Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinsulin C-peptide has been recently described as an endogenous peptide hormone, responsible for important physiological functions others than its role in proinsulin processing. Accumulating evidences that C-peptide exerts beneficial effects in the treatment of long term complications of patients with type 1 diabetes mellitus indicate that this molecule may be administered together with insulin in future therapies. Despite its clear pharmacological interest, the secondary and three-dimensional (3D) structures of human C-peptide are still points of controversy. In the present work we report molecular dynamics (MD) simulations of human, rat I and rat II C-peptides. A common experimental strategy applied to all peptides consisted of homology building followed by multinanosecond MD simulations in vacuum and water. Circular dichroism (CD) experiments of each peptide in the absence and presence of 2,2,2-trifluoroethanol (TFE) were performed to support validation of the theoretical models. A multiple sequence alignment of 23 known mammalian C-peptides was constructed to identify significant conserved sites that would be important for the maintenance of secondary and tertiary structures. The analysis of the molecular dynamics trajectories for the human, rat I and rat II molecules have shown quite different general behavior, being the human C-peptide more flexible than the two others. Human and rat C-peptides exhibit very stable turn-like structures at the middle and C-terminal regions, which have been described as potential active sites of C-peptides. Human C-peptide also presented a short alpha-helix throughout the MD, which was not found in the rat molecules. CD data is in very good agreement with the MD results and both methods were able to identify a greater structural stability and potential in rat C-peptides when compared to the human C-peptide. The simulation results are discussed and validated in the light of multiple sequence alignment, recent experimental data from the literature and our own CD experiments.
 ...
PMID:Molecular dynamics and circular dichroism studies of human and rat C-peptides. 1675 Jun 42

FAT/CD36 is a long-chain fatty acid transporter and scavenger receptor for oxidized LDL. Defects in FAT/CD36 have been linked to the hypertriglyceridemia and insulin resistance. Expression of FAT/CD36 was reported increase in type 1 diabetes; however, it remains unclear whether serum glucose or insulin plays an important role in this regulation. To elucidate the individual contribution of plasma glucose and insulin in the regulation of FAT/CD36 mRNA expression, we induced type 1 diabetes in male Sprague-Dawley rats using streptozotocin (STZ) and compared traditional insulin treatment with administration of the orally absorbed chemical agent vanadate, which reduces blood glucose levels via mechanisms that bypass insulin receptor action. STZ-exposed animals showed significant decreases in body weight (285.5 +/- 2.8 vs. 233.1 +/- 3.5 g, P < 0.001) and serum insulin levels (9.7 +/- 0.7 vs. 2.8 +/- 0.6 microU/ml, P < 0.05), accompanied by significant increases in blood glucose (71 +/- 3 vs. 433 +/- 11 mg/dl, P < 0.001), water intake (38.9 +/- 0.9 vs. 205.9 +/- 3.3 ml/day, P < 0.001) and food intake (22.0 +/- 0.4 vs. 36.9 +/- 1.0 g/day, P < 0.001). Diabetic animals demonstrated significant increases in FAT/CD36 mRNA levels in duodenum (2.2-fold), jejunum (1.8-fold), ileum (1.5-fold), adipose tissue (1.7-fold), and heart (2.5-fold) (P < 0.05). Insulin treatment reversed body weight loss and corrected hyperglycemia at diabetic rats as expected. Insulin treatment also corrected increased FAT/CD36 mRNA expression at diabetic rats. Vanadate significantly reduced serum glucose levels without increasing serum insulin or affecting body weight but reversed increased FAT/CD36 mRNA expression in diabetic rats. These data suggest that plasma glucose levels play more important role in the regulation of FAT/CD36 expression than concurrent changes in plasma insulin.
 ...
PMID:The role of hyperglycemia in FAT/CD36 expression and function. 1683 91

