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)

IGF-I and -II levels are altered in patients with atherogenic lipid profiles and may contribute to the development of macrovascular disease in NIDDM. We examined cardiovascular risk factors, IGF-I, IGF-II and IGFBP-1 in 74 NIDDM patients analysed as a whole group and according to treatment type. IGF-I was not significantly associated with cardiovascular risk factors but IGF-II levels correlated positively with total and LDL cholesterol most markedly in the diet treated group (0.72, p < 0.01 and 0.76, p < 0.01 respectively). In the whole group reduced IGFBP-1 levels were significantly associated with factors known to increase cardiovascular risk: i.e. low HDL cholesterol (0.31, p < 0.01) and elevated blood pressure (-0.35, p < 0.01), BMI (-0.37, p < 0.01), insulin (-0.29, p < 0.01) and proinsulin (-0.24, p < 0.01). In the treatment groups IGFBP-1 was lower in patients on diet alone (n = 11, 42.6 +/- 11.6 mu g/l) and sulphonylurea +/- insulin (n = 39, 53.2 +/- 7.6 mu g/l) relative to insulin treatment (n = 24, 103.0 +/- 19, 7 mu g/l, p < 0.05). The lower levels of IGFBP-1 were not due to a significant change in phosphorylation status from the highly phosphorylated circulating form since lesser and non-phosphorylated variants were undetectable in 53/74 patients. Multiple regression analysis revealed the best predictors of IGFBP-1 were BMI and MAP (R2 = 0.2. p < 0.001) and for blood pressure, IGFBP-1 and age (R2 = 0.47, p < 0.001). These findings indicate that in NIDDM patients low IGFBP-1 levels are associated with multiple factors predisposing to atherogenesis.
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PMID:Reduced insulin-like growth factor binding protein-1 (IGFBP-1) levels correlate with increased cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). 863 18

Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese.
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PMID:Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. 866 40

The Hoorn study has investigated the prevalence of impaired glucose tolerance (IGT) and diabetes in a random sample of the population, 50-75 years of age, in the small Dutch town of Hoorn. The percentage of the population identified as having IGT was 10.3%, while 8.4% had diabetes. The prevalence of both diabetes and IGT was higher in older subjects (70-74 years of age) than in younger subjects (50-54 years of age), suggesting that age is a major determinant of the prevalence of IGT and diabetes in a population. A prospective study of the development of non-insulin dependent diabetes mellitus (NIDDM) in the subjects identified as having IGT was then initiated. Preliminary results for the 158 subjects who have been followed for a mean of 2 years indicated that 28.5% (95% confidence interval, 15-42%) have progressed to NIDDM within this period. The progression rate calculated from this value is 13.8%/year (95% confidence interval, 3.5-24%/year). Analysis of possible determinants of conversion has revealed that 2-hour plasma glucose levels greater than 9.4 mmol/litre and increased fasting proinsulin levels are predictive of progression to NIDDM. This suggests that beta cell dysfunction, rather than increased insulin resistance, is responsible for the development of NIDDM.
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PMID:New data on the rate of progression of impaired glucose tolerance to NIDDM and predicting factors. 868 55

We describe a time-resolved fluoroimmunoassay specific for human proinsulin using a combination of two high-affinity monoclonal antibodies, one against insulin and the other specific for intact proinsulin and for split 65-66 and des 64-65 proinsulin forms. The assay employs only 200 microl of serum, with a detection limit of 0.1 pmol/l. The intra-assay variation coefficient was less than 3% between 3 and 1000 pmol/l. There was 0% cross-reaction with insulin, C-peptide, split 32-33 and des 31-32 proinsulin. Serum concentration of proinsulin was analyzed in 50 subjects during an oral glucose tolerance test (10 non-obese control, 10 obese controls, 10 subjects with impaired glucose tolerance, 10 patients with type II diabetes mellitus (DM) and fasting blood glucose (FBG) < 140 mg/dl, and 10 patients with type II DM and FBG > 150 mg/dl). Mean fasting serum proinsulin levels measured by this assay in non-obese controls (0.84 - 0.90 pmol/l; 0.1-2.4 pmol/l) were lower than the results reported by other investigators. There was an increase of proinsulin related to obesity and increased glucose levels, suggesting that proinsulin levels increase with insulin resistance.
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PMID:A specific and highly sensitive time-resolved fluoroimmunoassay for human proinsulin. 873 48

