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)

Amyloid deposits are found in pancreatic islets of 90% of type 2 (non-insulin-dependent) diabetic subjects at postmortem. Islet amyloid is formed from islet amyloid polypeptide (IAPP). IAPP is a 37 amino acid peptide which is a normal constituent of beta cells and is co-secreted with insulin in animals and in man. The causative factors for fibrillogenesis of IAPP are unclear, but could be related to the sequence of IAPP and abnormal production of the peptide. The lack of islet amyloid in rodent models of diabetes is due to proline substitutions in the amyloidogenic region of IAPP. Amyloid fibrils are deposited between beta cells and islet capillaries: fibrils in invaginations of the plasma membrane may interfere with membrane signalling and insulin release. Amyloid fibrils are formed within 2 days in culture in islets isolated from transgenic mice expressing the gene for human IAPP, but not in vivo. Overexpression and decreased clearance of human IAPP from islet spaces may be important factors. Progressive deposition of IAPP fibrils combined with the associated reduction in the insulin-secreting beta cells is likely to contribute to deterioration of islet function in the course of type 2 diabetes.
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PMID:Islet amyloid in type 2 (non-insulin-dependent) diabetes. 864 52

The biosynthesis of basement membrane components in Engelberth Holm Swarm-bearing mice with or without streptozotocin-induced diabetes and the effect of low-molecular-weight heparin derivatives (CY222, Sanofi Recherche/Institut Choay) on the relative rates of these synthetic activities were studied. In diabetic mice, the laminin mRNA level increased, whereas type IV collagen mRNA decreased. In vivo treatment with heparin fragments decreased the mRNA level of laminin to control values without altering the mRNA level of collagen IV. Biosynthetic studies with radiolabeled precursors ([3H]-proline for collagen and [35S]-methionine for laminin) confirmed these results. Laminin protein biosynthesis increased in diabetic mice. Treatment with CY222 corrected this alteration. Our results suggested an increased labeling of polymeric forms of collagen IV in diabetic mice. In addition, we showed that biosynthesis of acid-extractable collagen IV decreased in diabetic mice and that CY222 treatment corrected this disturbance. These experiments suggest that low-molecular-weight heparin fragments CY222 can modulate the biosynthesis of extracellular matrix macromolecules altered in diabetic animals by different pathways, including pretranslational and posttranslational steps.
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PMID:Expression of laminin and type IV collagen by basement membrane-producing EHS tumors in streptozotocin-induced diabetic mice: in vivo modulation by low-molecular-weight heparin fragments. 898 31

Hyperglycemia is a principal characteristic of diabetes, and has an influence on many cellular functions. In order to investigate whether the intracellular signaling pathways inducing proliferation, hypertrophy and matrix synthesis of mesangial cells are altered in a diabetic environment, we evaluated the effects of a high concentration of extracellular glucose(25 mM; 450 mg/dl) on [3H]thymidine uptake, hypertrophy, and [3H]proline incorporation into a collagenase-sensitive protein, induced by angiotensin II(Ang II) or transforming growth factor(TGF)-beta, in cultured rat mesangial cells. The exposure to a high glucose concentration for 7 days significantly inhibited Ang II(10(-6) M)-induced [3H]thymidine uptake, compared to normal glucose concentration (5 mM)(M +/- SD., 1050 +/- 100 cpm/well vs 550 +/- 97, p < 0.05), and markedly prevented the inhibition of [3H]thymidine uptake by TGF-beta(1 ng/ml)(132 +/- 10 vs 340 +/- 67, p < 0.05). The administration of H-7(50 microM), a protein kinase C(PKC) inhibitor, did not reverse these effects of high glucose on [3H]thymidine uptake. On flow cytometric analysis of cell size, the mean cell size was significantly greater for the cells exposed to high glucose or treated with Ang II or TGF-beta, compared to that for the untreated cells. But the addition of Ang II or TGF-beta to the cells exposed to high glucose did not show further enlargement in size. The exposure to high glucose and the treatment with Ang II or TGF-beta significantly increased collagen synthesis, measured by [3H]proline incorporation. The Ang II -or TGF-beta-induced increase of [3H]proline incorporation did not show changes under high glucose culture condition, compared to normal glucose concentration(Ang II, 27880 +/- 3560 cpm vs 26978 +/- 2284, TGF-beta, 26559 +/- 3700 vs 25800 +/- 1660, p > 0.05). In conclusion, although the signaling pathway for DNA synthesis by Ang II or TGF-beta are influenced, possibly mediated by PKC-independent mechanism(s), the pathway inducing hypertrophy or collagen synthesis by both agents appears to be unchanged under the high extracellular glucose concentration in cultured rat mesangial cells.
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PMID:The effects of high glucose concentration on angiotensin II- or transforming growth factor-beta-induced DNA synthesis, hypertrophy and collagen synthesis in cultured rat mesangial cells. 899 62

