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)

Disproportionate hyperproinsulinaemia is a manifestation of the beta-cell dysfunction observed in NIDDM. However, it is unclear when this abnormality develops and whether it predicts the development of the disease. To examine whether changes in proinsulin levels predict the development of NIDDM, baseline measurements of proinsulin and immunoreactive insulin levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM. Subjects were categorized at baseline using WHO criteria as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, subjects were recategorized as having NGT, IGT or NIDDM using the same criteria. During follow-up, 16 subjects developed NIDDM while 71 were NGT or IGT. At baseline, individuals who subsequently developed NIDDM were more obese as measured by intra-abdominal fat area on computed tomography (p = 0.046), had higher fasting glucose (p = 0.0042), 2-h glucose (p = 0.0002), fasting C-peptide (p = 0.0011), fasting proinsulin levels (p = 0.0033), and had disproportionate hyperproinsulinaemia (p = 0.056) when compared to those who remained NGT or IGT after 5 years of follow-up. These findings suggest that alterations in proinsulin levels may also predict the subsequent development of NIDDM.
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PMID:Proinsulin levels predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese-American men. 889 85

Small and disproportionate size at birth are associated with type 2 diabetes and coronary heart disease in adult life. Insulin has an important role in controlling growth in utero and we hypothesised that reduced fetal insulin secretion could be one factor underlying these associations. We therefore measured cord plasma concentrations of proinsulin, 32-33 split proinsulin, insulin and C-peptide in 391 babies born at term and related them to the weight of the placenta and to the babies' size and proportions at birth. Babies with a small placental weight and a lower birth weight had lower cord plasma concentrations of split proinsulin and insulin. Babies who were disproportionate, either having a high ratio of head to abdominal circumference or being thin, had lower concentrations of split proinsulin, split proinsulin and insulin. The relations with split proinsulin were especially strong, the geometric mean concentration (pmol/l) falling from 14.2 in babies with a head to abdominal circumference ratio of 101.6% or less to 7.2 in those with a ratio above 107.3% (P < 0.0001), and from 17.4 in babies with a ponderal index above 28.5 kg/m3 to 7.4 in those with a ponderal index of 25.5 kg/m3 or less (P < 0.0001). These findings support the hypothesis that reduced fetal insulin secretion may be one factor underlying the associations between reduced growth in utero and type 2 diabetes and coronary heart disease in adult life.
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PMID:Relation of cord plasma concentrations of proinsulin, 32-33 split proinsulin, insulin and C-peptide to placental weight and the baby's size and proportions at birth. 889 61

As insulin is a major fetal growth hormone, we have related the mother's nutrient intakes (assessed by a food frequency questionnaire) and other influences associated with fetal growth to the baby's concentrations of insulin and its propeptides in umbilical cord plasma. Among 391 term babies studied, those whose mothers had high energy intakes in early pregnancy and low protein intakes in late pregnancy had lower cord plasma concentrations of 32-33 split proinsulin, insulin, and C-peptide. Concentrations of split proinsulin fell by 0.66 (95% Cl 0.29 to 1.03, p = 0.0006) log pmol l-1 for each log kcal increase in the mother's energy intake in early pregnancy and by 0.005 (95% Cl 0.000 to 0.010, p = 0.04) log pmol l-1 for each g decrease in protein intake in late pregnancy. Insulin and propeptide concentrations were however unrelated to the mother's height and body mass index, and to smoking during pregnancy. These observations parallel recent studies relating the same pattern of dietary intakes to impaired fetal and placental growth. Although dietary intakes assessed by food frequency questionnaires allow only cautious conclusions, our findings could have implications for the offspring's risk of Type 2 diabetes mellitus in adult life.
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PMID:Nutrition in pregnancy and the concentrations of proinsulin, 32-33 split proinsulin, insulin, and C-peptide in cord plasma. 891 80

