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)

Leptin-receptor gene expression in hypothalamic tissue from lean and obese humans was examined. The full-length leptin receptor, that is believed to transmit the leptin signal, is expressed in human hypothalamus. There was no difference in the amount of leptin-receptor mRNA In seven lean (BMI 23.3 +/- 0.9 kg/m2) and eight obese (BMI 36.9 +/- 1.5) subjects as determined by reverse transcription-polymerase chain reaction. A sequence polymorphism (A-->G) was detected at position 668 of the leptin receptor cDNA. This second base substitution changed a glutamine to an arginine at position 223 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. The occurrence [correction of occurance] of the polymorphic allele(s) did not correlate with BMI in the population studied. The mutation responsible for the defect in the leptin receptor in db/db mice was not detected in any obese human, nor was the fa/fa rat mutation. These results provide evidence that the leptin resistance observed in obese humans is not due to a defect in the leptin receptor.
Diabetes 1996 Jul
PMID:The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations. 866 55

The autoimmune syndrome of the BB rat is associated with a marked increase in glutamine (Gln) metabolism in immune system cells of both diabetes-prone (BBdp) and diabetic (BBd) rats. To test whether inhibition of Gln metabolism prevents diabetes, 17 BBdp received acivicin (1 mg/kg) and 17 received saline subcutaneously every 2 days from age 48 days until diabetes onset or age 186 days. Twenty-seven non-diabetes-prone (BBn) rats served as controls. Acivicin caused some growth effects and a macrocytic anemia, but no other clinical or biochemical side effects. Only one acivicin-treated BBdp became diabetic (age 158 days), compared with saline-treated rats, of which 10 became diabetic and 2 became glucose intolerant (p < 0.001). Insulitis was moderate to severe in 88% of the saline-treated BBdp rats, but minimal in most acivicin-treated BBdp rats. Liver glutamine and glutamate tended to be higher in acivicin- than saline-treated BBdp rats. Acivicin caused no change in the proportions of T or B lymphocytes, NK cells, or macrophage phenotypes in spleen or blood; all BBdp rats were typically lymphopenic. Mitogenic responses of splenocytes in vitro were not affected. The results are consistent with the hypothesis that acivicin, by interfering with Gln metabolism, "targets" activated cells of the immune system and thereby attenuates the process and prevents overt diabetes, without major disturbance of Gln levels or generalized immunosuppression. This prevention is not due to a nutritional-growth retardation effect, as diabetes was prevented in females that showed no such effect.
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PMID:Prevention of diabetes in the spontaneously diabetic BB rat by the glutamine antimetabolite acivicin. 872 29

We describe a new alpha chain mutant accidentally found in a diabetic patient. The propositus is being treated for diabetes mellitus II with 4% glycated hemoglobin (Hb A1C). The variant, named Hb Gouda, is not detectable by starch gel electrophoresis but appears as a shoulder before the Hb A fraction during the chromatographic separation of Hb A1C. The hematological analysis revealed normal parameters with a normal serum iron value. No anomalies were reported in connection with Hb Gouda. The tryptic peptide map and sequencing of the alpha T-9 peptide revealed the substitution of a histidine by a glutamine at position 72. By selective amplification and sequencing of both the alpha genes, we have assigned the new mutation to the alpha 2 gene. Position 72 of the alpha chain is a moderately conserved site located between two non-conserved amino acids. This site is not involved in heme, dimer or tetramer contacts, or in Bohr effect or in 2,3-diphosphoglycerate binding.
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PMID:HB Gouda [alpha 72(EF1)His-->Gln], a new silent alpha chain variant. 874 29

The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of 14CO2 from labeled glucose or palmitate was not inhibited at 4 mM, a concentration of phenylacetic acid that inhibited gluconeogenesis from lactate/pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phenylacetyl CoA ester decreased pyruvate carboxylation in a concentration-dependent manner. Phenylacetic acid inhibited gluconeogenesis in isolated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [14C]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate carboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Student's t-test vs control)] and streptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0.01 (paired t-test vs basal)]. Hepatic glucose production in control and diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in vivo. The results suggest the possibility that the inappropriate overproduction of glucose can be controlled by inhibitors of pyruvate carboxylase. This class of inhibitors may be useful in the treatment of non-insulin-dependent diabetes mellitus.
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PMID:In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. 896 65

