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)

Proinsulin connecting peptide (C-peptide) has been initially regarded as deprived of biological functions other than correct scaffolding of insulin. This was caused by the lack of evident effect of C-peptide administration to healthy subjects or animals. At present, in view of numerous studies concerning its structure, membrane binding and biological functions, C-peptide seems to constitute a crucial role in the pathogenesis of complications in diabetes mellitus type 1 (DM1). Patients who maintain high remnant insulin secretion (and therefore also of C-peptide) develop complications such as nephropathy, neuropathy and later microangiopathy with a milder clinical course. In this article we have covered molecular and cellular aspects of C-peptide functioning, such as: activation of protein kinase C, Na+,K+- ATP-ase, nitric oxide synthase, MAP and ERK 1/2 kinases, improvement of nerve conduction velocity and interactions with exogenous and endogenous insulin. We also outline the clinical consequences of deficiency of this underestimated peptide along with its potential therapeutical possibilities in the primary and secondary prevention of DM1 complications.
Pediatr Endocrinol Diabetes Metab 2007
PMID:[Proinsulin C-peptide -- the bioactive peptide with a huge promise]. 1788 Aug 15

The incidence of stroke increases substantially after menopause, and in the United States it is the third leading cause of death. Data exist suggesting that women have worse outcomes for stroke than do men. Trials of aspirin use further suggest that there is a gender difference regarding stroke. While men may have a coronary benefit from aspirin, postmenopausal women do not; yet ischemic stroke may be decreased in women but not in men. Among the traditional risk factors for stroke (such as smoking, hypertension, diabetes, obesity), hormonal therapy (HT) has been suggested to be a risk as well, although the data are not consistent. The previous Position Statement of the IMS published in 2004 was relatively silent on the issue of stroke. The annual rate of stroke in women increases rapidly with aging in postmenopausal women. While the rate is approximately 0.6-0.8/1000/year at age 50-59, it is over 2/1000 after age 60. In white women in the USA, it is 4.2/1000 at 65-74 years of age, and 11.3/1000 between ages 75 and 84 years. Thus, in trials such as the Women's Health Initiative (WHI), most of the strokes occurred in older women. Both the conjugated equine estrogen/medroxyprogesterone acetate (CEE/MPA) and CEE-alone trials in the WHI reported an increased risk of stroke in the entire population using nominal statistics: 1.41 (95% confidence interval (CI) 1.07-1.85) and 1.39 (95% CI 1.10-1.77), respectively. The increased risk was related to ischemic stroke and not hemorrhagic stroke. The absolute risk for the entire population was 0.8/1000 and 1.2/1000 woman-years (<1/1000 signifies a 'rare' event using the CIOMS classification). However, the risk was not increased in the 50-59-year-old age group, although the numbers are small. Here, the background prevalence of stroke is much lower as noted above. The results of the observational trial of the WHI were not consistent with the randomized clinical trial data and were more in keeping with older observational data showing no increased risk of stroke. The authors reconcile these differences by suggesting differences in the timing of initiation of hormones, which was at an earlier age in the observational cohort. Several recent observational studies, which will be presented, show no increased risk of ischemic stroke in younger cohorts, but possibly an increase in the risk of transient ischemic attack. These recent studies suggested the risk to be less with lower doses of estradiol < or =1 mg and to be consistent with older studies showing no risk with doses < 0.625 mg CEE. In addition, the risk was possibly lower with non-oral therapy, and was reduced if started prior to menopause. The existence of hypertension was shown to substantially increase the risk. However, data on progestogen use versus unopposed estrogen have not been consistent. At the same time, a recent body of evidence from basic science studies has reaffirmed the neuronal and stroke protective effects of estrogen. Thus, the discrepancy between these data and clinical data showing no benefit or increased risk of stroke remains to be explained. Recent trials in older women with osteoporosis have suggested an increased risk of stroke with tibolone and of stroke mortality with raloxifene. In conclusion, the current data suggest no increased risk of stroke with hormone therapy in younger (50-59 years) normotensive postmenopausal women, particularly when lower doses are prescribed soon after menopause.
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PMID:Menopause and stroke and the effects of hormonal therapy. 1788 69

Angiogenesis is the main mechanism of vascular remodeling during late development and, after birth, in wound healing. Perturbations of angiogenesis occur in cancer, diabetes, ischemia, and inflammation. While much progress has been made in identifying factors that control angiogenesis, the understanding of the precise molecular mechanisms involved is incomplete. Here we identify a small GTPase, Rap1b, as a positive regulator of angiogenesis. Rap1b-deficient mice had a decreased level of Matrigel plug and neonatal retinal neovascularization, and aortas isolated from Rap1b-deficient animals had a reduced microvessel sprouting response to 2 major physiological regulators of angiogenesis: vascular endothelial growth factor (VEGF) and basic fibroblasts growth factor (bFGF), indicating an intrinsic defect in endothelial cells. Proliferation of retinal endothelial cells in situ and in vitro migration of lung endothelial cells isolated from Rap1b-deficient mice were inhibited. At the molecular level, activation of 2 MAP kinases, p38 MAPK and p42/44 ERK, important regulators of endothelial migration and proliferation, was decreased in Rap1b-deficient endothelial cells in response to VEGF stimulation. These studies provide evidence that Rap1b is required for normal angiogenesis and reveal a novel role of Rap1 in regulation of proangiogenic signaling in endothelial cells.
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PMID:Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice. 1799 8

