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

Endothelial progenitor cells (EPCs) have been shown to be involved in vascular regeneration and angiogenesis in experimental diabetes. Because insulin therapy mobilizes circulating progenitor cells, we studied the effects of insulin on outgrowth of EPCs from peripheral blood mononuclear cells of healthy volunteers and patients with type 2 diabetes. Insulin increased the formation of EPC colony-forming units in a dose-dependent manner, half-maximal at 1.5 nM and peaking at 15 nM. Inhibiting the insulin receptor with neutralizing antibodies or antisense oligonucleotides had no effect on EPC outgrowth.(1) In contrast, targeting the human insulin-like growth factor 1 (IGF-1) receptor with neutralizing antibodies significantly suppressed insulin-induced outgrowth of EPCs from both healthy controls and patients with type 2 diabetes. This IGF-1 receptor-mediated insulin effect on EPC growth was at least in part dependent on MAP kinases(2) and was abrogated when extracellular signal-regulated kinase 1/2 (Erk1/2) and protein kinase 38 (p38) activity was inhibited. To study the functional relevance of the observed insulin effects, we studied EPC-induced tube formation of bovine endothelial cells in vitro. Insulin-stimulated EPCs incorporated into the endothelial tubes and markedly enhanced tube formation. In conclusion, this is the first study showing an insulin-mediated activation of the IGF-1 receptor leading to an increased clonogenic and angiogenic potential of EPCs in vitro.
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PMID:Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling. 1838 19

Human insulin-like growth factor 1(hIGF-1) is essential for cell proliferation and used therapeutically in treating various diseases including diabetes mellitus. Here, we present that a recombinant hIGF-1(rhIGF-1) was expressed fused with the C-terminus of a rice luminal binding protein and accumulated highly in rice seeds, reaching 6.8+/-0.5% of total seed protein. The rhIGF-1 fusion was demonstrated to possess biological activity to stimulate cell proliferation. Importantly, the unprocessed transgenic seeds could significantly increase plasma rhIGF-1 level and reduce blood glucose of diabetic mice via oral delivery. Further studies suggested that transgenic seeds reduced blood glucose of diabetic mice by enhancing islet cells survival and increasing insulin secretion rather than increasing insulin sensitivity. These results indicated the potential of the novel fusion expression system in production and oral delivery of biologically active small peptides for diseases.
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PMID:A biologically active rhIGF-1 fusion accumulated in transgenic rice seeds can reduce blood glucose in diabetic mice via oral delivery. 1870 5

Distinct human neurodegenerative diseases share remarkably similar temporal emergence patterns, even though different toxic proteins are involved in their onset. Typically, familial neurodegenerative diseases emerge during the fifth decade of life, whereas sporadic cases do not exhibit symptoms earlier than the seventh decade. Recently, mechanistic links between the aging process and toxic protein aggregation, a common hallmark of neurodegenerative diseases, have been revealed. The insulin/insulin-like growth factor 1 (IGF1) signalling pathway - a lifespan, metabolism and stress-resistance regulator - links neurodegeneration to the aging process. Thus, although a reduction of insulin signalling can result in diabetes, its reduction can also increase longevity and delay the onset of protein-aggregation-mediated toxicity. Here we review this apparent paradox and delineate the therapeutic potential of manipulating the insulin/IGF1 signalling pathway for the treatment of neurodegenerative diseases.
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PMID:The insulin paradox: aging, proteotoxicity and neurodegeneration. 1876 45

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for approximately 175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-gamma-coactivator-1alpha may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.
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PMID:Making insulin-deficient type 1 diabetic rodents thrive without insulin. 1877 78

Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.
Diabetes Obes Metab 2008 Nov
PMID:The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. 1883 43

