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At least 505 records · Page 28Linked to original sources
PubMed2003

Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians.

Circulating levels of the cytokine interleukin 6 (IL-6) are elevated in obesity, correlate with body mass index (BMI), and predict the development of type 2 diabetes mellitus (T2DM). A promoter polymorphism in the IL6 gene is associated with obesity, altered levels of insulin sensitivity, and T2DM. IL-6 exerts its effects by binding to the IL-6 receptor (IL-6R) and levels of IL-6R have been correlated with BMI. It is possible that IL6R variants may also be related to obesity, but to our knowledge, no study has yet examined this relationship. The objective of this study was to examine the relationship between genetic variants in the IL6R gene and obesity in Pima Indians, a population prone to excess adiposity. We sequenced 6kb of the IL6R gene, corresponding to all exons, exon-intron boundaries, and 2kb of promoter in 30 Pima Indians. We identified six single nucleotide polymorphisms (SNPs) in the IL6R gene: a predicted Asp --> Ala substitution at position 358, a variant in the 3'-untranslated region, and 4 intronic SNPs. All SNPs were in strong linkage disequilibrium (D' >/= 0.90) and varied in minor allele frequency from 0.33 to 0.48. Association between IL6R genotype and BMI (kg/m(2)) was assessed in approximately 700 nondiabetic, full-heritage Pima Indians. For each SNP, individuals carrying the variant allele had a higher mean BMI compared to those with the wild-type allele (range: [37.3+/-7.2-38.2+/-7.0] vs. [35.5+/-7.3-36.0+/-7.5]; P=0.02-0.004). Our findings suggest that genetic variants in the IL6R gene may play a role in susceptibility to obesity. Assessment of these SNPs in other populations will be useful to determine the magnitude of obesity risk.

Arizona↗
PubMed2004

Alpha-endosulfine, a positional and functional candidate gene for type 2 diabetes: molecular screening, association studies, and role in reduced insulin secretion.

Impaired glucose stimulated insulin secretion is a prominent, early defect in type 2 diabetes. Insulin secretion is coupled to glucose metabolism by effects of the intracellular ATP/ADP ratio on the multimeric beta-cell potassium channel. The sulfonylurea receptor (SUR1 or ABCC8), the regulatory subunit of that channel, binds sulfonylurea agents and thus closes the channel and stimulates exocytosis of insulin-containing granules. alpha-Endosulfine (ENSA), has been proposed as the endogenous ligand for SUR1. We mapped ENSA in silico to chromosome 1q21 near a confirmed type 2 diabetes susceptibility locus, and derived the genomic structure of four exons and three introns. We identified four single nucleotide polymorphisms (SNP) and one insertion deletion polymorphism among 16 Caucasian and 16 African-American diabetic individuals. Only one SNP was common to both ethnic groups, and no SNP altered the coding sequence. No variant was associated with type 2 diabetes in Caucasian or African-American studies, but a single SNP in intron 3 (SNP 17) was associated with a reduced disposition index (insulin sensitivity x acute insulin response to glucose) in interaction with family membership in 126 members of 26 Caucasian families. Individuals homozygous for the rare allele showed a 70% reduction in insulin secretion (disposition index) relative to all other genotypes. Our data do not suggest that ENSA could explain the linkage of T2DM to this region, but ENSA SNP 17 may have an important role in reducing the ability of the beta-cell to compensate for reduced insulin sensitivity, which in turn would increase the susceptibility to T2DM.

Case-Control Studies↗
PubMed2004

A common functional variant in the interleukin-6 gene is associated with increased body mass index in subjects with type 2 diabetes mellitus.

