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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-cell dysfunction is prominent in Type 2 (non-insulin-dependent) diabetes mellitus. Four types of abnormalities have been described. Oscillatory pattern of insulin-secretion is impaired, with a loss of high frequency pulses and with a reduction in amplitude of slow oscillations. This impairment takes place early in the course of the disease, as does the loss of the first phase of insulin secretion after intravenous glucose. Quantitative (insulin deficiency in relative and absolute terms) and qualitative abnormalities (excess in proinsulin and in 32-33 split proinsulin) have been also observed in Type 2 diabetes. One or several genetic defects seem to be responsible for the development of this beta-cell dysfunction and for Type 2 diabetes mellitus.
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PMID:[Anomalies of insulin secretion and type 2 diabetes: recent information]. 782 75

The biosynthetic process of insulin in pancreatic beta cells consists of many steps including transcription of insulin gene to mRNA, translation of mRNA to preproinsulin, production of proinsulin by cleavage of signal peptide, and conversion of proinsulin to insulin and C-peptide. This process also includes intra-cellular trafficking (nucleus, cytoplasm, endoplasmic reticulum, Golgi apparatus, secretary granule, and extra-cellular secretion). The factors concerning and regulating these steps are discussed, although some of these have not been fully understood. The possible influences of insulin gene mutations (mutant insulin gene syndrome) to these steps are also discussed. Understanding of the molecular mechanism of insulin biosynthesis might be usefull to explain the defective insulin production of NIDDM.
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PMID:[The molecular mechanism of insulin biosynthesis and mutant insulin gene syndrome]. 798 72

This study was undertaken to clarify the effect of sulphonylurea therapy on beta cell function in 27 subjects with newly diagnosed Type 2 diabetes mellitus. Plasma glucose, insulin, intact and 32/33 split proinsulin were measured at diagnostic OGTT. After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 9 mmol l-1 (n = 12) were commenced on sulphonylurea therapy. At diagnosis, the sulphonylurea requiring group were more hyperglycaemic (p < 0.0001), less obese (p < 0.05) and more insulin deficient with a lower 30 min insulin (p < 0.0002) than the diet group. Following dietary intervention in the sulphonylurea group, weight remained unchanged but there was a reduction in fasting glucose (p < 0.009). Fasting insulin, intact proinsulin, and 32/33 split proinsulin remained unchanged. After 12 weeks of sulphonylurea therapy there was a weight gain of 1.5 kg (p < 0.01), but a reduction in fasting glucose (p < 0.0001). Fasting insulin and intact proinsulin increased (p < 0.004) but 32/33 split proinsulin remained unchanged. There was a significant increase in both the fasting insulin to glucose ratio (p < 0.005), and intact to 32/33 split proinsulin ratio (p < 0.02). Final fasting glucose following sulphonylurea therapy was positively correlated with the initial intact and 32/33 split proinsulin and the fasting glucose following dietary treatment. It is clear from this work that sulphonylureas have a complex effect on beta cell physiology and as well as stimulating release of insulin they increase the release of intact proinsulin but not that of 32/33 split proinsulin, hence they increase the intact to 32/33 split proinsulin ratio.
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PMID:Effect of sulphonylurea therapy on plasma insulin, intact and 32/33 split proinsulin in subjects with type 2 diabetes mellitus. 803 29

Elevated fasting proinsulin immunoreactive material (PIM) has previously been found in patients with type 2 (non-insulin-dependent) diabetes mellitus. It is not known whether this is a genetic trait or whether it is related to the manifestation of type 2 diabetes. Neither is it clear whether the raised fasting insulin immunoreactivity previously observed in first-degree relatives of patients with type 2 diabetes is due to raised PIM. Furthermore, it has not been investigated whether first-degree relatives have altered PIM responses to different secretagogues. To study this, PIM, insulin and C-peptide were measured in patients with type 2 diabetes, in their first-degree relatives and in healthy control subjects in the fasting state and in relatives and controls during a hyperglycemic clamp. At the end of the hyperglycemic clamp, 0.5 mg of glucagon was given intravenously to stress the beta cells further. Fasting PIM concentrations were significantly higher in patients with type 2 diabetes (P < 0.05). These patients did not have significantly elevated fasting insulin levels when corrected for PIM. In the relatives, fasting insulin concentrations were elevated but PIM levels were normal suggesting that the increase in fasting insulin concentrations reflected an increase in true insulin. The incremental PIM, insulin and C-peptide responses to glucose and glucagon in the relatives were not different from those in the controls. We conclude that elevated fasting PIM levels in patients with type 2 diabetes seem not to be a genetic trait.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proportional proinsulin responses in first-degree relatives of patients with type 2 diabetes mellitus. 811 Oct 72