Non-insulin dependent diabetes mellitus carries a markedly elevated risk of cardiovascular disease. For that reason the efficacy of any treatment modality for this disease should be assessed in terms of the known cardiovascular risk factors, as for example serum lipids. Sulfonylurea do not affect serum lipid levels to any significant extent. These drugs promote beta-cell secretion by dosing potassium ion channels. These channels are also present in vascular smooth muscle cells. Some, though not all, sulfonylureas are able to inhibit the vascular dilatory response to potassium ion openers, thereby adversely affecting the cardioprotective vascular response to ischaemia. Sulfonylureas, in contrast to insulin, seem able to inhibit the fibrinolytic system, possibly via the stimulating effect of proinsulin on the endothelial PAI-1 expression. These observations need further confirmation. Of clinical importance is the frequent occurrence of hypoglycaemia for which several risk factors are recognized.
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PMID:Role of sulfonylureas in non-insulin-dependent diabetes mellitus: Part II--"The cons". 891 91

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a genetic disorder which causes severe hypoglycaemia in the neonate. The beta cells fail to respond to changes in blood glucose levels in all the stages of the disease, which often ends with NIDDM. Fasting insulin, intact proinsulin and des 31,32 split proinsulin levels were measured in PHHI patients with active disease, patients after partial pancreatectomy, and those in clinical remission. All but one of the pancreatectomized patients developed diabetes and were hyperglycaemic on evaluation. Fasting insulin was comparable in pancreatectomized and medically treated patients. Des 31,32 split proinsulin levels were much higher in pancreatectomized compared to non-pancreatectomized patients (10.7 +/- 2.5 vs 3.4 +/- 0.8 pmol/l, p = 0.001) and age-matched control subjects (3.8 +/- 1.4 pmol/l, p = 0.018). Also the ratio of des 31,32 split proinsulin to total insulin plus proinsulin-like peptides was higher in pancreatectomized patients (18.7 +/- 2.8 vs 7.2 +/- 0.8% in non-pancreatectomized patients, p = 0.001, and 6.8 +/- 2.1% in normal control subjects, p = 0.004). Furthermore, des 31,32 split proinsulin was the dominating species of proinsulin-like molecules in the pancreatectomized patients (62.7 +/- 1.6% vs 45.5 +/- 3.8%, and 49.0 +/- 3.2% in non-pancreatectomized patients and control subjects, respectively, p = 0.001 and p = 0.0002). Intact proinsulin levels, and the proinsulin percentage, tended to be higher in pancreatectomized patients; however, the differences did not reach statistical significance. All parameters were similar in non-pancreatectomized patients and age-matched control subjects. Subgroup analysis showed comparable proinsulin-like peptide levels in patients with active disease and those in apparent clinical remission. Fasting levels of insulin and proinsulin-like peptides were also measured in a larger group of healthy children and young adults. Insulin and des 31,32 split proinsulin increased with age, the differences being most prominent when the young age group (0-8 years) was compared to the older groups (8-16 and > 16 years). The fasting levels of plasma insulin were correlated with those of intact proinsulin and des 31,32 split proinsulin (r = 0.82 and 0.81, respectively). Fasting insulin, intact proinsulin and des 31,32 split proinsulin were correlated with BMI (r = 0.55, 0.56 and 0.53, respectively). In summary, relative hyperproinsulinaemia was noted only in PHHI patients with increased secretory demand following pancreatectomy, but not in patients with active disease or those in spontaneous clinical remission. These findings suggest that abnormal proinsulin processing is not an intrinsic feature of PHHI despite the severe beta-cell dysfunction.
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PMID:Normal proinsulin processing despite beta-cell dysfunction in persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis). 893 2

Patients with noninsulin-dependent diabetes (NIDDM) show an increase in the relative plasma levels of proinsulin and proinsulin conversion intermediates, which is corrected by strict glycemic control. This observation suggests that hyperglycemia per se may be responsible for generating the aberrant plasma hormone profile. The question remains, however, whether a genetic predisposition to NIDDM underlies the failure of the insulin production machinery to meet a prolonged increase in secretory demand. In this study, islet monolayer cultures from the diabetes-prone Psammomys obesus and normal diabetes-resistant rats were exposed to RPMI 1640 medium containing either 11.1 or 33.3 mM glucose; insulin-related peptides were resolved by HPLC. Prolonged exposure (10 days) of rat islets to high glucose resulted in a reduced a secretory response to an acute glucose stimulus associated with a 37% reduction in the insulin content but no change in the proinsulin/insulin ratio. When subjected to a similar protocol, islets from prediabetic Psammomys lost the insulin response to glucose; beta-cell insulin content was reduced by about 70%, and the proportion of proinsulin-related peptides increased from 18% to 38%. In the in vivo situation, pancreatic extracts from nonfasted diabetic Psammomys contained 36% proinsulin-related peptides in contrast to 15% in pancreatic extracts from nondiabetic animals. Thus, prolonged in vitro exposure of prediabetic Psammomys islets to high levels of glucose could reproduce the modified beta-cell secretory profiles observed in vivo in the diabetic animal. These results support the hypothesis that hyperproinsulinemia in NIDDM is secondary to the inability of beta-cells to meet a sustained increase in insulin demand, whereas individuals with normal beta-cells may meet such demand with an adequate output of mature insulin.
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PMID:Increased susceptibility of islets from diabetes-prone Psammomys obesus to the deleterious effects of chronic glucose exposure. 894 Mar 91

