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)

Insulin-like growth factor I (IGF-I) is a potent anabolic peptide that mediates most of its pleiotropic effects through association with the IGF type I receptor. Biological availability and plasma half-life of IGF-I are modulated by soluble binding proteins (IGFBPs), which sequester free IGF-I into high affinity complexes. Elevated levels of specific IGFBPs have been observed in several pathological conditions, resulting in inhibition of IGF-I activity. Administration of IGF-I variants that are unable to bind to the up-regulated IGFBP species could potentially counteract this effect. We engineered two IGFBP-selective variants that demonstrated 700- and 80,000-fold apparent reductions in affinity for IGFBP-1 while preserving low nanomolar affinity for IGFBP-3, the major carrier of IGF-I in plasma. Both variants displayed wild-type-like potency in cellular receptor kinase assays, stimulated human cartilage matrix synthesis, and retained their ability to associate with the acid-labile subunit in complex with IGFBP-3. Furthermore, pharmacokinetic parameters and tissue distribution of the IGF-I variants in rats differed from those of wild-type IGF-I as a function of their IGFBP affinities. These IGF-I variants may potentially be useful for treating disease conditions associated with up-regulated IGFBP-1 levels, such as chronic or acute renal and hepatic failure or uncontrolled diabetes. More generally, these results suggest that the complex biology of IGF-I may be clarified through in vivo studies of IGFBP-selective variants.
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PMID:Binding protein-3-selective insulin-like growth factor I variants: engineering, biodistributions, and clearance. 1114 79

Insulin-like growth factor I (IGF-I) accumulates in the kidney following the onset of diabetes, initiating diabetic renal hypertrophy. Increased renal IGF-I protein content, which is not reflected in messenger RNA (mRNA) levels, suggests that renal IGF-I accumulation is due to sequestration of circulating IGF-I rather than to local synthesis. It has been suggested that IGF-I is trapped in the kidney by IGF binding protein 1 (IGFBP-1). We administered purified human IGFBP-1 (hIGFBP-1) to nondiabetic and diabetic mice as three daily sc injections for 14 days, starting 6 days after induction of streptozotocin diabetes when the animals were overtly diabetic. Markers of early diabetic renal changes (i.e., increased kidney weight, glomerular volume, and albuminuria) coincided with accumulation of renal cortical IGF-I despite decreased mRNA levels in 20-day diabetic mice. Human IGFBP-1 administration had no effect on increased kidney weight or albuminuria in early diabetes, although it abolished renal cortical IGF-I accumulation and glomerular hypertrophy in diabetic mice. Increased IGF-I levels in kidneys of normal mice receiving hIGFBP-1 were not reflected on kidney parameters. IGFBP-1 administration in diabetic mice had only minor effects on diabetic renal changes. Accordingly, these results did not support the hypothesis that IGFBP-1 plays a major role in early renal changes in diabetes.
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PMID:Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration. 1567 62

Insulin-like growth factor I (IGF-I) has significant structural homology with insulin. IGF-I has been shown to bind to insulin receptors to stimulate glucose transport in fat and muscle, to inhibit hepatic glucose output and to lower blood glucose while simultaneously suppressing insulin secretion. However, the precise role of IGF-I in maintaining normal glucose homeostasis and insulin sensitivity is not well defined. Studies in patients with diabetes have shown that in insulin-deficient states, serum IGF-I concentrations are low and increase with insulin therapy. Similarly, administration of insulin via the portal vein results in optimization of plasma IGF-I concentrations. A patient with an IGF1 gene deletion was shown to have severe insulin resistance that improved with IGF-I therapy. Studies conducted in experimental animals have shown that if IGF-I synthesis by the liver is deleted, the animals become insulin-resistant, and this is improved when IGF-I is administered. Likewise, deletion of the IGF-I receptor in muscle in mice induces severe insulin resistance. Administration of IGF-I to patients with type 2 diabetes mellitus has been shown to result in an improvement in insulin sensitivity and a reduction in the requirement for exogenously administered insulin to maintain glucose homeostasis. A polymorphism in the IGF1 gene that has been shown to reduce serum IGF-I results in an increased prevalence of type 2 diabetes. Taken together, these findings support the conclusion that IGF-I is necessary for normal insulin sensitivity, and impairment of IGF-I synthesis results in a worsening state of insulin resistance.
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PMID:Role of insulin-like growth factor iin maintaining normal glucose homeostasis. 1576 Dec 37