Approximately one-third of patients with type 1 diabetes develop a variety of complications as a result of mechanisms that are not completely understood. However, insufficient metabolic control seems to play a major role. Other factors such as magnesium (Mg) could also be of importance. We designed this study to elucidate the effect of oral magnesium administration on plasma lipid profile and mesenteric fat in male Wistar rats. Animals were divided into 4 groups (n=10 in each group): one group served as control, while the other groups were made diabetic with a single i.v. injection of 40 mg/kg streptozocin. Animals in which the diabetic state lasted for 10 days were referred as acute diabetic rats, whereas those in which the diabetes lasted for 8 weeks were defined as chronic diabetics. Mg-treated chronic diabetic received 10 g/l of MgSO(4) added to the drinking water (0.46 g/24 h) for eight weeks following which the left common carotid artery was cannulated for continuous recording of blood pressure. Blood glucose, magnesium and lipid profiles levels were also determined. Diabetes induction caused plasma glucose, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), total cholesterol and triglyceride concentrations to increase, however plasma Mg level was decreased. Administration of MgSO(4) for eight weeks caused the return of the above factors to their normal levels. Mg concentrations also increased but failed to reach normal levels. Diabetes induction caused mesenteric fat/body weight ratio to increase, but administration of MgSO(4) reduced the ratio to normal levels. In addition, Mg administration returned systolic blood pressure to the normal level. Our results support the hypothesis that Mg may play a part in the management of diabetes and the prevention of its vascular complications in streptozocin-induced diabetic rats and it may be useful in the treatment of hyperlipidaemia in diabetic case.
 ...
PMID:Effect of oral magnesium sulfate administration on blood pressure and lipid profile in streptozocin diabetic rat. 1729 79

To prevent diabetic complications derived from enhanced glucose flux via the polyol pathway the development of aldose reductase inhibitors (ARIs) has been established as a promising therapeutic concept. In order to identify novel lead compounds, a virtual screening (VS) was performed successfully suggesting carboxylate-type inhibitors of sub-micromolar to micromolar affinity. Here, we combine a structural characterization of the binding modes observed by X-ray crystallography with isothermal titration calorimetry (ITC) measurements providing insights into the driving forces of inhibitor binding, particularly of the first leads from VS. Characteristic features of this novel inhibitor type include a carboxylate head group connected via an alkyl spacer to a heteroaromatic moiety, which is linked to a further nitro-substituted aromatic portion. The crystal structures of two enzyme-inhibitor complexes have been determined at resolutions of 1.43 A and 1.55 A. Surprisingly, the carboxylic group of the most potent VS lead occupies the catalytic pocket differently compared to the interaction geometry observed in almost all other crystal structures with structurally related ligands and obtained under similar conditions, as an interstitial water molecule is picked up upon ligand binding. The nitro-aromatic moiety of both leads occupies the specificity pocket of the enzyme, however, adopting a different geometry compared to the docking prediction: unexpectedly, the nitro group binds to the bottom of the specificity pocket and provokes remarkable induced-fit adaptations. A peptide group located at the active site orients in such a way that H-bond formation to one nitro group oxygen atom is enabled, whereas a neighbouring tyrosine side-chain performs a slight rotation off from the binding cavity to accommodate the nitro group. Identically constituted ligands, lacking this nitro group, exhibit an affinity drop of one order of magnitude. In addition, thermodynamic data suggest a strongly favourable contribution to binding enthalpy in case the inhibitor is equipped with a nitro group at the corresponding position. To further investigate this phenomenon, we determined crystal structures and thermodynamic data of two similarly constituted IDD-type inhibitors addressing the specificity pocket with either a nitro or halogen-substituted aromatic moiety. As these data suggest, the nitro group provokes the enthalpic contribution, in addition to the H-bond mentioned above, by accepting two "non-classical" H-bonds donated by the aromatic tyrosine side-chain. In summary, this study provides the platform for further structure-guided design hypotheses of novel drug candidates with higher affinity and selectivity.
 ...
PMID:Structural and thermodynamic study on aldose reductase: nitro-substituted inhibitors with strong enthalpic binding contribution. 1736 68

Diabetes affects over 16 million Americans yearly, resulting in hyperglycaemia and microvascular complications, including retinopathy, neuropathy and nephropathy. Animal models have been developed to examine the immunological aspects of type 1 diabetes and the pathogenic mechanisms associated with diabetic retinopathy, but the methods of diabetes induction raise concerns regarding these models. Zebrafish (Danio rerio) have been used extensively to study developmental processes and mutant zebrafish strains have been used to examine vision disease present in humans. In this paper, we have induced hyperglycaemia in zebrafish by alternately immersing the fish in glucose solution or water. Eyes from untreated fish or fish exposed to alternating glucose/water solutions for 28 days were dissected, sectioned and stained to visualise cell bodies in the retina. In untreated fish retinas, the inner plexiform layer (IPL) and inner nuclear layer (INL) were approximately the same thickness, whereas in fish repeatedly exposed to glucose solutions the IPL was approximately 55% the thickness of the INL. Both the IPL and INL were significantly reduced in retinas of treated fish, compared to untreated fish, similar to that seen in other animal models of diabetes and in diabetic patients. These results suggest that zebrafish may be used as an animal model in which to study diabetic retinopathy.
 ...
PMID:Induction of hyperglycaemia in zebrafish (Danio rerio) leads to morphological changes in the retina. 1772 55