1. The aim of the present study was to determine the role of myocardial microvascular endothelial cells (MMVEC) in impaired angiogenesis of type 2 diabetic Goto-Kakizaki (GK) rats. 2. A microRNA (miRNA) microarray was used to assess miRNA expression in MMVEC from GK and Wistar rats. Upregulation of miRNA-320 was observed in MMVEC from GK rats using real-time reverse transcription-polymerase chain reaction (RT-PCR). 3. So far, nine miRNAs have been reported to target angiogenic factors and/or receptors, including kinase insert domain containing receptor (Flk-1), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R). The predicted genes targeted by miR-320 include Flk-1, IGF-1 and IGF-1R. Western blot analysis and RT-PCR were used to analyse the protein and mRNA expression, respectively, of the putative genes IGF-1 and IGF-1R. The expression of IGF-1 and IGF-1R proteins decreased significantly in diabetic MMVEC. However, the expression of IGF-1 mRNA increased rather than decreased. The mRNA expression of IGF-1R did not differ significantly between diabetic and control MMVEC. 4. Transfection of an miR-320 inhibitor into MMVEC from GK rats confirmed that miR-320 impaired angiogenesis. The proliferation and migration of diabetic MMVEC improved after transfection of the miR-320 inhibitor. In addition, the miR-320 inhibitor significantly increased the expression of IGF-1 protein, but had no effect on the expression of IGF-1R. 5. Eleven miRNAs were upregulated in MMVEC from GK rats compared with those in Wistar rats: let-7e, miR-129, miR-291-5p, miR-320, miR-327, mir-333, miR-363-5p, miR-370, miR-494, miR-503 and miR-664. 6. The results indicate that upregulation of miR-320 in MMVEC from GK rats may be responsible for the inconsistency between the expression of IGF-1 protein and mRNA and therefore related to impaired angiogenesis in diabetes. Transfection of an miR-320 inhibitor may be a therapeutic approach for the treatment of impaired angiogenesis in diabetes.
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PMID:MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. 1898 36

Impairment of glucose metabolism (in particular insulin resistance and type 2 diabetes mellitus) has been reported in patients who have undergone hematopoietic SCT (HSCT) during childhood, especially those treated with TBI. This pilot study was conducted to determine prevalence of and possible underlying mechanisms for impaired glucose homeostasis in young adults treated with HSCT and TBI and who were not previously known to have diabetes mellitus. A total of 10 subjects (6 males, 4 females) were evaluated. Mean ages were 13.0+/-1.0 years at the time of TBI and 24.0+/-1.1 years at the time of this study. Five subjects had laboratory evidence of insulin resistance using the homeostasis model assessment and the quantitative insulin sensitivity check index indices. Two of these subjects had impaired fasting glucose and four had decreased plasma insulin-like growth factor 1 levels. All 10 subjects had evidence of abdominal obesity. Insulin resistance is frequently observed in adult survivors of HSCT treated with TBI in childhood. Underlying mechanisms may include radiation-induced growth hormone deficiency and changes in body composition.
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PMID:Disorders of glucose homeostasis in young adults treated with total body irradiation during childhood: a pilot study. 1930 39

The secondary occurrence of type 2 diabetes with various hormonal diseases (e.g. pituitary, adrenal and/or thyroid diseases) is a recurrent observation. Indeed, impaired glucose tolerance (IGT) and overt diabetes mellitus are frequently associated with acromegaly and hypercortisolism (Cushing syndrome). The increased cardiovascular morbidity and mortality associated with acromegaly and Cushing syndrome may partly be a consequence of increased insulin resistance that normally accompanies hormone excess. Acromegalic patients are insulin resistant, both in the liver and in the periphery, displaying hyperinsulinemia and increased glucose turnover in the basal post-absorptive states. The prevalence of diabetes mellitus and that of IGT in acromegaly is reported to range 16-56%, whereas the degree of glucose tolerance seems correlated with circulating growth hormone (GH) levels, age, and disease duration. Moreover, a family history of diabetes and concomitant presence of arterial hypertension have been found to predispose to diabetes as well. GH has physiological effects on glucose metabolism, stimulating gluconeogenesis and lipolysis, which results in increased blood glucose and free fatty acid levels. Conversely, insulin-like growth factor 1 (IGF-I) enhances insulin sensitivity primarily on skeletal muscles. However, in acromegaly, increased IGF-I levels are unable to counteract the insulin-resistance status determined by GH excess. Therapy with somatostatin analogues (SSAs) induce control of GH and IGF-I excess in the majority of patients, but their inhibitory effect on pancreatic insulin secretion might complicate the overall effect of this treatment on glucose tolerance. Hypercortisolism produces visceral obesity, insulin resistance, and dyslipidemia that together with hypertension, hypercoagulability, and ventricular morphologic and functional abnormalities increase cardiovascular risk, and persist up to 5 years after resolution of hypercortisolism. Hypercortisolism leads to hyperglycaemia and reduced glucose tolerance, determines insulin resistance, stimulates hepatic gluconeogenesis and glicogenolisis. In Cushing syndrome the prevalence of diabetes varies between 20 and 50%, but probably this prevalence is underestimated, as not always an oral glucose tolerance test is performed in the presence of an apparently normal fasting glycaemia. Again, disease duration, rather than hormone levels, seems to be the major determinant in the occurrence of systemic complications in Cushing syndrome. Due to the impact they have on mortality and morbidity in both acromegaly and Cushing syndrome, these complications should be treated aggressively. In patients with neuroendocrine tumours (NETs) the occurrence of altered glucose tolerance may be due to a decreased insulin secretion, like it happens in patients who underwent pancreatic surgery and in those with pheochromocytoma, or to an altered counterbalance between hormones, such as in patients with glucagonoma and somatostatinoma. Moreover, SSAs represent a valid therapeutic choice in the symptomatic treatment of NETs, and also in this case the medical therapy of the primary disease, may have a significant impact on the prevalence of glucose metabolism imbalance. In thyroid disorders, an abnormal glucose tolerance may be principally encountered in hyperthyroidism. The pathogenesis is complex and scant data on prevalence and severity are found in the literature. Adequate treatment for glucose imbalance is mandatory in these peculiar patients in line with the American Diabetes Association and the European Association for the Study of Diabetes consensus statement. In particular, since traditional insulins have two features that may complicate therapy (absorption profiles, delayed onset of action and peak activity), the new insulin analogues could be of particular interest in the management of the secondary diabetes associated with endocrinopathies, considering the frailty of these patients. Indeed, it has been demonstrated that insulin glargine, given once daily, reduces the risk of hypoglycaemia compared with other formulations, and can facilitate a more aggressive insulin treatment in this class of patients.
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PMID:Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. 1932 13

