Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of hypertension accompanying diabetes mellitus (DM) may involve abnormalities in at least two major blood pressure (BP)--regulating systems. Exchangeable sodium (Naex) and the cardiovascular pressor responsiveness to norepinephrine are often increased, while blood volume is normal or low, regardless of age, insulin-dependence or non-dependence, or the presence or absence of retinopathy or clinical nephropathy. In hypertensive DM, systolic BP correlated (P less than 0.001) with Naex; diuretic treatment improved norepinephrine responsiveness, Naex and BP, while calcium entry blockade improved cardiovascular responsiveness and BP without changing Naex. Plasma catecholamine, renin and aldosterone levels are usually normal or sometimes low in stable DM. Antihypertensive therapy in DM is based on 3 legs, namely antidiabetic treatment, general measured aimed at reducing BP and associated risk correlates, and if necessary BP-lowering drugs. Due to their metabolic side effects, thiazide-diuretics given in moderate to high doses are not ideal step 1 drugs in DM. Certain beta 1-blockers have fewer, although still some, unwanted side effects. Preliminary data suggest that certain calcium antagonists may often lower BP without causing relevant metabolic impairment. These agents and converting enzyme inhibitors deserve further evaluation in the treatment of DM-associated hypertension.
 ...
PMID:Pathogenesis and treatment of hypertension associated with diabetes. 386 82

The use of beta-blockers in diabetes mellitus has largely been restricted because of the reported adverse effects. Clinical investigations aimed at elucidating the possible reactions associated with the use of beta-blockers have disclosed no evidence of masking or signs or insulin-induced hypoglycaemia or potentiation of the insulin effect. Prolonged hypoglycaemia may develop, however, as a result of physical effort. There is no proof that during insulin-induced hypoglycaemia the concentrations of counter-regulatory hormones are depressed, but that of glycerol, a gluconeogenic precursor, is slightly diminished. Intensification of the hypertensive reaction during hypoglycaemia is less likely to occur during treatment with beta-selective blockers. In insulin-dependent diabetics receiving beta 1-blockers there is no evidence of any change - either deterioration or improvement - in metabolic control. In one small controlled trial there was no sign of impairment of the peripheral arterial circulation over a short period of administration of a non-selective beta-blocker. In general, for patients suffering from insulin-dependent diabetes, cardioselective agents are preferable. Since cardioselectivity is a dose-dependent property, reasonable caution should also be observed when using this type of drug in diabetes.
 ...
PMID:beta-adrenergic blockade and diabetes mellitus. A review. 613 37

In order to assess the adrenergic contribution to hypoglycemic glucose counterregulation in type I diabetes mellitus and to determine whether the adrenergic contribution is mediated through beta 1- or beta 2-adrenergic receptors, hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 x min) for 60 min in 11 insulin-dependent diabetic patients (IDDM), 5 with normal plasma glucagon responses and 6 with blunted responses, and also in 7 age-weight-matched nondiabetic subjects. Rates of plasma glucose decrease and postnadir increase, as well as plasma concentrations of free insulin and of counterregulatory hormones, were measured when insulin was infused alone, and when insulin was infused along with propranolol (a beta 1- and beta 2-adrenergic receptor antagonist) or metoprolol (a selective beta 1-antagonist). Postnadir plasma glucose recovery was decreased in IDDM with blunted plasma glucagon responses (21 +/- 0.8 mumol x L-1 x min-1, P less than 0.001), but was normal in patients with normal plasma glucagon responses (30 +/- 0.4 versus 33 +/- 0.5 mumol x L-1 x min-1 in nondiabetic subjects, P = NS). Postnadir plasma glucose recovery was not affected by either propranolol or metoprolol in normal subjects and in IDDM with normal glucagon responses. However, in IDDM with blunted plasma glucagon responses, postnadir plasma glucose recovery was further decreased by propranolol (14 +/- 0.6 mumol x L-1 x min-1, P less than 0.01), but was unaffected by metoprolol (22 +/- 0.9 mumol x L-1 x min-1, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1983 Oct
PMID:The adrenergic contribution to glucose counterregulation in type I diabetes mellitus. Dependency on A-cell function and mediation through beta 2-adrenergic receptors. 631 52

To the extent that they have deficient glucagon secretory responses to plasma glucose decrements, as they commonly do, patients with insulin-dependent diabetes mellitus (IDDM) are dependent on epinephrine-mediated beta-adrenergic mechanisms to promote recovery from hypoglycemia. Thus, they are at increased risk for prolonged hypoglycemia if treated with a nonselective beta-adrenergic antagonist such as propranolol. If the hyperglycemic actions of epinephrine are mediated through beta 2-adrenergic mechanisms, therapeutic efficacy (e.g., for hypertension or ischemic heart disease) could be accomplished without increased risk of hypoglycemia by selective beta 1-adrenergic blockade in such patients. However, oral administration of the relatively selective beta 1-adrenergic antagonist metoprolol (100 mg) and of the nonselective beta-adrenergic antagonist propranolol (80 mg) both impaired recovery from insulin-induced hypoglycemia in patients with IDDM. Thus, at a dose of 100 mg, oral metoprolol is not safer than oral propranolol with respect to recovery from hypoglycemia in patients with IDDM.
Diabetes Care
PMID:Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus. 637 17

