Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylglyoxal (MG) may be an important cause of diabetic complications. Its primary source is dihydroxyacetone phosphate (DHAP) whose levels are partially controlled by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using a human red blood cell (RBC) culture, we examined the effect of modifying GAPDH activity on MG production. With the inhibitor koningic acid (KA), we showed a linear, concentration-dependent GAPDH inhibition, with 5 microM KA leading to a 79% reduction of GAPDH activity and a sixfold increase in MG. Changes in redox state produced by elevated pH also resulted in a 2.4-fold increase in MG production at pH 7.5 and a 13.4-fold increase at pH 7.8. We found substantial inter-individual variation in DHAP and MG levels and an inverse relationship between GAPDH activity and MG production (R=0.57, P=0.005) in type 2 diabetes. A similar relationship between GAPDH activity and MG was observed in vivo in type 1 diabetes (R=0.29, P=0.0018). Widely varying rates of progression of diabetic complications are seen among individuals. We postulate that modification of GAPDH by environmental factors or genetic dysregulation and the resultant differences in MG production could at least partially account for this observation.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes. 1252 13

Amino acids are essential for body protein synthesis. Moreover, they can be used to produce energy within the cells. For protein turnover, normal plasma amino acid concentration enhances proteolytic suppression by insulin; furthermore, hyperaminoacidemia can stimulate protein synthesis both in the presence of baseline insulin and in hyperinsulinemic subjects with type 1 diabetes. In humans, the availability of amino acids represents a factor more important than insulin in maintaining protein synthesis in skeletal muscle. Among amino acids, branched-chain amino acids exert an anabolic effect on heart protein metabolism, and their uptake by the myocardium is increased by increasing their circulating concentrations. An important aspect of branched-chain amino acid metabolism in the heart (mainly in the ischemic heart) is that branch-chain amino acid infusion can diminish myocardial lactate; in this way, the inhibition of anaerobic energy phosphate caused by accumulation of lactate can be overridden. Plasma amino acid availability plays an important role in promoting protein synthesis and in energy production, both in peripheral skeletal muscle and in the myocardium.
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PMID:Oral amino acid administration in patients with diabetes mellitus: supplementation or metabolic therapy? 1509 1

Total plasma homocysteine (tHcy) was measured by high pressure liquid chromatography (HPLC) method in 28 patients (12 females and 16 males) at the onset of type 1 diabetes mellitus (T1DM), 4 females during diabetes ketoacidosis (DKA) and 154 (68 females and 86 males) during follow-up. Serum folate, pyridoxal 5' phosphate (PLP) and Vitamin B12 (Vit B12) were also measured. Plasma tHcy levels were not found significantly different in T1DM patients known to have diabetes (males 9.2 +/- 7.7 and females 7.0 +/- 2.8 micromol/l) and in those who were newly diagnosed (males 9.7 +/- 4.8 and females 7.16 +/- 2.8 micromol/l) than in healthy controls (males 8.7 +/- 3.5 and females 7.8 +/- 2.55 micromol/l). Only a significant difference for sex was observed in known diabetes (p = 0.0281). Serum folate, PLP and Vit B12 were normal (12.6 +/- 3.6 ng/ml, 20.11 +/- 0.8 ng/ml and 416.7 +/- 41.9 pg/ml) in all T1DM patients. Age significantly correlated with plasma tHcy. Only in 4 patients, studied during DKA, plasma tHcy was significantly lower (2.76 +/- 1.33 micromol/l, p < 0.001) than the healthy controls.
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PMID:Hyper-homocysteinemia is not a main feature of juvenile uncomplicated type 1 diabetes. 1572 91

In this study, we aimed to compare bone calcium system changes from children with diabetic ketoacidosis or acute metabolic acidosis due to dehydration to find out the relative contribution of metabolic acidosis and diabetes-related factors on expected negative calcium balance. We studied a set of non-invasive parameters of bone remodeling in 16 children with diabetic ketoacidosis due to new onset type 1 diabetes and 25 children with acute metabolic acidosis due to dehydration complicating acute gastroenteritis before and after the correction of acidosis. The two groups of subjects were matched for age, sex, pubertal status, and degree of metabolic acidosis and dehydration. A group of 18 age and sex-matched healthy children served as the control group. Plasma ionized calcium levels were increased in both groups, significantly more so in diabetic ketoacidosis. While osteoblastic markers, osteocalcin and alkaline phosphatase, were depressed to a comparable degree in both groups, urinary calcium/creatinine ratio and hydroxyproline excretion were significantly greater in diabetic ketoacidosis. No significant changes in calcitrophic hormone (intact PTH, calcitonin, 25-hydroxy vitamin D3) levels were observed. All study parameters except for serum phosphate levels behaved in parallel in both clinical conditions, and abnormalities disappeared with the correction of acidosis except for IGF-1, which remained low in diabetic subjects. In conclusion, our results suggest that, in diabetic ketoacidosis, the observed severe negative calcium balance occurred through diminished bone formation mediated by metabolic acidosis per se and increased bone mineral dissolution and bone resorption because of severe insulin deficiency and secondarily via metabolic acidosis. Observed changes appear to be independent of calcitrophic hormones.
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PMID:Bone calcium changes during diabetic ketoacidosis: a comparison with lactic acidosis due to volume depletion. 1586 25

