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The E23K Variant of KCNJ11 Encoding the Pancreatic ß-Cell Adenosine 5'-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

Department of Experimental and Clinical Medicine (G.S., E.L., F.A., C.I., A.G., M.L.H., F.P.), University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy; Department of Internal Medicine (M.C., M.L.H., R.L.), University of Rome-Tor Vergata, 00133 Rome, Italy; and Department of Endocrinology and Metabolism (S.D.G., M.G., P.M.), Metabolic Unit, Cisanello Hospital, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Sperimentale e Clinica, Università Magna Græcia, Viale Europa, Località Germaneto, 88100 Catanzaro, Italy. E-mail: sesti{at}unicz.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking.

Objective: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure.

Design: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia.

Setting: The study was conducted in an ambulatory care facility.

Patients: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study.

Intervention: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment.

Main Outcome Measure: Secondary failure was the main outcome measure.

Results: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01–2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02–2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant.

Conclusions: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.

	Introduction

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MAINTENANCE OF NEAR-NORMAL glucose levels in type 2 diabetic patients has been shown to be associated with reduced risk of microvascular diabetes complications as well as a trend toward reduction of macrovascular events (1). Sulfonylurea monotherapy is initially successful in type 2 diabetes but it is often associated with secondary failure, which results in persistent hyperglycemia, thus contributing to the development of long-term diabetes complications (2). Secondary failure also occurs during multidrug therapy using a combination of sulfonylureas and oral antidiabetic agents with different mechanisms of action. It has been estimated that each year 5–7% of diabetic patients treated with sulfonylurea convert to insulin treatment progressively because sulfonylurea fails (3, 4), but the underlying mechanisms are still undefined. Although poor compliance with diet, gain in body weight, deterioration of insulin sensitivity, or presence of antiislet cell and glutamic acid decarboxylase antibodies have been evoked as causative factors, the progressive decline of pancreatic ß-cell function has been demonstrated to be the stronger predictor of the insulin-requiring stage in type 2 diabetes (5, 6, 7).

Sulfonylureas act by inhibiting the ATP-sensitive potassium (K_ATP) channels, which control the resting membrane potential of pancreatic ß-cells. A decrease in potassium outflow leads to plasma membrane depolarization, which results in the opening of voltage-gated calcium channels, influx of Ca²⁺, and eventually insulin exocytosis. K_ATP channels are heterooctameric protein complexes composed of four high-affinity sulfonylurea receptor (SUR1) subunits belonging to the ATP-binding cassette transporter family (8) coupled to four pore-forming inward-rectifier Kir6.2 subunits belonging to the Kir6.0 subfamily of the inward rectifier family (9). The human genes encoding Kir6.2 (KCNJ11) and SUR1 (ABCC8) are adjacent to one another on human chromosome 11p15.1 and have been considered plausible candidates for type 2 diabetes mellitus. Mice lacking the Kir6.2 gene are characterized by impaired glucose- and tolbutamide-induced insulin secretion (10). Loss-of-function polymorphisms in KCNJ11 have been associated with familial hyperinsulinemic hypoglycemia of infancy (11, 12), whereas gain-of-function polymorphisms have been associated with permanent neonatal diabetes (13) and classical form of type 2 diabetes (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). Among these, the common E23K polymorphism in KCNJ11 has been most extensively studied in classical form of type 2 diabetes. The E23K polymorphism was not significantly associated with type 2 diabetes in initial reports (14, 15, 16, 17), but more recent large-scale studies (20, 24, 25) and metaanalyses (18, 20, 22, 24) strongly indicate that the minor K allele is associated with type 2 diabetes. Some (22, 24) but not all studies (14, 15, 16, 17) have shown that carriers of the K allele exhibit decreased insulin secretion. At the cellular mechanistic level, electrophysiological studies in the COS-1 cell line have shown that K_ATP channels composed of the K variant have a significantly higher open probability, i.e. a reduced sensitivity toward inhibitory ATP; thus, in ß-cells they would increase the threshold of ATP concentration required for insulin secretion (26).

