UMLS:C0011860 - FACTA Search

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

It has been suggested that recombinant human IGF-I (rhIGF-I) is a potential therapeutic agent in diabetes mellitus. It is known to have glucose-lowering effects in normal individuals, in patients with non-insulin-dependent diabetes (NIDDM) and in extreme insulin-resistant states. IGF-binding proteins (IGFBPs) have the potential to affect the biological activity of rhIGF-I. We have studied the effect of infused rhIGF-I on IGFBP-1 and IGFBP-3 in a patient with Mendenhall's syndrome, a rare insulin-resistant state. During an infusion of 20 mg rhIGF-I, glucose concentrations fell from 44.1 +/- 7.2 to 31.5 +/- 7.2 (S.E.M.) mmol/l (P = 0.001), and insulin and C-peptide levels fell from 920 +/- 62 to 542 +/- 45 mU/l (P = 0.008) and 5466 +/- 633 to 3071 +/- 297 pmol/l (P = 0.02) respectively. Significant lowering of phosphate, magnesium and alkaline phosphatase concentrations was also noted. IGF-I levels rose from 48 +/- 10.2 to 410 +/- 50.1 micrograms/l (P = 0.001), and those of IGF-II fell from 279.8 +/- 8.3 to 104.3 +/- 7.9 micrograms/l (P = 0.001). IGFBP-1 concentrations did not significantly change during the infusion but those of IGFBP-3 increased from 1655 +/- 127 to 2197 +/- 334 micrograms/l (P = 0.002), despite a significant fall in GH concentrations from 10.7 +/- 2.6 to 4.1 +/- 1.1 mU/l (P = 0.007), suggesting that IGFBP-3 regulation is also IGF-I-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Response of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) and IGFBP-3 to IGF-I treatment in severe insulin resistance. 751 62

Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-I was significantly lower in the UPI group (n = 14, 7.8 +/- 0.6 micrograms l-1), than in either the SGA group (n = 22, 31.4 +/- 3.5 micrograms l-1, P = 0.0001) or the AGA group (n = 94, 36.3 +/- 1.9 micrograms l-1, P = 0.0001). IGFBP-3 showed similar changes (UPI: 682.6 +/- 50.0 micrograms l-1; SGA: 831.9 +/- 55.5 micrograms l-1; AGA: 847.7 +/- 19.8 micrograms l-1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition? 753 96

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic effects of IGFs. Although IGFBP-1 levels are abnormally high in insulin-dependent diabetes (IDDM), relatively little is known in NIDDM; conflicting data have suggested both high and low levels. We investigated whether treatment modifies IGFBP-1 levels in two groups of NIDDM patients. Study 1 examined fasting concentrations in groups of patients with NIDDM, comparable except for treatment type (sulfonylurea, n = 23; once daily insulin, n = 15; sulfonylurea plus once daily insulin, n = 14; multiple insulin injections, n = 9) and 25 nondiabetic subjects. In sulfonylurea-treated patients there were markedly reduced plasma IGFBP-1 concentrations (median, interquartile range in parentheses): control, 61.0 (36-96) micrograms/L; sulfonylureas alone, 31.5 (21-61) micrograms/L (P < 0.01); and sulfonylureas plus insulin, 31.5 (9-53) micrograms/L (P < 0.01). Once daily insulin was associated with values similar to those in the control group [62.0 (27-103) micrograms/L; P = NS], whereas IGFBP-1 levels were higher with multiple insulin injection therapy [156.0 (71-184) micrograms/L; P < 0.05]. Proinsulin levels were higher in sulfonylurea-treated patients, but there was no significant correlation between IGFBP-1 and proinsulin within any individual group. Study 2 examined the effects of treatment on the dynamics of IGFBP-1 levels between 0800-1900 h. In control subjects (n = 8), levels fell from 0800 h (mean +/- SEM, 22.4 +/- 5.2 micrograms/L) to 1000 h (14 +/- 5.2 micrograms/L), followed by a rise, more rapid after food, to a peak at 1240 h (20.6 +/- 3.7 micrograms/L). Levels then declined until 1500 h (10.7 +/- 2.9 micrograms/L), with a further postprandial peak at 1840 h (23.1 +/- 3.2 micrograms/L). Sulfonylurea therapy (n = 6) resulted in a complete loss of this pattern, with a marked fall in IGFBP-1 from 0800 h (22 +/- 2.7 micrograms/L) to less than 7 micrograms/L for the remainder of the study (area under the curve, 1150-1400 h, P < 0.001 vs. control). By contrast, in metformin-treated patients (n = 7), neither IGFBP-1 levels nor postprandial peaks were significantly different from those in the control group. Our findings suggest that in patients with NIDDM, the regulation of IGFBP-1 is markedly influenced by the choice of treatment.
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PMID:Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus. 753 8

