Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases ofnoninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-3 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGH at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P < .001), free PGH and total PGH correlated very closely (r = 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth.
 ...
PMID:Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth. 1072 53

The insulin-like growth factor (IGF) system has been implicated in the development of experimental diabetic nephropathy. IGF-binding protein-3 (IGFBP-3) modulates IGF actions, and proteolysis decreases its binding affinity for IGFs. The aim of this study was to explore the possibility that proteolysis of IGFBP-3 may be altered in diabetic nephropathy and may therefore modify the intrarenal effects of IGFs. IGFBP-3 proteolysis in urine from diabetic patients with normo- [albumin excretion rate (AER), <20 microg/min], micro- (AER, 20-200 microg/min), and macroalbuminuria (AER, >200 microg/min) was studied in 34 patients with noninsulin-dependent diabetes mellitus (NIDDM), 14 patients with insulin-dependent diabetes mellitus, and 9 controls. Urine samples were analyzed by Western ligand blotting and IGFBP-3 immunoblotting. Protease activity was quantitated using [125I]IGFBP-3 as a substrate. WLB showed three main bands (40-46, 35, and 26 kDa) in control urine and a fainter 18-kDa band. All but the 35-kDa band were immunoreactive with the IGFBP-3 antiserum. The same pattern of IGFBPs was seen in urine from normoalbuminuric diabetic patients. However, the urine of diabetic patients with micro- and macroalbuminuria contained little or no intact 40- to 46-kDa IGFBP-3. In patients with noninsulin-dependent diabetes mellitus, urinary IGFBP-3 protease activity in micro- (n = 13) and macroalbuminuric patients (n = 12; mean +/- SD[SCAP], 75 +/- 25% and 84 +/- 24%) was significantly higher than that in normoalbuminuric patients (29 +/- 9%; P = 0.0001). Similar results were observed in patients with insulin-dependent diabetes mellitus. Proteolytic activity in diabetic urine was due to a serine protease. In conclusion, diabetic nephropathy was associated with IGFBP-3 proteolysis in urine. As similar changes were not observed in patients' sera, this is likely to reflect changes in the kidney or urinary tract, resulting in increased local IGF bioavailability, and therefore may contribute to the structural changes of diabetic nephropathy.
 ...
PMID:Proteolysis of insulin-like growth factor-binding protein-3 is increased in urine from patients with diabetic nephropathy. 1072 56

The insulin/IGF binding protein-1 (IGFBP-1) axis is important in coordinating insulin- and IGF-mediated regulation of glucose metabolism and glycemia. Dysregulation of the axis may play a role in the pathophysiology of disorders of insulin deficiency and resistance. We have investigated this hypothesis by generating transgenic mice that overexpress hIGFBP-1. To study the axis in its true physiological context, we used a human (h) IGFBP-1 cosmid clone so that transgene expression is responsive to normal hormonal stimuli. hIGFBP-1 mRNA is expressed in a tissue-specific fashion, and measurement of serum protein levels by specific immunoassay indicates normal physiological regulation in response to fasting/feeding and appropriate post-translational modification as indicated by the detection of phosphorylated and nonphosphorylated isoforms of the protein. The hypoglycemic response to exogenous IGF-I is attenuated in transgenic mice. Transgenic mice exhibit an enhanced insulin secretory response to a glucose challenge, although basal and stimulated blood glucose levels are similar to controls. There is a sexual dimorphism in phenotypic expression: male transgenic mice had higher stimulated glucose and insulin levels than did females. Transgenic mice exhibit fasting hyperglycemia and hyperinsulinemia and glucose intolerance in later life, indicating an age-related decline in glucocompetence. These findings demonstrate the importance of the normal inverse relationship between serum insulin and IGFBP-1 levels in glucoregulation and that sustained dysregulation of the insulin/IGF-I/IGFBP-1 axis is associated with impaired glucose tolerance and abnormalities of insulin action.
Diabetes 2000 Mar
PMID:Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance. 1086 69