To test the intriguing hypothesis that diabetic patients carrying the KCNJ11 K allele are at increased risk for secondary failure to sulfonylurea, we proceeded to analyze the prevalence of the E23K variant in an Italian cohort of 525 type 2 diabetic patients with and without secondary failure to sulfonylurea. In addition, we evaluated insulin secretion in pancreatic islets isolated from 32 nondiabetic donors carrying the three genotypes.

	Subjects and Methods

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Experimental subjects

The study group consisted of 525 unrelated Caucasian type 2 diabetic patients who were consecutively recruited according to the following criteria: men and women with onset of diabetes after the age of 35 yr, absence of ketonuria at diagnosis, and negativity for antiglutamic acid decarboxylase antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria (27). Patients were excluded if they had chronic gastrointestinal diseases associated with malabsorption; chronic pancreatitis; history of any malignant disease; history of alcohol or drug abuse; liver or kidney failure; or clinical problems potentially causing hyperglycemia including infection, thyroid disease, surgery, and treatments known to modify glucose metabolism such as corticosteroids or estrogens. In addition to appropriate diet, all patients were treated with glibenclamide up to 15 mg/d until their plasma glucose rose to more than 300 mg/dl in two different determinations or they developed hyperglycemic symptoms (typically thirst or polyuria). At this point metformin was added in most patients (168 of 208) up to 1700 mg/d. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to rise in fasting plasma glucose more than 300 mg/dl despite sulfonylurea-metformin combined therapy, appropriate diet (i.e. iso- or hypocaloric diet depending on presence of overweight), and absence of any independent conditions causing hyperglycemia. The protocol was approved by the ethical committee, and informed written consent was obtained from all participants. All the investigations were performed in accordance with the principles of the Declaration of Helsinki.

Biochemical assays

Fasting glucose, total and high-density lipoprotein cholesterol, and triglyceride plasma concentrations were measured by enzymatic methods (Roche Diagnostics GmbH, Mannheim, Germany). Hemoglobin A1c concentrations were analyzed by HPLC (Menarini Diagnostics, Grassina, Florence, Italy), with coefficients of variation less than 4%.

DNA genotyping

Genomic DNA was isolated from peripheral blood according to standard procedures. The E23K variant of KCNJ11 (rs5219) was detected by digestion of PCR products with restriction enzyme BanII (New England Biolabs, Beverly, MA) as previously described (15, 22). To validate the fidelity of our genotyping method, the genotype of 150 patients was confirmed by direct sequencing.

Human pancreatic islet studies

Within the framework of a project aiming to evaluate the potential of human islet transplantation as a treatment for type 1 diabetic patients, we received and processed (with the approval of the Ethics Committee of the University of Pisa) pancreata (not suitable for whole-gland transplantation) from 32 nondiabetic, nonobese multiorgan donors (15 males, 17 females). The mean age of the donors was 49 ± 19 yr and mean body mass index (BMI) was 23.7 ± 3.2. Cause of death was trauma (14 cases) or cerebrovascular disease (18 cases). The islets were isolated by enzymatic digestion and density gradient purification, as previously described (28, 29, 30). At the end of the isolation procedure, the islets were placed in M199 culture medium containing 5.5 mmol/liter glucose, cultured in a CO₂ incubator, and studied within 3–4 d from isolation. Islet cell viability was assessed by the fluorescein diacetate/propidium iodide method (31), and insulin secretion studies were performed by the batch incubation method, as previously described (28, 29, 30). In these experiments, three to five batches at any given experimental condition were used for each separate islet preparation. After a 45-min preincubation period at 3.3 mmol/liter glucose in Krebs-Ringer bicarbonate solution (KRB), 0.5% albumin (pH 7.4), groups of approximately 30 islets of comparable size were kept at 37 C for 45 min in KRB containing 3.3 mmol/liter glucose. At the end of this period, medium was completely removed and replaced with KRB containing 3.3 mmol/liter glucose, 16.7 mmol/liter glucose, or 3.3 mmol/liter glucose plus 100 µmol/liter glibenclamide. After an additional 45-min incubation, medium samples were collected and stored at –20 C until insulin concentrations were measured by immunoradiometric assay (Pantec Forniture Biomediche, Turin, Italy). Whenever the amount of isolated islets allowed us to carry out additional experiments, we also performed insulin secretion studies after a 24-h preincubation in M199 medium containing 16.7 mmol/liter glucose.

