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)

Growth hormone (GH) has been used to treat GH deficiency since the late 1950s, and recombinant GH has been available since 1985. GH is also approved to treat non-GH-deficient short stature, such as that seen in Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome, children who are small for gestational age, and idiopathic short stature. There has been interest in using recombinant insulin-like growth factor I (IGF-I) to treat short stature, either alone or in combination with its binding protein, IGF binding protein (IGFBP)-3 (SomatoKine). IGF-I increases growth velocity in children with IGF deficiency, either as a result of growth hormone insensitivity syndrome (GHIS) or IGF-I gene deletion. However, there have been adverse events, particularly hypoglycemia, reported with administration of unbound IGF-I. In addition, the serum half-life of unbound IGF-I is shorter when administered to patients with GHIS, who have low serum concentrations of its primary binding protein IGFBP-3 than when administered to healthy individuals or to patients with an IGF-I gene deletion (who have normal levels of IGFBP-3). SomatoKine was developed to prolong the half-life and to counteract acute adverse events (particularly hypoglycemia) associated with IGF-I administration. SomatoKine appears to have a longer half-life in patients with GHIS than unbound IGF-I and fewer adverse events (including hypoglycemia) have been reported when administered to patients with diabetes.
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PMID:SomatoKine: is there a use in treating growth disorders? 1589 44

Early investigations into the insulin-like growth factor (IGF)-independent actions of insulin-like growth factor-binding protein (IGFBP)-3 have implicated a large array of signaling proteins with links to cell cycle control and apoptosis. However, the actual mechanism of IGFBP-3 action is still unclear. In an effort to clearly understand the mechanism of IGF-independent IGFBP-3 actions, a proteomic approach to identify the actual proteins involved in interaction with IGFBP-3 from different cell compartments, the phosphorylation status of IGFBP-3 under different physiologic conditions and the proteins upregulated by IGFBP-3 are briefly reviewed. The IGF system is a well-recognized key player in diseases such as cancer, diabetes and malnutrition. It is only after the signaling pathways of the IGF-independent actions of IGFBP-3 are clearly understood that the system can be manipulated to affect these disorders.
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PMID:Potential of proteomics towards the investigation of the IGF-independent actions of IGFBP-3. 1596 54

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.
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PMID:Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose. 1600 52

Previous studies have shown that intracavernous injection of vascular endothelial growth factor (VEGF) restored erectile function in diabetic rats. However, the mechanism of VEGF in diabetes-related erectile dysfunction (ED) has not been fully investigated. We hypothesize that intracavernous injection of VEGF may reverse diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To test this hypothesis the erectile function of treated and control rats was analyzed by measurement of intracavernous pressure (ICP) following electrostimulation of the cavernous nerves. Mean ICP was significantly lower in non-treated diabetic rats compared to controls. After VEGF injection, ICP was significantly higher than in non-treated diabetic rats. IGFBP-3 mRNA and protein expression was significantly higher in non-treated diabetic rat crura than controls, while VEGF-treated animals had control levels. ER-beta and PR mRNA and protein expression was significantly lower in non-treated diabetic rat crura. After VEGF injection, ER-beta and PR mRNA and protein expression was similar to control levels. Expression of AR and ER-alpha was the same in all groups. These findings suggest that orthotopic injection of VEGF may improve the functional recovery of diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To our knowledge, this is the first study demonstrating that VEGF treatment restores erectile function through restoration of the insulin-like growth factor system and sex hormone receptor genes at the mRNA and protein levels in diabetic rat crura. These results may be important in understanding the pathogenesis of diabetes-related ED and also in providing better strategies for management of this disease.
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PMID:Vascular endothelial growth factor restores erectile function through modulation of the insulin-like growth factor system and sex hormone receptors in diabetic rat. 1645 52

Growth hormone-insensitivity syndrome (GHIS) is usually caused by mutations in the growth hormone receptor. Recombinant IGF-I has been used to treat GHIS either alone (mecasermin) or in combination with IGF-binding protein (IGFBP)-3 (mecasermin rinfabate). IGF-I increases the growth velocity of children with IGF deficiency, which is either as a result of GHIS or an IGF-I gene deletion. Hypoglycaemia has been reported with administration of unbound IGF-I and, in addition, the serum half-life of unbound IGF-I is shorter when administered to patients with GHIS (who have low serum concentrations of its binding protein IGFBP-3) than when administered to normal volunteers or to patients with an IGF-I gene deletion (but normal IGFBP-3 levels). The IGF-I-IGFBP-3 combination was developed to prolong the half-life and counteract the acute adverse events (particularly hypoglycaemia) that are associated with administration of IGF-I. It seems that the IGF-I-IGFBP-3 combination has a longer half-life in patients with GHIS than unbound IGF-I, with fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes. There are no studies comparing the efficacy of mecasermin with mecasermin rinfabate; both drugs have been shown to be effective but cannot be differentiated in terms of efficacy.
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PMID:Investigational agents for the treatment of growth hormone-insensitivity syndrome. 1654 90