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l-1 vs IGT 41 pmol l-1, p < 0.01 and vs normals 34 pmol l-1, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 +/- 6.9 vs IGT 16.8 +/- 5.0, p < 0.001 and vs normals 17.1 +/- 6.9 AU ml-1, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 +/- 7.3 vs 16.5 +/- 6.4 AU ml-1, p = ns) and diabetic (22.8 +/- 7.3 vs 23.1 +/- 6.6 AU ml-1, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist-hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.
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PMID:Plasminogen activator inhibitor (PAI-1) activity is elevated in Asian and Caucasian subjects with non-insulin-dependent (type 2) diabetes but not in those with impaired glucose tolerance (IGT) or non-diabetic Asians. 874 14

To examine the effect of sulfonylurea withdrawal on the proinsulin (PI) to immunoreactive insulin (IRI) ratio in subjects with noninsulin dependent diabetes mellitus (NIDDM), we measured fasting and arginine-stimulated PI and IRI levels in 15 subjects with NIDDM (mean age, 64.4 yr; body mass index, 27.3 kg/m2) during chronic treatment with glyburide (n = 12) or other sulfonylureas (n = 3) and after withdrawal from the medication for 2-4 weeks. Additionally, we performed iv glucose tolerance tests to measure the insulin sensitivity index, glucose effectiveness at zero insulin, iv glucose tolerance, and the acute insulin response to glucose. Discontinuation of sulfonylurea therapy resulted in an increase in fasting plasma glucose from 10.5 +/- 0.8 to 13.1 +/- 0.9 mmol/L (P < 0.001). This was associated with a decrease in the fasting IRI concentration (120 +/- 21 to 92 +/- 21 pmol/L; P < 0.005) and the fasting PI concentration (58 +/- 10 to 41 +/- 7 pmol/L; P < 0.01); however, the PI/IRI ratio did not differ (50 +/- 6% during medication and 48 +/- 5% after withdrawal; P = 0.43). Similarly, the acute PI/IRI ratio did not change (8.6 +/- 2.4% on therapy; 8.4 +/- 1.2% off therapy; P = 0.91). No change was observed in other metabolic parameters, including insulin sensitivity index (0.76 +/- 0.21 x 10(-5) min-1/pM on therapy; 0.76 +/- 0.19 x 10(-5) min-1/pM off therapy), acute insulin response to arginine (225 +/- 37 pmol/L on therapy; 225 +/- 40 pmol/L off therapy), acute insulin response to glucose (10 +/- 6 pmol/L on therapy; 5 +/- 4 pmol/L off therapy), glucose effectiveness at zero insulin (0.0127 +/- 0.0007 min-1 on therapy; 0.0119 +/- 0.0009 min-1 off therapy), and iv glucose tolerance (0.85 +/- 0.05%/min on therapy; 0.71 +/- 0.07%/min off therapy). We conclude that sulfonylurea therapy does not correct the elevated PI/IRI ratio or absent first phase insulin response of NIDDM and does not have an effect on parameters of peripheral tissue glucose uptake.
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PMID:Effect of sulfonylurea withdrawal on proinsulin levels, B cell function, and glucose disposal in subjects with noninsulin-dependent diabetes mellitus. 878 86

The 75-g oral glucose tolerance test was performed in 38 normoglycaemic (World Health Organization criteria) non-diabetic volunteers, aged 31-40 years, of whom 20 had a non-insulin-dependent diabetic (NIDDM) mother and 18 had an NIDDM father. At the time of the study the offspring of NIDDM mothers had a somewhat higher body mass index (BMI) (males: 26.5 +/- 1.0 (mean +/- SEM), females: 27.5 +/- 1.5 kg/m2) than the offspring of NIDDM fathers (males: 23.4 +/- 0.9, females: 24.2 +/- 1.2 kg/m2). There was no difference in the time-course of glycaemia; however the serum concentrations of immunoreactive insulin (IRI), C-peptide and proinsulin were significantly higher in offspring of NIDDM mothers than in offspring of NIDDM fathers: area under the curve (AUC) serum IRI: 0.928 +/- 0.091 vs 0.757 +/- 0.056 nmol.l-1.h-1, p = 0.019; serum C-peptide: 6.379 +/- 0.450 vs 4.753 +/- 0.242 nmol.l-1.h-1, p = 0.004; serum proinsulin: 172 +/- 40 vs 51 +/- 7 pmol.l-1.h-1, p = 0.008). Serum IRI correlated with BMI, but C-peptide and proinsulin did not, and after accounting for BMI by covariance analysis they remained significantly higher in offspring of NIDDM mothers. In this group serum proinsulin was significantly higher in male than in female offspring (AUC serum proinsulin: 289 +/- 68 vs 77 +/- 27 pmol.l-1.h-1, P = 0.015). Male offspring of NIDDM mothers also had significantly higher serum triglyceride levels than females of the same group and than offspring of NIDDM fathers. The offspring (male and female) of NIDDM mothers had slightly lower serum apolipoprotein A-I levels than the offspring of NIDDM fathers. Significant correlations were found between serum triglycerides, HDL-cholesterol and apolipoprotein B, and serum concentrations of pancreatic beta-cell peptides, mostly in the offspring of NIDDM mothers; however, they did not display unequivocal association with gender within this group. The data are consistent with clinical observations of a greater risk of NIDDM transmission from the mother than from the father, and may suggest that male offspring are more exposed to this risk than female offspring.
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PMID:Difference in the influence of maternal and paternal NIDDM on pancreatic beta-cell activity and blood lipids in normoglycaemic non-diabetic adult offspring. 881 8