Insulin-like growth factors (IGF-I and IGF-II) are produced in most tissues, particularly liver. Via endocrine and paracrine or autocrine mechanisms, they play an essential role in cell proliferation and differentiation and complement the metabolic effects of insulin. Similarities between the effects of insulin and IGF in vitro are largely due to cross-reaction, owing to their structural homology as well as that of their receptors. At physiological concentrations, insulin is not mitogenic. Compared with insulin, IGFs have negligible metabolic effects on hepatocytes or adipocytes. However, the presence of the IGF-I receptor in muscle accounts for IGF physiological effects in vivo on glucose uptake and glycogen synthesis. Moreover, recombinant IGF-I administered subcutaneously to healthy subjects or patients with Type 2 diabetes causes a drop in plasma levels of triglycerides and VLDL as well as cholesterol and LDL, but not HDL, and also increases insulin sensitivity. All these responses reflect IGF-I inhibition of insulin and GH secretion. In biological media, IGF-I and IGF-II are reversibly associated with specific high-affinity (10(9)-10(11) M-1) binding proteins (IGFBP-1 to -6) differing in expression according to tissue of origin and playing a variety of roles in IGF transport and half-lives, delivery of IGFs to their target cells and modulation of IGF interactions with their receptors. In the blood, where IGF concentrations are 1,000 times those of insulin, IGFBP-3 (the major form) binds at least 80% of IGFs as 140-kDa complexes which do not cross the capillary endothelium and therefore prevent the insulin-like action of IGFs. Nevertheless, these circulating IGF reserves may be mobilized in response to metabolic needs via limited proteolysis of IGFBP-3 by serine proteases. In the case of IGFBP-1, whose hepatic synthesis is negatively regulated by insulin, plasma concentrations are subject to extensive nycthemeral variation, rising with fasting and dropping after feeding, which may be involved in controlling the access of free IGF-I to its cellular receptors and hence IGF-I-regulated glucose and amino acid uptake. Therapeutic applications of recombinant human IGF-I, currently under trial in the treatment of growth retardation resulting from GH receptor abnormalities, hypercatabolic states and would repair, may also be envisaged for cases of insulin resistance, particularly type 2 diabetes.
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PMID:The IGF system in metabolism regulation. 858 49

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

To evaluate the role of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) in excessive fetal growth (macrosomia) in diabetic pregnancy, 84 insulin-treated diabetic mothers and their infants were tested for serum concentrations of IGF-I, IFG-II, and IGFBP-1, -2 and -3. These parameters were correlated with the birth weight of neonates and placental weight. IGF-I and II levels were determined by specific radioimmunoassays (RIAs) after serum samples were extracted with aid-ethanol. IGFBPs were measured by Western immunoblot with specific antibodies to the respective IGFBP species. Serum concentrations of both IGF-I and IGF-II in mothers with either IDDM or NIDDM increased with the gestational period, reached a plateau at the third trimester, and returned to non-pregnant levels within 7 days after delivery. These values were not different from those in normal mothers before and throughout pregnancy. As previously reported, IGF-I concentrations in cord serum of neonates born to diabetic mothers were (P < 0.01) higher than those of newborns of normal mothers. Likewise, cord blood IGF-II levels were 2-fold higher in babies of diabetic mothers (P <0.001). Fetal IGF-I and IGF-II correlated with each other and with maternal HbA1C, and they positively correlated with either birth weight or placental weight. Cord IGFBP-3 concentrations were significantly higher in diabetic pregnancy, but IGFBP-2 concentrations were not different from those in normal pregnancy. Cord IGFBP-1 concentrations were significantly higher only in babies of mothers with IDDM. None of these cord IGFBP concentrations correlated with birth weight or placental weight. The data suggest that fetal IGF-II, like IGF-I, is involved in fetal and placental growth in diabetic pregnancy. The role of IGFBPs remained to be determined.
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PMID:Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBP-1, -2 and -3) in diabetic pregnancy: relationship to macrosomia. 902 69