Circulating levels of interleukin-6 (IL-6) are raised in insulin resistant states such as obesity, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). Growing evidence suggests that IL-6 is not only produced by fat cells but is also capable of inducing insulin resistance in these cells. The expected result of this in vivo, would be to increase adipose mass and subsequently body mass index (BMI). The IL-6 -174G > C common functional gene variant has consistently been associated with increased plasma IL-6, insulin resistance, and increased cardiovascular risk. We looked at the association between genotype and BMI in 571 Caucasian subjects with T2DM. There was a significant linear association between genotype and BMI: Median (interquartile range) GG 28.8 kg/m2 (26.0-31.6) vs GC; 29.4 kg/m2 (26.3-32.5) vs CC; 30.4 kg/m2 (26.1-33.0), p=0.05. When the group was divided by the median BMI (29.1 kg/m2), 62% of -174CC subjects were in the higher group compared to 38% in the lower group (p=0.008). By contrast, in 2,652 non-diabetic Caucasian men with a median BMI of 26.1 kg/m2, there was no difference in genotype distribution (p=0.288). The frequency of the -174C allele was lower in type 2 diabetes compared to the non-diabetic men (-174C allele frequency: 0.35[0.33-0.38] vs 0.43[0.42-0.45], p <0.00001; -174CC homozygotes: 12.3 vs 18.3%, respectively). The -174C allele is associated with higher BMI in type 2 diabetes, but not amongst healthy subjects. The increased cardiovascular risk associated with the -174C allele may account for the lower frequency of this allele in those with type 2 diabetes.

Body Mass Index↗
PubMed2006

Association between plasma IL-6, the IL6 -174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus.

Elevated plasma interleukin-6 (IL-6) is associated with coronary heart disease (CHD), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). We and others have described an association between the human interleukin-6 -174G>C gene variant and body mass index (BMI). Within our previous sample of subjects with T2DM, we measured plasma IL-6 and grouped subjects by the WHO-defined metabolic syndrome, in order to study the association between the -174G>C gene variant, plasma IL-6 and the metabolic syndrome (and component parts). Genotype was obtained in 571 Caucasian subjects with plasma IL-6 measures. There was a significant association between genotype and plasma IL-6 (GG vs GC vs CC: 3.23+/-0.93 pg/ml vs 3.42+/-0.95 pg/ml vs 4.16+/-1.18 pg/ml, p=0.02; for GG/GC vs CC p=0.008). No interactions were observed between genotype and the individual components of the metabolic syndrome in determining plasma IL-6. Increased plasma IL-6 was also associated with the number of components (none vs 1 vs 2 vs > or =3: 2.67+/-0.71 pg/ml vs 2.97+/-0.94 pg/ml vs 4.07+/-1.13 pg/ml, p<0.0001). Within the sample, 76% of CC compared to 56% of GG subjects had the metabolic syndrome (p=0.007). Further analysis of association between the genotype and the components of the metabolic syndrome revealed no further associations than that with BMI previously described. The association of this gene variant with the metabolic syndrome is intimately linked with obesity per se. Further prospective work is required to explore the effect of this gene variant in relation to obesity, the metabolic syndrome and 'prediabetes'.

Aged↗
PubMed2002

Toxicological consequences of altered peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the liver: insights from models of obesity and type 2 diabetes.

The pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in the liver, although important for the regulation of genes involved in glucose and lipid metabolism, has generally not been fully appreciated. This may be due to the fact that PPARgamma, in contrast to PPARalpha or PPARdelta, is not abundantly expressed in liver under normal conditions. However, recent findings have revealed that in several murine models of obesity and type 2 diabetes mellitus (T2DM), PPARgamma mRNA and receptor protein are highly up-regulated in the liver, and that the receptor causes increased transcriptional activity as demonstrated by the activation of PPARgamma-responsive genes in the liver. Prolonged treatment of obese and diabetic mice, but not of lean control mice, with the selective PPARgamma ligands and activators, thiazolidinediones (TZDs), including troglitazone, rosiglitazone, or pioglitazone, has resulted in the development of severe hepatic centrilobular steatosis. In contrast to these effects in hepatocytes, TZD-mediated effects on Kupffer cells (down-regulation of proinflammatory cytokines) seem to be PPARgamma-independent. In view of the findings that sustained hepatic steatosis can lead to steatohepatitis and/or fibrosis and that troglitazone (but not the other TZDs) has been associated with rare but serious hepatotoxicity in patients, further insight into PPARgamma-mediated versus non-PPARgamma-mediated effects of TZDs is desirable. It is concluded that liver-specific effects associated with TZD antidiabetics may become relevant under conditions of selective PPARgamma up-regulation in the liver. Therefore, receptor expression in human liver tissue of obese and T2DM patients should deserve increased consideration in the future.