Three forms of disulfide-linked insulin receptor complexes are labeled by covalent cross-linking to receptor-bound 125I-insulin in native adipocyte or liver membranes. These receptors of Mr 350,000 Mr 320,000, and Mr 290,000 are composed of alpha (Mr 125,000), beta(Mr 90,000), and beta 1(Mr 49,000) subunits in stoichiometries of (alpha beta)2, (alpha beta)(alpha beta 1), and alpha beta 1)2, respectively. In adipocyte membranes, these receptor structures can undergo a first step of reduction by dithiothreitol, dissociating into Mr 210,000 (alpha beta) and Mr 160,000 (alpha beta 1) partially reduced receptor fragments. Complete dissociation of such fragments into the free alpha, beta, and beta 1 receptor subunits is achieved at high reductant concentrations. In liver plasma membranes the partially reduced receptor species of Mr 210,000 and Mr 160,000 are observed even when electrophoresis is performed under nonreducing conditions. This observation indicates that native liver plasma membranes contain multiple redox states of the high affinity insulin receptor.
Diabetes 1980 Nov
PMID:Multiple redox forms of the insulin receptor in native liver membranes. 742 30

Inappropriate vascular smooth-muscle cell (VSMC) growth is the hallmark of vascular pathology in essential hypertension and diabetic macroangiopathy, whereas platelets constitute an important regulator of vessel wall homeostasis because of their content of various growth factors. Numerous abnormalities exist in platelet functions in diabetes and hypertension, such as enhanced activity and altered adhesion and aggregation. Increased thromboxane (TX2) production is characteristic of diabetes, and an elevation of intracellular free Ca2+ is found in platelets of hypertensive patients. By studying the growth patterns of VSMC from spontaneously hypertensive rats (SHRs) vs. those obtained from their normotensive counterparts, Wistar-Kyoto (WKY) rats, we have demonstrated that VSMC from SHRs exhibited a higher specific growth rate, abnormal contact inhibition, and accelerated entry into the S phase of the cell cycle. Moreover, they were hyperresponsive to many growth factors such as calf serum, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta 1 (TGF beta 1), and insulin. Additive effects were observed for EGF and PDGF or EGF and insulin. These intrinsic growth anomalies in cells of hypertensive origin persist in culture indicating their putative primary role in the pathogenesis of hypertension. Endogenous TGF beta 1 revealed an augmented expression of its message levels in SHR VSMC, the difference in mRNA between both strains being more pronounced at high cell density. Further, TGF beta 1 protein synthesis and secretion in VSMC culture were confirmed by immunoprecipitation of de novo labeled TGF beta 1. At high cell density, which most likely represents the physiological state of VSMC, plasmin, an activator of TGF beta 1, significantly stimulated DNA synthesis of VSMC in both strains. The reverse effect was obtained at low cell density. Yet, the fold stimulation was higher in WKY rats, suggesting that TGF beta 1 may be partially activated in SHR VSMC. This is supported by the inhibition of baseline DNA synthesis by TGF beta 1 neutralizing antibody in VSMC of hypertensive origin and not of normotensive controls. TGF beta 1 antisense oligodeoxynucleotide (ODN) nearly normalized the increased proliferation of SHR VSMC in culture. On the other hand, growth-promoting activity (GPA) in platelets of either diabetic or hypertensive patients was higher than in platelets of healthy controls and was found to be normalized by intensive insulin therapy in insulin-dependent diabetic patients. In hypertensive patients, however, hydrochlorothiazide (HCTZ)--even in low doses (25 mg/day)--enhanced the GPA in platelets, whereas other antihypertensive agents such as indapamide, atenolol, and captopril, had neutral effects.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Platelets, growth factors, and vascular smooth-muscle cells in hypertension and diabetes. 750 64

Evidence suggests a physiological role of the GABAA receptor in the pancreas. Clinically, an autoimmune reaction involving the GABA biosynthesizing enzyme, glutamic acid decarboxylase has been implicated in the development of insulin-dependent diabetes mellitus. To determine the subtypes of GABAA receptor expressed in human pancreas, we analyzed, with the use of the reverse-transcription/polymerase chain reaction technique human pancreatic tissue for the presence of GABAA receptor subunits alpha 1-6, beta 1-3, and gamma 1-2 transcripts. Unlike brain tissue, pancreatic tissue only expresses the alpha 2, beta 3 and gamma 1 subunits. Our results provide evidence of a specific GABAA receptor subtype expressed in human pancreatic tissue.
 ...
PMID:Identification of the GABAA receptor subtype mRNA in human pancreatic tissue. 751 97