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

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.
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PMID:The roles of MAPKs in disease. 1834 14

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM- (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM-, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA V(mean) (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07-0.15 Hz), the phase lead of the MAP-to-MCA V(mean) transfer function was 52+/-10 degrees in CTRL subjects, reduced in subjects with DM- (40+/-6 degrees ; P<0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30+/-5 degrees ; P<0.01 compared with subjects with DM-), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA V(mean) to postural change was comparable for all groups (-12+/-6% in CTRL subjects, -15+/-6% in subjects with DM- and -15+/-7% in subjects with DM+). HbA(1c) (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.
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PMID:Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes. 1834 13

The hyperactivation of platelets is involved in the cardiovascular complications associated with type 2 diabetes mellitus. Altered platelet behavior contributes to the angiopathies associated with diabetes. A number of mechanisms involved in platelet activation are altered in diabetes. Platelets from type 2 diabetic patients show an enhanced endogenous reactive oxygen species production and a reduced antioxidant capability, which increase the activity of several tyrosine kinases, such as the Bruton's tyrosine kinase, MAP kinases or proteins of the SRC family. Oxidative stress is also involved in the abnormal intracellular calcium homeostasis observed in platelets from type 2 diabetics, including an enhanced resting cytosolic calcium concentration and calcium release and entry in response to agonists. Moreover, diabetes alters the bioavailability of nitric oxide in platelets. Basal nitric oxide synthase activity is reduced in homogenates of platelets obtained from patients with type 2 diabetes mellitus. The study of these abnormalities might be helpful in the development of new pharmacological strategies to reduce platelet activation in type 2 diabetes mellitus.
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PMID:Platelet signalling abnormalities in patients with type 2 diabetes mellitus: a review. 1838 22

Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto-Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118+/-2 mmHg to 182+/-20 and 187+/-6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.
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PMID:Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats. 1845 44

The ambulatory arterial stiffness index (AASI) is a recently proposed index derived from 24-h ambulatory blood pressure monitoring (ABPM) for the evaluation of arterial stiffness. In this cross-sectional study we investigated whether AASI reflects arterial stiffness in patients with resistant hypertension by comparing AASI and ambulatory pulse pressure (PP) with aortic pulse wave velocity (PWV), a measure of arterial stiffness, in 391 resistant hypertensives. Clinical, laboratory and echocardiographic variables, 24-h ABPM and aortic PWV (measured using the Complior device) were obtained. AASI was calculated as 1--the regression slope of 24-h diastolic on systolic blood pressure (BP). Statistical analysis involved single and multiple linear regressions to assess the correlations between the two ABPM variables and PWV, both unadjusted and adjusted for potential confounders (age, gender, body height, presence of diabetes, 24-h mean arterial pressure [MAP], heart rate, and nocturnal BP reduction). Ambulatory PP and aortic PWV were independently associated with age, gender, presence of diabetes, and 24-h MAP, whereas AASI was associated with age, diabetes, and nocturnal diastolic BP reduction. PP showed stronger unadjusted (r=0.39, p<0.001) and adjusted (r=0.22, p<0.001) correlations with aortic PWV than AASI (r=0.12, p=0.032 and r= -0.04, p=0.47, respectively). In the analysis of subgroups stratified by gender, age, presence of atherosclerotic diseases and diabetes, dipping pattern, and ambulatory BP control, the superiority of PP over AASI was apparent in all subgroups. In conclusion, 24-h ambulatory PP was better correlated to arterial stiffness, as evaluated by aortic PWV, than the novel AASI, in patients with resistant hypertension.
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PMID:Ambulatory arterial stiffness index or pulse pressure: which correlates better with arterial stiffness in resistant hypertension? 1863 71

Micro- and macrovascular complications are major causes of disability and death in patients with diabetes mellitus. Functional impairment of endothelial activity precedes the development of morphological alterations during the progression of diabetes. This endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO), mainly due to accelerated NO degradation by reactive oxygen species (ROS). Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via several distinct mechanisms, increased oxidative stress seems to be the first alteration triggering several others. Mechanisms proposed to explain glucose- and lipid-induced vascular alterations in diabetes include accelerated formation of advanced glycation end-products (AGEs), protein kinase C activation, inflammatory signaling and oxidative stress. Insulin resistance with impaired PI 3-kinase effects decreases insulin mediated production of NO and reduces vasodilation, capillary recruitment and antioxidant properties of endothelium. Compensatory hyperinsulinemia enhances activation of intact MAP-kinase pathways and contributes to pro-atherogenic events by increasing secretion of endothelin-1 (ET-1), stimulating expression of adhesion molecules such as VCAM-1 and E-selectin, and inducing production of ROS. Conventional therapies to reduce hyperglycemia, dyslipidemia and insulin resistance may effectively improve endothelial function and delay the onset of vascular complications. Novel therapeutic approaches designed to inhibit AGEs formation, reduce PKC activation, decrease inflammatory signals and restore the ox/redox balance of endothelium may be predicted to ameliorate vascular function in diabetic state. This review summarizes the current knowledge on the most important mechanisms involved in endothelial dysfunction during diabetes. In addition, novel therapeutic strategies that may result from recently identified targets are also described.
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PMID:Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. 1914 64


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