We investigated the mechanism by which a selective increase in arterial insulin can suppress hepatic glucose production in vivo. Isotopic (3-3H-glucose) and arteriovenous difference methods were used in overnight-fasted, conscious dogs. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon infusions) was used to control the endocrine pancreas. Equilibration (100 min) and basal (40 min) periods were followed by a 180-min test period. In control dogs (n = 5), basal insulin delivery was continued throughout the study. In the other two groups, peripheral insulin was selectively increased at the beginning of the test period by stopping the portal insulin infusion and infusing insulin peripherally at twice the basal portal rate. One group (INS + FAT; n = 6) received an infusion of 20% intralipid + heparin (0.5 U x kg(-1) x min(-1)) to clamp the nonesterified fatty acid (NEFA) levels during hyperinsulinemia; the other group (INS; n = 7) received only saline during the experimental period. In the INS group, a selective increase in peripheral insulin of 84 pmol/l was achieved (36 +/- 6 to 120 +/- 24 pmol/l, last 30 min) while portal insulin was unaltered (84 +/- 18 pmol/l). In the INS + FAT group, a similar increase in peripheral insulin was achieved (36 +/- 6 to 114 +/- 6 pmol/l, last 30 min); again, portal insulin was unaltered (96 +/- 12 pmol/l). In the control group, basal insulin did not change. Glucagon and glucose remained near basal values in all protocols. In the INS group, NEFA levels dropped from 700 +/- 90 (basal) to 230 +/- 65 micromol/l (last 30 min; P > 0.05), but in the INS + FAT group changed minimally (723 +/- 115 [basal] to 782 +/- 125 micromol/l [last 30 min]). In the INS group, net hepatic glucose output dropped by 6.7 micromol x kg(-1) x min(-1) (P < 0.05), whereas in the INS + FAT group it dropped by 3.9 micromol x kg(-1) x min(-1) (P < 0.05). When insulin levels were not increased (i.e., in the control group), net hepatic glucose output dropped 1.7 micromol x kg(-1) x min(-1) (P < 0.05). In all groups, the net hepatic glucose output data were confirmed by the tracer-determined glucose production data. In the INS group, net hepatic gluconeogenic substrate uptake (alanine, glutamine, glutamate, glycerol, glycine, lactate, threonine, and serine) fell slightly (10.4 +/- 1.3 [basal] to 7.2 +/- 1.3 micromol x kg(-1) x min(-1) [last 30 min]), whereas in the INS + FAT group it did not change (7.3 +/- 1.5 [basal] to 7.4 +/- 0.6 micromol x kg(-1) x min(-1) [last 30 min]), and in the control group it increased slightly (9.6 +/- 1.3 [basal] to 10.3 +/- 1.4 micromol x kg(-1) x min(-1) [last 30 min). These results indicate that peripheral insulin's ability to regulate hepatic glucose production is partially linked to its inhibition of lipolysis. When plasma NEFA levels were prevented from falling during a selective arterial hyperinsulinemia, approximately 55% of insulin's inhibition of net hepatic glucose output (NHGO) was eliminated. The fall in NEFA levels brings about a redirection of glycogenolytically derived carbon within the hepatocyte such that there is an increase in lactate efflux and a corresponding decrease in NHGO.
Diabetes 1997 Feb
PMID:The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. 900 Jun 93

Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc beta-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residues on intracellular proteins. Increased activity of the hexosamine pathway is a putative mediator of glucose-induced insulin resistance but the mechanisms are unclear. We determined whether O-GlcNAc transferase is found in insulin-sensitive tissues and compared its activity to that of GFA in rat tissues. We also determined whether non-insulin-dependent diabetes mellitus (NIDDM) or acute hyperinsulinaemia alters O-GlcNAc transferase activity in human skeletal muscle. O-GlcNAc transferase was measured using 3H-UDP-GlcNAc and a synthetic cationic peptide substrate containing serine and threonine residues, and GFA was determined by measuring a fluorescent derivative of GlcN6P by HPLC. O-GlcNAc transferase activities were 2-4 fold higher in skeletal muscles and the heart than in the liver, which had the lowest activity, while GFA activity was 14-36-fold higher in submandibular gland and 5-18 fold higher in the liver than in skeletal muscles or the heart. In patients with NIDDM (n = 11), basal O-GlcNAc transferase in skeletal muscle averaged 3.8 +/- 0.3 nmol/mg.min, which was not different from that in normal subjects (3.3 +/- 0.4 nmol/mg.min). A 180-min intravenous insulin infusion (40 mU/m2.min) did not change muscle O-GlcNAc transferase activity in either group. We conclude that O-GlcNAc transferase is widely distributed in insulin-sensitive tissues in the rat and is also found in human skeletal muscle. These findings suggest the possibility that O-linked glycosylation of intracellular proteins is involved in mediating glucose toxicity. O-GlcNAc transferase does not, however, appear to be regulated by either NIDDM or acute hyperinsulinaemia, suggesting that mass action effects determine the extent of O-linked glycosylation under hyperglycaemic conditions.
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PMID:UDP-N-acetylglucosamine transferase and glutamine: fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues. 902 21