Animals↗
PubMed2000

Molecular scanning analysis of hepatocyte nuclear factor 1alpha (TCF1) gene in typical familial type 2 diabetes in African Americans.

Type 2 diabetes mellitus (T2DM) is strongly inherited, but the major genes for this disease have been elusive. In contrast, early-onset, autosomal-dominant diabetes results from at least 5 loci, of which hepatocyte nuclear factor 1a (HNF1alpha or TCF1) is the most common cause. Mutations in HNF1alpha also cause later-onset diabetes in some Caucasian populations, but the role of these mutations has not been tested in African American populations. We used a variety of screening methods, including both single-strand conformation polymorphism (SSCP) analysis and dideoxy fingerprint analysis, to search for mutations in 51 African American subjects with onset of diabetes before age 50 years. Potential mutations were confirmed by direct sequencing. We identified 21 different variants, of which 11 were unique to African Americans. Four mutations either altered the amino acid sequence (Gly52Ala and Gly574Ser) or were close to a splice site (intron 1 and intron 10). A 5-nucleotide insertion in intron 1 was present in both diabetic members of a small family, but Gly52Ala, Gly574Ser, and the intron 10 mutation did not segregate with diabetes. Gly574Ser was present in 2 large families and 5% of controls, all of which appeared to share the same common HNF1alpha haplotype. Surprisingly, radioactive SSCP analysis under 2 room-temperature conditions performed as well as methods using fluorescent labeling that were expected to be more sensitive. We conclude that in African American individuals under age 50, variation in the HNF1a gene is common but unlikely to be a significant cause of T2DM.

Adult↗
PubMed2003

Treating diabetes using oral agents.

Since the development and release of sulfonylureas for the treatment of T2DM, additional oral glycemic control agents with different mechanisms of action have allowed for more flexibility in targeting drug to patient. Based on available evidence, metformin monotherapy is preferred for the vast majority of T2DM patients who are overweight or obese. Combination therapy has further improved glycemic control. However, limitations in use, including the challenges of side effects, to that of secondary oral agent failure will inevitably occur over time. These challenges leave ample room for the development of agents that address the pathophysiology not only of treating insulin resistance and decreasing insulin production but also of preventing or delaying the development of diabetes in populations at risk.

Administration, Oral↗
PubMed2000

Potential new treatments for type 2 diabetes.

The heterogeneous pathogenesis and progressive natural history of type 2 diabetes mellitus (T2DM) contrive a formidable therapeutic challenge. Dual endocrine deficits of impaired insulin action (insulin resistance) and inadequate insulin secretion create an environment of chronic hyperglycaemia and general metabolic disarray. This inflicts a heavy burden of morbidity and premature mortality from cardiovascular diseases, microvascular disorders (e.g. retinopathy and nephropathy) and neuropathic conditions. Improving glycaemic control delays the onset and reduces the severity of these long-term complications. However, even with intensive use of current antidiabetic agents more than 50% of T2DM patients suffer poor glycaemic control and 18% develop serious complications within six years of diagnosis. Clearly, there is a need for new antidiabetic agents.

Animals↗
PubMed2003

Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese.

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.

Amino Acid Substitution↗
PubMed2000

Searching for type 2 diabetes genes in the post-genome era.

The discovery of genes encoding maturity onset diabetes of the young (MODY) type 2 diabetes mellitus (T2DM) represents a milestone in the study of the genetics of complex diseases. The genes were revealed, in large part, through positional cloning and linkage analysis in families. The genes are relatively rare and have strong genotype-phenotype correlations. Based on the results of several genome scans for genes encoding T2DM in various racial-ethnic groups, it appears that, as in other complex diseases, multiple genes are involved, each contributing a small amount to the overall risk. New strategies for patient sampling, phenotyping, genotyping technologies and genetic analysis must be employed to further define the genetic basis of this disease.

Animals↗
PubMed2002

Early programming of glucose-insulin metabolism.

