Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To metabolically characterize patients with slowly progressing autoimmune diabetes (LADA) of short duration we measured insulin, C peptide, and glucagon responses to glucose and arginine at three blood glucose levels (fasting and 14 and 28 mmol/L) in 11 patients with LADA, 11 patients with type 2 diabetes, and 14 healthy control subjects matched for age and body mass index. The acute insulin response to arginine was impaired in LADA vs. type 2 diabetes at all glucose levels, with the greatest impairment in the maximally stimulated insulin concentrations (P<0.04). In contrast, beta-cell sensitivity to glucose was unaltered in LADA and type 2 diabetes. The glucagon concentrations were elevated in both LADA and type 2 diabetic patients compared with healthy control subjects (P<0.02), but did not differ between the diabetic groups. In conclusion, patients with LADA share insulin resistance with type 2 diabetic patients, but display a more severe defect in maximally stimulated beta-cell capacity than patients with type 2 diabetes.
 ...
PMID:Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). 1063 67

A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and N(G)-monomethyl-L-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as mean+/-SE MCR (mL/kg per minute) were 7.22+/-0. 99 (C), 6.32+/-0.78 (H), and 5.06+/-0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1+/-5.6% (C), 17. 2+/-5.5% (H), and 12.3+/-6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9+/-5.1% (C), 37.5+/-2.3% (H), and 33.6+/-2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (r=0. 46, P<0.05), MCR and LNV (r=0.44, P<0.05), and IGMV and LNV (r=0.52, P<0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans.
 ...
PMID:Insulin action is associated with endothelial function in hypertension and type 2 diabetes. 1064 50

Several studies have shown that the activities of delta-6-desaturase and delta-5-desaturase are depressed in experimental diabetes and in humans with insulin- and non-insulin-dependent diabetes mellitus (type I and type II diabetes mellitus respectively). Furthermore, treatment with insulin is known to correct the defects in desaturases in rats and humans with diabetes, especially in type I. In a recent study, we demonstrated that L-arginine and nitric oxide can prevent alloxan-induced beta cell damage, and the severity of diabetes, and restore the antioxidant status to near normal levels. But, no information is available as to the relationship between L-arginine-nitric oxide system and the metabolism of essential fatty acids in diabetes mellitus. In the present study, it was noted that the plasma levels of saturated fatty acids: stearic and palmitic were increased where as unsaturated fatty acids such as oleic, linoleic, gamma-linolenic and eicosapentaenoic acids (OA, LA, GLA and EPA respectively) were decreased in alloxan-induced diabetic rats. In the liver phospholipid (PL) fraction, GLA, DGLA (dihomo-GLA) and alpha-linolenic acid (ALA) were decreased in the alloxan-treated group; in the muscle PL fraction, LA, GLA and DGLA were low, whereas an increase in the saturated fatty acid content was noted. L-arginine (the precursor of nitric oxide) and sodium nitroprusside (a nitric oxide donor) treatment of alloxan-induced diabetic rats enhanced the levels of LA, GLA and DGLA. Further, nitric oxide synthase inhibitor, L-NMMA, prevented this beneficial action of L-arginine-nitric oxide system on essential fatty acid metabolism. The abnormalities in the essential fatty acid metabolism observed also reverted to normalcy following control of diabetes with insulin. These results indicate that nitric oxide can enhance the activities of delta-6- and delta-5 desaturases, which are depressed in diabetes, and suggests that there is a close interaction between L-arginine-nitric oxide system and the metabolism of essential fatty acids.
 ...
PMID:Effect of L-arginine-nitric oxide system on the metabolism of essential fatty acids in chemical-induced diabetes mellitus. 1076 77

Insulin resistance appears to be a common feature and a possible contributing factor to several frequent health problems, including type 2 diabetes mellitus, polycystic ovary disease, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, certain hormone-sensitive cancers, and obesity. Modifiable factors thought to contribute to insulin resistance include diet, exercise, smoking, and stress. Lifestyle intervention to address these factors appears to be a critical component of any therapeutic approach. The role of nutritional and botanical substances in the management of insulin resistance requires further elaboration; however, available information suggests some substances are capable of positively influencing insulin resistance. Minerals such as magnesium, calcium, potassium, zinc, chromium, and vanadium appear to have associations with insulin resistance or its management. Amino acids, including L-carnitine, taurine, and L-arginine, might also play a role in the reversal of insulin resistance. Other nutrients, including glutathione, coenzyme Q10, and lipoic acid, also appear to have therapeutic potential. Research on herbal medicines for the treatment of insulin resistance is limited; however, silymarin produced positive results in diabetic patients with alcoholic cirrhosis, and Inula racemosa potentiated insulin sensitivity in an animal model.
 ...
PMID:Insulin resistance: lifestyle and nutritional interventions. 1076 68

