Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of insulin secretion from pancreatic beta-cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K+ channels (K(ATP) channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the K(ATP) channels in pancreatic beta-cells is regulated by changes in the ATP and ADP concentrations (ATP/ADP ratio) caused by glucose metabolism. Thus, the K(ATP) channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. K(ATP) channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic beta-cell K(ATP) channel, Kir6.2 (an inward rectifier K+ channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K+ ion-permeable pore and primarily confer inhibition of the channels by ATP, while SUR1 subunits confer activation of the channels by MgADP and K+ channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to ATP. To determine the physiological roles of K(ATP) channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 specifically in the pancreatic beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the K(ATP) channels in endocrine pancreatic function: 1) the K(ATP) channels are the major determinant of the resting membrane potential of pancreatic beta-cells, 2) both glucose- and sulfonylurea-induced membrane depolarization of beta-cells require closure of the K(ATP) channels, 3) both glucose- and sulfonylurea-induced rises in intracellular calcium concentration in beta-cells require closure of the K(ATP) channels, 4) both glucose- and sulfonylurea-induced insulin secretions are mediated principally by the K(ATP) channel-dependent pathway, 5) the K(ATP) channels are important for beta-cell survival and architecture of the islets, 6) the K(ATP) channels are important in the differentiation of islet cells, and 7) the K(ATP) channels in glucose-responsive cells generally participate in coupling glucose sensing with cell excitability. Interestingly, despite the severe defect in glucose-induced insulin secretion, Kir6.2 knockout mice show only a very mild impairment in glucose tolerance. However, when the knockout mice become obese with age, they develop fasting hyperglycemia and glucose intolerance, while neither fasting hyperglycemia nor glucose intolerance is evident in the aged knockout mice without obesity, suggesting that both the genetic defect in glucose-induced insulin secretion and the acquired insulin resistance due to environmental factors are necessary to develop diabetes in Kir6.2 knockout mice. Thus, Kir6.2G132S Tg mice and Kir6.2 knockout mice provide a model of type 2 diabetes and clarify the various roles of K(ATP) channels in endocrine pancreatic function.
 ...
PMID:Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. 1086 50

The ATP-sensitive potassium channel (KATP channel) is an essential ion channel involved in glucose-induced insulin secretion. The KATP channel is composed of an inwardly rectifying potassium channel, Kir6.2, and the sulfonylurea receptor (SUR 1); in the pancreas it is reported to be shared by all endocrine cell types. A previous study by our research group showed that Kir 6.2-knockout mice lacked KATP channel activities and failed to secrete insulin in response to glucose, but displayed normal blood glucose levels and only mild impairment in glucose tolerance at younger ages. In some aged knockout mice, however, obesity and hyperglycemia were recognizable. The present study aimed to reveal morphological changes in pancreatic islets of Kir 6.2-knockout mice throughout life. At birth, there were no significant differences in the islet cell arrangement between the knockout mice and controls. At 14 postnatal weeks glucagon cells appeared in the central parts of islets, and this image became more pronounced with aging. In animals older than 50 weeks insulin cells decreased in numbers and intensity of insulin immunoreactivity; most islets in 70- and 80-week-old mice were predominantly composed of glucagon cells and peptide YY (PYY)-containing cells. Staining of serial sections and double staining of single sections from these old mice demonstrated the frequent coexpression of glucagon and PYY, which is a phenotype for the earliest progenitor cells of pancreatic endocrine cells. These findings suggest that the KATP channel is important for insulin cell survival and also regulates the differentiation of islet cells.
 ...
PMID:Morphological changes in pancreatic islets of KATP channel-deficient mice: the involvement of KATP channels in the survival of insulin cells and the maintenance of islet architecture. 1131 May 6