There has been interest in using recombinant human (rh) insulin-like growth factor (IGF)-I (rhIGF-I) to treat short stature, either alone or in combination with its binding protein (insulin-like growth factor binding protein [IGFBP]-3). IGF-I has been shown to increase growth velocity in children with IGF deficiency, either as a result of growth hormone insensitivity syndrome (GHIS) or IGF gene deletion. However, there have been adverse events, particularly hypoglycaemia, reported with administration of unbound rhIGF-I. In addition, the serum half-life of unbound rhIGF-I is shorter when administered to patients with GHIS, who have low serum concentrations of its binding proteins IGFBP-3 and acid-labile subunit (ALS), than when administered to normal volunteers or to the patient with an IGF-I gene deletion (who had normal levels of IGFBP-3). iPlex (mecasermin rinfabate), an equimolar mixture of IGF-I and its binding protein IGFBP-3, was developed to prolong the half-life and to counteract acute adverse events (particularly hypoglycaemia) associated with administration of IGF-I. Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders, it does appear that mecasermin rinfabate has a longer half-life in patients with GHIS than unbound IGF-I, and fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes.
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PMID:Efficacy and safety of mecasermin rinfabate. 1661 Sep 82

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg x kg(-1) x day (-1)) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU x kg(-1) x min (-1)) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (R(a)) (P = 0.004), while peripheral glucose uptake (R(d)) was not different from placebo. The increase in glucose R(d) during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol R(a), a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.
Diabetes 2006 Aug
PMID:Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes. 1687 2

IGF-I is recognized as an insulin sensitizer at the liver and muscle, while recent evidence suggests that IGF-binding protein (IGFBP)-3 acts as an insulin antagonist. As there is a paucity of IGF-I receptors in the liver and as the IGF-IGFBP system in the central nervous system is emerging as physiologically relevant, we examined whether the effects of IGF-I and IGFBP-3 on insulin action are mediated through central mechanisms. Intracerebroventricular (ICV) infusion of IGF-I during the insulin clamp (3 mU x kg(-1) x min(-1)) resulted in significant improvement in hepatic insulin action (50%, P < 0.05). In contrast, ICV infusion of IGFBP-3 significantly impaired insulin action at the liver (45% increase in hepatic glucose production, P < 0.01). While IGF-I marginally increased peripheral glucose uptake, IGFBP-3 significantly decreased peripheral glucose uptake (approximately 30%, P < 0.01). As the nuclear localization signal mutant IGFBP-3, which has a normal affinity to IGFs but binds other IGFBP-3 partners poorly and fails to normally internalize, has reduced central activity on metabolism, we conclude that the effects of IGFBP-3 on the hypothalamus involve activity mediated by interfacing with other molecules in addition to IGFs. Marked, opposing, and independent physiological effects of IGF-I and IGFBP-3 through central mechanisms may have implications on potential strategies in specific modulation of peripheral insulin action.
Diabetes 2006 Oct
PMID:Central and opposing effects of IGF-I and IGF-binding protein-3 on systemic insulin action. 1700 44

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.
Diabetes Res Clin Pract 2007 May
PMID:Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy. 1701 63

1. Insulin-like growth factors (IGFs) are associated with the development of diabetes mellitus. The liver, kidney and heart have been implicated as important organs in the onset of diabetes mellitus. However, the effect of diabetes on the IGF system in these organs has not been fully described. Thus, we investigated changes in IGF-I, IGF-II and IGF binding proteins (IGFBPs) in male steptozotocin-induced diabetic rats, as well as in a high glucose-induced in vitro model. 2. Serum levels of IGF-I were decreased, but the levels of IGF-II were increased, in diabetic rats compared with controls. The expression of IGFBP-3 in the serum was markedly decreased; in contrast, the expression of IGFBP-1 and -2 was increased in diabetic rats. The expression of IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-4 in the liver of the diabetic group was similar to that in the serum of diabetic rats. 3. In heart tissue of the diabetic group, IGF-I levels were decreased, but IGF-II levels were increased. In addition, the expression of IGFBP-3, IGFBP-1 and IGFBP-2 was decreased in diabetic rats. 4. In the kidney of the diabetic group, IGF-I and IGF-II levels were increased. There was only slight expression of IGFBP-3 in the kidney and this was not altered in diabetic rats. Levels of IGFBP-1 and -2 were markedly increased in the kidney of diabetic rats. 5. Insulin treatment recovered the changes in expression of IGF-I, IGF-II and IGFBPs in the serum, liver, heart and kidney. In the liver, heart and kidney, the expression of the insulin receptor was increased in male diabetic rats. 6. In conclusion, diabetes tissue-specifically alters the IGF system in the liver, heart and kidney in rats; this effect can be recovered by insulin treatment.
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PMID:Tissue-specific regulation of insulin-like growth factors and insulin-like growth factor binding proteins in male diabetic rats in vivo and in vitro. 1718 97


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