IA-2 is an enzymatically inactive member of the transmembrane protein tyrosine phosphate family located in dense core secretory vesicles and a major autoantigen in type 1 diabetes. Recent studies showed that targeted disruption of the IA-2 gene in mice resulted in impairment of insulin secretion and glucose intolerance. Insulin homeostasis, however, is a complex process involving a cascade of regulatory factors, and IA-2 is widely expressed in neuroendocrine cells throughout the body. Consequently, it is uncertain whether the impairment of insulin secretion in IA-2 knockout mice is a direct result of the knockout of IA-2 in beta cells or to counter regulatory alterations resulting from IA-2 knockout in other neuroendocrine cells. To define the function of IA-2, we studied the secretion of insulin in a single cell type, MIN-6, by overexpressing and knocking down IA-2. Our experiments showed that overexpression of IA-2 resulted in a 6-fold increase in glucose- or K+-induced insulin secretion and a approximately 3-fold increase in the number of secretory vesicles and the insulin content of cells. In contrast, knockdown of endogenous IA-2 by short interfering RNA resulted in nearly a complete loss of glucose-induced insulin secretion and a 50% decrease in basal insulin release. The half-life of insulin in cells overexpressing IA-2 was nearly twice as great as that in mock-transfected cells, suggesting that IA-2 was stabilizing the insulin-containing vesicles. From these results we conclude that in beta cells, IA-2 is an important regulator of dense core vesicle number and glucose-induced and basal insulin secretion.
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PMID:The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. 1593 93

Osteopenia was reported in patients with type I diabetes mellitus (DM). Also, serum levels of advanced glycation endproducts (AGEs) were reported to be elevated in DM. In this review, we showed the effect of AGEs on primary human osteoblasts, the precursor of human osteoclast like cells and parathyroid cells in culture. AGEs were made from incubating bovine serum albumin with glucose 6 phosphate for 8 weeks (AGEs-BSA). AGEs-BSA (1,000 microg/mL) showed inhibitory effect for human osteoblasts in terms of the productions of procolagen c propeptide and osteocalcin, which were regarded as bone forming parameters. On the other hand, the same concentration of AGEs-BSA inhibited the increase in the parathyroid hormone secretion from the cultured human parathyroid cells induced by low calcium medium concentration. AGEs-BSA increased time dependently intracellular calcium levels of HEK 293 cells, which expressed the wild type human calcium-sensing receptor. Also, AGEs-BSA increased IL-6 synthesis by primary human osteoblast. Our preliminary data also showed that AGEs-BSA increased osteoclast-like cells formation in number from the osteoclast precursor rich bone marrow cells. These data suggested the important role of AGEs for the pathogenesis of osteopenia in patients with DM through decreased bone formation and increased bone resorption.
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PMID:[The role of AGEs for the pathogenesis of osteopenia in diabetes mellitus]. 1688 40

Monocyte recruitment and adhesion to vascular endothelium are key early events in atherosclerosis. We examined the role of sphingosine-1-phosphate (S1P) on modulating monocyte/endothelial interactions in the NOD/LtJ (NOD) mouse model of type 1 diabetes. Aortas from nondiabetic and diabetic NOD mice were incubated in the absence or presence of 100 nmol/L S1P. Fluorescently labeled monocytes were incubated with the aortas. Aortas from NOD diabetic mice bound 7-fold more monocytes than nondiabetic littermates (10+/-1 monocytes bound/field for nondiabetic mice vs 74+/-12 monocytes bound/field for diabetic mice, P<0.0001). Incubation of diabetic aortas with 100 nmol/L S1P reduced monocyte adhesion to endothelium by 90%. We found expression of S1P1, S1P2, and S1P3 receptors on NOD aortic endothelial cells. The S1P1 receptor-specific agonist SEW2871 inhibited monocyte adhesion to diabetic aortas. Studies in diabetic S1P3-deficient mice revealed that the S1P3 receptor did not play a pivotal role in this process. S1P reduced endothelial VCAM-1 induction in type 1 diabetic NOD mice, most likely through inhibition of nuclear factor kappaB translocation to the nucleus. Thus, S1P activation of the S1P1 receptor functions in an antiinflammatory manner in type 1 diabetic vascular endothelium to prevent monocyte/endothelial interactions. S1P may play an important role in the prevention of vascular complications of type 1 diabetes.
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PMID:Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor. 1700 96

