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)

Cloning of the insulin-like growth factor I (IGF-I) gene led to the development in 1987 of recombinant IGF-I available for clinical use. Trials were started targeting endocrine, metabolic and neurological disorders, and beneficial results have been demonstrated in IGF-I deficiency states caused by IGF-I gene deletion and growth hormone (GH) receptor deficiency, type 1 and type 2 diabetes mellitus, and severe insulin resistance syndromes. Results of equivocal benefit have also been reported in osteoporosis and amyotrophic lateral sclerosis. Recent encouraging data using the IGF-I-IGF-binding protein 3 (IGFBP-3) complex in diabetes mellitus suggest that this preparation may eventually replace recombinant free IGF-I. The lack of an established therapeutic indication for IGF-I has resulted in its supplies being severely limited. It will probably be decided during the next decade whether use of IGF-I or the IGF-I-IGFBP-3 complex becomes firmly established as an accepted endocrine therapy.
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PMID:Is there a medical need to explore the clinical use of insulin-like growth factor I? 1152 91

Development of diabetes generally reflects an inadequate mass of insulin-producing beta-cells. beta-cell proliferation and differentiation are regulated by a variety of growth factors and hormones, including insulin-like growth factor I (IGF-I). GRF1 is a Ras-guanine nucleotide exchange factor known previously for its restricted expression in brain and its role in learning and memory. Here we demonstrate that GRF1 is also expressed in pancreatic islets. Interestingly, our GRF1-deficient mice exhibit reduced body weight, hypoinsulinemia and glucose intolerance owing to a reduction of beta-cells. Whereas insulin resistance is not detected in peripheral tissues, GRF1 knockout mice are leaner due to increased lipid catabolism. The reduction in circulating insulin does not reflect defective glucose sensing or insulin production but results from impaired beta-cell proliferation and reduced neogenesis. IGF-I treatment of isolated islets from GRF1 knockouts fails to activate critical downstream signals such as Akt and Erk. The observed phenotype is similar to manifestations of preclinical type 2 diabetes. Thus, our observations demonstrate a novel and specific role for Ras-GRF1 pathways in the development and maintenance of normal beta-cell number and function.
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PMID:Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. 1280 18

Thirty-three patients with type 2 diabetes mellitus (16 men, 17 women) were divided into 3 groups based on urinary excretion of albumin (U-Alb)--group A: U-Alb < 30 mg/d; group B: 30 mg/d < or = U-Alb < or = 300 mg/d; and group C: 300 mg/d < U-Alb. Serum creatinine levels were lower than 2.0 mg/dL in all the subjects. There was no difference in age, sex, therapy, body weight, body mass index (BMI), lean body mass (LBM), or hemoglobin A(1c) (HbA(1c)) levels among the 3 groups. Resting metabolic rate (RMR) (kJ/h/m(2)) and adjusted RMR for lean body mass (kJ/h/m(2)) were significantly increased in group C compared with groups A and B. Hb concentrations, serum albumin levels, and creatinine clearance were much lower in group C than in groups A and B (P < .001). There were no difference in serum urea nitrogen, total cholesterol, cholinesterase and free thyroxine, or plasma insulin-like growth factor I (IGF-I) levels among the 3 groups. Linear regression analysis revealed an inverse correlation between RMR and serum albumin levels, correlation between RMR and U-Alb, and inverse correlation between RMR and Hb concentrations, respectively, in these patients. In conclusion, RMR in diabetic patients correlated directly with U-Alb and inversely with serum albumin and Hb concentration. These findings suggest that RMR is related with urinary albumin loss and anemia in patients with type 2 diabetes mellitus accompanied by diabetic nephropathy.
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PMID:Increased resting metabolic rate in patients with type 2 diabetes mellitus accompanied by advanced diabetic nephropathy. 1553 91

The effects of circulating insulin-like growth factor I (IGF-I) on glucose metabolism are well recognized. IGF-I is also important in maintaining beta-cell mass and regulating endogenous growth hormone (GH) levels. Low IGF-I levels could explain links between small birth size and the risk of developing type 2 diabetes mellitus in short, obese adults. In a recent prospective study, childhood insulin secretion was related to IGF-I levels and statural growth, whereas insulin sensitivity was related to early post-natal weight gain. Common genetic polymorphisms in the IGF1 gene have been linked to small birth size, post-natal growth and future diabetes risk, but these results have been inconsistent. Recent adult studies have demonstrated that lower baseline IGF-I levels predict the subsequent development of impaired glucose tolerance (IGT), type 2 diabetes and cardiovascular disease. Administration of low-dose GH therapy, at a dose that minimizes the lipolytic effects of GH and has the ability to increase IGF-I levels, enhances insulin sensitivity in young healthy adults and in GH-deficient adults and increases insulin secretion in individuals with IGT. Whether the administration of low-dose GH, recombinant IGF-I or combined IGF-I/IGF-binding protein 3 therapy prevents future development of IGT or type 2 diabetes in high-risk normoglycaemic and GH-deficient individuals merits further long-term studies.
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PMID:Insulin-like growth factor I and impaired glucose tolerance. 1576 Dec 41