Arginine vasopressin (AVP) is known to a neuropeptide that plays important roles in water conservation, sodium homeostasis, and in the regulation of serum osmolality. Several studies have reported that the elevated AVP level is related with diabetes mellitus as an acute or chronic stressor using type 1 diabetes mellitus animal models. However, it is unclear as to how the immunoreactivity and protein level of AVP in the brain is regulated in animal models of type 2 diabetes mellitus. In the present study, Zucker diabetic fatty (ZDF) rats were employed as a type 2 diabetes mellitus model and were compared with Zucker lean control (ZLC) rats with respect to AVP protein expression. Furthermore, in order to verify the regulation of AVP expression before and after the onset of diabetes mellitus, pre-diabetic rats (4 week-old) and obese-diabetic rats (12 week-old) were used. Blood glucose levels and water consumption were also measured and the results showed significantly high in 12 week-old ZDF than any other groups. AVP expression levels in the paraventricular nucleus and supraoptic nucleus were found to be significantly higher in 12 week-old ZDF rats than in 12 week-old ZLC rats and than in 4 week-old rats by immunostaining and western blotting. Enhanced expression of AVP in these animals may be associated with type 2 diabetes mellitus.
 ...
PMID:Enhanced expressions of arginine vasopressin (Avp) in the hypothalamic paraventricular and supraoptic nuclei of type 2 diabetic rats. 1794 Aug 75

The effects of long-term diabetes in the presence of established nephropathy on tubular function remains poorly understood. We evaluated the levels of the main sodium and water transport proteins expressed in the kidney after long-term (8 weeks) of streptozotocin (STZ)-induced type 1 diabetes mellitus (DM) in untreated (D) and insulin (4 U/s.c./day)-treated (D+I) rats. D animals presented upregulation ( approximately 4.5-fold) of Na/glucose cotransporter (SGLT1), whereas the alpha-subunit of the epithelial sodium channel (alpha-ENaC) and aquaporin 1 (AQP1) were downregulated ( approximately 20 and 30% respectively) with no change in the Na/H exchanger (NHE3), Na/Cl cotransporter (TSC) and AQP2. Insulin replacement partially prevented these alterations and caused increases in the expression of alpha-ENaC and AQP2. These effects suggest an action of insulin in the tubular transport properties. The upregulation of SGLT1 may constitute a mechanism to prevent greater glucose losses in the urine but it may result in glucotoxicity to the proximal epithelial cells contributing to the diabetic nephropathy. The decrease of alpha-ENaC in D animals may compensate for the increased sodium reabsorption via SGLT1 resulting in discrete natriuresis. DM-induced polyuria was not due to changes in AQP2 expression.
 ...
PMID:Effect of long-term type 1 diabetes on renal sodium and water transporters in rats. 1794 18