We describe an immunoradiometric assay for human intact proinsulin in serum. In this method, one monoclonal antibody, coated onto polyacrylamide beads, cross-reacts with proinsulins and insulin. A sandwich is formed with intact proinsulin, split (65-66) proinsulin, and des (64-65) proinsulin binding with an 125I-labeled monoclonal antibody specific for an epitope at the intact B-C junction of proinsulin. Because split (65-66) and des (64-65) proinsulin concentrations are very low in serum, this assay essentially measures intact proinsulin. When we used 1-mL serum samples, the mean detection limit was 0.4 pmol/L. Mean proinsulin concentrations (pmol/L) were 3.4 (range 1-9.1) in healthy fasting subjects, 28.5 (9.7-101) in patients with type 2 diabetes (treated with metformin and sulfonylureas), 5.0 (1.6-9.3) in women with hyperandrogenism and normal insulinemia, 10.3 (2.6-36) in women with hyperandrogenism and hyperinsulinemia, and 8.5 (4.8-21.3) in patients with impaired glucose tolerance.
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PMID:Immunoradiometric assay of human intact proinsulin applied to patients with type 2 diabetes, impaired glucose tolerance, and hyperandrogenism. 817 47

The plasma ratio of proinsulin/insulin is raised in people with NIDDM. A relative hypersecretion of proinsulin is thought to be the cause, because pancreas extracts from diabetic rats have a raised proinsulin/insulin ratio. We tested the hypothesis that the pancreatic proinsulin/insulin mismatch results from hyperglycemia-induced beta-cell degranulation. Normal rats made hyperglycemic with 48-h glucose infusions had a raised pancreatic percentage of proinsulin. In contrast, rats infused with enough glucose to induce compensatory hyperinsulinemia without changing the plasma glucose level had a normal percentage of proinsulin. The raised percentage of proinsulin in the hyperglycemic rats reflected a reduction in pancreatic insulin content. Administering an inhibitor of insulin release, diazoxide, to hyperglycemic rats blocked the fall in pancreatic insulin content and prevented the rise in the percentage of proinsulin. Normal rats infused with tolbutamide for 3 days and enough glucose to maintain euglycemia had a 50% reduction in pancreatic insulin content. The beta-cell degranulation from this nonhyperglycemic mechanism resulted in a raised pancreatic percentage of proinsulin. In summary, chronic hyperglycemia causes beta-cell degranulation primarily because of hyperstimulated insulin release. The net result is a rise in the ratio of immature (proinsulin-rich) to mature (insulin-rich) granules, which is reflected as an increased relative proportion of proinsulin. Mobilization of these proinsulin-enriched granules may explain the relative hypersecretion of proinsulin that occurs with diabetes.
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PMID:Increased proinsulin/insulin ratio in pancreas extracts of hyperglycemic rats. 842 Aug 18

We investigated the effects of different intravenous (IV) glucose challenges on insulin and proinsulin secretion. On separate occasions, seven normal controls and five obese and five non-insulin-dependent diabetic (NIDDM) subjects each received an IV glucose tolerance test (IVGTT), a hyperglycemic clamp (HY), and a 60-minute, standardized, low-dose, continuous infusion of glucose (CIG) in a randomized fashion. Basal proinsulin concentrations in NIDDM subjects (8.4 +/- 5.0 pmol/L) were significantly higher compared with those of normal (1.1 +/- 0.2) and obese subjects (1.5 +/- 0.4; both P < .05). Basal molar proinsulin:insulin ratio (P:I) was also significantly higher in NIDDM subjects (22% +/- 12%) compared with normal (1.0%) and obese subjects (1.6% +/- 0.8%; both P < .01). Proinsulin concentrations did not increase significantly in any group during the first 10 minutes of the IV glucose challenges. However, during HY, significant increases in proinsulin concentration occurred after 60 minutes in each group. In normal and obese subjects, IV glucose administration resulted in significant acute increases in insulin concentrations compared with the characteristic blunted response in NIDDM subjects. The P:I ratio in normal and obese subjects did not change in the first 10 minutes after IV glucose administration. However, by the end of HY, the P:I ratio had increased significantly in normal subjects by 1% to 5% +/- 2% (P < .05), and in obese subjects by 1% to 5% +/- 1% (P < .02). In NIDDM subjects, both HY (19% +/- 10% to 27% +/- 12%) and IVGTT (18% +/- 9% to 43% +/- 16%) resulted in a transient increase in the basal P:I ratio by 5 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proinsulin and insulin concentrations following intravenous glucose challenges in normal, obese, and non-insulin-dependent diabetic subjects. 844 45