This cross-sectional study investigated electrophysiological abnormalities in type 2 diabetics with normal and reduced insulin-like growth factor I (IGF-I) levels. Sixty patients and 20 non-diabetic controls were included in the study. The fasting serum glucose was measured and IGF-I levels were determined by radioimmunoassay in all patients. Nerve conduction tests were performed in all the study participants on the ulnar nerve and lower extremities. Compared with the controls, all the patients showed a reduction in the peak amplitude of the motor response, 58% showed a reduction in the motor conduction velocity and 55% showed a reduction in the sensory conduction velocity. There was no statistically significant correlation between the electrophysiological changes and the glucose or IGF-I levels. In conclusion, there does not appear to be a correlation between serum glucose or IGF-I levels and electrophysiological abnormalities in patients with type 2 diabetes mellitus.
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PMID:Electrophysiological abnormalities in type 2 diabetic patients with reduced levels of insulin-like growth factor I. 1660 20

Supraphysiological doses of growth hormone (GH) therapy are generally thought to antagonize the effects of insulin, whereas the insulin-like growth factor I (IGF-I) potentiates insulin-like actions. Paradoxically, adults with GH deficiency and patients with acromegaly are both predisposed to glucose intolerance and insulin resistance; however, one cannot extrapolate from these pathological conditions to determine the true metabolic roles of GH and IGF-I in glucose homeostasis. Growth hormone also promotes lipolysis, which has been shown to be the principal determinant of its insulin-antagonistic properties; on the other hand, IGF-I, which acts as an insulin sensitizer, does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is evident only after feeding, when the bioavailability of circulating IGF-I is increased. In contrast to supraphysiological GH doses, low doses of GH treatment have been shown to increase circulating IGF-I levels and IGF-I bioavailability and, thus, may theoretically enhance insulin sensitivity without inducing lipolysis. We have recently reported that a fixed administration of a very low GH dose (1.7 microg/kg/day or 0.1mg/day) improved insulin sensitivity in adults with GH deficiency and increased peripheral glucose uptake in subjects with impaired glucose tolerance and the metabolic syndrome. Our data raise the possibility that this very low GH dose may play a role in maintaining beta-cell function and possibly delay the progression to type 2 diabetes in these high-risk patients.
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PMID:Impact of treatment with recombinant human GH and IGF-I on visceral adipose tissue and glucose homeostasis in adults. 1662 5

Growth hormone (GH) is generally considered to exert anti-insulin actions, whereas insulin-like growth factor I (IGF-I) has insulin-like properties. Paradoxically, GH deficient adults and those with acromegaly are both predisposed to insulin resistance, but one cannot extrapolate from these pathological conditions to determine the normal metabolic roles of GH and IGF-I on glucose homeostasis. High doses of GH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects, whereas IGF-I acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is only evident after feeding when the bioavailability of circulating IGF-I is increased. In contrast, many studies in GH deficient adults have consistently shown that GH replacement improves the body composition profile although these studies differ considerably in terms of age, the presence or absence of multiple pituitary hormone deficiency, and whether GH deficiency was childhood or adult-onset. However, the improvement in body composition does not necessarily translate into improvements in insulin sensitivity presumably due to the anti-insulin effects of high doses of GH therapy. More recently, we have found that a very low dose GH therapy (0.1 mg/day) improved insulin sensitivity without affecting body composition in GH-deficient adults and in subjects with metabolic syndrome, and we postulate that these effects are mediated by its ability to increase free 'bioavailable' IGF-I without the induction of lipolysis. These results raise the possibility that this low GH dose may play a role in preventing the decline of beta-cell function and the development of type 2 diabetes in these "high risk" subjects.
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PMID:Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults. 1719 14

