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

KATP channels are a newly defined class of potassium channels based on the physical association of an ABC protein, the sulfonylurea receptor, and a K+ inward rectifier subunit. The beta-cell KATP channel is composed of SUR1, the high-affinity sulfonylurea receptor with multiple TMDs and two NBFs, and KIR6.2, a weak inward rectifier, in a 1:1 stoichiometry. The pore of the channel is formed by KIR6.2 in a tetrameric arrangement; the overall stoichiometry of active channels is (SUR1/KIR6.2)4. The two subunits form a tightly integrated whole. KIR6.2 can be expressed in the plasma membrane either by deletion of an ER retention signal at its C-terminal end or by high-level expression to overwhelm the retention mechanism. The single-channel conductance of the homomeric KIR6.2 channels is equivalent to SUR/KIR6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane. Coexpression with SUR restores the normal channel properties. The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity. KATP channels set the resting membrane potential of beta-cells, and their loss results in a constitutive depolarization that allows voltage-gated Ca2+ channels to open spontaneously, increasing the cytosolic Ca2+ levels enough to trigger continuous release of insulin. The loss of KATP channels, in effect, uncouples the electrical activity of beta-cells from their metabolic activity. PHHI mutations have been informative on the function of SUR1 and regulation of KATP channels by adenine nucleotides. The results indicate that SUR1 is important in sensing nucleotide changes, as implied by its sequence similarity to other ABC proteins, in addition to being the drug sensor. An unexpected finding is that the inhibitory action of ATP appears to be through a site located on KIR6.2, whose affinity for ATP is modified by SUR1. A PHHI mutation, G1479R, in the second NBF of SUR1 forms active KATP channels that respond normally to ATP, but fail to activate with MgADP. The result implies that ATP tonically inhibits KATP channels, but that the ADP level in a fasting beta-cell antagonizes this inhibition. Decreases in the ADP level as glucose is metabolized result in KATP channel closure. Although KATP channels are the target for sulfonylureas used in the treatment of NIDDM, the available data suggest that the identified KATP channel mutations do not play a major role in diabetes. Understanding how KATP channels fit into the overall scheme of glucose homeostasis, on the other hand, promises insight into diabetes and other disorders of glucose metabolism, while understanding the structure and regulation of these channels offers potential for development of novel compounds to regulate cellular electrical activity.
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PMID:Molecular biology of adenosine triphosphate-sensitive potassium channels. 1020 14

The phenomenal growth in the rate of type 2 diabetes presents an enormous burden to society. Diabetes and its complications cost billions and significantly impact quality of life in individuals with diabetes. Diabetes management has transitioned from focusing exclusively on glycemic control to an approach that addresses both glucose abnormalities and the chronic complications of the disease. Increased understanding of the underlying mechanisms of disease and the multifactorial basis of diabetes complications suggest the importance of early diagnosis and treatment of all diabetes complications. Preventive approaches emphasizing risk factor reduction strategies are essential. The American Diabetes Association Standards of Medical Care for People with Diabetes assist both the health care provider and the individual with diabetes to appreciate the comprehensive treatment goals in diabetes and provide specific guidelines for achieving these goals. This article presents these guidelines in an easy-to-remember ABC format.
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PMID:Glycemic control and beyond: the ABCs of standards of care for type 2 diabetes and cardiovascular disease. 1180 67

Little information is available on cholesterol absorption and synthesis in human type 1 diabetes. We studied these variables using serum cholesterol precursor sterol ratios to cholesterol as surrogate markers of cholesterol synthesis and those of cholestanol and plant sterols to reflect cholesterol absorption in seven type 1 diabetic subjects and in five age- and body weight-matched control subjects. Total and lipoprotein cholesterol levels were similar, but triglycerides in intermediate-density lipoprotein (IDL) and LDL were higher in type 1 diabetic than in control subjects. Most of the marker sterols were transported by LDL and HDL in both groups. The percentage of esterified cholesterol was lower in triglyceride-rich lipoproteins in diabetic patients than in control subjects. The ratios of the absorption marker sterols in serum were higher, and those of the synthesis markers were lower in type 1 diabetic than in control subjects. The increased cholestanol ratios were seen in all lipoproteins, and those of free and total plant sterols were mainly in LDL, whereas the decreased free and total synthesis markers were mainly in all lipoproteins. In conclusion, high absorption and low synthesis marker sterols seem to characterize human type 1 diabetes. These findings could be related to low expression of ABC G/5 G/8 genes, resulting in high absorption of cholesterol and sterols in general and low synthesis of cholesterol compared with type 2 diabetes.
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PMID:Cholesterol metabolism in type 1 diabetes. 1533 30

