The E23K polymorphism of the KCNJ11gene is associated with lower insulin release in patients with Autosomal Dominant Polycystic Kidney Disease
, Maria Pietrzak-Nowackab, Krzysztof Safranowc, Agnieszka Binczak-Kuletad, Leszek Domanskib, Andrzej Ciechanowiczd, Kazimierz Ciechanowskib
b Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland,
c Department of Biochemistry and Medical Chemistry, Pomeranian Medical University., Szczecin, Poland,
d Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University, Szczecin, Poland,
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Some studies<span class="elsevierStyleSup">1,5</span> have shown that the K allele may have a diabetogenic effect by impairing glucose-induced insulin release.</p><p class="elsevierStylePara">The aim of our study was to investigate an association between E23K <span class="elsevierStyleItalic">KCNJ11 </span>gene polymorphism with anthropometric, biochemical, b-cell secretion and insulin sensitivity parameters among adult ADPKD patients with normal kidney function and no diagnosis of diabetes. The comparison of genotype-phenotype associations between ADPKD and non-ADPKD subjects could reveal a hypothetical mechanism of genetic determination of diabetes specific for ADPKD patients.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">METHODS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The study group included 49 adult individuals with diagnosed ADPKD (19 males, 30 females) while the control group comprised 50 gender- and age-matched healthy individuals (22 males, 28 females).</p><p class="elsevierStylePara">The oral glucose tolerance test (OGTT) was performed according to WHO guidelines (with 75 g of glucose).<span class="elsevierStyleSup">6</span> Venous blood was collected to measure fasting glucose, insulin, total cholesterol, LDL, HDL and triglyceride levels. Glucose concentration was measured by an enzymatic-amperometric method (Super GL; Dr Müller Gerätebau GmbH, Freital, Germany). Insulin concentration was measured by microparticle enzyme immunoassay (AxSYM MEIA; Abbott Laboratories, Abbot Park, USA. For serum creatinine and lipid levels a Cobas Integra 800 bioanalyser was used.</p><p class="elsevierStylePara">The beta-cell function indexes were used in our study; ratios of insulin-to-glucose concentrations for each OGTT time point (INS/GLU 0, 30, 60, 90, 120), ratio of the area under curve of insulin (AUC Insulin) and glucose (AUC Glucose) concentrations (SECR AUC), secretory 1<span class="elsevierStyleSup">st</span> phase (SECR1P) and 2<span class="elsevierStyleSup">nd</span> phase (SECR2P) calculated from the first 30 or 60 minutes of OGTT (SECR1P 30 min, SECR1P 60 min, SECR2P 30 min, SECR2P 60 min), insulinogenic index (INSGENIN), and insulin sensitivity indexes: insulin sensitivity composite index (ISI COMP), and Cederholm sensitivity index (ISI CEDE). The formulas of these indexes were presented in our previous study.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">The genotypes of G67A (E23K) <span class="elsevierStyleItalic">KCNJ11 </span>polymorphism (rs5219) were determined using a by PCR-RFLP technique, as described previously.<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">Mann-Whitney test was used for quantitative variables, while the Fisher exact test was implemented for qualitative variables.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Differences in E23K <span class="elsevierStyleItalic">KCNJ11 </span>genotype distribution among ADPKD patients (33% EE, 51% EK, 16% KK) and controls (46% EE, 42% EK, 12% KK) proved insignificant (p=.39). Both distributions were consistent with Hardy-Weinberg equilibrium (p>.7).</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">ADPKD group</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">KK homozygotes were significantly younger than allele E carriers. Other anthropometric parameters were not associated with genotype (Table 1).</p><p class="elsevierStylePara">There was a trend to lower serum total cholesterol concentration among KK homozygotes if compared to E allele carrriers, but HDL-cholesterol was significantly lower among K allele carriers in comparison to EE homozygotes (Table 1). Glucose levels during OGTT did not differ significantly between the genotypes, but we have found trend to lower insulin levels among K allele carriers than in EE homozygotes in the 30<span class="elsevierStyleSup">th</span> minute of OGTT (Table 2). Similarly, in the 60<span class="elsevierStyleSup">th</span> minute of the test, there was a trend to lower insulin levels among KK homozygotes than in E allele carriers. INS/GLU 30 min ratio and values of the SECR1P 30 min, SECR2P 30 min and INSGENIN indexes were significantly lower among K allele carriers than in EE homozygotes. No significant associations between <span class="elsevierStyleItalic">KCNJ11 </span>E23K genotype and other carbohydrate metabolism parameters were observed (Table 2).