Dysfunction of the pancreatic beta-cell is an important defect in the pathophysiological changes of type 2 diabetes, and type 2 diabetes is evidently associated with obesity. But the role of the adipocyte in the dysfunction of the pancreatic beta-cell remains unknown. In the present study, we examined the direct effects of 3T3-L1 adipocytes on the expression of ATP-sensitive potassium channels (K(ATP) channels) in MIN6 insulin-secreting cells. MIN6 cells were divided into two groups as control group, where MIN6 cells were cultured in normal culture medium, and coculture group, where MIN6 cells were cocultured with differentiated 3T3-L1 adipocytes for 1 week. Semi-quantitative RT-PCR was employed to measure the expression of K(ATP) channel subunit Kir6.2 in MIN6 cells. Fura-2 was used to reflect changes in intracellular calcium concentration ([Ca(2+)](i)) in MIN6 cells. The secretary function of MIN6 cells from both groups was estimated by radioimmunoassay method. The results showed that the Kir6.2 cDNA levels corrected by GAPDH cDNA levels after densitometric analysis were 0.989+/-0.035 in control group and 0.726+/-0.087 in coculture group. The expression of Kir6.2 was significantly decreased in MIN6 cells in the coculture group as compared with that in control. MIN6 cells cocultured with 3T3-L1 adipocytes lost the ability to increase [Ca(2+)](i) when stimulated by tolbutamide (0.1 mmol/L), a highly selective KATP channel closer. In contrast, MIN6 cells in control group had typical responses to tolbutamide with a significant increase in [Ca(2+)](i). The magnitudes to basal levels of [Ca(2+)](i) after tolbutamide stimulation were 1.520+/-0.203 in control and 1.114+/-0.097 in coculture group (P<0.05, n=6). MIN6 cells in control showed a significant increase in insulin secretion from 0.38+/-0.099 mU/min to 2.87+/-0.248 mU/min after being stimulated by tolbutamide, whereas MIN6 cells in coculture group did not increase insulin secretion when stimulated by tolbutamide (0.21+/-0.055 mU/min to 0.22+/-0.082 mU/min). It is demonstrated that 3T3-L1 adipocytes decrease the expression of K(ATP) channels in MIN6 cells through secreting certain factors, which impair the secretary function of MIN6 cells. The present results indicate that adipocytes are directly involved in pancreatic beta-cell dysfunction, which may facilitate the development of type 2 diabetes.
 ...
PMID:[3T3-L1 adipocytes reduces Kir6.2 channel expression in MIN6 insulin-secreting cells in vitro]. 1512 39

The ATP-sensitive potassium (KATP) channel couples membrane excitability to cellular metabolism and is a critical mediator in the process of glucose-stimulated insulin secretion. Increasing numbers of KATP channel polymorphisms are being described and linked to altered insulin secretion indicating that genes encoding this ion channel could be susceptibility markers for type-2 diabetes. Genetic variation of KATP channels may result in altered beta-cell electrical activity, glucose homeostasis, and increased susceptibility to type-2 diabetes. Of particular interest is the Kir6.2 E23K polymorphism, which is linked to increased susceptibility to type-2 diabetes in Caucasian populations and may also be associated with weight gain and obesity, both of which are major diabetes risk factors. This association highlights the potential contribution of both genetic and environmental factors to the development and progression of type-2 diabetes. In addition, the common occurrence of the E23K polymorphism in Caucasian populations may have conferred an evolutionary advantage to our ancestors. This review will summarize the current status of the association of KATP channel polymorphisms with type-2 diabetes, focusing on the possible mechanisms by which these polymorphisms alter glucose homeostasis and offering insights into possible evolutionary pressures that may have contributed to the high prevalence of KATP channel polymorphisms in the Caucasian population.
 ...
PMID:Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. 1556 84

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior.
 ...
PMID:Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children? 1567 Nov 13

ATP-sensitive K+ channels (K(ATP) channels) play an important role in glucose homeostasis. A single nucleotide polymorphism (SNP) in the Kir6.2 subunit causes a point mutation of Glu23 to lysine and reduces the ATP sensitivity of pancreatic K(ATP) channels. The SNP found in 58% of Caucasians accounts for 15% of type 2 diabetes. Here we show evidence for dysregulations of muscular K(ATP) channels with the E23K variation. We were particularly interested in the channel modulation by intracellular protons, as pH changes widely and frequently in skeletal muscles. Surprisingly, we found that the defect of the E23K variant was more related to pH than ATP. A level of intracellular acidification seen during exercise not only activated the E23K channel more readily than the wild type, but also relieved the channel inhibition by ATP, leading to a vast increase in the channel open-state probability by approximately sevenfold at pH 6.8 over the wild-type channel at pH 7.4. Considering the reduction in sarcolemmal excitability, muscle fatigue, and impairment of muscular glucose uptake found previously by genetically disrupting K(ATP) channels, it is likely that the E23K variant in muscular K(ATP) channels affects systemic glucose homeostasis and poses an important risk factor for type 2 diabetes and obesity.
 ...
PMID:Single nucleotide polymorphisms in K(ATP) channels: muscular impact on type 2 diabetes. 1585 51

