Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin and insulin-like growth factor I (IGF-I) exhibit vasoactivity. To examine the role of the endothelium in mediating the vascular responses to insulin and IGF-I, we exposed both isolated intact rat mesenteric arteries and rat aortic rings to these growth factors in the presence and absence of endothelium. Perfusion of rat mesenteric arteries with insulin, IGF-I, or IGF-II resulted in the potentiation of arginine vasopressin (AVP)-induced vasoconstriction. Of these growth factors, IGF-I was the most potent, with a significant effect at 0.6 nM and maximal effects at 6.0 nM, followed by IGF-II and insulin. Endothelial denudation or addition of cycloheximide prevented the growth-factor effects. Tissue cGMP levels in the mesenteric artery were minimally affected by growth factors. Insulin and IGF-I vascular effects were not inhibited by BQ123, an endothelin (ET) antagonist that blocked ET-1 enhancement of AVP response. Perfusion of mesenteric arteries with IGF-I for 1 h did not alter vessel ET-1 or ET-1 mRNA contents. Addition of indomethacin markedly inhibited the IGF-I effect on AVP contraction. Thus, the mesenteric vascular effect of insulin and IGF-I is not associated with ET-1 release but appears to link to an increased release of an endothelial-derived contracting factor or the decreased production of an endothelial-derived relaxing factor from the cyclooxygenase pathway. In contrast to their action in the mesenteric artery, insulin (exceeding 100 nM) and IGF-I (1-30 nM) attenuated AVP- and norepinephrine-induced contraction in rat aortic rings. Endothelial-denudation abolished this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Aug
PMID:Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. 803 96

Glomerular hypertrophy is reported in several endocrine disorders such as acromegaly and diabetes mellitus, where abnormalities of growth hormone and insulin-like growth factor (IGF-I) have been reported. In the present report, we have cultured bovine and human glomerular endothelial cells, and bovine glomerular epithelial and mesangial cells, and characterized the expression of IGF-I mRNA and its receptor in these cells. High affinity, specific receptors for IGF-I were identified in all three types of cells by radioreceptor assays. Receptor number (Ro) derived by Scatchard analysis revealed an unusually high number of Type I IGF receptors, approx. 1.2 x 10(5) receptors/cell in glomerular endothelial cells. Affinity crosslinking studies and immunoprecipitation with antibodies against the Type I IGF receptor identified the alpha-subunit of the IGF-I receptor as having a molecular mass of 140 kDa. Biologically, IGF-I was more potent than insulin or IGF-II in stimulating DNA synthesis in glomerular endothelial cells. Northern blot analysis showed that glomerular and aortic endothelial cells expressed IGF-1 mRNA of 1.7 kb. In contrast, renal glomeruli showed several IGF-1 mRNAs of 7.5, 1.7 and 1.2 kb. Thus, the demonstration of both a prepondence of Type I IGF receptors coupled with the growth promoting effects of IGF-I in glomerular endothelial and epithelial cells, as well as the local production of IGF-I mRNA suggests that IGF-I serves an important role as an autocrine or paracrine regulator of the growth of renal glomeruli.
...
PMID:Characterization of type I IGF receptor and IGF-I mRNA expression in cultured human and bovine glomerular cells. 826 20

For some considerable time, there has been a growing awareness that defective essential fatty acid metabolism plays a causal role in the pathogenesis of both schizophrenia and non-insulin-dependent diabetes mellitus (NIDDM) but the influence of defective essential fatty acid metabolism in the pathogenesis of rheumatoid arthritis and cancer is less well appreciated. An EFA deficiency, or defective EFA metabolism, negatively influences prostaglandin synthesis and glucose regulation and transport. Moreover, defective EFA metabolism negatively influences estrogen availability which contributes to the observed gender bias some of these illnesses manifest. While fluctuations of estrogen are known to contribute to the pathogenesis of these conditions, so also do fluctuations of IGF-II and there is some suggestion that IGF-II and insulin may well be inversely regulated. In addition, insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, and schizophrenia are thought to be autoimmune disorders, while cancer is associated with immune system failure. Consequently, this paper aims to examine the pathophysiological similarities and differences between mental illness, diabetes, rheumatoid arthritis and cancer in respect of which the causal relationship that obtains between essential fatty acids, estrogen, IGF-II, glucose regulation and autoimmunity will be addressed.
...
PMID:The estrogen connection: the etiological relationship between diabetes, cancer, rheumatoid arthritis and psychiatric disorders. 853 40

