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)

Nateglinide is a short-acting, pancreatic, beta-cell-selective, K(ATP) potassium channel blocker that improves overall glycemic control in type 2 diabetes. Although nateglinide's mechanism of action is related to that of sulphonyl-ureas and repaglinide, important differences do exist. Nateglinide binds rapidly to the sulfonylurea SUR1 receptor with a relatively low affinity, and it dissociates from it extremely rapidly in a manner of seconds. This rapid association and dissociation gives nateglinide a unique "fast on-fast off" effect. Thus, nateglinide has a rapid onset and short duration of action stimulating insulin secretion in vivo and providing good control of postprandial hyperglycemia when taken immediately prior to meals. The rapid action of nateglinide on the beta cells stimulates and restores the normal physiological first and early phase of insulin secretion, consequently reducing postprandial hyperglycemia. This hypoglycemic effect of nateglinide leads to improved glycemic control, while the short duration avoids delayed hyperinsulinemia and hypoglycemia after meals. Nateglinide is not a sulfonylurea, but it shares the mechanism of action of commonly used oral hypoglycemic agents such as glibenclamide and glipizide. Like the recently introduced, short-acting agent, repaglinide, it does not incorporate a sulfonylurea moiety. However, nateglinide's effects on insulin secretion and glycemic control differ significantly from the sulfonylureas and repaglinide in that it preferentially stimulates acute phase insulin, better controls postprandial glucose excursions and spikes, and causes less hyperinsulinemia and hypoglycemia. Compounds with such a profile should not only achieve improved overall glucose control, but also reduce the risk of vascular complications which is the most important feature of nateglinide. Clinical studies with nateglinide have confirmed that it acts rapidly and both restores insulin release and attenuates the postprandial glucose spike. Nateglinide is both effective and well tolerated in the treatment of type 2 diabetes. The reported overall profile of adverse effects appears to be superior to that of other K(ATP) potassium channel blockers, the glucose modulator metformin and PPARgamma agonists such as troglitazone. Clinical comparisons of these agents have shown nateglinide to be more effective in attenuating postprandial glucose than any other oral hypoglycemic agent, and that treatment with both nateglinide and metformin provides additive effects that afford improved control of plasma glucose levels. The administration regimen for nateglinide, immediately prior to meals, also facilitates patient compliance. (c) 2001 Prous Science. All rights reserved.
 ...
PMID:Nateglinide: A structurally novel, short-acting, hypoglycemic agent. 1276 27

It is the position of the American Dietetic Association and Dietitians of Canada that appropriately planned vegetarian diets are healthful, nutritionally adequate, and provide health benefits in the prevention and treatment of certain diseases. Approximately 2.5% of adults in the United States and 4% of adults in Canada follow vegetarian diets. A vegetarian diet is defined as one that does not include meat, fish, or fowl. Interest in vegetarianism appears to be increasing, with many restaurants and college foodservices offering vegetarian meals routinely. Substantial growth in sales of foods attractive to vegetarians has occurred, and these foods appear in many supermarkets. This position paper reviews the current scientific data related to key nutrients for vegetarians, including protein, iron, zinc, calcium, vitamin D, riboflavin, vitamin B-12, vitamin A, n-3 fatty acids, and iodine. A vegetarian, including vegan, diet can meet current recommendations for all of these nutrients. In some cases, use of fortified foods or supplements can be helpful in meeting recommendations for individual nutrients. Well-planned vegan and other types of vegetarian diets are appropriate for all stages of the life cycle, including during pregnancy, lactation, infancy, childhood, and adolescence. Vegetarian diets offer a number of nutritional benefits, including lower levels of saturated fat, cholesterol, and animal protein as well as higher levels of carbohydrates, fiber, magnesium, potassium, folate, and antioxidants such as vitamins C and E and phytochemicals. Vegetarians have been reported to have lower body mass indices than nonvegetarians, as well as lower rates of death from ischemic heart disease; vegetarians also show lower blood cholesterol levels; lower blood pressure; and lower rates of hypertension, type 2 diabetes, and prostate and colon cancer. Although a number of federally funded and institutional feeding programs can accommodate vegetarians, few have foods suitable for vegans at this time. Because of the variability of dietary practices among vegetarians, individual assessment of dietary intakes of vegetarians is required. Dietetics professionals have a responsibility to support and encourage those who express an interest in consuming a vegetarian diet. They can play key roles in educating vegetarian clients about food sources of specific nutrients, food purchase and preparation, and any dietary modifications that may be necessary to meet individual needs. Menu planning for vegetarians can be simplified by use of a food guide that specifies food groups and serving sizes.
 ...
PMID:Position of the American Dietetic Association and Dietitians of Canada: Vegetarian diets. 1277 49

