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

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor that plays an important role in regulation of gene expression in pancreatic beta-cells and in the liver. Heterozygous mutations in the HNF-4alpha gene are responsible for maturity-onset diabetes of the young 1 (MODY1), which is characterized by pancreatic beta-cell-deficient insulin secretion. HNF-4alpha is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-4alpha mutations. In this study, we have identified HNF-4alpha target genes that are mainly expressed in the liver, including alpha1-antitrypsin, alpha1-antichymotrypsin, alpha-fetal protein, ceruloplasmin, IGF binding protein 1, transferrin, apolipoprotein(AI) [apo(AI)], apo(AII), apo(B), and apo(CIII). Serum levels of these proteins and Lp(a) and triglycerides were measured in 24 members of the HNF-4alpha/MODY1 RW pedigree (Q268X mutation), including 12 diabetic patients with HNF-4alpha mutations (D-HNF4+/-), 6 nondiabetic subjects with HNF-4alpha mutations (N-HNF4+/-), 6 normal relatives (N-HNF4+/+), 6 unrelated normal matched control subjects (N-HNF4+/+), and 12 matched diabetic (non-MODY1-5) patients (D-HNF4+/+). Serum levels of apo(AII), apo(CIII), lipoprotein(a) [Lp(a)], and triglyceride were significantly reduced in HNF4+/- subjects (26.9, 19.8, 12.1, and 72.1 mg/dl, respectively) compared with HNF4+/+ subjects (37.4, 26.5, 45.2, and 124.2 mg/dl, respectively) (P = 0.00001, P = 0.01, P = 0.00006, and P = 0.000003, respectively). This reduction was not found when apo(AII), apo(CIII), Lp(a), and triglyceride levels were compared in D-HNF4+/- versus N-HNF4+/- or in D-HNF4+/+ versus N-HNF4+/+ subjects, which indicates that HNF-4alpha haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum protein and triglyceride concentrations. Furthermore, we determined that genetic or environmental modifiers other than HNF-4alpha do not appear to contribute to the observed decrease of HNF-4alpha-regulated serum proteins. This study demonstrates that a heterozygous HNF-4alpha mutation leads to an HNF-4alpha-dependent hepatocyte secretory defect of liver-specific proteins.
Diabetes 2000 May
PMID:Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. 1090 94

End-stage renal failure (ESRF) is associated with a higher risk of cardiovascular disease (CVD) than predicted by the major risk factors. We investigate the hypothesis that metalloproteins such as transferrin and ceruloplasmin and the inflammatory response are associated with CVD risk in this population. In this cross-sectional study of 81 subjects stable on haemodialysis (HD), 43 with CVD and/or peripheral vascular disease (PAD) were compared to 38 subjects without clinical evidence of CVD/PAD. Serum concentrations of metalloproteins and acute phase reactants were compared by univariate analysis and logistic regression modelling. Body mass index, gender ratios, prevalence of diabetes, iron status, and homocysteine concentrations did not differ significantly between the groups. Those with CVD were older (P< 0.001) and had been on dialysis for longer (P = 0.004). CVD subjects had significantly higher concentrations of ceruloplasmin (325 vs 284 mg/L, P = 0.011), copper (18.2 vs 15.7 micromol/L, P = 0.002), and C-reactive protein (CRP) (median 9.0 vs 3.8 mg/L, P = 0.002). Transferrin iron binding capacity tended to be higher in the CVD group (P = 0.088). CVD risk for subjects with serum concentrations in the upper tertile was increased 9.4-fold (CI 2.8-31.0) for copper, 4.2-fold (CI 1.5-12.2) for ceruloplasmin, 3.9-fold (CI 1.3-12.1) for transferrin iron binding capacity, and 2.3-fold (CI 0.9-6.1) for CRP. In multivariate logistic regression models, age (P = 0.001) and time on dialysis (P = 0.002) were the strongest risk factors for CVD. After adjustment for age and time on dialysis, transferrin iron binding capacity (P = 0.013) and copper (P = 0.019) continued to be associated with CVD risk but ceruloplasmin (P = 0.065) and CRP (P = 0.634) were not. Total cholesterol was associated with a lower risk of CVD (ie protective), presumably due to cholesterol-lowering therapy in high-risk patients. In conclusion, copper and transferrin iron binding capacity may be associated with CVD risk in HD subjects.
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PMID:Are metalloproteins and acute phase reactants associated with cardiovascular disease in end-stage renal failure? 1094 71

