Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autonomic neuropathy and gastrointestinal problems are among the most common complications of diabetes. In this report it is shown that a possible correlation between the two disorders might exist, since diabetes causes a profound alteration of the peptidergic innervation of the gut. It is reported that 14 weeks after diabetes induction with alloxan the levels of substance P and methionine-enkephalin are markedly reduced throughout the intestine, while vasoactive intestinal polypeptide content is dramatically increased. Therefore the enteric innervation of diabetic animals is completely disorganized, with some systems undergoing atrophy and others undergoing hypertrophy. Treatment of diabetic animals with acetyl-L-carnitine prevents the onset of the marked peptide changes described above. The results suggest a potential for acetyl-L-carnitine in the treatment of autonomic neuropathies.
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PMID:Peptide alterations in autonomic diabetic neuropathy prevented by acetyl-L-carnitine. 128 98

Although L-carnitine is not considered as an essential nutrient, endogenous synthesis may fail to ensure adequate L-carnitine levels in neonates, especially those born prematurely. Free L-carnitine is found in many foods, mainly those from animal sources. Absorption of free L-carnitine is virtually complete. Lysine and methionine are necessary ingredients for the biosynthesis of L-carnitine. All tissues in the body can produce deoxy-carnitine but, in humans, the enzyme that enables hydroxylation of deoxy-carnitine to carnitine is found only in the liver, brain and kidneys. Complex exchanges of carnitine and its precursors occur between tissues. Muscles take up carnitine from the bloodstream and contain most of the body carnitine stores. L-carnitine and L-carnitine esters are eliminated mainly through the kidneys, which may play a central role in the homeostasis of this compound. Thyroid hormones adrenocorticotrophin (ACTH), and diet all influence urinary excretion of L-carnitine. Free L-carnitine can be assayed in plasma and urine and is occasionally measured in muscle biopsy specimens. Plasma L-carnitine levels may not accurately reflect L-carnitine body stores. L-carnitine ensures transfer of fatty acids to the mitochondria where they undergo oxidation. This process is associated with production of short-chain acylcarnitine which exit from the mitochondria or peroxisomes. L-carnitine ensures regeneration of coenzyme A and is thus involved in energy metabolism. L-carnitine also ensures elimination of xenobiotic substances. Carnitine deficiencies are common. Currently, these deficiencies are classified into two groups. In deficiencies with myopathy, only the muscles are deficient in L-carnitine, perhaps as a result of a primary anomaly of the L-carnitine transport system in muscles. In systemic deficiencies, L-carnitine levels are low in the plasma and in all body tissues. Systemic L-carnitine deficiencies are usually the result of a variety of disease states including deficient intake in premature infants or long-term parenteral nutrition; renal failure; organic acidemias; and Reye's syndrome. Modifications in L-carnitine metabolism have also been reported in patients with diabetes mellitus, malignancies, myocardial ischemia, and alcohol abuse. A large number of supplementation trials have been carried out.
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PMID:[L-carnitine: metabolism, functions and value in pathology]. 129 65

DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism.
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PMID:Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. 150 86

This study examined the relationship between insulin secretion and expression of the 64 kDa/glutamic acid decarboxylase autoantigen in pancreatic islets. Islets isolated from Wistar rats were cultured for 3 days under different conditions: in 5.5 mmol/l glucose with or without alpha-ketoisocaproic acid or glipizide and in 28 mmol/l glucose with or without diazoxide. The 64 kDa/glutamic acid decarboxylase autoantigen was precipitated from lysates of [35S]-methionine-labelled islets with sera from patients with Type 1 (insulin-dependent) diabetes mellitus and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. In parallel, insulin contents of the islets and the media were determined as well as the rates of glucose-stimulated (pro)insulin biosynthesis. alpha-Ketoisocaproic acid and glipizide were found to stimulate the expression of the 64 kDa/glutamic acid decarboxylase autoantigen and also the rate of insulin secretion. Diazoxide on the other hand reduced the rate of the 64 kDa/glutamic acid decarboxylase autoantigen synthesis in parallel with an inhibition of glucose-stimulated insulin release. Under most of the conditions employed, (pro)insulin biosynthesis was not affected. The correlation found between the rate of insulin release and expression of the 64 kDa/glutamic acid decarboxylase autoantigen might provide an explanation for the earlier observed relationship between the functional demands on the Beta cells and their rate of destruction which may result in diabetes.
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PMID:Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion. 152 32