Recent research indicates that islet amyloid pancreatic polypeptide (IAPP) might have a regulatory effect on beta-cell insulin processing and secretion. To study such interaction in more detail, IAPP secretion and kinetics and the serum concentrations of proinsulin were assessed both before and after delivery in lean pregnant women with gestational diabetes mellitus (GDM patients) in comparison to those with normal glucose tolerance (NGT) and to nonpregnant healthy lean (control) and obese insulin-resistant women during oral glucose tolerance tests. Kinetic analysis of IAPP was performed with mathematical modeling, providing indirect estimates of its secretion and fractional clearance. Total insulin secretion per 180 min was elevated by 30% in GDM patients (35 +/- 3 pmol/l) versus control subjects (27 +/- 1 pmol/l) (P < 0.05), but increased even more (190-250%) in obese insulin-resistant women, compared with all other groups (68 +/- 7 pmol/l, P < 0.0005). Pregnancy induced a more marked fourfold increase in apparent total IAPP secretion rate (TIR) (GDM patients, 172 +/- 31 pmol x 1(-1) x 3 h(-1); NGT subjects, 166 +/- 31 pmol x 1(-1) x 3 h(-1); control subjects, 40 +/- 1 pmol 1(-1) x 3 h(-1)) and a twofold rise in its fractional clearance versus control subjects (P < 0.01), whereas in GDM patients a 30% increase of IAPP secretion and a decreased clearance was found, compared with obese insulin-resistant women (TIR, 112 +/- 14 pmol x 1(-1) x 3 h(-1)). The increase in IAPP secretion in both pregnant groups was much higher than that of the insulin groups, resulting in a marked change of the IAPP-insulin cosecretion factor when compared with lean or obese nonpregnant women (P < 0.0005). Associated serum proinsulin and the postprandial (total divided by 180 min) proinsulin-to-insulin ratio were greater in GDM patients versus NGT and control subjects (0.11 +/- 0.01 vs. 0.07 +/- 0.01 and 0.08 +/- 0.01 pmol/l, P < 0.05), while the fasting proinsulin-to-insulin ratio was only increased in GDM patients versus control subjects (0.22 +/- 0.03 vs. 0.13 +/- 0.01 pmol/l, P < 0.05). After delivery, total IAPP secretion (52.4 +/- 1.5 pmol/l) was completely normalized in the GDM group, as were the clearance rate and the IAPP-insulin cosecretion factor. Similarly, serum proinsulin concentrations returned to normal, whereas proinsulin-to-insulin ratios remained elevated. In conclusion, IAPP hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion. Increased proinsulin concentrations and a raised proinsulin-to-insulin ratio, which did not abate following delivery, are specific to GDM and might thus serve as its marker and potentially even identify subjects at high risk for the development of NIDDM.
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PMID:Elevated islet amyloid pancreatic polypeptide and proinsulin in lean gestational diabetes. 907