Epidemiological studies have revealed strong inverse relationships between birthweight and the risk of developing type 2 diabetes mellitus (T2DM) and the metabolic syndrome. The mechanistic basis of these relationships remains the subject of research and debate. Evidence for the importance of the fetal environment has been obtained from both human and rodent studies. Studies of monozygotic twins have shown that genetic effects cannot explain these relationships entirely, if at all. Fetal and early postnatal growth restriction produced by feeding a reduced protein diet to rat dams leads to T2DM in old male offspring and, if combined with an obesity-inducing diet after weaning, to all the features of the metabolic syndrome.

Animals↗
PubMedDate not supplied

Novel targets and therapeutic strategies for type 2 diabetes.

The number of people diagnosed with type 2 diabetes mellitus (T2DM) is increasing at an alarming rate in western societies and has become a major health concern. During the past decade, studies using transgenic animals, gene transfer and pharmacological agents have yielded many data that have helped understand the molecular alterations characteristic of T2DM. This has opened the possibility for the development of potentially more-effective therapies, mainly focused on attenuating hepatic glucose production, enhancing glucose-dependent insulin secretion, enhancing the insulin signal transduction pathway, inhibiting lipolysis from the adipose tissue and promoting fatty acid oxidation.

Animals↗
PubMed2003

Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome.

Insulin resistance is common and plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). Precedents in biomedical research indicate that evaluation of monogenic syndromes can help to understand a common complex phenotype. Monogenic forms of insulin resistance, such as familial partial lipodystrophy, which results from mutations in either LMNA (encoding lamin A/C) or PPARG (encoding peroxisome proliferator-activated receptor gamma), and congenital generalized lipodystrophy, which results from mutations in either AGPAT2 (encoding 1-acylglycerol-3-phosphate O-acyltransferase) or BSCL2 (encoding seipin), can display features seen in the common metabolic syndrome. In addition, insulin resistance is seen in disorders associated with insulin receptor mutations, progeria syndromes and in inherited forms of obesity. Although insulin resistance in such rare monogenic syndromes could simply be secondary to fat redistribution and/or central obesity, the products of the causative genes might also produce insulin resistance directly, and might illuminate new causative mechanisms for insulin resistance in such common disorders as T2DM and obesity.

Humans↗
PubMedDate not supplied

Endothelial dysfunction in patients with type 2 diabetes and the effects of thiazolidinedione antidiabetic agents.

Endothelial dysfunction is increasingly recognised as a key event in the pathogenesis of atherosclerosis, which occurs in association with insulin resistance early in the course of type 2 diabetes mellitus (T2DM). Thiazolidinediones (TZDs), such as rosiglitazone, are a class of oral antidiabetic agents that act primarily as insulin sensitisers, reducing insulin resistance with associated improvements in glycemic control. Available data indicate that thiozolidinediones also have beneficial effects on numerous markers of endothelial function and profound antiinflammatory activity, indicative of potential antiatherogenic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis in T2DM patients.

Coronary Disease↗
PubMed2003

Hepatic glucose metabolism in humans--its role in health and disease.

The liver is mainly responsible for maintaining normal concentrations of blood glucose by its ability to store glucose as glycogen and to produce glucose from glycogen breakdown or gluconeogenic precursors. During the last decade, new techniques have made it possible to gain further insight into the turnover of hepatic glucose and glycogen in humans. Hepatic glycogen varies from approximately 200 to approximately 450 mM between overnight fasted and postprandial conditions. Patients with type-1 diabetes (T1DM), type 2 diabetes (T2DM) or partial agenesis of the pancreas exhibit increased endogenous glucose production and synthesize only 25-45% of hepatic glycogen compared with non-diabetic humans. This defect can be partly restored in T1DM by combined long- and short-term optimized treatment with insulin. In T2DM, increased gluconeogenesis was identified as the main cause of elevated glucose production and fasting hyperglycaemia. These patients also exhibit augmented intracellular lipid accumulation which could hint at a link between deranged glucose and lipid metabolism in insulin-resistant states.

Blood Glucose↗
PubMed2017

Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus.