Plasma cell membrane glycoprotein-1 or ectonucleotide pyrophosphatase/phosphodiesterase (PC-1/ENPP1) has been shown to inhibit insulin signaling, and its genetic polymorphism or increased expression is associated with type 2 diabetes in humans. Therefore, PC-1 inhibition represents a potential strategy in treating diabetes. Since patients with phosphodiesterase/pyrophosphatase deficient PC-1 manifest abnormal calcification, enhancing insulin signaling by inhibiting PC-1 for the treatment of diabetes will be feasible only if PC-1 phosphodiesterase/pyrophosphatase activity needs not be significantly diminished. However, whether inhibition of insulin receptor signaling by PC-1 is dependent upon its phosphodiesterase/pyrophosphatase activity remains controversial. In this study, the extracellular domain of the human PC-1 in its native form or with a T256A or T256S mutation was overexpressed and purified. Enzymatic assays showed that both mutants have less than 10% of the activity of the wild-type protein. In HEK293 cells stably expressing recombinant insulin receptor or insulin-like growth factor 1 (IGF1) receptor, transient expression of wild-type full length PC-1 (PC-1.FL.WT) but not the T256A or T256S mutants inhibits insulin signaling without affecting IGF1 signaling. Western blot and FACS analysis showed that the wild-type and mutant full length PC-1 proteins are expressed at similar levels in the cells, and were localized to the similar levels on the cell surface. Overexpression of PC-1.FL.WT did not affect insulin receptor mRNA level, total protein and cell surface levels. Together, these results suggest that the inhibition of insulin signaling by PC-1 is somewhat specific and is dependent upon the enzymatic activity of the phosphodiesterase/pyrophosphatase.
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PMID:Evidence that inhibition of insulin receptor signaling activity by PC-1/ENPP1 is dependent on its enzyme activity. 1937 58

Acromegaly is a rare disease caused by a growth-hormone-secreting pituitary adenoma. Symptoms include enlargement of the hands, feet, and jaw with growing dental interspaces, as well as hypertrophy of the tongue and nasal and sinusoidal mucosa. The two latter symptoms are mostly responsible for the accompanying obstructive sleep apnea syndrome. Besides these "cosmetic" symptoms, the disease is associated with hypertension and diabetes mellitus, as well as with an increased risk for adenomas and carcinomas of the colon. The average time span from first symptom to diagnosis is well over 6 years; a single determination of insulin-like growth factor 1 in serum can confirm the disease. The treatment of choice remains surgical resection of the adenoma in suitable patients, whereas in extensive disease with invasion of surrounding tissue, drug therapy and/or radiotherapy may be necessary.
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PMID:[Acromegaly-associated lesions of the nasal mucosa. Case report]. 1955 21


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