Currently, 16 loci that contribute to the development of IDDM in the NOD mouse have been mapped by linkage analysis. To fine map these loci, we used congenic mapping. Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene. Segregation analysis of the known variations within this interval indicated that only one variant, a serine-to-proline substitution at position 6 of the mature interleukin-2 (IL-2) protein, consistently segregates with IDDM in crosses between NOD and a series of nondiabetic mouse strains. These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium.
Diabetes 1997 Apr
PMID:Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. 907 13

A 58-yr-old obese white Caucasian male type 2 diabetic, entered into the UK Prospective Diabetes Study, was found to have raised fasting total proinsulin levels 708 pmol/L(-1) (normal range, 3-16 pmol/L(-1)) and normal specific plasma insulin level 29 pmol/L(-1) (normal range, 21-75 pmol/L(-1)). Immunoreactive plasma insulin, measured by RIA, was 503 pmol/L(-1). DNA was extracted, the insulin gene amplified by the PCR, and by direct sequencing, a novel point mutation, G1552C, was identified, which resulted in the substitution of proline (CCT) for arginine (CGT) at position 65. This prevented cleavage of the C-peptide A-chain dibasic cleavage site (lys-arg) by the processing protease in the pancreatic beta-cells. The plasma proinsulin and insulin levels were in accord with expression of both the wild-type and the mutant alleles. The G1552C mutation was not linked with diabetes, because it was present in a 37-yr-old nondiabetic daughter and not in a 35-yr-old daughter who had had gestational diabetes.
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PMID:A novel point mutation in the insulin gene giving rise to hyperproinsulinemia. 914 61

Excessive production and deposition of extracellular matrix proteins are characteristic features of diabetic nephropathy. This study tests the hypothesis that cells from diabetic patients who develop nephropathy have a disturbance in collagen metabolism compared with cells from diabetic patients without complications. Kinetics of overall collagen metabolism and total protein synthesis were examined in serially passaged, subconfluent, quiescent skin fibroblasts cultured in either normal (5 mM) or high (25 mM) glucose concentrations from 14 insulin-dependent diabetic (IDDM) patients with nephropathy; 14 IDDM patients without nephropathy matched for age, diabetes duration, and body mass index; and 14 healthy subjects. Fibroblasts were incubated in the presence of 2 microCi/ml [3H]proline, and after labeling the incorporation of [3H]proline into total protein, collagen (collagenase-sensitive material), and noncollagen proteins (collagenase-resistant material) was determined at different time points. Collagen degradation was determined in pulse-chase experiments by following the residual collagen-bound radioactivity after incubation for 8 h with 10 microCi/ml [3H]proline. In high glucose concentrations (25 mM), overall collagen synthesis (measured as [3H]proline incorporation into extracellular and intracellular collagenase-sensitive material) was significantly greater in the patients with nephropathy (mean +/- SEM after a 24-h labeling period: 7189 +/- 671 dpm/10(6) cells) than in the patients without (4341 +/- 267 dpm/10(6) cells; P < 0.01) or healthy control subjects (3836 +/- 234 dpm/10(6) cells; P < 0.01). No significant differences were observed in noncollagen protein production or in collagen degradation rates among the three groups of subjects. In the presence of normal glucose concentrations (5 mM), collagen synthesis was lower in all groups studied, but the differences between IDDM patients with nephropathy and those without remained unaltered. These results suggest that long-term cultured fibroblasts derived from diabetic patients with nephropathy exhibit an abnormality in collagen metabolism. Cells from long-standing diabetic patients without nephropathy have normal collagen metabolism. The increased collagen synthesis is likely to be intrinsic to those diabetic patients susceptible to nephropathy and may play an important role in the sclerotic processes that occur in the kidneys, arteries, and heart.
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PMID:Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy. 921 63