Changes of serum ceruloplasmin (Cp) levels have been reported in many conditions including diabetes mellitus (DM), in which the serum Cp levels were increased. In this study, we have examined the influence of aging on serum Cp levels in normal individuals and in individuals with DM. Serum Cp levels were measured in 85 outpatients with type 2 diabetes (type 2 DM group) as well as in 71 healthy individuals (control group). All patients recruited for this study were negative for the glutamic acid decarboxylase (GAD) antibody. The subjects were sub-grouped based on their ages (<55 and 55 < or =). The serum Cp levels in the control group increased significantly with aging (r=0.325, p<0.0055), while levels in the type 2 DM group did not (r=0.091, p=0.4079). The levels in the type 2 DM group (<55) were significantly higher than those in the control group (<55) (p = 0.0029), while the Cp levels in the type 2 DM group (55 < or =) were not different from those in the control group (55 < or =) (p=0.4187). An age-related increase of serum Cp levels was observed in normal individuals, but this change was not observed in type 2 DM patients since serum Cp levels in type 2 DM patients of all ages were similar to the levels in normal elderly individuals.
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PMID:Increase in serum ceruloplasmin with aging is not observed in type 2 diabetes. 1103 63

We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux.
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PMID:Hepatic iron overload in aceruloplasminaemia. 1107 87

To examine the influence of oxidative stress on oxidative protein damage, we studied 51 young Type 1 diabetic patients clinically free of complications and 48 healthy normolipidaemic age-matched controls. We determined: (1) plasma carbonyl (PCO), plasma total thiol (T-SH), and nitrotyrosine (NT) levels as markers of oxidative protein damage; (2) plasma lipid hydroperoxide (LHP), and nitric oxide (NO) levels as markers of oxidative stress; (3) plasma total antioxidant capacity (TAO), ceruloplasmin (Cp), transferrin (TRF), unsaturated iron binding capacity (UIBC), erythrocyte glutathione (GSH), and erythrocyte superoxide dismutase (SOD) as markers of free radical scavengers. There were no significant differences in the levels of these markers between prepubertal diabetic patients and the controls. The levels of both of PCO and LHP were increased in adolescent and young adult Type 1 diabetic patients with respect to their controls. In the adolescent group, patient versus control values for PCO were 1.04+/-0.067 versus 0.67+/-0.0274 nmol/mg and for LHP they were 2. 10+/-1.09 versus 1.00+/-0.4 nmol/mg. In the young adult group, patient versus control values for PCO were 0.99+/-0.054 versus 0. 66+/-0.02 nmol/mg and for LHP they were 1.96+/-0.78 versus 1.15+/-0. 4 nmol/mg. TAO levels were significantly decreased in adolescent diabetic patients compared to their controls (0.92+/-0.27 vs. 1. 86+/-0.37) and in young adult diabetic patients compared to their controls (0.80+/-0.27 vs. 2.11+/-0.54 nmol/mg). T-SH was not different between diabetic patients and the controls. Serum NT, NO, and erythrocyte SOD levels were not different either between three groups of diabetic patients or between the patients and their controls. We attribute this lack of difference to limited disease duration. Changes in markers of oxidative stress other than NT, NO, and SOD observed in adolescent and young adult early stage Type 1 diabetic patients contribute to the imbalance in the redox status of the plasma. We attribute this imbalance to metal-catalyzed protein oxidation in both groups of Type 1 diabetic patients clinically free from complications.
Diabetes Res Clin Pract 2000 Dec
PMID:Oxidative protein damage in early stage Type 1 diabetic patients. 1110 36