We assessed the effect of chronic hyperglycemia on bone mineral density (BMD) and bone remodeling in patients with type 2 diabetes mellitus. We investigated 42 patients with type 2 diabetes under stable control for at least 1 year, 22 of them with good metabolic control (GMC: mean age = 48.8 +/- 1.5 years, 11 females) and 20 with poor metabolic control (PMC: mean age = 50.2 +/- 1.2 years, 8 females), and 24 normal control individuals (CG: mean age = 46.5 +/- 1.1 years, 14 females). We determined BMD in the femoral neck and at the L2-L4 level (DEXA) and serum levels of glucose, total glycated hemoglobin (HbA1), total and ionic calcium, phosphorus, alkaline phosphatase, follicle-stimulating hormone, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OH-D), insulin-like growth factor I (IGFI), osteocalcin, procollagen type I C propeptide, as well as urinary levels of deoxypyridinoline and creatinine. HbA1 levels were significantly higher in PMC patients (12.5 +/- 0.6 vs 7.45 +/- 0.2% for GMC and 6.3 +/- 0.9% for CG; P < 0.05). There was no difference in 25-OH-D, iPTH or IGFI levels between the three groups. BMD values at L2-L4 (CG = 1.068 +/- 0.02 vs GMC = 1.170 +/- 0.03 vs PMC = 1.084 +/- 0.02 g/cm(2)) and in the femoral neck (CG = 0.898 +/- 0.03 vs GMC = 0.929 +/- 0.03 vs PMC = 0.914 +/- 0.03 g/cm(2)) were similar for all groups. PMC presented significantly lower osteocalcin levels than the other two groups, whereas no significant difference in urinary deoxypyridine was observed between groups. The present results demonstrate that hyperglycemia is not associated with increased bone resorption in type 2 diabetes mellitus and that BMD is not altered in type 2 diabetes mellitus.
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PMID:Lack of relationship between glycemic control and bone mineral density in type 2 diabetes mellitus. 1727 58

Diabetic retinopathy continues to be the leading cause of legal blindness among working-age individuals. The earliest histological features of diabetic retinopathy include neuroretinal damage, capillary basement membrane thickening, loss of pericytes and loss of endothelial cells. At advanced stages, neovascularization, the hallmark of proliferative diabetic retinopathy (PDR) occurs, and blindness can result from relentless abnormal fibrovascular proliferation with subsequent bleeding and retinal detachment. Macular oedema is another retinal complication of diabetes that is responsible for a major part of vision loss, particularly in type 2 diabetes. The breakdown of the blood retinal barrier and the consequent vascular leakage and thickening of retina are the main events involved in its pathogenesis. Although a tight control of both blood glucose levels and hypertension are essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients. Laser photocoagulation treatment soon after the onset of PDR significantly reduces the incidence of severe vision loss. However, the optimal timing for laser treatment is frequently passed and, in addition, it is not uniformly successful in halting visual decline. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of diabetic retinopathy have been developed in recent years. There is mounting evidence to suggest that angiogenic factors play a crucial role in PDR development, vascular endothelial growth factor (VEGF) being the most relevant. Other growth factors or cytokines such as insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), pro-inflammatory cytokines and angiopoetins, are also involved in the pathogenesis of PDR. However, the intraocular synthesis of angiogenic factors is counterbalanced by the synthesis of antiangiogenic factors. Therefore, the balance between the angiogenic and antiangiogenic factors rather than angiogenic factors themselves will be crucial in determining the progression of PDR. The main antiangiogenic factor is the pigment epithelium derived factor (PEDF) but the transforming growth factor beta (TGF-beta), thrombospondin (TSP) and somatostatin are also among the intraocullary synthesized antiangiogenic factors.
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PMID:Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. 1822 Jun 19

Glomerular hyperfiltration and mesangial expansion have been described in mouse models of a hyperinsulinemic early stage of type 2 diabetes mellitus (DM). Large-conductance Ca(2+)-activated K(+) channels (BK) have been linked to relaxation of human mesangial cells (MC) and may contribute to MC expansion and hyperfiltration. We hypothesized that high insulin levels increase BK activity in MC by increasing the number and/or open probability (P(o)) of BK in the plasma membrane. With the use of the patch-clamp technique, BK activity was analyzed in cultured MC exposed to normal insulin (1 nM) and high insulin (100 nM) for a 48-h period. The mean P(o) and the percentage of patches (cell attached) with detected BK increased by 100% in the insulin-treated cells. Real-time PCR revealed that insulin increased mRNA of BK-alpha. Western blot revealed an insulin-stimulated increase in BK-alpha from both total cellular and plasma membrane protein fractions. The mitogen-activated protein kinase (MAPK) inhibitors PD-098059 and U-0126 attenuated the insulin-induced increase in BK-alpha expression. PD-098059 inhibited insulin-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 in MC. An insulin-stimulated increase also was found for total cellular BK-beta(1), the accessory subunit of BK in MC. A similar increase in BK-alpha mRNA and protein was evoked by an insulin-like growth factor I analog. Glomeruli, isolated from hyperinsulinemic early stage type 2 DM mice, exhibited increased BK-alpha mRNA by real-time PCR and protein by immunohistochemical staining and Western blot. These results indicate that insulin activates BK in the plasma membrane of MC and stimulates, via MAPK, an increase in cellular and plasma membrane BK-alpha.
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PMID:Insulin increases the activity of mesangial BK channels through MAPK signaling. 1836 63


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