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)

Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.
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PMID:Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. 1634 83

It has been shown that combined high local hyperinsulinism and hyperglycemia after low-number islet transplantation into the livers of streptozotocin-diabetic rats lead to the development of hepatocellular neoplasms but a substantial cocarcinogenic effect of genotoxic streptozotocin could not be ruled out completely. Thus, we herein investigated this model in BB/Pfd rats (n = 805; nine experimental groups), which develop spontaneous autoimmune diabetes similar to human type 1 diabetes. After low-number islet transplantation (n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione-S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-alpha. After 12 to 15 and 15 to 18 months, 52% and 100% of the animals showed one or multiple hepatocellular adenomas or hepatocellular carcinomas (HCCs), respectively. Conclusively, this study identifies combined hyperinsulinism and hyperglycemia as a carcinogenic mechanism for the development of HCCs in diabetic rats. Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-alpha.
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PMID:Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats. 1645 45

Mesangial cells (MC) isolated from glomerulosclerosis-prone ragged, olygosyndactilism, pintail (ROP) mice retain a stable phenotype after exposure to elevated glucose concentrations, whereas MC from glomerulosclerosis-resistant C57BL/6 (C) mice do not. In NOD and db/db mice, the stable phenotype induced by diabetes consists of autocrine activation of the IGF-I signaling pathway. We hypothesized that high ambient glucose activates the IGF-I pathway in ROP but not in C MC. MC were propagated in either 6 or 25 mm glucose. Isolated murine glomeruli were used to confirm in vitro experiments. 25 mm glucose induced increased insulin receptor substrate (IRS)-1 phosphorylation in ROP but not C MC. However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. This occurred without a change in IGF-I binding sites, suggesting a role for IGF binding protein (IGFBP). ROP MC and glomeruli expressed less IGFBP-2 than C MC and glomeruli. Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. Renal biopsies from patients with diabetic nephropathy also showed markedly decreased IGFBP-2 expression when compared with patients without nephropathy. In summary, glucose induces IRS-1 phosphorylation in MC isolated from ROP mice susceptible to glomerulosclerosis. IGFBP-2 expression was low in ROP MC and glomeruli from patients with diabetic nephropathy, suggesting that this may represent a new marker of susceptibility to diabetic nephropathy. Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role.
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PMID:Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. 1655 65

The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, active glycogen synthase kinase 3beta, phospho-tau, ubiquitin, and amyloid-beta. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.
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PMID:Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. 1662 31

Type I diabetes is characterized by little or no insulin production and hyperglycemic conditions. It is also associated with significant bone loss and increased bone marrow adiposity. To examine the role of reduced insulin signaling in type I diabetic bone loss without inducing hyperglycemia, we used genetically reconstituted insulin receptor knockout mice (IRKO-L1) that are euglycemic as a result of human insulin receptor transgene expression in the pancreas, liver, and brain. RT-PCR analyses demonstrated undetectable levels of insulin receptor expression in IRKO-L1 bone, yet IRKO-L1 bones exhibit similar (and trend toward greater) bone density compared with wild-type animals as determined by microcomputed tomography. More detailed bone analyses indicated that cortical bone area was increased in tibias of IRKO-L1 mice. Osteoblast markers (osteocalcin and runx2 mRNA levels) and resorption markers (serum pyridinoline levels) were similar in wild-type and IRKO-L1 bones. When marrow adiposity was examined, we noticed a decrease in adipocyte number and fatty-acid-binding protein 2 expression in IRKO-L1 mice compared with wild-type mice. Bone marrow stromal cell cultures obtained from wild-type and IRKO-L1 mice demonstrated similar adipogenic and osteogenic potentials, indicating that systemic factors likely contribute to differences in marrow adiposity in vivo. Interestingly, IGF-I receptor mRNA levels were elevated in IRKO-L1 bones, suggesting (in combination with hyperinsulinemic conditions) that increased IGF-I receptor signaling may represent a compensatory response and contribute to the changes in cortical bone. Taken together, these results suggest that reduced insulin receptor signaling in bone is not a major factor contributing to bone loss in type I diabetes.
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PMID:Normal bone density obtained in the absence of insulin receptor expression in bone. 1697 25

Insulin deficiency downregulates HSP60 and IGF-I receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle. Our previous studies had shown that IGF-I receptor signaling can be modulated by the abundance of HSP60. Since HSP60 localizes to the cytoplasmic compartment and mitochondria, this study was carried out to determine the distribution of cytosolic and mitochondria HSP60 in diabetic myocardium and to explore whether cytosolic HSP60 can modulate IGF-I receptor signaling in cardiac muscle cells. In streptozotocin-induced diabetes, both the cytosolic and mitochondrial fractions of HSP60 were decreased in the myocardium. Incubating primary cardiomyocytes with insulin leads to increased abundance of HSP60 in the cytosolic and mitochondria compartments. To determine whether cytosolic HSP60 can modulate IGF-I receptor signaling, we used rhodamine 6G to deplete functional mitochondria in cardiomyocytes. In the mitochondria-depleted cells, overexpression of HSP60 with adenoviral vector increased the abundance of IGF-I receptor, enhanced IGF-I-activated receptor phosphorylation, and augmented IGF-I activation of Akt and ERK. Thus overexpressing HSP60 in the cytosolic compartment enhanced IGF-I receptor signaling through upregulation of IGF-I receptor protein. However, IGF-I receptor signaling was significantly reduced in the mitochondria-depleted cells, which suggested that maintaining normal IGF-I receptor signaling in cardiomyocytes required functioning mitochondria. The effect of cytosolic HSP60 involved suppression of ubiquitin conjugation to IGF-I receptor in cardiomyocytes. These data suggest two different mechanisms that can regulate IGF-I signaling, one via cytosolic HSP60 suppression of IGF-I receptor ubiquitination and the other via mitochondria modulation. These findings provide new insight into the regulation of IGF-I signaling in diabetic cardiomyopathy.
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PMID:Regulation of IGF-I receptor signaling in diabetic cardiac muscle: dysregulation of cytosolic and mitochondria HSP60. 1698 60

