treated cells. However, palmitate also increased expression of calcyclin and 25-kDa synaptosomal-associated protein (SNAP25), which control distal secretory processes. Consistent with these findings, secretory responses to noncarbohydrate stimuli, especially palmitate itself, were upregulated in palmitate-treated cells (much less so with oleate). Indeed, glucose-stimulated secretion was slightly sensitized by chronic palmitate exposure but inhibited by oleate treatment, whereas both lipids enhanced basal secretion. Oleate and palmitate also induced expression of chemokines (MCP-1 and GRO1 oncogene) and genes of the acute phase response (serum amyloid A3). Increases in transcriptional modulators such as ATF3, CCAAT/enhancer binding protein-beta (C/EBPbeta), C/EBPdelta, and c-fos were also seen. The results highlight links between regulated gene expression and phenotypic alterations in palmitate versus oleate-pretreated beta-cells.
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PMID:Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function. 2194

Mutations in the transcription factor IPF1/PDX1 have been associated with type 2 diabetes. To elucidate beta-cell dysfunction, PDX1 was suppressed by transduction of rat islets with an adenoviral construct encoding a dominant negative form of PDX1. After 2 days, there was a marked inhibition of insulin secretion in response to glucose, leucine, and arginine. Increasing cAMP levels with forskolin and isobutylmethylxanthine restored glucose-stimulated insulin secretion, indicating normal capacity for exocytosis. To identify molecular targets implicated in the altered metabolism secretion coupling, DNA microarray analysis was performed on PDX1-deficient and control islets. Of the 2640 detected transcripts, 70 were up-regulated and 56 were down-regulated. Transcripts were subdivided into 12 clusters; the most prevalent were associated with metabolism. Quantitative reverse transcriptase-PCR confirmed increases in succinate dehydrogenase and ATP synthase mRNAs as well as pyruvate carboxylase and the transcript for the malate shuttle. In parallel there was a 50% reduction in mRNA levels for the mitochondrially encoded nd1 gene, a subunit of the NADH dehydrogenase comprising complex I of the mitochondrial respiratory chain. As a consequence, total cellular ATP concentration was drastically decreased by 75%, and glucose failed to augment cytosolic ATP, explaining the blunted glucose-stimulated insulin secretion. Rotenone, an inhibitor of complex I, mimicked this effect. Surprisingly, TFAM, a nuclear-encoded transcription factor important for sustaining expression of mitochondrial genes, was down-regulated in islets expressing DN79PDX1. In conclusion, loss of PDX1 function alters expression of mitochondrially encoded genes through regulation of TFAM leading to impaired insulin secretion.
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PMID:Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets. 1515 93

Islet beta-cell proliferation is a very important component of beta-cell adaptation to insulin resistance and prevention of type 2 diabetes mellitus. However, we know little about the mechanisms of beta-cell proliferation. We now investigate the relationship between pyruvate carboxylase (PC) pathway activity and islet cell proliferation 5 days after 60% pancreatectomy (Px). Islet cell number, protein, and DNA content, indicators of beta-cell proliferation, were increased two- to threefold 5 days after Px. PC and pyruvate dehydrogenase (PDH) activities increased only approximately 1.3-fold; however, islet pyruvate content and malate release from isolated islet mitochondria were approximately threefold increased in Px islets. The latter is an indicator of pyruvate-malate cycle activity, indicating that most of the increased pyruvate was converted to oxaloacetate (OAA) through the PC pathway. The contents of OAA and malate, intermediates of the pyruvate-malate cycle, were also increased threefold. PDH and citrate content were only slightly increased. Importantly, the changes in cell proliferation parameters, glucose utilization, and oxidation and malate release were partially blocked by in vivo treatment with the PC inhibitor phenylacetic acid. Our results suggest that enhanced PC pathway in Px islets may have an important role in islet cell proliferation.
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PMID:Enhanced rat beta-cell proliferation in 60% pancreatectomized islets by increased glucose metabolic flux through pyruvate carboxylase pathway. 1550 31

Biotin-dependent multifunctional enzymes carry out metabolically important carboxyl group transfer reactions and are potential targets for the treatment of obesity and type 2 diabetes. These enzymes use a tethered biotin cofactor to carry an activated carboxyl group between distantly spaced active sites. The mechanism of this transfer has remained poorly understood. Here we report the complete structure of pyruvate carboxylase at 2.0 angstroms resolution, which shows its domain arrangement. The structure, when combined with mutagenic analysis, shows that intermediate transfer occurs between active sites on separate polypeptide chains. In addition, domain rearrangements associated with activator binding decrease the distance between active-site pairs, providing a mechanism for allosteric activation. This description provides insight into the function of biotin-dependent enzymes and presents a new paradigm for multifunctional enzyme catalysis.
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PMID:Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme. 1771 83

Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. During postprandial periods an elevated level of plasma glucose rapidly stimulates insulin secretion to decrease hepatic glucose output and promote glucose uptake into other tissues, principally muscle and adipose tissues. Beta cell mitochondria play a key role in this process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites (anaplerosis) that can act, both intra- and extramitochondrially, as factors that couple glucose sensing to insulin granule exocytosis. ATP on its own, and possibly modulated by these coupling factors, triggers closure of the ATP-sensitive potassium channel, resulting in membrane depolarisation that increases intracellular calcium to cause insulin secretion. The metabolic imbalance caused by chronic hyperglycaemia and hyperlipidaemia severely affects mitochondrial metabolism, leading to the development of impaired glucose-induced insulin secretion in type 2 diabetes. It appears that the anaplerotic enzyme pyruvate carboxylase participates directly or indirectly in several metabolic pathways which are important for glucose-induced insulin secretion, including: the pyruvate/malate cycle, the pyruvate/citrate cycle, the pyruvate/isocitrate cycle and glutamate-dehydrogenase-catalysed alpha-ketoglutarate production. These four pathways enable 'shuttling' or 'recycling' of these intermediate(s) into and out of mitochondrion, allowing continuous production of intracellular messenger(s). The purpose of this review is to present an account of recent progress in this area of central importance in the realm of diabetes and obesity research.
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PMID:Regulation of insulin secretion: role of mitochondrial signalling. 2022 32


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