Experimental streptozotocin-induced diabetes resulted in important changes in body weight which were associated with abnormalities in water and food intake. In addition, diabetic rats showed a clear muscle atrophy involving a decrease in both skeletal muscle size and protein content. This was accompanied by a marked loss of total carcass nitrogen. These changes were related to important alterations in protein turnover in skeletal muscle. Thus, the diabetic animals showed changes in the fractional protein rates of both synthesis (decreased by 37%) and degradation (increased by 140%). The increased protein degradation observed in the muscle of the diabetic animals was associated with important changes in the concentration of both circulating and muscle amino acids. Interestingly, the diabetic animals did not show important changes in either liver or kidney protein turnover rates, in spite of having a clear increase (over 50%) in kidney mass. In addition, and although the total amino acid concentration was not affected by the diabetic state, the chemically induced diabetic animals showed important elevations of branched-chain amino acids (leucine, isoleucine, and valine) in both blood and skeletal muscle. Similarly, important decreases in the blood concentrations of glutamate+glutamine, alanine, glycine, proline, serine, and threonine were also observed. These observations reinforce the idea of the association between muscle protein wasting, increased protein turnover, and alterations in branched-chain amino acids previously proposed by our group.
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PMID:The increased skeletal muscle protein turnover of the streptozotocin diabetic rat is associated with high concentrations of branched-chain amino acids. 923 2

Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. The resultant reduced capacity for self-association in solution translates into more rapid absorption of insulin lispro than human regular insulin from subcutaneous sites. Maximum insulin concentrations are higher and are reached earlier with insulin lispro than with human regular insulin, and insulin concentrations return to baseline values more quickly with insulin lispro; consequently, insulin lispro has a more rapid onset and a shorter duration of glucose-lowering activity. These pharmacological properties provided the rationale for comparative clinical trials of subcutaneous insulin lispro (administered within 15 minutes before meals, preferably immediately before meals) and subcutaneous human regular insulin (administered 20 to 45 minutes before meals) in patients with type 1 diabetes (insulin-dependent diabetes mellitus) or type 2 diabetes (non-insulin-dependent diabetes mellitus) requiring premeal insulin therapy plus basal insulin therapy. Available clinical trials are well designed and results suggest that 1- and 2-hour postprandial blood glucose levels with insulin lispro are similar to or lower than those with human regular insulin; 1- and 2-hourpostprandial glucose excursions are similar to or less pronounced than those with human regular insulin. Glycated haemoglobin A values were generally similar with both agents. Continuous subcutaneous insulin infusion was associated with greater improvements in postprandial blood glucose levels and glycated haemoglobin A1 values with insulin lispro than with human regular insulin. Confirmatory data are required. The incidence of hypoglycaemia with insulin lispro was similar to or lower than that with human regular insulin. In particular insulin lispro appears to be associated with a lower incidence of night-time and severe hypoglycaemic episodes. Evidence also suggests that patients perceive their quality of life to be improved with insulin lispro compared with human regular insulin, and that satisfaction with treatment is greater with the insulin analogue. Thus, in patients with type 1 or 2 diabetes requiring premeal insulin therapy, insulin lispro appears to provide greater postprandial glycaemic control than human regular insulin without increasing the risk of hypoglycaemia. Furthermore, the reduced injection-meal interval with this agent offers greater convenience for the patient than regular human insulin. If longer term clinical experience supports these promising results it is likely that insulin lispro will offer important advantages over human regular insulin.
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PMID:Insulin lispro: a review of its pharmacological properties and therapeutic use in the management of diabetes mellitus. 933 63