Small non-coding RNAs, in particular microRNAs (miRNAs), regulate fine-tuning of gene expression and can impact a wide range of biological processes. However, their roles in normal and diseased limbal epithelial stem cells (LESC) remain unknown. Using deep sequencing analysis, we investigated miRNA expression profiles in central and limbal regions of normal and diabetic human corneas. We identified differentially expressed miRNAs in limbus vs. central cornea in normal and diabetic (DM) corneas including both type 1 (T1DM/IDDM) and type 2 (T2DM/NIDDM)&#xa0;diabetes. Some miRNAs such as miR-10b that was upregulated in limbus vs. central cornea and in diabetic vs. normal limbus also showed significant increase in T1DM vs. T2DM limbus. Overexpression of miR-10b increased Ki-67 staining in human organ-cultured corneas and proliferation rate in cultured corneal epithelial cells. MiR-10b transfected human organ-cultured corneas showed downregulation of PAX6 and DKK1 and upregulation of keratin 17 protein expression levels. In summary, we report for the first time differential miRNA signatures of T1DM and T2DM corneal limbus harboring LESC and show that miR-10b could be involved in the LESC maintenance and/or their early differentiation. Furthermore, miR-10b upregulation may be an important mechanism of corneal diabetic alterations especially in the T1DM patients.

Adult↗
PubMed2005

Characterization of the action of S 21403 (mitiglinide) on insulin secretion and biosynthesis in normal and diabetic beta-cells.

S 21403 (mitiglinide) is a new drug for type 2 diabetes mellitus (T2DM). Its action on insulin release and biosynthesis was investigated in several experimental systems utilizing pancreas from normal and T2DM animals. At high concentrations (10 microM), S 21403, like classical sulphonylurea, induced insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 microM) concentrations, S 21403 amplified insulin secretion glucose dose-dependently and with similar magnitude in normal and diabetic GK rat islets. In perfused GK rat pancreas, S 21403 induced normal kinetics of insulin secretion including first-phase response. The effect of S 21403 was strongly modulated by physiological factors. Thus, 0.1 microM adrenaline inhibited S 21403-induced insulin release. There was marked synergism between S 21403 and arginine in GK rat islets, combination of the two normalizing insulin secretion. In primary islet cultures from normal rats or prediabetic Psammomys obesus, prolonged exposure to S 21403 did not induce further depletion of insulin stores under normal or 'glucotoxic' conditions. Proinsulin biosynthesis was not affected by 2-h exposure of rat or prediabetic P. obesus islets to 1 microM S 21403. Yet, 24-h exposure of rat islets to S 21403 resulted in 30% increase in proinsulin biosynthesis at 8.3 mM glucose. Amplification by S 21403 of glucose-induced insulin secretion in diabetic GK beta-cells with restoration of first-phase response, a strong synergistic interaction with arginine and marked inhibition by adrenaline, make it a prime candidate for successful oral antidiabetic agent.

Animals↗
PubMed2004

Gender differences in TNF-alpha levels among obese vs nonobese Latino children.

OBJECTIVE: To examine the relationships between TNF-alpha, obesity, and insulin resistance among prepubescent children. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: Data were collected from 112 nondiabetic Latino schoolchildren from public schools in three South Florida communities. Of the enrolled participants, 43.8% were obese (BMI 95th percentile) and 51.8% presented with a family history of type 2 diabetes mellitus (T2DM). With one exception, all demonstrated normal glucose tolerance. INTERVENTIONS: Plasma TNF-alpha levels were determined with enzyme-linked immunosorbance assay (ELISA). Homeostasis model assessment (HOMA-IR) was calculated as an index of insulin resistance. Mean levels of TNF-alpha among obese vs nonobese children were compared with a one-way analysis of variance with two groups, and the association between TNF-alpha and HOMA-IR was assessed with a Pearson's correlation. RESULTS: Higher circulating TNF-alpha levels were revealed among nonobese vs obese children. Nonobese girls demonstrated higher TNF-alpha levels than obese girls, whereas there were no significant differences for boys. There were no significant differences after stratifying for family history of T2DM. There was a modest relationship between increased TNF-alpha levels and decreased insulin resistance. CONCLUSIONS: The observed elevated circulating TNF-alpha concentrations among leaner participants may reflect an inflammatory process that has been associated with higher levels of physical fitness in both adults and prepubescent children. This effect may remain stronger for prepubescent girls, and the mechanism may be attenuated by the hormonal changes that occur with the onset of puberty.

Body Mass Index↗