ABC (ATP binding cassette) transporters consist of transmembrane domains which confer specificity, and structurally conserved nucleotide binding domains that contain highly conserved amino acid motifs. They act not only as transporters but also as receptors or channels that use energy generated by ATP hydrolysis. ABC transporters are widely dispersed in nature. They are found in cells ranging from prokaryotes (bacteria) to eukaryotes (including humans) and several are considered to play crucial roles in cellular homeostasis. Defects in ABC transporters in humans are associated with severe diseases such as type 2 diabetes and cystic fibrosis. Some ABC transporters extrude xenobiotics and confer resistance to chemotherapeutics on microbial pathogens and cancer cells. Thus ABC transporters are of considerable medical importance. Structure-function analysis of ABC transporters has begun to elucidate their mechanisms of substrate recognition, the functional regulation of ATP-binding and hydrolysis and to identify intrinsic physiological functions. In pathogenic fungi, ABC transporters contribute to the clinical problem of drug resistance. The application of new technologies to the examination of fungal ABC transporter function is providing new insights into the use of antifungal drugs in medical mycology and contributing to a better understanding of these important membrane proteins.
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PMID:[ABC transporters of pathogenic fungi: recent advances in functional analyses]. 1628 67

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3+/-15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-alpha SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin.
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PMID:Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study. 1739 Jan 49

Recent findings from several groups demonstrate that ABC-A1 participates in the pathogenesis of the metabolic syndrome and type 2 diabetes. A variant of the ABC-A1 gene (R230C) is associated with the metabolic syndrome and its co-morbidities in Mexicans. Its presence is associated with an increased risk for obesity, the metabolic syndrome and type 2 diabetes. R230C is found exclusively in Amerindian and Amerindian-derived populations. Moreover, animal models confirm the participation of ABC-A1 in the pathogenesis of diabetes. Mice lacking AbcA1 specifically in beta cells had glucose intolerance at 8 weeks of age. The absence of ABC-A1 led to cholesterol accumulation within the beta cell plasma membrane, suggesting that cholesterol may play a role in the insulin secretory pathway. In conclusion, ABC-A1 may be more than a determinant of HDL-cholesterol. It may provide a link between components of the metabolic syndrome and atherosclerosis.
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PMID:The ATP-binding cassette transporter subfamily A member 1 (ABC-A1) and type 2 diabetes: an association beyond HDL cholesterol. 1822 Jun 85

Our understanding of the relationship between physical activity and health is constantly evolving. Therefore, the British Association of Sport and Exercise Sciences convened a panel of experts to review the literature and produce guidelines that health professionals might use. In the ABC of Physical Activity for Health, A is for All healthy adults, B is for Beginners, and C is for Conditioned individuals. All healthy adults aged 18-65 years should aim to take part in at least 150 min of moderate-intensity aerobic activity each week, or at least 75 min of vigorous-intensity aerobic activity per week, or equivalent combinations of moderate- and vigorous-intensity activities. Moderate-intensity activities are those in which heart rate and breathing are raised, but it is possible to speak comfortably. Vigorous-intensity activities are those in which heart rate is higher, breathing is heavier, and conversation is harder. Aerobic activities should be undertaken in bouts of at least 10 min and, ideally, should be performed on five or more days a week. All healthy adults should also perform muscle-strengthening activities on two or more days a week. Weight training, circuit classes, yoga, and other muscle-strengthening activities offer additional health benefits and may help older adults to maintain physical independence. Beginners should work steadily towards meeting the physical activity levels recommended for all healthy adults. Even small increases in activity will bring some health benefits in the early stages and it is important to set achievable goals that provide success, build confidence, and increase motivation. For example, a beginner might be asked to walk an extra 10 min every other day for several weeks to slowly reach the recommended levels of activity for all healthy adults. It is also critical that beginners find activities they enjoy and gain support in becoming more active from family and friends. Conditioned individuals who have met the physical activity levels recommended for all healthy adults for at least 6 months may obtain additional health benefits by engaging in 300 min or more of moderate-intensity aerobic activity per week, or 150 min or more of vigorous-intensity aerobic activity each week, or equivalent combinations of moderate- and vigorous-intensity aerobic activities. Adults who find it difficult to maintain a normal weight and adults with increased risk of cardiovascular disease or type 2 diabetes may in particular benefit from going beyond the levels of activity recommended for all healthy adults and gradually progressing towards meeting the recommendations for conditioned individuals. Physical activity is beneficial to health with or without weight loss, but adults who find it difficult to maintain a normal weight should probably be encouraged to reduce energy intake and minimize time spent in sedentary behaviours to prevent further weight gain. Children and young people aged 5-16 years should accumulate at least 60 min of moderate-to-vigorous-intensity aerobic activity per day, including vigorous-intensity aerobic activities that improve bone density and muscle strength.
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PMID:The ABC of Physical Activity for Health: a consensus statement from the British Association of Sport and Exercise Sciences. 2040 89