The interaction of vascular cell adhesion molecule-1 and very late antigen-4 (alpha 4 beta 1-integrin) has been recently known to be profoundly involved in the trafficking of lymphocytes from the circulation into the inflammatory tissues. To elucidate the role of these molecules in the development of autoimmune diabetes, the expression of these adhesion molecules on inflamed islets and the effects of administration of monoclonal antibodies to these molecules on insulitis and overt diabetes were evaluated in nonobese diabetic (NOD) mice. Immunohistochemical study revealed the overexpression of vascular cell adhesion molecule-1 on vascular endothelium near or within inflamed islets and alpha 4-integrin on islet-infiltrating mononuclear cells. Either anti-vascular cell adhesion molecule-1 or anti-alpha 4-integrin monoclonal antibody prevented the transfer of diabetes in irradiated NOD mice which received spleen cells from acutely diabetic NOD mice. When both monoclonal antibodies were administrated to NOD mice during 2-30 weeks of age, neither lymphocytic infiltration to islets nor overt diabetes was observed. Furthermore, administration of these antibodies even from 10 weeks of age could inhibit the development of insulitis and diabetes, whereas administration during 2-5 weeks of age could not. Splenocytes obtained from these treated mice showed no significant change of cytokine production and preserved the ability to transfer diabetes into NOD scid/scid mice. This suggests that treatment with antibodies against these adhesion molecules can inhibit insulitis and diabetes without affecting the Th1/Th2 balance or effector T cells. The blockade of vascular cell adhesion molecule-1/very late antigen-4 interaction would be suitable for therapeutical treatment of the predisposing and latent type I (insulin-dependent) diabetic subjects.
 ...
PMID:Administration of monoclonal antibodies against vascular cell adhesion molecule-1/very late antigen-4 abrogates predisposing autoimmune diabetes in NOD mice. 755 83

The insulin autoimmune syndrome (IAS), or Hirata's disease, is characterized by the combination of fasting hypoglycemia, high concentration of total serum immunoreactive insulin, and presence of autoantibodies to native human insulin in serum. Autoantibody production is classified as monoclonal or polyclonal, with the majority of IAS cases classified as polyclonal. Previously, we observed a striking association between the human leukocyte antigen (HLA) class II alleles DRB1*0406/DQA1* 0301/DQB1*0302 and Japanese IAS patients with polyclonal insulin autoantibodies (IAAs) and T-cell recognition of human insulin in the context of DRB1*0406 molecules. Because of such a strong HLA association in IAS, we performed intra- and interethnic studies on IAS-associated DRB1 alleles and searched for the critical amino acid residue(s) for IAS pathogenesis. Glutamate at position 74 in the HLA-DR4 beta 1-chain was presumed to be essential to the production of polyclonal IAA in IAS, whereas alanine at the same position of the HLA-DR beta 1-chain might be important in the production of monoclonal IAA.
Diabetes 1995 Oct
PMID:Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome. 755 62

Primary cardiac abnormalities have been frequently reported in patients with diabetes probably due to metabolic consequences of the disease. Approximately 2,000 mRNA species from the heart of streptozotocin-induced diabetic and control rats were compared by the mRNA differential display method, two of eight candidate clones thus isolated (DH1 and 13) were confirmed by Northern blot analysis. The expression of clone 13 was increased in the heart by 3.5-fold (P < 0.05) and decreased in the aorta by twofold (P < 0.05) in diabetes as compared to control. Sequence analysis showed that clone 13 is a rat mitochondrial gene. DH1 was predominantly expressed in the heart with an expression level 6.8-fold higher in the diabetic rats than in control (P < 0.001). Insulin treatment significantly (P < 0.001) normalized the expression of DH1 in the hearts of diabetic rats. DH1 expression was observed in cultured rat cardiomyocytes, but not in aortic smooth muscle cells or in cardiac derived fibroblasts. The expression in cardiomyocytes was regulated by insulin and glucose concentration of culture media. The full length cDNA of DH1 had a single open-reading frame with 85 and 92% amino acid identity to human and mouse UDP-GlcNAc:Gal beta 1-3GalNAc alpha R beta 1-6 N-acetylglucosaminyltransferase (core 2 GlcNAc-T), respectively, a key enzyme determining the structure of O-linked glycosylation. Transient transfection of DH1 cDNA into Cos7 cells conferred core 2 GlcNAc-T enzyme activity. In vivo, core 2 GlcNAc-T activity was increased by 82% (P < 0.05) in diabetic hearts vs controls, while the enzymes GlcNAc-TI and GlcNAc-TV responsible for N-linked glycosylation were unchanged. These results suggest that core 2 GlcNAc-T is specifically induced in the heart by diabetes or hyperglycemia. The induction of this enzyme may be responsible for the increase in the deposition of glycoconjugates and the abnormal functions found in the hearts of diabetic rats.
 ...
PMID:Identification and characterization of a gene regulating enzymatic glycosylation which is induced by diabetes and hyperglycemia specifically in rat cardiac tissue. 756 67


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