The major risk factors appear to explain only a small proportion of the excess risk of coronary heart disease in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM). Among novel risk markers that have been-proposed to explain the susceptibility of NIDDM subjects to coronary heart disease are insulin resistance, elevated concentrations of proinsulin-line molecules, plasminogen activator inhibitor, and microalbuminuria. Several prospective studies have shown that hyperinsulinemia predicts coronary heart disease, perhaps independently of established risk factors. Some of this excess risk may be through the dyslipidemia, or the elevation in activity of plasminogen activator inhibitor, an inhibitor of fibrinolysis, which relate to hyperinsulinemia. However proinsulin-like molecules show similar relationships with both risk factors and with prevalent coronary heart disease as does insulin, despite low concentrations of these molecules in the circulation, suggesting a causative relationship is improbable. Furthermore, the link between insulin resistance and microalbuminuria, a powerful predictor of vascular disease in its own right, is poorly understood through known mechanisms. This clustering leads to the possibility of a link with coronary heart disease through other mechanisms. It is proposed that the pathogenesis of this link is endothelial dysfunction, which may predicate both impaired insulin action, through effects of blood flow and insulin transport, and the associated dyslipidemia, impaired fibrinolysis, microalbuminuria, and atherogenesis. In terms of etiology, the links of all these risk factors with evidence of growth retardation in early life may suggest a role of the thirfty phenotype hypothesis-impaired organogenesis resulting from poor maternal nutrition during pregnancy.
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PMID:The Deidesheimer meeting: significance of classical and new risk factors in non-insulin-dependent diabetes mellitus. 910 95

Elevated plasminogen activator inhibitor type 1 (PAI-1) activity has been shown to correlate with plasma insulin, proinsulin-like molecules, serum triglycerides and insulin sensitivity in both non-insulin dependent diabetic (NIDDM) subjects and subjects with coronary heart disease. We examined the relative roles of these variables in determining PAI-1 activity in four groups of male caucasian subjects: non-diabetic subjects with (n = 38) and without (n = 38) previous myocardial infarction (MI) and NIDDM subjects with (n = 26) and without (n = 30) previous MI. Insulin and proinsulin-like molecules were measured using specific two-site immunometric assays and insulin sensitivity estimated using the Homeostasis Model Assessment (HOMA) model. Subjects were comparable in age and body mass index. In univariate analysis, there were significant correlations of PAI-1 activity with intact and des-31,32-proinsulin and serum triglycerides in non-diabetic subjects with (r = 0.52, P = 0.001; r = 0.58, P < 0.001; r = 0.41, P = 0.010) and without (r = 0.31, P = 0.056; r = 0.46, P = 0.006; r = 0.41, P = 0.011) MI, but not with plasma insulin or insulin sensitivity. In NIDDM subjects, PAI-1 activity correlated significantly with intact and des-31,32-proinsulin and serum triglyceride (r = 0.47, P = 0.015; r = 0.58, P = 0.002; r = 0.44, P = 0.026) only in subjects with MI. In multiple regression analysis, MI was the most important determinant of PAI-1 activity levels (r2 = 0.31, F = 55.6, P < 0.001). In conclusion, concentrations of proinsulin-like molecules and serum triglycerides appear to be stronger determinants of PAI-1 activity than plasma insulin or insulin sensitivity in both NIDDM subjects and non-diabetic subjects with and without MI. However, the relationship of MI with PAI-1 activity is independent of these variables.
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PMID:Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction. 912 61

Psammomys obesus fed a high-calorie diet develops a NIDDM-like syndrome. The use of reverse-phase high-performance liquid chromatography (HPLC) to study Psammomys insulin biosynthesis and release revealed a very delayed elution time for the Psammomys insulin peak appearing near the position of human proinsulin. This unusual peak was initially thought to represent partially processed insulin on the basis of its molecular size and susceptibility to trimming by carboxypeptidase B (CpB). However, the findings of an active carboxypeptidase E (CpE) enzyme and the normal amidated forms of gastrin and cholecystokinin octapeptide (CCK-8) in Psammomys tissues were inconsistent with CpE-related aberrant processing of insulin. Moreover, amino acid sequencing of the delayed peak of Psammomys insulin revealed fully processed insulin with amino acid sequence as predicted by the cDNA. The unique presence of a B-30 phenylalanine residue, resulting in an increased hydrophobicity of the insulin molecule, probably underlies the marked delay in elution time on HPLC. The unusual structure of Psammomys insulin does not appear to contribute to the proinsulinemia observed in diabetic Psammomys since the HPLC-purified molecule did not inhibit PC1 and PC2 convertase activities in an in vitro assay.
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PMID:Characterization of the unusual insulin of Psammomys obesus, a rodent with nutrition-induced NIDDM-like syndrome. 916 65


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