Insulin-like growth factor-I (IGF-I) has significant structural homology with proinsulin. IGF-I binds to insulin receptors, stimulates insulin-like actions and enhances insulin sensitivity. However, because circulating IGF-I is bound to high-affinity binding proteins and has relatively low affinity for insulin receptors, most of its ability to alter insulin sensitivity is mediated indirectly (i.e. through suppression of growth hormone, a known insulin antagonist). Direct effects of IGF-I on insulin actions are tissue specific, occurring principally in skeletal muscle and kidney. Genetic manipulations in experimental mouse models have been used to analyze the role of endogenous IGF-I on insulin action. These studies have shown that suppression of growth hormone is important for enhancing insulin action in the liver and that deletion of the IGF-I receptor in skeletal muscle results in severe insulin resistance. IGF-I also suppresses renal gluconeogenesis, which might contribute to its glucose-lowering actions. In humans, IGF-I enhances insulin sensitivity and lowers blood glucose in patients with either extreme insulin resistance or type 2 diabetes. It also decreases insulin requirement in patients with insulin-deficient diabetes. Taken together, these findings suggest that IGF-I is functioning coordinately with insulin to regulate glucose homeostasis.
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PMID:Involvement of insulin-like growth factor-I in the control of glucose homeostasis. 1703 15

We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.
Diabetes 2006 Dec
PMID:C-Peptide reverses nociceptive neuropathy in type 1 diabetes. 1713 May 7

Decorin, a small leucine-rich proteoglycan, affects the synthesis of the elastic fiber component fibrillin-1 in the kidney via hitherto unknown mechanisms. Here, we show that decorin binds to and induces phosphorylation of insulin-like growth factor-I (IGF-I) receptor in renal fibroblasts. Inhibition of the IGF-I receptor tyrosine kinase and its downstream target phosphoinositide-3 kinase prevented decorin-mediated synthesis of fibrillin-1. Furthermore, decorin induced phosphorylation of phosphoinositide-dependent kinase 1, protein kinase B/Akt, mammalian target of rapamycin (mTOR), and p70 S6 kinase. Accordingly, the enhanced synthesis of fibrillin-1 was blocked by rapamycin, an inhibitor of mTOR. Notably, IGF-I, which signals through the same pathway, also stimulated fibrillin-1 synthesis. Systemic administration of rapamycin to mice subjected to unilateral ureteral obstruction, a model of renal fibrosis and increased fibrillin-1 synthesis, markedly reduced the number of interstitial fibroblasts and fibrillin-1 deposition. In streptozotocin-induced diabetes, IGF-I receptor was up-regulated in the kidneys from decorin-null mice. However, this could not compensate for the decorin deficiency, resulting ultimately in decreased fibrillin-1 content. This study provides evidence for the involvement of decorin and the IGF-I receptor/mTOR/p70 S6 kinase signaling pathway in the translational regulation of fibrillin-1.
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PMID:Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin. 1720 Feb 3

Cell death is increased in the anterior pituitary of poorly controlled diabetic rats, but anti-apoptotic mechanisms are also activated. We hypothesized that specific cell types are selectively protected against diabetes-induced cell death. To determine when anti-apoptotic mechanisms are activated, streptozotocin-induced diabetic rats were killed after 1, 4, 6 and 8 weeks of evolution. Anterior pituitaries were processed for western blot analysis to determine changes in the intrinsic cell death pathway and upstream kinases involved in cell protection mechanisms. An increase in cell death was detected by ELISA at 4 weeks of diabetes. TUNEL labelling demonstrated that this corresponded to death of primarily lactotrophs, a few somatotrophs, and no thyrotrophs, corticotrophs or gonadotrophs. Levels of phosphorylated (p) Akt were increased at 1 week of diabetes, while pERK1/2 levels increased at 4 weeks and pJNK at 6 weeks. Activation of caspase 3 decreased and anti-apoptotic members of the Bcl-2 protein family increased as early as 1 week after diabetes onset. These changes were coincident with increased IGF-I receptor levels. Levels of X-linked inhibitor of apoptosis protein (XIAP) increased significantly after 6 weeks of diabetes, as did activation of nuclear factor (NF)kappaB. Double immunohistochemistry indicated that XIAP was expressed in less than 1% of lactotrophs and gonadotrophs, approximately 50% of somatotrophs and more than 90% of corticotrophs and thyrotrophs. These results suggest that some cell survival mechanisms are rapidly activated in the anterior pituitary, even before increased cell death can be detected, while others are more delayed. Furthermore, both pituitary cell death and expression of protective mechanisms such as XIAP are cell-type specific.
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PMID:Cell-specific expression of X-linked inhibitor of apoptosis in the anterior pituitary of streptozotocin-induced diabetic rats. 1721 Jul 59


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