Type 2 diabetes is characterized by increased acute phase serum proteins. We wanted to study how these proteins are related to complement activation in type 2 diabetes and how improvement of glycemic control affects them or complement activation. A total of 29 type 2 diabetic patients (age, 55.2 +/- 1.8 years, glycosylated hemoglobin [HbA(1c)] 8.9% +/- 0.2%, body mass index [BMI] 30.9 +/- 0.8 kg/m(2), duration 5.9 +/- 1.3 years) participated in the study. They were previously treated either with diet alone or in combination with 1 oral antihyperglycemic medication. After a period of at least 4 weeks run-in on diet only, the patients were randomized to pioglitazone, glibenclamide, or placebo. Blood samples were taken before the treatments and at the end of the 6-month therapy. Basal C-reactive protein (CRP) level was related to acylation-stimulating protein (ASP) concentration (r =.55, P <.01), and many acute phase serum protein concentrations were associated with each other. The treatment reduced HbA(1c) level in the pioglitazone (from 9.1 +/- 0.3% to 8.0 +/- 0.5%, P <.05) and glibenclamide (from 8.9 % +/- 0.3% to 7.7% +/- 0.2%, P <.05) groups. Glibenclamide treatment was associated with a reduction in alpha-1-antitrypsin (P <.05), ceruloplasmin (P <.01), and complement C3 protein (C3) (P <.05). Although ASP did not change significantly in any of the treatment subgroups, in the whole patient population, the change in HbA(1c) during the treatments correlated positively with the change in ASP, (r =.43, P <.05). The changes in many acute phase serum proteins and ASP were related to each other. In conclusion, (1) inflammatory factors and complement activation are associated in patients with type 2 diabetes, and (2) changes in hyperglycemia are related to changes in the concentration of the complement activation product, ASP.
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PMID:Concentration of the complement activation product, acylation-stimulating protein, is related to C-reactive protein in patients with type 2 diabetes. 1123 Jul 79

Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains greater than 95% of the copper present in human plasma. It is synthesized mainly in the liver. Aceruloplasminemia is an autosomal recessive disorder affecting iron metabolism, originally called familial apoceruloplasmin deficiency, which manifests late-onset blepharospasm and retinal degeneration. Subsequent investigations have found patients with late adult onset of ataxia and diabetes mellitus. Our patients have also shown diabetes. Clinically, aceruloplasminemia is a triad consisting of neurologic disease, retinal degeneration, and diabetes. This disease is characterized by mutations in the ceruloplasmin gene and iron accumulation in the retina and basal ganglia as well as in parenchymal tissues caused by a complete deficiency of ceruloplasmin ferroxidase activity. The neurological symptoms in affected patients include involuntary movements, ataxia, and dementia reflecting the sites of iron deposition detected by MRI as well as the regions of neurodegeneration observed at autopsy. Consistent with this observation, ceruloplasmin gene expression is detected in the retina and basal ganglia revealing that this protein is essential for iron homeostasis neuron survival in the central nervous system. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders.
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PMID:[Aceruloplasminemia]. 1146 82

The metabolism of apolipoprotein (apo) A-IV in diabetes mellitus (DM) is poorly understood. Several factors, such as dietary fat intake, fat malabsorption, acute inflammation, and hormonal dysregulation can disturb the plasma apo A-IV concentration. We have compared the plasma apo A-IV concentrations in patients with type 1 DM and DM secondary to chronic pancreatitis to determine the effects of combinations of these factors. We examined 4 groups of male patients with chronic pancreatitis without diabetes (ND-CP) (n = 12), diabetes secondary to chronic pancreatitis and insulin-treated (CP-DM) (n = 32), type 1 diabetes (n = 25), and controls (n = 20). Plasma apo A-IV was significantly lower in the chronic pancreatitis patients (ND-CP and CP-DM) than in the other patients. Inflammatory proteins (fibrinogen, ceruloplasmin, and haptoglobin) were significantly elevated in the 2 chronic pancreatitis groups. The apo A-IV concentration was positively correlated with hemoglobin A(1c) (HbA(1c)) percentage in each group of diabetic patients (CP-DM, r =.35; P =.046; type 1 DM, r =.53; P =.010), in both groups of diabetic patients (r =.472; P <.0001) and negatively correlated with ceruloplasmin concentration in each group of diabetic patients (CP-DM, r = -.48; P =.0052; type 1 DM, r = -.66; P =.003), in both groups of diabetic patients (r = -.561; P <.0001), and in the whole population (r = -.463; P <.0001). Apo A-IV was also negatively correlated with haptoglobin in type 1 DM patients (r = -.434; P =.0435), in the both groups of diabetic patients (r = -.349; P =.0154), and in the whole population (r = -.351; P =.0019). Multiple linear regression analysis revealed that only HbA(1c) and ceruloplasmin were independent explanatory variables. Plasma apo A-IV is positively correlated with HbA(1c) suggesting that hyperglycemia per se selectively affects apo A-IV metabolism. The correlation between the concentrations of inflammatory protein and apo A-IV suggest a link between chronic inflammation and apo A-IV synthesis or catabolism. As apo A-IV is involved in reverse cholesterol transport, its low level in CP-DM may contribute to the accelerated development of atherosclerosis in these patients.
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PMID:Effect of the inflammation, chronic hyperglycemia, or malabsorption on the apolipoprotein A-IV concentration in type 1 diabetes mellitus and in diabetes secondary to chronic pancreatitis. 1155 32

