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)

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

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

It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
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PMID:Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. 940 43

The insulin receptor (IR) shares structural and functional homology with the IGF-I receptor (IGF-IR). Hybrid receptors composed of an IR alphabeta-heterodimer and an IGF-IR alphabeta-heterodimer are formed in tissues expressing both molecules. Hybrids behave as IGF-IR rather than IR with respect to ligand binding affinity, receptor autophosphorylation, and hormone internalization and degradation. Factors regulating hybrid formation in vivo are unknown. We recently reported that in skeletal muscle of NIDDM patients, expression of hybrids is increased and correlated with a decrease in IR number and an increase in fasting insulin levels. However, it is not clear whether increased expression of hybrid receptors is a primary defect specifically associated with NIDDM or a secondary event caused by hyperinsulinemia. To address this issue, we used a quantitative microwell-based immunoassay to measure hybrid receptor abundance in skeletal muscle of 11 normal subjects and 12 patients with insulinoma, a state of primary nongenetically determined hyperinsulinemia. Total insulin binding was lower in insulinoma patients than in normal subjects (0.70 +/- 0.18 vs. 4.59 +/- 0.77; P < 0.0001). Total IGF-I binding did not differ between the two groups (0.81 +/- 0.27 and 0.85 +/- 0.10, respectively). The amount of hybrids, expressed as bound/total (B/T), was higher in patients with insulinoma than in normal subjects (0.57 +/- 0.19 vs. 0.36 +/- 0.03; P < 0.0006) and was inversely correlated with total insulin binding (r = -0.64, P < 0.0004). Increased abundance of hybrid receptors was positively correlated with insulin levels (r = -0.82, P < 0.0009) and inversely correlated with insulin-mediated glucose uptake (r = -0.80, P < 0.01). No correlations were observed between insulin-mediated glucose uptake and maximal specific insulin binding (r = 0.19, P = 0.64). These results indicate that insulin-induced IR downregulation may lead to the formation of a higher proportion of hybrid receptors, whose abundance is negatively correlated with in vivo insulin sensitivity. These results, therefore, support a role for insulin in the regulation of hybrid receptors formation and suggest that increased expression of hybrids in NIDDM may be a secondary event caused by hyperinsulinemia rather than a primary defect.
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PMID:Expression of insulin/IGF-I hybrid receptors is increased in skeletal muscle of patients with chronic primary hyperinsulinemia. 942 79

Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40-0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49-0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43-0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.
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PMID:Studies of the variability of the genes encoding the insulin-like growth factor I receptor and its ligand in relation to type 2 diabetes mellitus. 1077 Feb 5

Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. There is now convincing evidence that this is associated with a reduction in GH secretion resulting in an improvement in insulin sensitivity and glycaemic control. The mechanism may simply be reduced GH-secretion, but pre- and post-receptor effects on insulin sensitivity are also likely. It is not clear what effect IGF-I treatment has on IGF binding proteins, but with the restoration of a more normal GH/IGF-I axis they are likely to be restored to normal concentrations which may in turn have a direct effect on glucose metabolism. In NIDDM, the mechanism of action of IGF-I remains unclear. At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. The exact mechanism and interaction remains to be elucidated. In severe insulin-resistant states, IGF-I-treatment appears to be effective, and may be the only realistic therapeutic measure in the near future, and warrants further investigation. Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. Thus, IGF-I appears to have a future as a therapeutic agent in treating diabetes, but long-term studies addressing safety and short-term studies addressing mechanisms are essential. With only a few pharmaceutical companies having the capability to produce IGF-I for scientific and therapeutic investigation, it is important that short-term marketing strategy does not prevent the proper exploration of this exciting peptide hormone as a therapeutic agent for all types of diabetes.
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PMID:Insulin-like growth factor-I and diabetes. A review. 1098 75

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.
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PMID:Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis. 1282 45

Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5-6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, beta-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.
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PMID:Muscle-specific overexpression of CD36 reverses the insulin resistance and diabetes of MKR mice. 1523 93

Autocrine activation of the IGF-I system in mesangial cells (MC) promotes glomerular scarring in a model of type 1 diabetes. Although estrogens protect against progressive nondiabetic glomerulosclerosis (GS), women with diabetes seem to loose the estrogen-mediated protection against cardiovascular disease. However, little is known about the local IGF-I system and its interactions with estrogens in the pathogenesis of type 2 diabetic GS. Therefore, we examined db/db B6 (db/db) mice, a model of type 2 diabetes and diabetic GS. The IGF-I system was activated in the glomeruli and MC of female diabetic db/db mice, but not in nondiabetic db/+ littermates. We found increased IGF-I receptor (IGFR) expression and activation, including activation of MAPK. Surprisingly, estrogens, via an estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and insulin receptor substrate phosphorylation, and extracellular signal-regulated kinase activation in db/db MC. In contrast, ER expression was decreased in MC and glomeruli of db/db mice. Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD98059 increased ER expression and transcriptional activity. This suggests that the local prosclerotic IGF-I system is activated in type 2 diabetes and diminishes ER-mediated protection against GS. Although estrogens may stimulate protective ER signaling, they also activate the IGF-I system via ER-independent mechanisms in db/db MC. The later estrogen effects appear to outweigh the antisclerotic effects of ER activation. This may in part account for loss of estrogen protection against the progression of diabetic GS in women with type 2 diabetes.
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PMID:Autocrine activation of the local insulin-like growth factor I system is up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts for decreased ER expression in type 2 diabetic mesangial cells. 1555 May 5

We have created a liver-specific igf1 gene-deletion mouse model (LID) with markedly reduced circulating IGF-I levels. They demonstrate that while they have normal growth and development they develop insulin resistance secondary to the elevation of circulating growth hormone. When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation. In a separate transgenic mouse we created a model of severe insulin resistance and type 2 diabetes by the overexpression of a dominant-negative IGF-I receptor in skeletal muscle. In this model we show that lipotoxicity plays a major role in the progression of the disease and is affected by treatment with a fibrate, which reverses the insulin resistance and diabetic state. These models are therefore very useful in studying human physiology and disease states.
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PMID:The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting. 1564 8


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