The structure of IGF-I is similar to that of insulin, having 43% sequence homology with human proinsulin. Both peptides can induce metabolic and mitogenic effects through their own specific receptors, which also share many structural and functional similarities. Primarily involved in the regulation of growth, IGF-I may have a role in the control of glucose homeostasis, facilitated by changes in its binding proteins. RhIGF-I can reduce hyperglycaemia in patients with severe insulin resistance by direct effects mediated via the IGF-I receptor. Improvements in insulin sensitivity, and reductions in blood glucose levels and HbA1c values have also been seen in subjects with NIDDM. Enhanced insulin sensitivity with low dose rhIGF-I has been observed in adolescents and young adults with IDDM. These effects are closely related to reductions in growth hormone levels, but there is also evidence of complex interactions with insulin at the post receptor level and with IGFBP-1. In recent randomised, double-blind, placebo controlled trials, rhIGF-I given as an adjunct to insulin therapy reduced to HbA1c values. Although the ideal dosage to obtain therapeutic efficacy without complications has yet to be determined, rhIGF-I may have an important role in the treatment of hyperglycaemia and insulin resistance in diabetes.
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PMID:Does recombinant human insulin-like growth factor-1 have a role in the treatment of diabetes? 930 Feb 21

HIV-lipodystrophy (HIV-LD) is characterized by the loss of body fat from the limbs and face, an increase in truncal fat, insulin resistance, and hyperlipidemia, factors placing affected patients at increased risk for vascular disease. This study evaluated insulin sensitivity and inflammatory status associated with HIV-LD and provides suggestions about its etiology. Insulin sensitivity and immune activation markers were assessed in 12 control subjects and 2 HIV-positive groups, 14 without and 15 with LD syndrome. Peripheral insulin sensitivity (mostly skeletal muscle) was determined with the hyperinsulinemic-euglycemic clamp. Circulating insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) and free fatty acid (FFA) levels, and their response to insulin infusion were indicative of insulin responsiveness of liver and adipose tissue, respectively. Serum levels of soluble type 2 tumor necrosis factor-alpha (TNF-alpha) receptor (sTNFR2) were used as an indicator of immune activation. HIV-LD study subjects had significantly reduced (twofold) peripheral insulin sensitivity, but normal levels of FFA and reduced levels of IGFBP-1, relative to the nonlipodystrophy groups, indicating that the loss of insulin sensitivity was more pronounced in skeletal muscle than in liver or fat. The significant loss of peripheral fat in the HIV-LD group (34%; p <.05) closely correlated with the reduced peripheral insulin sensitivity (p =. 0001). Levels of sTNFR2 were elevated in all HIV-infected study subjects, but they were significantly higher in those with lipodystrophy than without, and sTNFR2 levels strongly correlated with the reduction in insulin sensitivity (p =.0001). Loss of peripheral fat, normal levels of FFA, and reduced levels of IGFBP-1 indicate that insulin resistance in HIV-LD is distinct from type 2 diabetes and obesity. The relationship between the degree of insulin resistance and sTNFR2 levels suggests an inflammatory stimulus is contributing to the development of HIV-associated lipodystrophy.
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PMID:Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. 1151 29