Theoretical and experimental research data as well as human epidemiological studies on large populations suggest a great difference in influencing cardiovascular processes and alterations among the oral antidiabetic drugs used in the treatment of type II diabetes mellitus. Drugs delaying or inhibiting carbohydrate absorption as well as insulin sensitizers have an unambiguous reducing effect on diabetic cardiovascular complications. Only fluid retention needs precaution during the treatment with thiazolidinedions in patients suffering from heart disease. Among insulin secretizers repaglinid, glibenclamid and glipizide have an ATP-sensitive potassium channel inhibiting effect in the vascular smooth muscle cells, too, reducing hereby vasodilation. Glibenclamide also inhibits ischaemic preconditioning. Therefore, the antidiabetic drug of choice can be decisive in diabetic patients suffering from ischaemic heart diseases or peripheral obliterative disorders. In the case of secondary sulphonylurea resistance and/or severe ischaemic alterations insulin treatment becomes necessary to avoid further cardiovascular complications.
 ...
PMID:[Oral antidiabetic therapy and cardiovascular complications: theoretical problem or clinical evidence?]. 1279 25

It is the position of the American Dietetic Association and Dietitians of Canada that appropriately planned vegetarian diets are healthful, nutritionally adequate, and provide health benefits in the prevention and treatment of certain diseases. Approximately 2.5% of adults in the United States and 4% of adults in Canada follow vegetarian diets. A vegetarian diet is defined as one that does not include meat, fish, or fowl. Interest in vegetarianism appears to be increasing, with many restaurants and college foodservices offering vegetarian meals routinely. Substantial growth in sales of foods attractive to vegetarians has occurred and these foods appear in many supermarkets. This position paper reviews the current scientific data related to key nutrients for vegetarians including protein, iron, zinc, calcium, vitamin D, riboflavin, vitamin B-12, vitamin A, n-3 fatty acids, and iodine. A vegetarian, including vegan, diet can meet current recommendations for all of these nutrients. In some cases, use of fortified foods or supplements can be helpful in meeting recommendations for individual nutrients. Well-planned vegan and other types of vegetarian diets are appropriate for all stages of the life-cycle including during pregnancy, lactation, infancy, childhood, and adolescence. Vegetarian diets offer a number of nutritional benefits including lower levels of saturated fat, cholesterol, and animal protein as well as higher levels of carbohydrates, fibre, magnesium, potassium, folate, antioxidants such as vitamins C and E, and phytochemicals. Vegetarians have been reported to have lower body mass indices than non-vegetarians, as well as lower rates of death from ischemic heart disease, lower blood cholesterol levels, lower blood pressure, and lower rates of hypertension, type 2 diabetes, and prostate and colon cancer. While a number of federally funded and institutional feeding programs can accommodate vegetarians, few have foods suitable for vegans at this time. Because of the variability of dietary practices among vegetarians, individual assessment of dietary intakes of vegetarians is required. Dietetics professionals have a responsibility to support and encourage those who express an interest in consuming a vegetarian diet. They can play key roles in educating vegetarian clients about food sources of specific nutrients, food purchase and preparation, and any dietary modifications that may be necessary to meet individual needs. Menu planning for vegetarians can be simplified by use of a food guide that specifies food groups and serving sizes.
 ...
PMID:Position of the American Dietetic Association and Dietitians of Canada: vegetarian diets. 1282 28

ATP-sensitive potassium (K(ATP)) channels are present in many tissues, including pancreatic beta-cells, heart, skeletal muscle, vascular smooth muscle and brain, in which they couple the cell metabolic state to membrane potential. K(ATP) channels are hetero-octameric proteins composed of the pore-forming subunits Kir6.x (Kir6.1 or Kir6.2) of the inwardly rectifying K(+) channel family and the regulatory subunits SURx (SUR1, SUR2A or SUR2B), the receptor of the sulphonylureas widely used in treatment of type 2 diabetes mellitus. Different combinations of Kir6.x and SURx comprise K(ATP) channels with distinct electrophysiological and pharmacological properties, but their physiological functions in the various tissues are unclear. Our studies of Kir6.2 null (knockout) and Kir6.1 null mice have shown that K(ATP) channels are critical metabolic sensors in protection against acute metabolic stress such as hyperglycaemia, hypoglycaemia, ischaemia and hypoxia.
 ...
PMID:Gene targeting approach to clarification of ion channel function: studies of Kir6.x null mice. 1282 53

A novel potassium channel opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive potassium channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 +/- 82 mmol. l(-1). min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol.l(-1).min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.
 ...
PMID:NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat. 1451 34