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.
 ...
PMID:Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels. 1085 63

Subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha gene (RW pedigree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory responses to arginine. To determine if pancreatic polypeptide (PP) secretion is likewise involved, we studied PP responses to insulin-induced hypoglycemia in 17 RW pedigree members: 6 nondiabetic mutation-negative [ND(-)], 4 nondiabetic mutation-positive [ND(+)], and 7 diabetic mutation-positive [D(+)]. Subjects received 0.08 U/kg body wt human regular insulin as an intravenous bolus to produce moderate self-limited hypoglycemia. PP areas under the curve (PP-AUCs) were compared among groups. With hypoglycemia, the PP-AUC was lower in the D(+) group (14,907 +/- 6,444 pg/ml, P = 0.03) and the ND(+) group (14,622 +/- 6,015 pg/ml, P = 0.04) compared with the ND(-) group (21,120 +/- 4,158 pg/ml). In addition, to determine if the beta-cell secretory defect in response to arginine involves amylin in addition to insulin secretion, we analyzed samples from 17 previously studied RW pedigree subjects. We compared the AUCs during arginine infusions for the 3 groups both at euglycemia and hyperglycemia as well as their C-peptide-to-amylin ratios. The D(+) and ND(+) groups had decreased amylin AUCs during both arginine infusions compared with the ND(-) group, but had similar C-peptide-to-amylin ratios. These results suggest that the HNF-4alpha mutation in the RW/MODY1 pedigree confers a generalized defect in islet cell function involving PP cells in addition to beta- and alpha-cells, and beta-cell impairment involving proportional deficits in insulin and amylin secretion.
 ...
PMID:Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4alpha/MODY1 gene. 1086 48

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.
 ...
PMID:The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus. 1098 54

Type 2 diabetes mellitus (type 2 DM) is a polygenic disorder with a variable phenotype that includes both insulin resistance and insulin secretory dysfunction. The Arg 64 beta-3-adrenergic receptor variant allele is associated with an earlier age of onset of type 2 DM. The purpose of this study was to examine the in vivo pathophysiology of this variant allele to determine its contribution to the components of glucose metabolism. We used the frequently sampled iv glucose tolerance tests, minimal model analysis, and analysis of covariance to examine age- and fat-mass-adjusted differences among genotypes. The results demonstrate that individuals homozygous for the Arg 64 allele secrete significantly less insulin in response to a glucose infusion (562+/-116 vs. 962+/-94 pmol/microL), have the highest fasting glucose levels (100.4+/-1.9 vs. 92.48+/-1.60 mg/dL), and have lower glucose effectiveness (0.014+/-0.003 vs. 0.019+/-0.002 min(-1)), compared with those homozygous for the Trp 64 allele. This first report of decreased acute insulin release and lower glucose effectiveness in the Arg 64 genotype may help explain the earlier onset of type 2 DM observed in several populations of individuals with the Arg64 beta-3-adrenergic receptor variant allele.
 ...
PMID:Insulin response to glucose is lower in individuals homozygous for the Arg 64 variant of the beta-3-adrenergic receptor. 1109 26

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT(1)) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3+/-0.5 versus 6.9+/-0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P<0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats (P<0.01) compared with control rats, whereas heart rates were not different. Heart weight- and kidney weight-to-body weight ratios were higher in GK rats (P<0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition (P<0.05), whereas the sodium nitroprusside-induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K(+) channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P<0.05). The serum level of 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT(1) receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT(1) receptor expression, medullary and cortical angiotensin type 2 (AT(2)) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT(1), AT(2), ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT(1) receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT(1) receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure-independent mechanisms.
 ...
PMID:Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. 1123 Mar 14

The objective of this study was to investigate possible defects in the insulin sensitivity and/or the acute insulin response in a group of Mexican patients displaying early-onset type 2 diabetes and to evaluate the contribution of mutations in three of the genes linked to maturity-onset diabetes of the young. We studied 40 Mexican patients with an age of diagnosis between 20 and 40 yr in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to maturity-onset diabetes of the young was carried out by PCR-single strand conformation polymorphism analysis. A low insulin secretory capacity (AIRg = 68.5 +/- 5 muU/mL.min) and a near-normal insulin sensitivity (3.43 +/- 0.2 min/muU.mL x 10(4)) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1alpha (HNF-4alpha) gene (Asp(126)-->His/Tyr and Arg(154)-->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1alpha gene (Gln(486)-->stop codon); 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 yr of age. Mutations in either the HNF-1alpha or the HNF-4alpha genes are present among the individuals who develop early-onset diabetes in our population. These particular sequence changes have not been previously reported and therefore represent putative new mutations. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile.
 ...
PMID:Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population. 1123 4


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