A number of dramatic changes have been documented in the insulin-like growth factors (IGFs-I and -II) and their binding proteins (IGFBPs) during pregnancy. In this study we have tested the hypothesis that a failure of the normal proteolytic modification of IGFBP-3 is responsible for gestational diabetes by examining serum samples taken in the third trimester from 29 women with uncomplicated pregnancies, 21 women with established Type 1 diabetes and 20 women with gestational diabetes. Analysis of IGFBP-3 by Western immunoblotting revealed that it was present in a modified form, migrating at around 29 kDa, in the circulation of all of the women investigated. Semiquantification of the activity of the protease which modifies the IGFBP-3 demonstrated considerable variation between individuals in their ability to fragment radiolabelled IGFBP-3 following a 45-min co-incubation. Surprisingly, in one individual (with gestational diabetes) there was no detectable protease activity even though her endogenous IGFBP-3 had been modified. However, overall there was no clear-cut difference in protease activity between the different groups. Radioimmunometric analysis of IGF-I revealed significantly higher levels in women with gestational diabetes than either of the other two groups (P < 0.05). Similarly IGFBP-3 levels were also increased in these same women (P < 0.05). In contrast, IGF-II levels did not alter between the three groups. In conclusion, our hypothesis was not supported by these data and gestational diabetes was found not to be associated with any reduction in the activity of the circulating IGFBP-3 protease which could have decreased the availability of the IGF nor with any alteration in IGFs which could explain the onset of diabetes in these women.
...
PMID:Could abnormalities in insulin-like growth factors and their binding proteins during pregnancy result in gestational diabetes? 854 22

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.
...
PMID:The IGF system in metabolism regulation. 858 49

Diabetic neuropathy is a debilitating disorder whose causation is poorly understood. A new theory proposes that neuropathy may arise as a consequence of loss of neurotrophic insulin-like growth factor (IGF) activity due to diabetes, superimposed on a slow continual loss due to aging. The prediction that IGF-I and IGF-II gene expression are reduced in diabetic nerves was recently tested and validated. Here we tested the prediction that IGF administration can prevent or reverse diabetic sensory neuropathy. Subcutaneous infusion of IGF-I or IGF-II, but not vehicle, halted (P < 0.01) the progression of hyperalgesia in streptozotocin-diabetic rats. Moreover, impaired sensory nerve regeneration was partially reversed within 2 weeks after treatment of diabetic rats with IGFs (P < 0.01). Impaired regeneration could also be prevented by daily subcutaneous IGF injections. The low replacement doses of IGFs were effective despite unabated hyperglycemia and weight loss. These results show that IGF replacement therapy can reverse or prevent diabetic sensory neuropathy independently of hyperglycemia or weight loss.
...
PMID:Insulin-like growth factors reverse or arrest diabetic neuropathy: effects on hyperalgesia and impaired nerve regeneration in rats. 869 62

Diabetic encephalopathy, characterized by structural, electrophysiological, neurochemical, and cognitive abnormalities, is observed in insulin-dependent diabetes mellitus (IDDM) and non-IDDM (NIDDM). Identification of early biochemical lesions potentially may provide clues pointing to its pathogenesis. Insulin-like growth factors (IGFs) are neurotrophic factors that recently have been implicated in the pathogenesis of diabetic neuropathy. Because IGF-II is the predominant IGF in adult brain, we tested the hypothesis that IGF-II gene expression is decreased in the CNS in both IDDM and NIDDM. Brain and spinal cord were isolated from streptozotocin-diabetic rats, a model of IDDM with weight loss and impaired insulin production. IGF-II mRNA content was measured by northern and slot blots. After 2 weeks of diabetes, IGF-II mRNA content per milligram of tissue wet weight, as well as per unit of poly(A)+ RNA, declined significantly (p < or = 0.05) in brain and spinal cord. Insulin replacement therapy partially restored IGF-II mRNA levels in brain, cortex, medulla, and spinal cord. The obese, hyperinsulinemic, and spontaneously diabetic (fa/fa) Zucker rat was used as a model of NIDDM. Brain weight (p < 0.025) and IGF-II mRNA contents (p < 0.01) were significantly decreased in (fa/fa) versus lean nondiabetic (+ /?) rats. Therefore, the decline in IGF-II mRNA levels in diabetic brain was independent of the type of diabetes, the direction of change in body weight, and the insulinemic state. We speculate that this early biochemical lesion may contribute to the development of diabetic encephalopathy.
...
PMID:Brain insulin-like growth factor-II mRNA content is reduced in insulin-dependent and non-insulin-dependent diabetes mellitus. 876 3