Much has been learned over the last two decades regarding the management of growth hormone (GH) deficiency (GHD) in children and adolescents. However, significant divergence and debate continue to exist on the ideal approach to the management of GHD. Despite active controversy, several paradigms have recently emerged which should guide the treatment of GHD patients as we head into the new millennium. The primary objectives of GH therapy remain the normalization of height in childhood and the attainment of normal adult height, but the recognition of the metabolic roles of GH define additional therapeutic benefits. A daily subcutaneous injection of recombinant human GH in a dose range of 25-50 microg/kg/day has been established as the mainstay of therapy. Alternative modes of treatment including GH-releasing hormone (GHRH), GH secretagogues and depot GH have been developed, but evaluation of their clinical utility remains incomplete. Careful monitoring and follow-up of pediatric GHD patients by a pediatric endocrinologist are essential. Accurate determination of height velocity and interval height increases (expressed as the change in height z score) continue to be the most important parameters in monitoring the response to treatment. Monitoring serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 has gained utility in the assurance of compliance and safety, but does not always correlate well with the growth response. A clear role for a biochemical as well as an auxological monitoring approach has nonetheless been established. The comparison of attained growth response to that which has been calculated by various modeling approaches is also becoming a valuable monitoring tool. Significant side effects of GH therapy are quite rare and are easily identified and addressed during close follow-up. Despite previous concerns, it now appears that in the absence of additional risk factors there is no evidence that long-term recipients of GH are at any increased risk of developing diabetes, slipped capital femoral epiphysis, brain tumor recurrence or leukemia. Although GHD may or may not persist into adult life, adult GHD diagnostic criteria and the importance of GH therapy in adult GHD patients have recently been established. Therefore, the pediatric endocrinologist now has a crucial role in guiding the transition to adult GHD management in collaboration with the adult endocrinologist. In the years to come, with the continued investigation and collaborationof experts from around the world, the approach to GH treatment will undoubtedly continue to evolve and improve.
 ...
PMID:New paradigms for growth hormone therapy in children. 1097 Nov 1

Data on growth of children with insulin-dependent diabetes mellitus (IDDM) before the onset of disease are conflicting, and although the insulin-like growth factor (IGF) system has almost invariably been found altered at diagnosis, most of previous studies are affected by the small number of patients investigated. We studied 60 IDDM children at the onset of disease, comparing their stature with target height, normal growth standards, and height of 102 sex- and age-matched controls. Furthermore, we assessed serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and IGFBP-3 circulating forms. IDDM children were subdivided into 2 groups according to an age above (n = 26) or below (n = 34) 6 yr. The values of endocrine variables of diabetics older than 6 yr were compared with those of 34 age-matched controls. Although the height of diabetics was higher than growth reference values (mean height +/- SD, 0.64+/-1.4 z-score) and their target height (mean target height +/- SD, 0.1+/-0.84 z-score; P < 0.005), no significant difference in height was found between IDDM children and controls (mean height +/- SD, 0.64+/-0.95 z-score) even analyzing the 2 age groups separately. Overall, IDDM children showed reduced levels of IGF-I (mean +/- SD, -0.65+/-1.9 z-score) and normal levels of IGF-II (mean +/- SD, -0.05+/-1.2 z-score) and IGFBP-3 (mean +/- SD, -0.06+/-1.2 z-score). However, whereas patients younger than 6 yr showed normal values of IGF-I, IGF-II, and IGFBP-3, these peptides were significantly reduced in older subjects compared with either younger IDDM children or controls (P < 0.01). IGFBP-3 immunoblot analysis revealed the presence of an approximately 18-kDa fragment of IGFBP-3 in addition to the major approximately 29-kDa fragment and the intact form (approximately 42-39 kDa) in 46 of 60 IDDM patients, whereas the approximately 18-kDa band was absent in all 34 control sera. No relationship was found between the endocrine variables and stature at diagnosis. In conclusion, our results indicate that IDDM children at the onset of disease are not taller than healthy peers and have increased IGFBP-3 proteolytic activity. Finally, although the IGF system is normal in younger IDDM children, older patients have reduced IGF levels.
 ...
PMID:Growth and insulin-like growth factors (IGFs) in children with insulin-dependent diabetes mellitus at the onset of disease: evidence for normal growth, age dependency of the IGF system alterations, and presence of a small (approximately 18-kilodalton) IGF-binding protein-3 fragment in serum. 1109 48