We studied the roles of acidosis, plasma osmolality, and organic osmolytes in the pathogenesis of cerebral edema in an animal model of diabetes mellitus. Normonatremic rats with streptozotocin-induced non-ketotic (NKD) and ketotic (DKA) diabetes were sacrificed before or after treatment with hypotonic saline and insulin. Brains were analyzed for water, electrolyte, and organic osmolyte content. Brain water decreased by 2% in untreated DKA and NKD despite a 12% increase in plasma osmolality due to hyperglycemia. After treatment of both NKD and DKA, brain water increased equivalently by 8%. The cerebral edema that occurred after treatment was associated with decreased brain sodium content and no change in total major brain organic osmolytes in both NKD and DKA. However, brain content of the individual osmolytes glutamine and taurine increased after treatment of DKA. In a separate study, brain water and solute content of rats with DKA were compared after treatment with either hypotonic or isotonic fluid. Animals treated with isotonic fluid had significantly less cerebral edema and higher brain sodium content than those treated with hypotonic fluid. In our studies, brain swelling after treatment of DKA and NKD was primarily due to a rapid reduction of plasma glucose and osmolality, and was not caused by sodium movement into the brain. Acidosis did not appear to play a major role in the pathogenesis of cerebral edema after treatment of DKA.
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PMID:Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis. 908 92

To compare steady-state glutamine turnover using nitrogen, carbon, and hydrogen tracers and to test the validity of monocompartmental equations to determine plasma glutamine turnover under non-steady-state conditions, we infused 10 normal postabsorptive volunteers simultaneously with [3,4-3H]glutamine, [2-15N]glutamine, and [U-14C]glutamine for 4 h to isotopic steady state. Eight of the ten subjects were subsequently infused in a stepwise fashion with exogenous glutamine. Plasma glutamine enrichment and specific activities fit a monoexponential model well (r = 0.89, 0.92, and 0.92 for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively). Volumes of distribution for each tracer (362 +/- 58, 433 +/- 51, and 446 +/- 63 ml/kg) and the transfer rate constants (0.0224 +/- 0.0020, 0.0222 +/- 0.0020, and 0.0240 +/- 0.0023 min(-1)) for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively, were not significantly different from one another. However, turnover of glutamine determined with [3,4-3H]glutamine (6.14 +/- 0.54 micromol x kg(-1) x min(-1)) exceeded that determined with [U-14C]glutamine (5.72 +/- 0.541 micromol x kg(-1) x min(-1); P < 0.03), which in turn exceeded that determined with [2-15N]glutamine (4.67 +/- 0.39 micromol x kg(-1) x min(-1), P < 0.01). The monocompartmental non-steady-state equations of both DeBodo et al. (DeBodo, R., R. Steele, A. Dunn, and J. Bishop. Rec. Prog. Horm. Res. 19: 445-448, 1963) and Finegood et al. (Finegood, D., R. Bergman, and M. Vranic. Diabetes 36: 914-924, 1987) yielded acceptable approximations of predicted rates of glutamine plasma appearance with deviations from predicted rates from 0.2 to 1.6% (Finegood et al.) and from 0.1 to 8.2% (DeBodo et al.). Use of a 0.75 pool fraction most closely approximated predicted rates.
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PMID:Steady-state and non-steady-state measurements of plasma glutamine turnover in humans. 914 83