A variety of epidemiological researches culminated in the fact that patients with diabetes mellitus (DM) are at high risk of cardiovascular diseases including myocardial infarction. Recently, observational researches showed that impaired glucose tolerance (IGT) is also a risk factor for cardiovascular disease, and STOP-NIDDM study demonstrated that the treatment of IGT patients with acarbose reduced the risk of cardiovascular events as well as the progression to diabetes mellitus. However, there are no reports on the secondary prevention of anti-diabetic drugs for cardiovascular disease in IGT patients. To this end, we are conducting two clinical studies: PPAR Study and ABC Study, and the results of these studies are expected to establish the involvement of metabolic disorders in cardiovascular medicine.
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PMID:[Anti-diabetic drugs for secondary prevention of cardiovascular disease in mild diabetic and IGT patients: ABC study and PPAR study]. 2044 88

In contrast to the widely reported ethnic differences in prevalence, the incidence of type 2 diabetes was surprisingly similar (approximately 11%) among individuals from the different US ethnic groups in the Diabetes Prevention Program (DPP). Because DPP participants had impaired glucose tolerance (IGT) at baseline, we hypothesized that ethnic disparities are initiated at the pre-IGT stage during evolution of type 2 diabetes. The Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) is designed to test that hypothesis by tracking the natural history of early dysglycemia in a biracial cohort comprising offspring of parents with type 2 diabetes. The POP-ABC study has an enrollment target of 400 participants (200 African American, 200 Caucasian), aged 18-65 years, with at least 1 parent with type 2 diabetes. All subjects must have normal fasting glucose and/ or normal glucose tolerance, as determined by a 75-gram oral glucose tolerance test (OGTT). Subjects are recruited over approximately 3 years and followed for another 2 years, with repeated metabolic assessments. The latter include OCTT, body composition, indirect calorimetry, euglycemic clamp, beta cell function, and biochemistries. Repository specimens (DNA, RNA and proteome) are obtained for future studies. The primary outcome is the occurrence of prediabetes (ICT and/or impaired fasting glucose). The sample size provides 85% power to detect a hazard ratio of 1.75 between Black and White offspring in the primary outcome (alpha = .05). Secondary endpoints include behavioral, biochemical and socioeconomic predictors of dysglycemia. The POP-ABC study will elucidate the nosogeny of ethnic disparities in glucose dysregulation.
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PMID:Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC): design and methods. 2146 27

Uptake transporters (e.g., members of the SLC superfamily of solute carriers) and export proteins (e.g., members of the ABC transporter superfamily) are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere with drug transport may alter the kinetics of drug substrates. In vitro and in vivo studies indicate that many drugs used for the treatment of metabolic disorders and cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are substrates for uptake transporters and export proteins expressed in the intestine, the liver and the kidney. Since most patients with type 2 diabetes receive more than one drug, transporter-mediated drug-drug interactions are important molecular mechanisms leading to alterations in oral antidiabetic drug pharmacokinetics with the risk of adverse drug reactions. This review focuses on uptake transporters of the SLCO/SLC21 (OATP) and SLC22 (OCT/OAT) family of solute carriers and export pumps of the ABC (ATP-binding cassette) transporter superfamily (especially P-glycoprotein) as well as the export proteins of the SLC47 (MATE) family and their role for transporter-mediated drug-drug interactions with oral antidiabetic drugs.
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PMID:Transporter-mediated drug-drug interactions with oral antidiabetic drugs. 2430 3


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