Clinical islet transplantation for type 1 diabetes mellitus currently requires potent immunosuppressive drugs, which limits the procedure to the most severe forms of the disease, and many of the drugs are directly beta-cell toxic. A class of compounds called sphingosine-1-phosphate receptor modulators has been explored in transplantation and shown to be highly effective in multiple sclerosis and other autoimmune conditions. While FTY720, the first drug in this class, may not move forward initially in transplantation, this class requires detailed investigation to assess direct impact upon human beta-cell function and survival. We set out to evaluate the effects of FTY720 on human islets in vitro by investigating glucose-stimulated insulin and apoptosis; and in vivo, after transplantation into immunodeficient mice with chemically induced diabetes, by examining blood glucose levels, oral glucose tolerance tests and stimulated human C-peptide over a 50-day follow-up period. Our data showed that neither in vitro, nor in vivo human islet function was impaired by FTY720 exposure. Since FTY720 demonstrated no detrimental effects on human islet function in vitro or in vivo, emerging S1PR modulators may prove to be useful adjuncts in clinical islet transplantation through lack of diabetogenicity and potent immunological protection.
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PMID:Human islet function is not impaired by the sphingosine-1-phosphate receptor modulator FTY720. 1761 68

A 64-years-old man referred to a hospital because of high-grade fever. He was diagnosed as having influenza B by "POCTEM Influenza A/B", a rapid influenza diagnostic kit which detect some antigens of influenza virus. Six days after medication of oseltamivir phosphate, his flu-symptoms disappeared, but he complained sever thirsty. And after 2days, he suffered from loss of consciousness and was admitted to the hospital. Laboratory data on admission showed diabetes ketoacidosis, slight elevation of HbA1c level despite sever hyperglycemia, and increase of serum amylase concentration. Anti GAD antibody and anti IA-2 antibody were not detected. Urinary C-peptide excretion was undetectable and serum C-peptide levels were also undetectable after glucagon and arginin load, suggesting disappearance of endogeneous insulin secretion. Class II HLA was susceptible to fulminant type1 diabetes. Based on these findings, we diagnosed him with fulminant type1 diabetes. In Japan, only three viruses in three cases have been reported to be the trigger in the development of fulminant type 1 diabetes. They were human herpes virus 6, herpes simplex virus and Coxsackie B3 virus. This is the fourth report of fulminant type 1 diabetes developed after the established diagnosis of viral infection and the first after influenza B virus infection. The fact that fulminant type 1 diabetes developed after the infection of such a common virus suggest that factors within host will play more important roles than virus itself in the etiology of fulminant type 1 diabetes.
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PMID:A case of fulminant type 1 diabetes mellitus after influenza B infection. 1817 74

The progression of diabetic nephropathy can be halted by keeping blood glucose levels close to normal values. Three therapeutic approaches can be considered: intensive insulin treatment, islet of Langerhans transplantation, and pancreas transplantation. 1) The Diabetes Control and Complication Trials, a clinical study conducted from 1983 to 1993, showed that intensive insulin treatment prevented the development and slowed the progression of diabetic kidney disease by 50%. 2) In 2003, P. Fiorina studied the potential effects of islet transplantation on the renal function of 36 patients with type 1 diabetes and kidney transplant. An improvement in kidney graft survival rate and functioning [Na(+)/K(+)-ATP activity] was observed when compared with 12 patients with unsuccessful islet transplant. 3) P. Fioretto et al, in 2006, confirmed that normoglycemia for 10 years following pancreas transplantation alone reversed diabetic glomerulopathy lesions in native kidneys. This study also demonstrated that interstitial expansion was reversible and atrophic tubules were reassorbed. 4) P. Fiorina, in 2007, confirmed that simultaneous kidney-pancreas transplantation was associated with a better high-energy phosphate metabolism (as assessed by 31P-magnetic resonance spectroscopy) than in kidney- alone transplanted diabetic patients, suggesting that restoration of Beta cell function positively affects kidney graft metabolism.
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PMID:[Treatment of end-stage diabetic nephropathy]. 1904 88


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