Although insulin secretion is commonly increased and glucose tolerance decreased in young obese patients, there is a wide individual variability of these parameters. We investigated whether common variants at the Kir6.2 (KCNJ11) and insulin variable number of tandem repeat (INS VNTR) loci are associated with insulin or glucose levels in 388 obese children. The E23K and INS VNTR alleles showed no significant association when each locus was examined individually but a clear effect when the two loci were combined for analysis. In obese children with Kir6.2 KK and class III VNTR alleles, fasting glucose was slightly but consistently greater (4.76 +/- 0.05 mM) than in those with Kir6.2 EE and class I/I VNTR alleles (4.63 +/- 0.06 mM, P = 6.10(-4)) or other genotypes (4.64 +/- 0.03 mM, P = 1.10(-3)). Obese children with KK and class III VNTR genotypes also had an early response to oral glucose diminished by approximately 36% [insulinogenic index (IGI) = 50 +/- 4] compared with Kir6.2 EE and class I/I (IGI = 78 +/- 7, P = 0.026) or other genotypes (IGI = 69 +/- 3, P = 0.001). In young European obese, the polymorphisms of Kir6.2 and INS VNTR are thus associated with a trend for lower insulin and higher glucose levels, which may reveal a possible epistatic genetic effect that may influence a prediabetic trait in young obese children.
 ...
PMID:Association of Kir6.2 and INS VNTR variants with glucose homeostasis in young obese. 1595 17

About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. It is manifested when pancreatic beta cells are no longer able to compensate for the increased insulin resistance during pregnancy, but the pathogenesis of the disease is still largely unknown. GDM is considered to result from interaction between genetic and environmental risk factors. Genetic predisposition to GDM has been suggested since GDM clusters in families. Also, women with mutations in MODY (Maturity onset diabetes of the young) genes often present with GDM. In addition, common variants in several candidate genes (e.g. potassium inwardly rectifying channel subfamily J, member 11 [KCNJ11], Glucokinase [GCK], Hepatocyte nuclear factor-1alpha [HNF1A] etc.) have been demonstrated to increase the risk of GDM. Old age, obesity and high fat diet represent some important non-genetic factors. There are several approaches to search for genes predisposing to a polygenic disease like GDM including linkage and association studies, expression profiling and animal models. A combination of several methods is usually necessary. Identification of the underlying genetic causes of GDM will eventually give a better view of the mechanisms that contribute to the pathophysiology of the disease. Furthermore, it may improve options to possibly prevent GDM and complications for the mother and her child. This review focuses on the genetics of GDM and possible implications in clinical practice.
 ...
PMID:Genetics of gestational diabetes mellitus. 1734 48

Pancreatic beta-cell dysfunction is an important pathological change in type 2 diabetes, which is tightly related to obesity. However, the direct role of adipose tissue in beta-cell dysfunction has not been well understood. In this study, we examined the effects of 3T3-L1 adipocytes on MIN6 insulin-secreting cells in a co-culture system. MIN6 cells used here kept most of beta-cell functions but less sensitive to glucose stimulation. Tolbutamide, the KATP channel blocker, was therefore used to stimulate insulin secretion in this report. MIN6 cells co-cultured with 3T3-L1 adipocytes had significantly reduced intracellular calcium concentration ([Ca2+]i) and lost the ability to secrete insulin in response to tolbutamide, compared to the control cells. 3T3-L1 adipocytes significantly decreased the expression of insulin, glucokinase and Kir6.2 genes but increased the expression of uncoupling protein-2 (UCP-2) in MIN6 cells after one week of co-culture, as measured by semi-quantitative RT-PCR. 3T3-L1 adipocyte-conditioned medium also significantly decreased insulin secretion and the expression of insulin, glucokinase and Kir6.2 genes in MIN6 cells. The conditioned medium also reduced tyrosine kinase activity in MIN6 cells. The inhibitor of protein tyrosine kinase, genistein, decreased the expression of glucokinase and Kir6.2 in MIN6 cells, while two free fatty acids, oleic acid and linoleic acids, were found to increase UCP-2 expression. The present study demonstrates that 3T3-L1 adipocytes directly impair insulin secretion and the expression of important genes in MIN6 cells. The effects of T3-L1 adipocytes on MIN6 cells are ascribed to secreted bioactive factors and may be mediated via multiple pathways, which include the upregulation of UCP-2 expression via free fatty acids, and downregulation of glucokinase and Kir6.2 expression via decreasing protein tyrosine kinase activity.
 ...
PMID:3T3-L1 adipocytes induce dysfunction of MIN6 insulin-secreting cells via multiple pathways mediated by secretory factors in a co-culture system. 1770 98

A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
 ...
PMID:Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. 1772 16


1 2 3 Next >>