The difficulties of achieving good glycaemic control in insulin-dependent diabetes are due in large part to the inadequacies of subcutaneously administered insulin. In particular, resorption with the long acting form is variable from one subject to another and from one day to another and irregular over time, whereas the action of the rapid acting form is too late and prolonged. The slowness of absorption of the rapid acting form is attributable to the need for hexamer dissociation. The Lilly Laboratories, by inverting the amino acids lysine and proline in positions 28 and 29 in the B chain, have created an insulin (Lispro) which more rapidly dissociates into monomers after injection. The stability of Lispro is good, probably because of its phosphate buffer. In our experience, in conditions simulating use in portable insulin pumps, Lispro proved to be more stable than insulins specially intended for this use. The affinity in vitro was identical to that of insulin for its receptor. The affinity for insulin-like growth factor-I (IGF-I) receptor has been found to be 1.5 times as high as that of fast insulin in some models and comparable in others, and nearly 1,000 times less than that of IGF-1. Studies on in vivo potency and ex vivo cell growth, as well as of tolerance in the animal (mutagenicity, toxicity and carcinogenicity), have not shown a different effect from regular insulin (contrary to results for analogue Asp B10). The pharmacokinetics has shown an earlier and higher insulinaemic peak and a more rapid return to baseline values than regular insulin. On the basis of pharmacokinetic studies in normal subjects and diabetic patients, the characteristics retained by the licensing authorities are onset of action at 15 min, insulinemic peak between 30 and 70 min, and duration of action 2 to 5 h. Some clinical studies have shown a shortened action period of 1 to 3 h as compared to regular insulin and less influence of dose and injection site, notably with a return to normal insulin levels. The time required for normalisation is increased by 1 h if the injection is made in the thigh rather than the abdomen, as compared to 2 to 3 h for conventional insulin. This suggests that Lispro should be administered just before the meal (0 to 15 min). In some patients, an insulin with prolonged action can be added if the interval between injections is prolonged, i.e. always at the evening meal but possibly also at the noon meal. Lispro can be mixed with Umuline NPH or Umuline zinc without any alteration in its pharmacokinetics and potency if the injection is performed immediately. The few studies that have considered glycaemic stability and reproducibility have shown a tendency toward improvement in glycaemic excursions during the day, as measured by MAGE, and in insulinaemia variability expressed in area under the curve, which was reduced by half in the same individual or from one individual to another, with less marked impact on the variability from one day to another of glycaemic excursions. On the whole, Lispro provides faster kinetics, greater stability and possibly better reproducibility than fast insulin. These advantages, if confirmed by clinical experience, should allow an improvement in the comfort and glycaemic stability of diabetic patients.
Diabetes Metab 1997 Sep
PMID:[From the concept of fast acting analogs to the properties of the insulin Lispro]. 941 May 52

Human and mouse major histocompatibility complex class II beta chain alleles associated with predisposition to type I diabetes often encode a non-charged residue at position 57 rather than the negatively charged aspartate residue characteristic of non-susceptible haplotypes. The mechanism(s) whereby this polymorphism promotes eventual pancreatic beta cell destruction is unclear. The type I diabetes-susceptible mouse strain NOD (H2(g7)) encodes serine at Ab position 57 and is one of the few mouse class II molecules not encoding aspartate at this position. To gain insight into the structural impact of this amino acid substitution and any influence it may have on T-cell selection, we assessed whether T-cell repertoires selected by diabetogenic class II (Ag7) are tolerant of mutant Ab (residues 56 and 57) H2-Ag7. We find that NOD mice mount an allogeneic response to skin grafts expressing mutant position 57 (serine to aspartate) Abg7; but not to grafts expressing mutant position 56 (histidine to proline) Abg7. Graft rejection correlates with the presence of CD4(+) T cells specific for the mutant H2-Ag7 heterodimer. Genetic analyses are consistent with Ab position 57 aspartate/non-aspartate dimorphism influencing peptide selection and hence repertoire selection. Direct evidence for the serine to aspartate substitution at position 57 influencing T-cell selection is found by analysis of peripheral T-cell receptor (TCR) usage and the CD4/CD8 T-cell ratio.
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PMID:MHC class II Ab diabetogenic residue 57 Asp/non-Asp dimorphism influences T-cell recognition and selection. 943 40


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