Atrial natriuretic peptide (ANP) exerts beneficial effects on the cardiovascular system in part by exerting antioxidant activity. Given that oxidant stress is a key cause of endothelial dysfunction in diabetes, we investigated whether ANP improves endothelial function in rats with diabetes. Rats were injected with streptozotocin (55 mg/kg iv) to induce type 1 diabetes or the citrate vehicle as controls (n=12). After 4 weeks the diabetic rats were treated with ANP (10 pmol/kg/min sc, n=12) or the antioxidant tempol (1.5 mmol/kg/day sc, n=11), both by osmotic minipump, ramipril (1 mg/kg per day in the drinking water) or remained untreated (n=11). After a further 4 weeks, anaesthetised rats were killed by exsanguination and the thoracic aortae collected for examination of vascular activity and measurement of superoxide generation. Diabetic rats showed elevated plasma glucose concentration (45+/-3 mM) compared to controls (10+/-1 mM) and this was not affected by ANP (43+/-3 mM), ramipril (41+/-2 mM) or tempol (43+/-2 mM). Endothelium-dependent relaxation ex vivo in response to acetylcholine was impaired in diabetic rats (Rmax=66+/-4%) compared to control rats (Rmax=94+/-1%) but treatment with ANP (Rmax=80+/-4%), ramipril (Rmax=88+/-2%) or tempol (Rmax=81+/-5%) significantly improved those responses. Relaxant responses to the endothelium-independent vasodilator sodium nitroprusside were enhanced by treatment of diabetic rats with ANP or ramipril and their combination; but not by tempol. Superoxide generation was significantly elevated in aorta from untreated diabetic rats (649+/-146% of control). In diabetic rats, superoxide generation was significantly attenuated by ANP (to 229+/-78%) or tempol (to 186+/-64%). This study demonstrates that ANP improves vascular oxidant stress in concert with endothelial function, independent of any effect on plasma glucose levels. These studies may lead to new therapies, based on natriuretic peptide and/or antioxidant approaches, for ameliorating the vascular complications of diabetes.
 ...
PMID:Atrial natriuretic peptide prevents diabetes-induced endothelial dysfunction. 1830 65

It is well established that gluten-free diet reduces the incidence of type 1 diabetes mellitus (T1D) in non-obese diabetic (NOD) mice, though the mechanism is not known. However, regulatory T cells (Treg) are likely to play an important role. Also, it is known that dietary gluten induces an intestinal increase in the bacterium Lactococcus garvieae, but the importance of this phenomenon for T1D development is doubtful. Our hypothesis is that gluten is responsible for mediating its effect on T1D through the influence on Treg development independent of gluten-induced Lactococci. Four groups of female NOD and BALB/c mice of 3 week old were fed either a gluten-free diet or a standard diet. Lactococcus garvieae or saline water was administered per oral to one of each dietary group. Spleen and Peyer's patches were sampled from BALB/c mice for flow cytometric monitoring of IL-10 and Treg. NOD mice were diagnosed diabetic with blood glucose level >12 mmol/l. Dietary gluten significantly decreased the occurrence of Tregs by 10-15% (P < 0.05) in mice compared with those fed a standard diet. These results and the diabetes incidence were independent of the gluten-induced bacterial factor Lactococci. The prevalence of Treg was 5- to 10-fold more abundant in the Peyer's patches than in the spleen (P < 0.001). In conclusion, dietary gluten has a significant negative quantitative impact on the generation of Treg in mice, independent of gluten-induced Lactococcus garvieae, and Treg are far more abundant in Peyer's patches than in the spleen.
 ...
PMID:Dietary gluten reduces the number of intestinal regulatory T cells in mice. 1847 78

Whether the functional structure of ecological communities is deterministic or historically contingent is still quite controversial. However, recent experimental tests did not find effects of species composition variation on trait convergence and therefore the environmental constraints should play the major role on community convergence into functional groups. Seasonal cerrados are characterized by a sharp seasonality, in which the water shortage defines the community functioning. Hyperseasonal cerrados experience additionally waterlogging in the rainy season. Here, we asked whether waterlogging modifies species convergences into life-forms in a hyperseasonal cerrado. We studied a hyperseasonal cerrado, comparing it with a nearby seasonal cerrado, never waterlogged, in Emas National Park, central Brazil. In each area, we sampled all vascular plants by placing 40 plots of 1 m(2) plots in four surveys. We analyzed the species convergences into life-forms in both cerrados using the Raunkiaer's life-form spectrum and the index of divergence from species to life-form diversity (IDD). The overall life-form spectra and IDDs were not different, indicating that waterlogging did not affect the composition of functional groups in the hyperseasonal cerrado. However, there was a seasonal variation in IDD values only in the hyperseasonal cerrado. As long as we did not find a seasonal variation in life-form diversity, the seasonal variation of convergence into life-forms in the hyperseasonal cerrado was a consequence of the seasonal variation of species diversity. Because of high functional redundancy of cerrado plants, waterlogging promoted a floristic replacement without major changes in functional groups. Thus, waterlogging in the hyperseasonal cerrado promoted seasonal changes in species convergence into life-forms by reducing species diversity.
 ...
PMID:Species convergence into life-forms in a hyperseasonal cerrado in central Brazil. 1866 Sep 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>