The commonly occurring E23K and I337V Kir6.2 polymorphisms in the ATP-sensitive potassium (KATP) channel are more frequent in Caucasian type 2 diabetic populations. However, the underlying cellular mechanisms contributing to the pathogenesis of type 2 diabetes remain uncharacterized. Chronic elevation of plasma free fatty acids observed in obese and type 2 diabetic subjects leads to cytosolic accumulation of long-chain acyl CoAs (LC-CoAs) in pancreatic beta-cells. We postulated that the documented stimulatory effects of LC-CoAs on KATP channels might be enhanced in polymorphic KATP channels. Patch-clamp experiments were performed on inside-out patches containing recombinant KATP channels (Kir6.2/SUR1) to record macroscopic currents. KATP channels containing Kir6.2 (E23K/I337V) showed significantly increased activity in response to physiological palmitoyl-CoA concentrations (100-1,000 nmol/l) compared with wild-type KATP channels. At physiological intracellular ATP concentrations (mmol/l), E23K/I337V polymorphic KATP channels demonstrated significantly enhanced activity in response to palmitoyl-CoA. The observed increase in KATP channel activity may result in multiple defects in glucose homeostasis, including impaired insulin and glucagon-like peptide-1 secretion and increased glucagon release. In summary, these results suggest that the E23K/I337V polymorphism may have a diabetogenic effect via increased KATP channel activity in response to endogenous levels of LC-CoAs in tissues involved in the maintenance of glucose homeostasis.
 ...
PMID:Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes? 1451 49

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States and worldwide. In this review, we examine the scientific evidence in support of current dietary recommendations to increase fruit and vegetable intake for CVD prevention. Available evidence indicates that persons who consume more fruits and vegetables often have lower prevalence of important risk factors for CVD, including hypertension, obesity, and type 2 diabetes mellitus. Recent large, prospective studies also show a direct inverse association between fruit and vegetable intake and the development of CVD incidents such as coronary heart disease and stroke. However, the biologic mechanisms whereby fruits and vegetables may exert their effects are not entirely clear and are likely to be multiple. Many nutrients and phytochemicals in fruits and vegetables, including fiber, potassium, and folate, could be independently or jointly responsible for the apparent reduction in CVD risk. Functional aspects of fruits and vegetables, such as their low dietary glycemic load and energy density, may also play a significant role. Although it is important to continue our quest for mechanistic insights, given the great potential for benefits already known, greater efforts and resources are needed to support dietary changes that encourage increased fruit and vegetable intake.
 ...
PMID:Dietary intake of fruits and vegetables and risk of cardiovascular disease. 1452 83

Although cardiovascular mortality rates for the general population have declined during the past several decades, mortality among individuals with diabetes mellitus has increased. Given that the prevalence of type 2 diabetes is increasing dramatically and that current treatment strategies appear inadequate, there is a critical need for well-designed studies to address treatment of coronary artery disease in patients with diabetes to help guide clinical decision making in this setting. The Bypass Angioplasty Revascularization Investigation (BARI)-2D focuses on 2 specific treatment issues in the management of patients with type 2 diabetes. The first issue is the incremental value of early use of coronary revascularization procedures, and the second is the value of treating with an insulin-sensitizing agent versus an insulin-providing therapy. It is essential to determine whether treatment to enhance insulin sensitivity improves cardiovascular survival. Data indicate that outcomes of patients with diabetes and myocardial infarction are improved by administration of insulin or a regimen of glucose, insulin, and potassium (GIK). The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study showed that administration of an insulin infusion followed by subcutaneous insulin therapy for > or =3 months improved the long-term prognosis of diabetic patients with acute myocardial infarction. However, there appears to be a lack of acceptance of these interventions by health care providers. Clinical trials of GIK and insulin sensitizers are needed to define further the optimal treatment of patients with type 2 diabetes and cardiovascular disease.
 ...
PMID:Optimal care of patients with type 2 diabetes mellitus and coronary artery disease. 1467 73

ATP-sensitive potassium (K(ATP)) channels are crucial to pancreatic endocrine function and their activation by acyl coenzyme A esters (acyl CoAs) may disrupt hormone secretion, contributing to the pathophysiology of type 2 diabetes. The molecular mechanism of this activation is potentially important in our further understanding of this disease. We use excised patch-clamp techniques to assess the effects of N- and C-terminal Kir6.2 mutations on the activation of recombinant K(ATP) channels by palmitoyl CoA. We demonstrate that several residues previously shown to be involved in channel activation by the structurally related lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) also play a role in activation by acyl CoAs, including R54, R176, R192, and R301. Mutation of these residues caused decreased open probability in the absence of ATP and slower and greater relative activation by both PIP(2) and acyl CoAs. By contrast, K185Q, which probably alters ATP binding, had no effect on either PIP(2) or palmitoyl CoA activation. These findings suggest that activation by the two classes of lipids involves multiple common residues. We use the crystal structure of a related channel, KirBac1.1, as a template to locate the residues of interest in this study within a putative three-dimensional model of Kir6.2. We propose a model in which these residues mediate both direct electrostatic interactions and allosteric modulations of open state stability.
 ...
PMID:Activation of adenosine triphosphate-sensitive potassium channels by acyl coenzyme A esters involves multiple phosphatidylinositol 4,5-bisphosphate-interacting residues. 1469 85


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