Statistical analysis

Categorical variables were compared by ² test. Continuous data are shown as means ± SD. Normal distribution of variables was checked with the Kolmogorov-Smirnov (Lilliefors) test, and logarithmic transformation was used for those not normally distributed. For some statistical comparisons with the E/E homozygous, patients carrying the K allele (E/K heterozygous and K/K homozygous) were combined. Comparisons between genotypes were made using the unpaired Student’s t test (E/E vs. E/K plus K/K) or ANOVA for the three genotypes groups. The Hardy-Weinberg equilibrium between the two genotypes was evaluated by ² test. The odds ratio (OR) for a possible influence of the E23K variant on secondary failure to sulfonylurea was calculated using a logistic regression analysis and adjusting for age, gender, fasting plasma glucose levels, glycosylated hemoglobin concentrations, BMI, age at diagnosis, and duration of diabetes. Relative risk is presented as OR with 95% confidence intervals (CIs). All tests were two sided, and P < 0.05 was considered statistically significant. All analyses were performed using SPSS software (version 12.0 for Windows, SPSS Inc., Chicago, IL). The false-positive report probability was calculated according to Wacholder et al. (31) using an Excel spreadsheet included with the online material (http://jncicancerspectrum.oupjournals.org/jnci/content/vol96/issue6).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We first investigated whether the KCNJ11 E23K variant was associated with increased risk for secondary failure to sulfonylurea in 525 patients with type 2 diabetes. The clinical characteristics of the study subjects stratified according to therapy and genotype are reported in Table 1. Patients with secondary failure to sulfonylurea showed significant differences in age (P < 0.001), duration of the disease (P < 0.0001), age at clinical diagnosis (P < 0.0001), fasting plasma glucose levels (P < 0.0001), and glycosylated hemoglobin concentrations (P < 0.001), as compared with patients who did not fail to sulfonylurea. Of the total patients, 202 (38.5%) were E23E homozygous, 270 were E23K heterozygous (51.4%), and the remainder (10.1%) were K23K homozygous. The genotype frequency was in Hardy-Weinberg equilibrium. Among patients who did not fail to sulfonylurea, carriers of the K allele were younger (P < 0.03) and had an earlier age at diagnosis of diabetes (P < 0.03) as compared with E23E homozygous (Table 1). In addition, carriers of the K allele showed an increase in fasting plasma glucose (P < 0.0001) and glycosylated hemoglobin concentrations (P < 0.01, Table 1). Among patients with secondary failure, no differences in age, and age at diagnosis of diabetes were observed between carriers of the K allele and E23E homozygous (Table 1). Carriers of the K allele showed a tendency toward shorter duration of therapy with oral agents before failure (P < 0.41). Furthermore, the frequency of carriers of the K allele (E23K heterozygous + K23K homozygous) was 58% among diabetic patients who did not fail to sulfonylurea and 66.8% among patients with secondary failure to sulfonylurea (Table 1). Thus, the KCNJ11 E23K variant was associated with secondary failure to sulfonylurea with carriers of the K allele having a relative risk of 1.45 (95% CI 1.01–2.09; P = 0.04) as compared with E23E homozygous. Adjustment for age, gender, fasting plasma glucose levels, glycosylated hemoglobin concentrations, BMI, age at diagnosis, and duration of diabetes in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (OR 1.69, 95% CI 1.02–2.78; P = 0.04). The false-positive report probability calculation suggests that these data are compatible with a true association.