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 +/- 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 +/- 2.5 vs placebo: 12.0 +/- 2.3 mmol l-1, p r2 0.001;). Concentrations of intact (median change -2.9 (range -28.4 to +2.5 pmol l-1), p = 0.02) and des 31,32 proinsulin (median change -1.6 (range -14.1 to +5.4 pmol l-1), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change -6% (range -16% to +6%), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r1 = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.
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PMID:Effect of metformin on intact proinsulin and des 31,32 proinsulin concentrations in subjects with non-insulin-dependent (type 2) diabetes mellitus. 886 52

Postprandial lipid profiles and release of insulin (INS), intact proinsulin (PI), and 32-33 split proinsulin (SPI) in response to a mixed meal with a high fat content were determined over a 12 h period in non-obese control subjects (n = 10) and non-insulin-dependent (Type 2) diabetic (NIDDM) patients with normotriglyceridaemia (NTG; n = 11) and hypertriglyceridaemia (HTG; n = 10), by calculation of the 'areas under the curves' (AUC). The postprandial triglyceride-AUC was significantly greater in HTG-NIDDM patients (p < 0.05) than in NTG-NIDDM or control subjects. Chylomicron clearance was impaired only in HTG-NIDDM patients (p < 0.05). Chylomicron-remnant clearance was impaired in both groups of NIDDM patients (p < 0.05). The postprandial suppression of plasma non-esterified fatty acid (NEFA) content was impaired in HTG-NIDDM patients (p < 0.05). The postprandial INS-, PI- and SPI-AUCS were significantly greater than in the control subjects (p < 0.05). In NIDDM, triglyceride-AUC correlated significantly with PI and SPI release (triglyceride-AUC vs PI, p < 0.05; triglyceride-AUC vs SPI, p < 0.01). Chylomicron AUC was unrelated to the fasting plasma INS, PI or SPI content, unlike chylomicron-remnant-AUC (Chylomicron-remnant-AUC vs INS, p = NS; chylomicron-remnant-AUC vs PI, p < 0.01; chylomicron-remnant-AUC vs SPI, p < 0.01). The NEFA response was associated with fasting plasma SPI content (NEFA-AUC vs SPI, p < 0.05). Postprandial chylomicron AUC was not related to the overall secretion of INS, PI or SPI. However, triglyceride-, chylomicron-remnant- and NEFA-AUCs were all associated positively with the release of PI and SPI (p < 0.05). In multivariate analyses, chylomicron-remnant clearance had the major relationship with the release of insulin precursors, accounting for 23% of the variability (p < 0.01). Inclusion of overall response of free fatty acids improved the model, with both parameters together accounting for 30% of the variability (p < 0.01). The output of the beta-cell over the postprandial period differed between the NIDDM patients and the control subjects in that when glycaemic stimulation was moderate, the proportion of insulin-like molecules as a percentage of the total output was greater than in control subjects but this was not the situation when glycaemia was greatest. We conclude that abnormal postprandial lipaemia in NIDDM is associated with beta-cell output, possibly mediated by the availability of free fatty acids.
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PMID:Postprandial lipid metabolism and beta-cell function in non-insulin-dependent (type 2) diabetes mellitus after a mixed meal with a high fat content. 889 57

Major genes for NIDDM appear to be rare. Therefore, phenotypic characterization of the pathophysiological changes contributing to hyperglycaemia are assuming increasing importance. Assessment of beta-cell function has been hampered by two major confounding factors during functional testing: variable insulin sensitivity and plasma glucose levels. These and other methodological variables are discussed with recommendations for ameliorating or accounting for their impact. A group of tests as used by the Seattle Group for phenotypic characterization is described including basal immunoreactive insulin (IRI), proinsulin, and proinsulin intermediates (PI); the acute insulin response to glucose (AIRg); maximal (AIRmax), and half-maximal (PG50) capacity to potentiate a non-glucose secretagogue; and insulin-sensitivity (S1). Specific examples in the use of this battery of tests are given. It is concluded that such phenotyping will be an important tool for studies of the epidemiology and genetics of NIDDM.
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PMID:Normal physiology and phenotypic characterization of beta-cell function in subjects at risk for non-insulin-dependent diabetes mellitus. 889 77


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