Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enteroendocrine (EE) cells represent complex, rare, and diffusely-distributed intestinal epithelial cells making them difficult to study in vivo. A specific sub-population of EE cells called Gut K-cells produces and secretes glucose-dependent insulinotropic peptide (GIP), a hormone important for glucose homeostasis. The factors that regulate hormone production and secretion, as well as the timing of peptide release, are remarkably similar for K-cells and islet beta-cells suggesting engineering insulin production by K-cells is a potential gene therapeutic strategy to treat diabetes. K-cell lines could be used to study the feasibility of this potential therapy and to understand Gut K-cell physiology in general. Heterogeneous STC-1 cells were transfected with a plasmid (pGIP/Neo) encoding neomycin phosphotransferase, driven by the GIP promoter-only cells in which the GIP promoter was active survived genetic selection. Additional clones expressing pGIP/Neo plus a GIP promoter/insulin transgene were isolated-only doubly transfected cells produced preproinsulin mRNA. Bioactive insulin was stored and then released following stimulation with arginine, peptones, and bombesin-physiological GIP secretagogues. Like K-cells in vivo, the GIP/insulin-producing cells express the critical glucose sensing enzyme, glucokinase. However, glucose did not regulate insulin or GIP secretion or mRNA levels. Conversely, glyceraldehyde and methyl-pyruvate were secretagogues, indicating cells depolarized in response to changes in intracellular metabolite levels. Potassium channel opening drugs and sulphonylureas had little effect on insulin secretion by K-cells. The K-cell lines also express relatively low levels of Kir 6.1, Kir 6.2, SUR1, and SUR2 suggesting secretion is independent of K(ATP) channels. These results provided unexpected insights into K-cell physiology and our experimental strategy could be easily modified to isolate/characterize additional EE cell populations.
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PMID:Novel insulin/GIP co-producing cell lines provide unexpected insights into Gut K-cell function in vivo. 1212 79

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to carbohydrate and fat in the diet. Despite the interest in GLP-1 as an antidiabetic agent, very little is known about the mechanism of stimulus-secretion coupling in L-cells. We investigated the electrophysiological events underlying glucose-induced GLP-1 release in the GLP-1-secreting cell line, GLUTag. Cells were studied using perforated-patch and standard whole-cell patch clamp recordings. GLUTag cells were largely quiescent and hyperpolarized in the absence of glucose. Increasing the glucose concentration between 0 and 20 mmol/l decreased the membrane conductance, caused membrane depolarization, and triggered the generation of action potentials. Action potentials were also triggered by tolbutamide (500 micro mol/l) and were suppressed by diazoxide (340 micro mol/l) or the metabolic inhibitor azide (3 mmol/l), suggesting an involvement of K(ATP) channels. Large tolbutamide-sensitive washout currents developed in standard whole-cell recordings, confirming the presence of K(ATP) channels. RT-PCR detected the K(ATP) channel subunits Kir6.2 and SUR1 and glucokinase. GLP-1 secretion was also stimulated by glucose over the concentration range 0-25 mmol/l and by tolbutamide. Our results suggest that glucose triggers GLP-1 release through closure of K(ATP) channels and action potential generation.
Diabetes 2002 Sep
PMID:Glucose-sensing in glucagon-like peptide-1-secreting cells. 1219 69

Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules.
Diabetes 2002 Sep
PMID:Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. 1219 72

An association between type 2 diabetes and genetic variation in the KIR6.2 gene has been reported in several populations. Based on in vitro studies with cell lines expressing the Glu(23)Lys (E23K) mutation, it was recently suggested that this mutation might result in altered insulin secretion. We have examined glucose-stimulated insulin secretion in relation to this KIR6.2 gene variant in two independent Dutch cohorts. Subjects with normal (n = 65) or impaired (n = 94) glucose tolerance underwent 3-h hyperglycemic clamps at 10 mmol/l glucose. We did not observe significant differences in first- or second-phase insulin secretion between carriers and noncarriers of the gene variant in either of the study populations (all P > 0.45). Furthermore, we found no evidence for a significant interaction with disease-associated gene variants in the sulfonylurea receptor (SUR1) gene. We conclude that the E23K mutation in the KIR6.2 gene is not associated with detectable alterations in glucose-stimulated insulin secretion in two independent populations from the Netherlands.
Diabetes 2002 Oct
PMID:Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta-cell. 1235 59

The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.
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PMID:Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. 1243 93

Sulfonylureas are widely used to treat type 2 diabetes because they stimulate insulin secretion from pancreatic beta-cells. They primarily act by binding to the SUR subunit of the ATP-sensitive potassium (K(ATP)) channel and inducing channel closure. However, the channel is still able to open to a limited extent when the drug is bound, so that high-affinity sulfonylurea inhibition is not complete, even at saturating drug concentrations. K(ATP) channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of different SUR subunits that confer different drug sensitivities. Thus tolbutamide and gliclazide block channels containing SUR1 (beta-cell type), but not SUR2 (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. This difference has been exploited to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea block is decreased by mutations or agents (e.g., phosphatidylinositol bisphosphate) that increase K(ATP) channel open probability. We now propose a kinetic model that explains this effect in terms of changes in the channel open probability and in the transduction between the drug-binding site and the channel gate. We also clarify the mechanism by which MgADP produces an apparent increase of sulfonylurea efficacy on channels containing SUR1 (but not SUR2).
Diabetes 2002 Dec
PMID:Sulfonylurea stimulation of insulin secretion. 1247 77