View larger version (22K): [in this window] [in a new window]   FIG. 1. Insulin secretion in four E23E homozygous donors and four donor carriers of the K allele (three E23K heterozygous and one K23K homozygous). Islets were precultured in M199 culture medium containing 16.7 mmol/liter glucose for 24 h and then acutely (45 min) challenged with 3.3 mmol/liter glucose (black bars), 16.7 mmol/liter glucose (gray bars), or 100 µmol/liter glibenclamide (white bars). Results are expressed as mean ± SD.

	Discussion

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Our observations are consistent with biochemical studies with the COS-1 cell line expressing the Kir6.2 E23K variant, showing that the channels composed from either one or two mutant alleles exhibited altered functionality (26). However, we did not observe altered secretory response to glucose stimulus. These ex vivo data are in agreement with some (16, 17) but not all previous in vivo studies (22, 23, 24). It is possible that differences in the route of glucose administration (orally vs. iv) might in part account for these discrepancies. In addition, it has been shown that the E23K variant is associated with a diminished suppression of glucagon secretion in response to glucose (36). Although in the present study we did not measure glucagon release from human islets, it is possible that the presence of the E23K variant perturbs normal intraislet communication between - and ß-cells, resulting in impaired insulin secretion in vivo.

In the genotype-phenotype study, we found that the E23K variant in KCNJ11 was associated with an early onset of diabetes and worsening metabolic control in the subgroup of patients who did not fail with sulfonylurea. However, in the group of patients with secondary failure, no differences in age at diagnosis of diabetes and metabolic control were observed between carriers of the K allele and E23E homozygous, although carriers of the K allele showed a tendency toward shorter duration of therapy with oral agents before failure. The reasons for this discrepancy are unclear. More importantly, we showed that the KCNJ11 E23K variant is associated with increased risk for secondary sulfonylurea failure. This finding is in accordance with the present ex vivo observation showing that the E23K variant is associated with reduced insulin secretion in response to sulfonylurea as well as with the previous in vitro study, demonstrating that this variant is associated with reduced ATP sensitivity of the Kir6.2/SUR1 channel complex (26).

Our data are in contrast with a previous study carried out in a cohort of 364 newly diagnosed diabetic patients participating in the U.K. Prospective Diabetes Study (UKPDS) (19). The authors did not find any significant association of the E23K variant with the response to sulfonylurea therapy. It is possible that differences in the definition of secondary sulfonylurea failure might account for these divergent results. In the UKPDS report, authors classified as failures the patients on sulfonylurea therapy who required additional therapy (sulfonylurea + metformin, sulfonylurea + insulin, or insulin alone) when their fasting plasma glucose rose to more than 300 mg/dl. In our study, patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose > 300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any independent condition causing hyperglycemia. Further differences that may explain the divergent results between the two studies include the mean duration of therapy with oral agents before failure (1 yr after randomization in the UKPDS vs. 12 yr in the present study), the type of sulfonylurea (chlorpropamide in the UKPDS vs. glibenclamide in the present study), and the clinical characteristics of patients (newly diagnosed patients aged 25–65 yr in the UKPDS vs. patients with known diabetes diagnosed at older than 35 yr in the present study).

Our study has limitations that require consideration. First, the two diabetic groups differ in some characteristics such as age, duration of diabetes, age at diagnosis, and glycemic control. Although we adjusted in a logistic regression analysis for these confounders, it is possible that the association observed is related to other characteristics, such as mortality. Second, although there is evidence that the type of sulfonylurea may influence the development of secondary failure (4), our data do not allow comparison between different types of sulfonylurea. Third, the design of our study did not allow evaluation of dose-response effects. However, the dose of glibenclamide used is the highest routinely given for this agent. Finally, the proportion of the variance that can be explained by the E23K variant in KCNJ11 is small in comparison with the expected influence of clinical determinants such as compliance and diet. Future longitudinal studies comparing different types of sulfonylurea and different doses are needed to address these issues.