Raloxifene is the first selective estrogen receptor modulator registered for the prevention and treatment of postmenopausal osteoporosis. In addition to direct effects on bone cells, estrogen and raloxifene may act indirectly via changes in hormonal homeostasis. However, the menopause-related decrease in serum insulin-like growth factor I (IGF-I) and the increase in insulin or glucose are not always reversed by estrogen replacement. Especially orally administered estrogen was reported to decrease serum IGF-I levels. Understanding the effects of estrogens and raloxifene on the GH-IGF axis and insulin-glucose homeostasis are important because of their link to bone metabolism and cardiovascular health. We investigated the effects of raloxifene on the GH-IGF-I axis and insulin-glucose homeostasis in a cross-sectional study in the third year of the Multiple Outcomes of Raloxifene Evaluation trial, a double blind, placebo-controlled, prospective study in postmenopausal women with osteoporosis (T-score of -2.5 or less or at least two moderate vertebral fractures). Patients with diabetes mellitus were excluded from this additional study. A fasting blood sample was obtained (0 h), and women received an sc injection of 0.05 mg recombinant human GH (Humatrope)/kg BW. The second blood sample was obtained 24 h later (24 h). GH, IGF-I, IGF-binding protein-3 (IGFBP-3), insulin, and glucose were measured. Group characteristics were tested by nonparametric ANOVA. The dose-response to raloxifene was tested by linear regression models, with age and body mass as covariates. Seven women were taking placebo, 16 were taking raloxifene (60 mg/day), and 9 were taking raloxifene (120 mg/day). Patients from the 60 mg raloxifene group were the oldest (mean +/- SD, 64.4 +/- 4.2 vs. 69.3 +/- 6.9 and 63.3 +/- 5.9 yr for placebo, 60 mg/day raloxifene, and 120 mg/day raloxifene, respectively; P = 0.05). Compared with placebo users, patients taking raloxifene had higher body mass index (24.7 +/- 1.7 vs. 25.0 +/- 3.1 and 28.8 +/- 5.8 kg/m(2); P = 0.03). At 0 h, raloxifene use was associated with lower IGF-I/IGFBP-3 ratio (4.3 +/- 0.7 vs. 2.9 +/- 0.7 and 3.0 +/- 0.7 nmol/mg; P = 0.001) and insulin/glucose ratio (13.7 +/- 5.2 vs. 11.9 +/- 5.9 and 9.5 +/- 2.3 pmol/mmol; P = 0.04). Similarly, raloxifene use was associated with lower IGF-I/IGFBP-3 and insulin/glucose ratios at 24 h (P = 0.01 and 0.07). Glucose, GH, and IGFBP-3 levels were similar among the groups (0.12 < P < 0.67). In conclusion, raloxifene use is associated with decreased serum IGF levels and insulin/glucose ratio before and 24 h after one rhGH injection in nondiabetic postmenopausal women with osteoporosis. Therefore, raloxifene may decrease liver sensitivity to GH. Other explanations are increased clearance or increased tissue sensitivity to IGF-I or insulin. The raloxifene-induced increases in bone mineral density do not appear to be mediated by reversing the age- and menopause-related decreases in IGF-I levels. The results of this small cross-sectional study need confirmation by longitudinal studies.
 ...
PMID:Effects of the selective estrogen receptor modulator, raloxifene, on the somatotropic axis and insulin-glucose homeostasis. 1139 84

Type 1 diabetes mellitus (DM) is a disease of insulin deficiency, resulting from the autoimmune-mediated destruction of pancreatic beta cells. However, as a likely consequence of intraportal insulin deficiency, patients with type 1 DM also exhibit abnormalities of the growth hormone (GH)/IGF/IGF-binding protein (IGFBP) axis, including GH hypersecretion, reduced circulating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels of IGFBP-1. These abnormalities not only exacerbate hyperglycemia in patients with type 1 DM, but may contribute to the pathogenesis of diabetes-specific complications, including diabetic neuropathy, nephropathy, and retinopathy. Therefore, therapeutic modalities aimed at restoring the GH-IGF-IGFBP axis are being considered. Herein, we review the efficacy of one such therapy, specifically IGF-I replacement therapy. To date, short-term beneficial metabolic effects of recombinant human IGF (rhIGF)-I therapy have been demonstrated in numerous diabetic conditions, including type 1 DM, type 2 DM, and type A insulin resistance. However, the long- term safety and metabolic efficacy of rhIGF-I therapy remains to be established. Moreover, the potential impact of rhIGF-I on the natural history of diabetic complications has yet to be explored.
Diabetes Technol Ther 2000
PMID:Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility. 1146 25