The NH(2)- and COOH-termini of the ATP-sensitive potassium (K(ATP)) channel pore-forming subunit, Kir6.2, both lie intracellularly and interact with one another. To study this interaction, cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) were fused to the NH(2)- and COOH-termini of Kir6.2, respectively (CFP-Kir6.2-YFP). These fluorescent proteins have sufficient spectral overlap to allow distance-dependent fluorescence resonance energy transfer (FRET). When CFP-Kir6.2-YFP was expressed in human embryonic kidney cells and illuminated at 440 nm to excite CFP, significant fluorescence was recorded at 535 nm, the peak of the YFP emission spectrum. This indicated that FRET was occurring and thus that the NH(2)- and COOH-termini of Kir6.2 lie in close proximity to one another. The emission ratio, F(535)/F(480), was increased by co-expression of SUR2A, but not SUR1, suggesting that SUR2A but not SUR1 influences the Kir6.2 NH(2)- and COOH-terminal interaction. This interaction was reduced by the sulfonylureas tolbutamide and gliclazide, but not by the pore blocker barium. The properties of the tolbutamide response indicate that the drug disrupts the interaction between the NH(2)- and COOH-termini of Kir6.2 by binding to a low-affinity site on Kir6.2.
Diabetes 2002 Dec
PMID:Interaction of the cytosolic domains of the Kir6.2 subunit of the K(ATP) channel is modulated by sulfonylureas. 1247 78

With ATP sites on K(ir)6.2 that inhibit activity and ADP sites on SUR1 that antagonize the inhibition, ATP-sensitive potassium channels (K(ATP) channels) are designed as exquisite sensors of adenine nucleotide levels that signal changes in glucose metabolism. If pancreatic K(ATP) channels localize to the insulin secretory granule, they would be well positioned to transduce changes in glucose metabolism into changes in granule transport and exocytosis. Tests for pancreatic K(ATP) channels localized to insulin secretory granules led to the following observations: fluorescent sulfonylureas that bind the pancreatic K(ATP) channel specifically label intracellular punctate structures in cells of the endocrine pancreas. The fluorescent glibenclamides colocalize with Ins-C-GFP, a live-cell fluorescent reporter of insulin granules. Expression of either SUR1-GFP or K(ir)6.2-GFP fusion proteins, but not expression of GFP alone, directs GFP fluorescence to insulin secretory granules. An SUR1 antibody specifically labels insulin granules identified by anti-insulin. Two different K(ir)6.2 antibodies specifically label insulin secretory granules identified by anti-insulin. Immunoelectron microscopy showed K(ir)6.2 antibodies specifically label perimeter membrane regions of the secretory granule. Relatively little or no labeling of other structures, including the plasma membrane, was found. Our results demonstrate that the insulin secretory granule is the major site of K(ATP) channels of the endocrine pancreas.
Diabetes 2003 Mar
PMID:The insulin secretory granule is the major site of K(ATP) channels of the endocrine pancreas. 1260 19

K(ATP) channels are present in pancreatic and extrapancreatic tissues such as heart and smooth muscle, and display diverse molecular composition. They contain two different structural subunits: an inwardly rectifying potassium channel subunit (Kir6.x) and a sulfonylurea receptor (SURX). Recent studies on genetically engineered Kir6.2 knockout mice have provided a better understanding of the physiological and pathophysiological roles of Kir6.2-containing K(ATP) channels. Kir6.2/SUR1 has a pivotal role in pancreatic insulin secretion. Kir6.2/SUR2A mediates the effects of K(ATP) channels openers on cardiac excitability and contractility and contributes to ischemic preconditioning. However, controversy remains on the physiological properties of the K(ATP) channels in vascular smooth muscle cells. Kir6.1 knockout mice exhibit sudden cardiac death due to cardiac ischemia, indicating that Kir6.1 rather than Kir6.2 is critical in the regulation of vascular tone. This article summarizes current understanding of the physiology and pathophysiology of Kir6.1- and Kir6.2-containing K(ATP) channels.
J Diabetes Complications
PMID:Physiology and pathophysiology of K(ATP) channels in the pancreas and cardiovascular system: a review. 1262 61

The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs exhibit differences in tissue specificity, as the drugs interact to varying degrees with different types of SUR. Gliclazide and tolbutamide are beta-cell selective and reversible. Glimepiride, glibenclamide, and repaglinide, however, inhibit cardiac and smooth muscle K(ATP) channels in addition to those in beta-cells and are only slowly reversible. Similar properties have been observed by recording K(ATP) channel activity in intact cells and in Xenopus oocytes expressing cloned K(ATP) channel subunits. While K(ATP) channels in cardiac and smooth muscle are largely closed under physiological conditions (but open during ischaemia), they are activated by antianginal agents such as nicorandil. Under these conditions, they may be inhibited by sulphonylureas that block SUR2-type K(ATP) channels (e.g., glibenclamide). Care should, therefore, be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K(ATP) channels are to be avoided.
J Diabetes Complications
PMID:Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. 1262 63


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