First-degree relatives of NIDDM patients have an approximately 40% lifetime risk of developing diabetes, and insulin resistance is the best predictor. However, insulin resistance is altered by many other factors, including age, diet, exercise, and medications. To investigate the metabolic and endocrine alterations associated with insulin resistance when all the above confounding factors are excluded, we examined the first phase of insulin secretion and insulin sensitivity in 49 white normoglycemic (4.99 +/- 0.51 vs. 4.95 +/- 0.41 mmol/l) nonexercising lean (BMI, 24 +/- 3 vs. 23 +/- 2 kg/m2; 105 +/- 3 vs. 104 +/- 3% of ideal body weight) offspring of NIDDM patients. These subjects were compared with 29 matched healthy control subjects by means of an intravenous glucose bolus (0.3 g/kg body wt), immediately followed by a euglycemic-hyperinsulinemic (approximately 420 pmol/l) clamp, along with lipid and amino acid profiles. The offspring showed fasting hyperinsulinemia (40.6 +/- 15.8 vs. 30.9 +/- 13.6 pmol/l; P = 0.005) and higher free fatty acid (FFA) levels (582 +/- 189 vs. 470 +/- 140 micromol; P = 0.007), whereas triglycerides, total cholesterol, and HDL and LDL cholesterol levels were comparable with those of control subjects. Alanine (320 +/- 70 vs. 361 +/- 73 micromol/l; P = 0.017), serine (P = 0.05), and glutamine and glycine (P = 0.02) were lower in the offspring than in the control subjects, whereas branched-chain amino acids (343 +/- 54 vs. 357 +/- 54 micromol/l; P = 0.28) were not different. Insulin sensitivity was lower (4.86 +/- 1.65 vs. 6.17 +/ 1.56 mg x kg(-1) x min(-1); P = 0.001), and an inverse correlation with fasting FFAs in the offspring (adjusted R2 = 0.21, P = 0.0005), but not in control subjects (adjusted R2 = 0.03, P = 0.368), was found. Because insulin sensitivity in the offspring appeared to be a mixture of three distributions, they were subdivided into three subgroups: very low, low, and normal insulin sensitivity (20, 47, and 33%, respectively). The same alterations in amino acid and FFA metabolism were observed in the very low and low subgroups but not in the normal subgroup. The first phase of insulin secretion appeared to compensate significantly for insulin resistance in the low subgroup versus the normal subgroup and controls, but was inappropriately low in the subgroup with very low insulin sensitivity considering its degree of insulin resistance. In conclusion, lean insulin-resistant offspring of NIDDM parents showed 1) trimodal distribution of insulin sensitivity, 2) high fasting plasma FFA concentrations, 3) an inverse correlation between insulin sensitivity and FFA concentration, 4) low plasma gluconeogenic amino acid concentrations, and 5) defective insulin secretion when related to insulin sensitivity in the subgroup of very resistant offspring. These results suggest that, in this white population, insulin sensitivity may be determined by a single major gene and that alterations in FFA metabolism may play a role in the pathogenesis of NIDDM.
Diabetes 1997 Jun
PMID:Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. 916 72

Serum paraoxonase/arylesterase (PONA) is associated with high-density lipoprotein and may prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides. A recent report suggested an association of glutamine (A type)/arginine (B type) polymorphism at position 192 of PONA gene with coronary heart disease (CHD) among Caucasian patients with noninsulin-dependent diabetes mellitus (NIDDM). However, conflicting results have also been reported. To investigate the significance of this polymorphism in the pathogenesis of CHD, we performed an association study of this polymorphism with CHD in Japanese NIDDM patients. We genotyped 164 patients with NIDDM, 42 with CHD, and 122 without CHD. Other known risk factors for CHD were matched between the 2 groups. AB+BB isoforms were detected in 41 of 42 diabetic patients with CHD. The proportion of B allele carriers (AB+BB) was significantly higher than that of AA carriers among diabetic patients with CHD compared with those without CHD (chi 2 = 7.68, P = 0.003). Multivariate logistic regression analyses showed a markedly increased odds ratio (OR: 8.823, CI, 1.13-68.7) in B allele carriers, while ORs of other risk factors remained between 1.01 and 1.92. Carriers of the B allele of the Gln192Arg polymorphism in the PONA gene proved to be at increased risk for developing CHD in Japanese NIDDM patients. This association was independent of other known risk factors for CHD, suggesting an important role of the paraoxonase B isoform in the pathogenesis of CHD.
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PMID:Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus. 921 3


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