Insulin-like growth factor I (IGF-I) has many potential therapeutic uses because of its varied effects--growth promotion, insulin-like influence on glucose metabolism, and neuroprotection resulting from cell-proliferative and antiapoptotic properties--but they have not been investigated systematically in clinical situations. The growth-promoting effect of recombinant human IGF-I (rhIGF-I) in the extensively studied growth hormone insensitivity syndrome (GHIS; Laron syndrome) signifies an endocrine role for the GH-IGF system. The metabolism of (adult) patients with severe insulin resistance is improved by rhIGF-I, which--together with insulin therapy--also improves metabolic control in type 1 and 2 diabetes. Further studies on IGF-I metabolic effects and growing understanding of the IGF-I-IGF-binding protein system could open new therapeutic avenues.
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PMID:Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance. 1586 Apr 16

Insulin-like growth factor I (IGF-I) is normally produced from hepatocytes and various other cells and tissues, including the pancreas, and is known to stimulate islet cell replication in vitro, prevent Fas-mediated beta-cell destruction and delay the onset of diabetes in nonobese diabetic mice. Recently, however, the notion that IGF-I stimulates islet cell growth has been challenged by the results of IGF-I and receptor gene targeting. To test the effects of a general, more profound increase in circulating IGF-I on islet cell growth and glucose homeostasis, we have characterized MT-IGF mice, which overexpress the IGF-I gene under the metallothionein I promoter. In early reports, a 1.5-fold-elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. We demonstrated that the transgene expression, although widespread, was highly concentrated in the beta-cells of the pancreatic islets. Yet, islet cell percent and pancreatic morphology were unaffected. IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, and improved glucose tolerance but normal insulin secretion and sensitivity. Pyruvate tolerance test indicated significantly suppressed hepatic gluconeogenesis, which might explain the severe hypoglycemia after fasting. Finally, due to a partial prevention of beta-cell death against onset of diabetes and/or the insulin-like effects of IGF-I overexpression, MT-IGF mice (which overexpress the IGF-I gene under the metallothionein I promoter) were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia and prevention of weight loss and death. Although IGF-I might not promote islet cell growth, its overexpression is clearly antidiabetic by improving islet cell survival and/or providing insulin-like effects.
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PMID:A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes. 1827 Mar 1

Peripheral and central diabetic neuropathies were studied in streptozotocin-diabetic rats, using behavioral, biochemical and electrophysiological techniques. Diabetic rats showed thermal hypoalgesia and decreasing motor nerve conduction velocity at 4 and 8 weeks of diabetes. In addition, amplitude of the evoked potential recorded in primary somatosensory cortex after stimulation of the sciatic nerve was markedly reduced at 8 weeks of diabetes. This decrease was accompanied by decreases in GluR2/3 AMPA receptor subunits. These changes seem to be specific to the somatosensory system and to originate in higher centers since they were not present in the hippocampus and were not observed at the level of gracilis nucleus. Insulin-like growth factor I (IGF-I) treatment reversed the reduced thermal sensitivity and peripheral nerve conduction velocity but did not reverse changes in the CNS, suggesting that once initiated, both anomalies may develop independently in this model of diabetic neuropathy. In conclusion, the results indicate that diabetes induces a wide spectrum of alterations in the central somatosensory system that are independent of the decreases in peripheral sensory transmission that could be responsible for the disturbances in somatosensory perception observed in diabetes.
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PMID:Independent alterations in the central and peripheral somatosensory pathways in rat diabetic neuropathy. 1926 10


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