Both the insulin response to glucose and the sensitivity to insulin show large variation in the normal population. Many subjects have either a markedly low insulin response or low sensitivity to insulin, with nevertheless normal glucose tolerance. For such subjects to become diabetic, insulin secretion or insulin action must further deteriorate with time, or other factors are added which tip the balance towards diabetes. Most evidence to date indicates that reduced beta-cell responsiveness and reduced insulin sensitivity co-exist in subjects prior to developing NIDDM. Both insulin secretion and insulin action are genetically controlled and influenced by intrauterine and neonatal factors. Insulin secretion and insulin action vary inversely in a closely linked manner; inability to fully compensate for changes in one variable may generate a functional deficit in glucose homeostasis. Subjects combining low functions would run a proportionately larger risk of decompensating the glucose tolerance and be more vulnerable, in terms of diabetes susceptibility, to factors that further reduce insulin output or insulin action. Careful analysis of existing data prompts us to ascribe a dominating role to the impairment of insulin secretion in the pathogenesis of IGT and NIDDM. Patients with NIDDM also exhibit increased proportions of proinsulin and proinsulin conversion intermediates. We used hyperinsulinaemic diabetic and non-diabetic Psammomys obesus to study the possible relationship between steady-state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and the pancreas. A marked increase in these peptides was associated with 90% reduction in insulin stores of the pancreas. After food deprivation, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio normalized. In contrast, non-diabetic psammomys showed only 50% reduction in pancreatic insulin stores under non-fasting conditions, with no change in proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, pancreatic capacity for storage/production of insulin is limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycaemia, which may in itself further exacerbate the pancreatic dysfunction.
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PMID:Insulin secretion in obese and non-obese NIDDM. 852 16

Recent large-scale epidemiological studies demonstrate that blood concentrations of immunoreactive insulin predict the development of NIDDM and IDDM and are associated with the risk of several degenerative diseases, such as coronary and peripheral vessel atherosclerosis, hypertension, and dyslipidemia. The reliability of these measurements is dependent on a biological assay that has not been well standardized between laboratories. Recognizing this, the American Diabetes Association organized a task force to assess comparability of blood insulin measurements between laboratories and to suggest techniques to improve comparability. The task force found that identical serum and plasma samples measured in different laboratories produced widely disparate values that were unacceptable for population comparisons. Use of a single reference standard did little to improve comparability. Assay characteristics such as linearity, recovery, accuracy, and cross-reactivity to proinsulin and its primary conversion intermediates varied among the laboratories, and they did not readily explain differences in the measurements made from assay to assay. Use of the same assay kit in different laboratories did not always ensure comparable measurements. Linear regression of assay results from one laboratory to an arbitrarily chosen reference assay greatly improved comparability and demonstrated the potential value in comparing each assay to a reference method. The task force report defines acceptable assay characteristics and proposes a three-step process of insulin assay proficiency and comparability. A central reference assay and ongoing sample exchange will be needed to allow reliable comparisons of insulin measurements made in different laboratories. Rigorous quality control and continuous quality improvement are needed to maintain reliability of the insulin measurement.
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PMID:Report of the American Diabetes Association's Task Force on standardization of the insulin assay. 854 70

GENETIC PREDISPOSITION: Insulin resistance and reactive hyperinsulinemia occur not only with obesity, impaired glucose tolerance or non-insulin-dependent (type 2) diabetes mellitus, but also in many non-obese, non-diabetic patients with essential hypertension and their currently normotensive, lean, young offspring, as well as in some other conditions known to promote hypertension. Insulin resistance impairs glucose tolerance, while insulin resistance and/or hyperinsulinemia promote dyslipidemia, body fat deposition and probably atherogenesis. Therefore, the common coexistence of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent, although temporally often dissociated, occurrence of hypertension together with dyslipidemia, obesity and type 2 diabetes in a given patient. INSULIN RESISTANCE AND HYPERINSULINEMIA AS SLOW PRESSOR MECHANISMS: In the pathogenesis of hypertension, inappropriate vasoconstriction (due to an imbalance of vasoactive substances and/or raised cytosolic calcium) and/or structural vasculopathy is particularly important. Among the mosaic of assumed pressor mechanisms, distinct Na+ retention is almost invariably involved in diabetes mellitus, while sympathetic activation tends to occur in essential hypertension, particularly in association with obesity. Insulin resistance may develop as a consequence of an intracellular excess of Ca2+ or a decrease in Mg2+, an impaired insulin-mediated rise in skeletal muscle blood flow, increased sympathetic activity or excess body weight. Acute hyperinsulinemia causes arterial vasodilation on one hand and increases sympathetic activity and renal Na+ reabsorption on the other. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis, while insulin resistance may be associated with certain transmembraneous cation transporters, leading to an increase in cytosolic Ca2+. Hyperinsulinemia and/or insulin resistance may also be associated with an increased blood pressure sensitivity to high salt intake. In the mosaic of many different blood pressure-raising mechanisms, insulin resistance and/or hyperinsulinemia is likely to represent an amplifying slow or very slow pressor factor.
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PMID:Insulin resistance and hyperinsulinemia in hypertension. 857 90


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