In conclusion, the present data demonstrate that the common E23K variant in KCNJ11 is associated with increased risk for secondary failure to sulfonylurea in type 2 diabetes patients. In vivo and ex vivo studies support the idea that this variant may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes mellitus.

	Acknowledgments

 
We are grateful to Drs. Simona Frontoni and Maria Adelaide Marini for their help in patient recruitment and to Cristina Ricasoli for her expert technical assistance in genotyping.

	Footnotes

 
This work was supported in part by grants from the European Community’s FP6 EUGENE2 no. LSHM-CT-2004-512013 (to G.S.); Progetto di Ricerca Finalizzata, Ministero della Sanità (to G.S.); and PRIN-COFIN 2003 (no. 2003067733-02), Ministero dell’Università e Ricerca Scientifica e Tecnologica (to G.S.).

First Published Online April 4, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; K_ATP, ATP-sensitive potassium; KRB, Krebs-Ringer bicarbonate solution; OR, odds ratio; SUR1, sulfonylurea receptor; UKPDS, U.K. Prospective Diabetes Study.

Received October 21, 2005.

Accepted March 29, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. U.K. Prospective Diabetes Study Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). U.K. Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853[CrossRef][Medline]
2. Pontiroli AE, Calderara A, Pozza G 1994 Secondary failure to oral hypoglycaemic agents: frequency, possible causes, and management. Diabetes Metab Rev 10:31–43[Medline]
3. U.K. Prospective Diabetes Study Group 1995 U.K. Prospective Diabetes Study 16-overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258[Abstract]
4. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC 1998 UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Med 15:297–303[CrossRef][Medline]
5. Fukui M, Nakano K, Shigeta H, Yoshimori K, Fujii M, Kitagawa Y, Mori H, Kajiyama S, Nakamura N, Abe N, Obayashi H, Fukui I, Ohta K, Ohta M, Kondo M 1997 Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy. Diabet Med 14:148–152[CrossRef][Medline]
6. Taverna MJ, Pacher N, Bruzzo F, Slama G, Selam JL 2001 ß-Cell function evaluated by HOMA as a predictor of secondary sulphonylurea failure in type 2 diabetes. Diabet Med 18:584–588[CrossRef][Medline]
7. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR 1998 ß-Cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med 15:290–296[CrossRef][Medline]
8. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, Gonzblez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA 1995 Cloning of the ß cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268:423–426[Abstract/Free Full Text]
9. Seino S, Inagaki N, Namba N, Gonoi T 1996 Molecular biology of the ß-cell ATP-sensitive K⁺ channel. Diabetes Rev 4:177–190
10. Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S 1998 Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci USA 95:10402–10406[Abstract/Free Full Text]
11. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, Landau H, Stanley CA, Thornton PS, Seino S, Permutt MA 1997 A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46:1743–1748[Abstract]
12. Thomas P, Ye Y, Lightner E 1996 Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycaemia of infancy. Hum Mol Genet 5:1809–1812[Abstract/Free Full Text]
13. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT 2004 Activating mutations in the gene encoding the ATP-sensitive potassium channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849[Abstract/Free Full Text]
14. Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM 1996 Sequence variations in the human Kir6.2 gene, a subunit of the ß-cell ATP-sensitive K-channel: no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia 39:1233–1236[Medline]
15. Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, Elbein SC, Hampe CL, Suarez BK, Inagaki N, Seino S, Permutt MA 1997 Sequence variants in the pancreatic islet ß-cell inwardly rectifying K channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes 46:502–507[Abstract]
16. Hansen L, Echwald SM, Hansen T, Urhammer SA, Clausen JO, Pedersen O 1997 Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes 46:508–512[Abstract]