Insulin resistance syndrome (IRS) is a cluster of prevalent conditions including glucose intolerance, hypertension and dyslipidemia, which commonly predispose to cardiovascular disease. However, the mechanism by which IRS is related with cardiovascular disease is not yet settled. Recently, it has been hypothesized that atherosclerosis is an inflammatory disease and that an increase in oxidative stress plays a key role in causing endothelial dysfunction associated with atherosclerosis. There has been, however, no study directly relating IRS with oxidative stress in human subjects. We measured various markers of oxidative stress among subjects who participated in a population-based epidemiological study performed in 1996. IRS was defined as non-diabetic subjects having more than two of three salient features of the syndrome (glucose intolerance, hypertriglyceridemia/low high density lipoprotein (HDL)-cholesterol and hypertension). The subjects with IRS (n=70) showed higher plasma malondialdehyde (MDA; 2.10+/-1.43 vs. 1.63+/-1.21 micromol/ml, P=0.009), homocysteine (16.32+/-8.34 vs. 13.06+/-6.49 micromol/l, P=0.002) and ceruloplasmin concentrations (29.80+/-5.28 vs. 27.39+/-5.10 mg/dl, P=0.002) than control subjects (n=196). Plasma MDA concentration was positively correlated with waist-to-hip ratio (r=0.124, P=0.044), and with plasma triglyceride (TG; r=0.163, P=0.008), ferritin (r=0.200, P=0.002) and homocysteine concentrations (r=0.136, P=0.032). These results suggest that increase in oxidative stress may contribute to the development of cardiovascular disease in IRS.
Diabetes Res Clin Pract 2001 Dec
PMID:Oxidative stress markers in Korean subjects with insulin resistance syndrome. 1173 6

This study was carried out to investigate whether Nigella sativa could decrease the lipid peroxidation, increase the anti-oxidant defence system and also prevent the lipid-peroxidation-induced liver damage in experimentally induced diabetic rabbits. Fifteen New Zealand male rabbits were divided into three experimental groups: control, diabetic and diabetic and N. sativa-treated. The diabetes mellitus (DMI) was induced in the rabbits using 150 mg/kg of 10% alloxan. The diabetic + N. sativa-treated group was given extract of N. sativa seeds orally every day for 2 months after induction of DM. At the end of the 2-month experiment, blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), ceruloplasmin and glucose concentration, and livers were harvested for histopathological analysis. Treatment with N. sativa decreased the elevated glucose and MDA concentrations, increased the lowered GSH and ceruloplasmin concentrations, and prevented lipid-peroxidation-induced liver damage in diabetic rabbits. It was concluded that N. sativa might be used in diabetic patients to prevent lipid peroxidation, increase anti-oxidant defence system activity and also prevent liver damage.
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PMID:Effect of Nigella sativa on glucose concentration, lipid peroxidation, anti-oxidant defence system and liver damage in experimentally-induced diabetic rabbits. 1184 52


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