Biosynthetic regulation of renal glomerular heparan sulfate-proteoglycans by various aldohexoses (mannose, glucose, and galactose) was investigated. Isolated kidneys were perfused for 5 hr with medium containing [35S]sulfate, to label sulfated proteoglycans, or [35S]methionine, to label total glomerular proteins. All the hexoses, above 10 mM concentration, caused a significant decrease in the de novo synthesis of [35S]sulfate-labeled proteoglycans. The relative effectiveness of the hexoses was as follows: mannose much greater than glucose greater than galactose. The proteoglycans were of relatively lower molecular weights and exhibited reduced charge-density characteristics. Autoradiographic studies revealed a 2- to 3-fold decrease of grain density over the glomerular basement membrane and mesangial compartments, and immunoprecipitable heparan sulfate-proteoglycans were similarly decreased 2- to 3-fold. There was no significant decrease in the total [35S]methionine-labeled glomerular proteins or immunoprecipitable type IV collagen and laminin. Cellular ATP levels were dramatically reduced in all groups, and the maximal depletion was caused by mannose. Addition of ATP (0.1-1.0 mM) to the perfusion medium resulted in the normalization of the de novo synthesis and of the biochemical characteristics of heparan sulfate-proteoglycans. The relevance of decreased de novo synthesis of proteoglycans due to the depletion of ATP in hyperglycemic states is discussed in terms of increased glomerular permeability to plasma proteins, as seen in diabetes mellitus.
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PMID:Biosynthetic regulation of proteoglycans by aldohexoses and ATP. 152 71

Studies of streptozotocin-induced diabetes in rats have demonstrated that hepatic apo B and apo E production are reduced. To determine if reductions are related to decreases in hepatic mRNAs, we performed blotting analysis of total liver RNA with rat apo B, apo E, and albumin cDNA probes. The expected reduction in albumin mRNA levels to 48% of control livers occurred in diabetic rat liver, while apo B and apo E mRNA levels were unchanged. The proportion of translational stop codon (BSTOP) mRNA averaged 43% of total in diabetic rats similar to control levels. Long-term labeling experiments using [35S]methionine in primary cultures of rat hepatocytes and specific immunoprecipitations demonstrated production of apo B and apo E, and albumin by hepatocytes from diabetic rats was reduced to 37%, 53%, and 23% of controls. Pulse-chase studies, together with mRNA analyses, suggest that reduced hepatic secretion of apo B and apo E in diabetics is primarily a result of impaired translation and not intracellular degradation. Ribosome transit studies directly confirmed the prolonged elongation rates for apo B and apo E mRNAs in hepatocytes derived from diabetic rats. This effect was more pronounced on apo BH (higher molecular weight) than on apo BL (lower molecular weight). Treatment of diabetic rats with insulin for 7 d led to normalization of hepatic albumin mRNA levels with no substantial change in apo E mRNA levels. In contrast, insulin treatment resulted in significant increases in hepatic apo B mRNA over control levels. Results suggest hepatic albumin and apo B mRNA levels are responsive to insulin in the diabetic state.
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PMID:Impaired hepatic apolipoprotein B and E translation in streptozotocin diabetic rats. 153 30