At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced beta-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the beta-cell mass deficit could represent the primary defect leading to type 2 diabetes in the adult. The aim of this work was to investigate, in GK fetuses at the end of fetal age (21.5 dpc), whether impaired availability of growth factors such as insulin, growth hormone, and IGFs and their IGF binding proteins (IGFBPs) could be instrumental in this anomaly. Although it confirms that GK fetuses are hypoinsulinemic despite enhanced plasma glucose level due to maternal hyperglycemia, the present study shows for the first time that IGF-2 expression in the liver and pancreas and IGF-2 serum levels are decreased in GK fetuses. Serum level as well as liver and pancreatic mRNA expression of IGFBP-2 were found to be normal in GK fetuses, whereas serum level and liver mRNA expression of IGFBP-1 were increased. Finally, we found that the maximal beta-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK beta-cells is not grossly impaired. In conclusion, in GK fetuses at 21.5 dpc, the defective IGF-2 production appears to be an early landmark in the pathological sequence leading to retardation of beta-cell growth in the fetal GK rat.
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PMID:Fetal insulin-like growth factor-2 production is impaired in the GK rat model of type 2 diabetes. 1181 46

The IGF system is increasingly implicated in the development of cardiovascular disease. The effects of circulating IGFs on the vasculature are largely modulated by IGFBPs, which control their access to cell-surface IGF receptors. IGFBP-1 has been proposed as the acute regulator of IGF bioavailability because of its metabolic regulation by glucoregulatory hormones. Posttranslational phosphorylation of IGFBP-1 significantly increases its affinity for IGF-I and therefore represents a further mechanism for controlling IGF bioavailability. We have therefore examined the IGF system and IGFBP-1 phosphorylation status, using specifically developed immunoassays, in a cohort of 160 extensively characterized type 2 diabetic subjects on two occasions 12 months apart. Total IGFBP-1 (tIGFBP-1), which is predominantly highly phosphorylated, was significantly lower in subjects with known macrovascular disease (geometric mean [95% CI], 48.7 microg/l [33.7-63.6]) than in patients with no vascular pathology (80.0 microg/l [52.2-107]; F = 5.4, P = 0.01). A similar relationship was found for highly phosphorylated IGFBP-1 (hpIGFBP-1) concentration (known macrovascular disease, 45.1 microg/l [35.1-55.2]; no macrovascular disease, 75.8 microg/l [56.2-95.3]; F = 4.8, P = 0.01). Logistic regression showed that for every decrease of 2.73 microg/l in IGFBP-1 concentration, there was a 43% increase in the odds of a subject having macrovascular disease (odds ratio 0.57 [95% CI 0.40-0.83]; P = 0.001). hpIGFBP-1 correlated negatively with systolic blood pressure (rho = -0.30, P < 0.01), diastolic blood pressure (rho = -0.45, P < 0.001), and mean arterial pressure (MAP) (rho = -0.41, P < 0.001). Linear regression modeling showed that 40% of the variance in tIGFBP-1 was accounted for by MAP, triglycerides, and nonesterified fatty acids. In contrast, levels of nonphosphorylated and lesser-phosphorylated IGFBP-1 (lpIGFBP-1) were unrelated to macrovascular disease or hypertension but did correlate positively with fasting glucose concentration (rho = 0.350, P < 0.01). tIGFBP-1 concentrations were higher in subjects treated with insulin alone (n = 29) than for any other group. This effect persisted after adjustment of tIGFBP-1 levels for BMI, C-peptide, age, and sex (F = 6.5, P < 0.001, rho = - 0.46). Such an effect was not apparent for lpIGFBP-1. We conclude that low circulating levels of hpIGFBP-1 are closely correlated with macrovascular disease and hypertension in type 2 diabetes, whereas lpIGFBP-1 isoforms are associated with glycemic control, suggesting a dual role for IGFBP-1 in the regulation of IGF actions in type 2 diabetes. Our data suggest that high circulating concentrations of highly phosphorylated IGFBP-1 may protect against the development of hypertension and cardiovascular disease by reducing the mitogenic potential of IGFs on the vasculature.
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PMID:Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. 1214 80

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