17. ’t Hart LM, van Haeften TW, Dekker JM, Bot M, Heine RJ, Maassen JA 2002 Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K⁺ channel in the ß-cell. Diabetes 51:3135–3138[Abstract/Free Full Text]
18. Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P 1998 Missense mutations in the pancreatic islet ß cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 41:1511–1515[CrossRef][Medline]
19. Gloyn AL, Hashim Y, Ashcroft SJH, Ashfield R, Wiltshire S, Turner RC 2001 Association studies of variants in promoter and coding regions of ß-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53). Diabet Med 18:206–212[CrossRef][Medline]
20. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM 2003 Large-scale association studies of variants in genes encoding the pancreatic ß-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572[Abstract/Free Full Text]
21. Love-Gregory L, Wasson J, Lin J, Skolnick B, Suarez B, Permutt MA 2003 An E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPAR- Pro12Ala variant. Diabetologia 46:136–137[Medline]
22. Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O 2003 The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 52:573–577[Abstract/Free Full Text]
23. Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ 2003 Candidate gene association study in type 2 diabetes indicates a role for genes involved in ß-cell function as well as insulin action. PLoS Biol 1:41–55
24. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D 2004 Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53:1360–1368[Abstract/Free Full Text]
25. Hansen SK, Nielsen E-MD, Ek J, Andersen G, Glumer C, Carstensen B, Mouritzen P, Drivsholm T, Borch-Johnse K, Jørgensen T, Hansen T, Pedersen O 2005 Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J Clin Endocrinol Metab 90:3629–3637[Abstract/Free Full Text]
26. Schwanstecher C, Meyer U, Schwanstecher M 2002 KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic ß-cell ATP-sensitive K+ channels. Diabetes 51:875–879[Abstract/Free Full Text]
27. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1998 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 21:S5–S19
28. Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, Torri S, Pollera M, Boggi U, Mosca F, Del Prato S, Marchetti P 2005 Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54:727–735[Abstract/Free Full Text]
29. Federici M, Hribal ML, Ranalli M, Marselli L, Porzio O, Lauro D, Borboni P, Lauro R, Marchetti P, Melino G, Sesti G 2001 The common Arg⁹⁷² polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. FASEB J 15:22–24[Free Full Text]
30. Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, Del Guerra S, Patane G, Piro S, Anello M, Bergamini E, Purrello F, Lauro R, Mosca F, Sesti G, Del Prato S 2002 Insulin secretory function is impaired in isolated human islets carrying the Gly(972)->Arg IRS-1 polymorphism. Diabetes 51:1419–1424[Abstract/Free Full Text]
31. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N 2004 Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442[Abstract/Free Full Text]
32. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H 2003 Glucose toxicity in ß-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581–587[Abstract/Free Full Text]
33. Davalli AM, Pontiroli AE, Socci C, Bertuzzi F, Fattor B, Braghi S, Di Carlo V, Pozza G 1992 Human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely: evidence supporting specific desensitization rather than ß-cell exhaustion. J Clin Endocrinol Metab 74:790–794[Abstract]
34. Lupi R, Del Guerra S, Tellini C, Giannarelli R, Coppelli A, Lorenzetti M, Carmellini M, Mosca F, Navalesi R, Marchetti P 1999 The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose. Eur J Pharmacol 364:205–209[CrossRef][Medline]
35. Rustenbeck I 2002 Desensitization of insulin secretion. Biochem Pharmacol 63:1921–1935[CrossRef][Medline]
36. Tschritter O, Stumvoll M, Machicao F, Holzwarth M, Weisser M, Maerker E, Teigeler A, Sring H, Fritsche A 2002 The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia. Diabetes 51:2854–2860[Abstract/Free Full Text]

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