Amino-oligopeptidase (AOP, aminopeptidase N), a major glycoprotein hydrolase in intestinal and kidney brush border membranes, plays a crucial role in digesting peptide nutrients and salvaging filtered peptides. The molecular structure of rat intestinal and kidney AOP was compared for normal Wistar and congenitally diabetic BB Wistar (BBd) rats. Brush border membranes were isolated, solubilized with Triton X-100, and the AOP specifically immunoprecipitated with polyvalent rabbit antiserum and analyzed on 7% sodium dodecyl sulfate (SDS)-acrylamide electrophoresis. While the specific hydrolytic activity was maintained, BBd rats displayed an altered migration of AOP on SDS gels. Intestinal AOP migrated as a smaller species (130 kd) in the BBd than in the normal Wistar (135 to 140 kd). In some BBd rats, additional intestinal AOP species were observed (a 130- to 135-kd doublet or a 125-, 130-, or 135-kd triplet). Kidney AOP migrated as a broader band (125 to 140 kd) than intestine for all rat groups, probably due to carbohydrate chain heterogeneity, and was approximately 5 kd smaller in the BBd rat than in the normal Wistar. In contrast, no mass change was found in diabetes induced by streptozotocin (STZ). The altered intestinal AOP in the BBd rat was present when first inserted into the brush border membrane (6 hours after intraperitoneal [35S]methionine labeling), and hence was not due to nonenzymatic glycosylation (NEG). Abnormal intestinal and kidney AOP structure appeared in early diabetes, irrespective of high plasma glucose levels or ketoacidosis, and was reversed following evolution of the diabetes under prolonged (21 to 120 days) insulin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered intestinal and renal brush border amino-oligopeptidase structure in diabetes and metabolic acidosis: normal and biobreed (BB) rats. 153 46

Patients with diabetes commonly manifest hypertriglyceridemia along with decreased adipose tissue lipoprotein lipase (LPL) activity, and improved diabetes control tends to reverse these abnormalities. To better understand the mechanism of regulation of LPL in diabetes, 11 diabetic patients (3 type I, 8 type II) were brought under improved glycemic control, and adipose tissue LPL gene expression was assessed by performing paired fat biopsies. Six of the 11 patients attained improved control with insulin, with a decrease in glycohemoglobin (glyc Hgb) from 13.8 +/- 0.9 to 10.4 +/- 0.6%; 5 patients attained improved control with glyburide (glyc Hgb fell from 14.2 +/- 2.4 to 8.8 +/- 0.6%), and together they demonstrated a lowering of serum triglycerides and total cholesterol. No changes were observed in HDL cholesterol. Improved diabetes control resulted in a significant increase in LPL activity in both the heparin-releasable (HR) and extractable (EXT) fractions of adipose tissue, as well as in LPL immunoreactive mass. The change in LPL activity with improved control was variable, and showed a positive correlation with the HDL levels prior to treatment (r = 0.74, P less than 0.02). When adipose tissue was pulse-labeled with [35S]methionine, there was an increase in isotope incorporation into LPL after treatment, indicating an increase in LPL synthetic rate. However, improved diabetes control resulted in no significant change in LPL mRNA levels. Thus, improved glycemic control resulted in an increase in LPL activity which correlated with each patient's basal high density lipoprotein. This increase in LPL activity was accompanied by an increase in LPL immunoreactive mass, and an increase in LPL synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. 155 36

The hepatic asialoglycoprotein receptor is the first studied mammalian lectin. Modulations in vivo by diabetes and in vitro by the carboxylic ionophore monensin gave rise to similar apparent alterations on its biosynthesis, structure and ligand binding capacity. In normal rats, the receptor (whether purified by ligand or antibody-affinity chromatography) presented a similar pattern in SDS-PAGE analysis, with a major 42-kDa band and two minor ones (49 and 52-54 kDa). In diabetic rats, a new 38-kDa band appeared, but only after antibody-affinity purification. In vitro biosynthesis of the receptor by normal hepatocytes in the presence of 35S-methionine showed that this 38-kDa band was present at the end of a 30-min pulse but decreased during a 180-min chase, in association with an increase in the major 42-kDa band. In diabetic cells, this evolution was retarded. Using a 30-min pulse followed by a 120-min chase in the presence of 100 microM monensin, we showed that this carboxylic ionophore had similar effects on diabetes, leading to a delay in the maturation process of the 42-kDa band and the persistent emergence of the 38-kDa species. Allowing incubation in the presence of 25 or 100 microM monensin, we observed a decrease in the number of ligand binding sites both at the surface (40%) and within the cell (28%). In hepatocytes from diabetic rats, monensin showed no additional effect on the partial diabetes-induced inactivation.
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PMID:Comparative effects of diabetes and monensin on the lectin asialoglycoprotein receptor: biosynthesis, structure and function in rats. 157 3

Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
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PMID:Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. 164 80


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