Impaired wound healing is a well-documented phenomenon in diabetes mellitus, yet little is known of the fundamental cause of this pathology. This study examined the effects of streptozotocin (STZ)-induced diabetes on the healing process using three wound models: (i) a linear skin incision (tensile strength), (ii) subcutaneously implanted polyvinyl alcohol sponge PVAs (collagen deposition), and (iii) stainless steel mesh chamber (TGF-beta, IGF-I and its binding proteins, extracellular matrix remodeling enzymes). RIA specific for IGF-I revealed that diabetes induced a 42% (wound fluid) and a 48% (serum) reduction in IGF-I levels. IGF-II western ligand blots found that diabetes produced a marked reduction in the level of a wound fluid 46 kDa IGF binding proteins. A proliferation-based bioassay indicates that TGF-beta level is also reduced in diabetic wound fluid (55%). Diabetes of graded metabolic severity induced by variable doses of STZ (25 mg-200 mg/kg) showed stepwise reduction in wound tensile strength and PVAs collagen deposition. In contrast, zymographic analysis of extracellular matrix proteases revealed that the diabetic wound fluid contains increased levels of 21, 69, and 72 kDa gelatinases. A single dose of TGF-beta (2 micrograms) in a collagen vehicle partially reversed the diabetes-related decrease in the tensile strength of standardized incisions. These data support the premise that wound-healing impairment in diabetes is due, at least in part, to a deficiency in growth factor activity within the wound environment.
...
PMID:Transforming growth factor-beta and insulin-like growth factor-I in relation to diabetes-induced impairment of wound healing. 876 52

Insulin and glucose are thought to act as important modulators of the expression of the IGFs, their binding proteins and their receptors. It has been postulated that changes of the IGF system after diabetes onset contribute to the development of diabetes late complications. We have measured the expression of IGF-II/M6P receptor mRNA in rat kidney, lung and heart after streptozotocin induction of diabetes. Adult rats were injected with streptozotocin, and, after the onset of diabetes, were treated with either insulin or vehicle. The rats were sacrificed on days 1, 2, 3, 4 and 9. Kidneys, lungs and hearts were removed aseptically and RNA was extracted from the tissues. In solution hybridization/RNAse protection experiments, specific IGF-II/M6P receptor and beta-actin transcripts were detected in the RNA samples from all tissues examined. To gain additional evidence for the expression of IGF-II/M6P receptor RNA in the tissues examined, Northern blotting experiments were performed: a major 9 kb RNA species was detected on the blots. Interestingly, streptozotocin-induced onset of diabetes led to a significant increase in the expression of IGF-II/M6P receptor mRNA in the kidney but not in lung and heart whereas no change in actin mRNA expression was measured. Insulin treatment did not prevent the increase of IGF-II/M6P receptor mRNA expression during short-term treatment (1-9 days). Alterations of the IGF system during diabetes onset might be of relevance for the development of early renal changes during the course of the disease.
...
PMID:Streptozotocin induction of diabetes in rats leads to increased insulin-like growth factor-II/mannose-6-phosphate receptor mRNA expression in kidney but not in lung or heart. 878 82

Recent evidence suggests that several growth factors participate in diabetic glomerular disease by mediating increased extracellular matrix accumulation and altered cell growth and turnover leading to mesangial expansion. Transforming growth factor (TGF)-beta has been demonstrated to be upregulated both in vivo and in vitro, whereas studies on the activity of the renal insulin-like growth factor (IGF) system in experimental diabetes have provided conflicting results. We investigated the effects of prolonged exposure (4 weeks) of cultured human and rat mesangial cells to high (30 mmol/l) glucose vs iso-osmolar mannitol or normal (5.5 mmol/l) glucose levels on: 1) the autocrine/paracrine activity of the IGF system (as assessed by measuring IGF-I and II, IGF-I and II receptors, and IGF binding proteins); and, in parallel, on 2) TGF-beta 1 gene expression; 3) matrix production; and 4) cell proliferation. High glucose levels progressively increased the medium content of IGF-I and the mRNA levels for IGF-I and IGF-II, increased IGF-I and IGF-II binding and IGF-I receptor gene expression, and reduced IGF binding protein production. TGF-beta 1 transcripts and matrix accumulation and gene expression were increased in parallel, whereas cell proliferation was reduced. Iso-osmolar mannitol did not affect any of the above parameters. These experiments demonstrated that high glucose levels induce enhanced mesangial IGF activity, together with enhanced TGF-beta 1 gene expression, increased matrix production, and reduced cell proliferation. It is possible that IGFs participate in mediating diabetes-induced changes in matrix turnover leading to mesangial expansion, by acting in a paracrine/autocrine fashion within the glomerulus.
...
PMID:Increased activity of the insulin-like growth factor system in mesangial cells cultured in high glucose conditions. Relation to glucose-enhanced extracellular matrix production. 881 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---