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40 microg/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg x h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg x night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean +/- SEM:IGF-I, 401 +/- 22 ng/ml; placebo, 256 +/- 20 ng/ml (P = 0.0002); IGF-I, 0.108 +/- 0.006; placebo, 0.074 +/- 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 +/- 0.03; placebo, 0.23 +/- 0.03 U/kg x min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r = -0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 +/- 1.5; placebo, 12.2 +/- 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 +/- 6.8; placebo, 82.2 +/- 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.
 ...
PMID:The role of IGF-binding proteins in mediating the effects of recombinant human IGF-I on insulin requirements in type 1 diabetes mellitus. 1150 96

Insulinlike growth factor (IGF) I and IGF-II are synthesized in osteoblasts and stimulate proliferation, differentiation, and matrix synthesis in these cells. There is some evidence that IGFs act on bone cells not only by paracrine but also by endocrine pathways, suggesting that circulating IGFs may be of importance for the regulation of bone metabolism. On the other hand, the serum IGF-I level is also thought to be a good indicator of the nutritional conditions in hemodialysis patients. The present study was performed to analyze the correlations of circulating levels of IGF-I, IGF-II, IGF-binding protein (IGFBP) 1 and IGFBP-3 with biochemical markers of bone metabolism and parameters of the urea kinetic model which reflect nutritional conditions in hemodialysis patients. We also examined the differences between these relationships in male and female patients on hemodialysis. Sixty-two hemodialysis patients, 36 men (male group) and 26 women (female group), were included in this study. We measured the serum levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. The bone mineral content (BMC) of the radius was measured by dual-energy X-ray absorptiometry. We calculated Kt/V, protein catabolic rate, and percent creatinine generation rate (%CGR). We also examined the relationships between serum levels of IGFs and BMC and the parameters of the urea kinetic model. It was found that the serum levels of IGF-I in the hemodialysis patients were almost the same as those in the control group. However, the serum levels of IGF-II, IGFBP-1, and IGFBP-3 in the hemodialysis patients were significantly higher than those in the control group. In the male group, the serum IGF-I levels showed a significant correlation with both serum intact parathyroid hormone levels and BMC, but no significant correlations between these indices were found in the female group. The serum levels of both IGF-I and IGF-II showed significant correlations with %CGR in the male group, but not in the female group. Stepwise multiple regression analysis was performed to clarify the relationship between serum levels of IGFs and BMC or %CGR. It was found that age, hemodialysis duration, serum intact parathyroid hormone levels, and sex were independent factors associated with BMC. The %CGR was associated independently with serum levels of IGF-I, and IGF-II and with the presence of diabetes mellitus. In conclusion, it is thought that serum levels of IGF-I and IGF-II can be used as indices of nutritional conditions in hemodialysis patients. However, the serum IGF-I level cannot be used as a marker of bone metabolism in hemodialysis patients.
 ...
PMID:Relationships of serum levels of insulinlike growth factors with indices of bone metabolism and nutritional conditions in hemodialysis patients. 1154 96

Little is known about the metabolic or cardiovascular effects of selective ER modulators (SERMs), such as raloxifene hydrochloride (RLX), in postmenopausal women with type 2 diabetes mellitus (DM). Therefore, the effect of RLX vs. placebo (PL) on glycemic control, insulin sensitivity, as well as effects on a number of hormone, lipid, coagulation, and safety factors were determined in 30 postmenopausal women with type 2 DM in a randomized, double blind, cross-over trial. All participants had a SHBG serum concentration below 60 nmol/liter at baseline and had stable diabetes controlled by either oral hypoglycemic agents or diet for 1 month. In the first treatment period, participants received 12 wk of either PL or RLX, followed by an 8-wk washout before the second treatment period. In the second treatment period, participants were crossed over to the other treatment. Compared with PL, RLX did not significantly affect fasting blood glucose, hemoglobin A(1c), lipids, fasting insulin, or insulin sensitivity (as measured by the euglycemic clamp technique). Compared with PL, RLX reduced fibrinogen levels by 0.77 g/liter (P < 0.001), IGF-I by 2.4 nmol/liter (P < 0.001), and free T by 0.73 pmol/liter (P = 0.038) and increased SHBG by 5.5 nmol/liter (P = 0.001) and IGF-binding protein-3 by 0.57 ng/ml (P = 0.007). Our results demonstrate that RLX does not significantly affect glycemic control and has favorable or neutral effects on selected surrogate markers of cardiovascular risk in postmenopausal women with type 2 diabetes mellitus while decreasing hyperandrogenicity in these patients.
 ...
PMID:Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial. 1178 34


<< Previous 1 2 3 4 5 6 7 Next >>