</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Control group</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Among KK homozygotes, in comparison to E allele carriers, significantly lower glucose levels in the 60<span class="elsevierStyleSup">th</span> minute of OGTT as well as lower insulin levels in the 60<span class="elsevierStyleSup">th</span> and 120<span class="elsevierStyleSup">th</span> minute of OGTT were observed – a similar trend was observed for insulin in the 90<span class="elsevierStyleSup">th</span> minute. Moreover, lower values of INS/GLU 60 min and INS/GLU 120 min ratios as well as area under curve (AUC) for insulin were observed among KK homozygous subjects. A trend to lower SECR AUC and SECR2P 60 secretory indexes was found in KK homozygotes when compared to E allele carriers. The remaining indexes of the pancreatic b-cell secretory function, insulin sensitivity (Table 2), lipid metabolism and anthropometric parameters (Table 1) did not significantly differ between the genotype groups.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Our report is the first evaluation of the association between E23K polymorphism of the <span class="elsevierStyleItalic">KCNJ11</span> gene and anthropometry, lipid and glucose metabolism parameters in a homogenous group of patients with ADPKD.</p><p class="elsevierStylePara">The results obtained in this study reveal an association between the <span class="elsevierStyleItalic">KCNJ11 </span>E23K variant and lower insulin secretion during OGTT among non-diabetic patients with ADPKD and non-ADPKD controls. In patients with ADPKD such an influence was observed for carriers of one or two K alleles, while among controls it was significant only among KK homozygotes. Results of clinical studies on the E23K polymorphism indicated that among non-diabetic subjects<span class="elsevierStyleSup">9</span> IGT diagnosed individuals<span class="elsevierStyleSup">10</span> or patients with diabetes type 2<span class="elsevierStyleSup">11</span> the K23 variant is significantly associated with lower insulin secretion during OGTT. Our study confirmed this association for ADPKD patients, but it is possible that the model of genotype-phenotype association in ADPKD and non-ADPKD subjects is different (eg. dominant vs. recessive). Such results support the necessity for further study on the influence of this variant on the risk of pre- and post-transplant diabetes development among ADPKD patients. It is possible that contrasting research results on the frequency of post-transplant diabetes in this group of patients will be clarified in the future by genetic studies.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article.</p><p class="elsevierStylePara"><a href="grande/12111_16025_46176_en_t112111.jpg" class="elsevierStyleCrossRefs"><img src="12111_16025_46176_en_t112111.jpg" alt="Association between the G67A (rs5219 E23K) variant of the KCNJ11 gene and anthropometric and biochemical parameters among ADPKD and control groups"></img></a></p><p class="elsevierStylePara">Table 1. Association between the G67A (rs5219 E23K) variant of the KCNJ11 gene and anthropometric and biochemical parameters among ADPKD and control groups</p><p class="elsevierStylePara"><a href="grande/12111_16025_46179_en_t2121112.jpg" class="elsevierStyleCrossRefs"><img src="12111_16025_46179_en_t2121112.jpg" alt="Association between (rs5219 E23K) variant of the KCNJ11 gene and insulin sensitivity and pancreatic beta-cell secretory function parameters among ADPKD and control groups"></img></a></p><p class="elsevierStylePara">Table 2. Association between (rs5219 E23K) variant of the KCNJ11 gene and insulin sensitivity and pancreatic beta-cell secretory function parameters among ADPKD and control groups</p>" "pdfFichero" => "P1-E562-S4417-A12111-EN.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12111_16025_46176_en_t112111.jpg" "Alto" => 1113 "Ancho" => 2164 "Tamanyo" => 834766 ] ] "descripcion" => array:1 [ "en" => "Association between the G67A (rs5219 E23K) variant of the KCNJ11 gene and anthropometric and biochemical parameters among ADPKD and control groups" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12111_16025_46179_en_t2121112.jpg" "Alto" => 983 "Ancho" => 2151 "Tamanyo" => 782718 ] ] "descripcion" => array:1 [ "en" => "Association between (rs5219 E23K) variant of the KCNJ11 gene and insulin sensitivity and pancreatic beta-cell secretory function parameters among ADPKD and control groups" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al. 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The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 2003;52:573-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12540638" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, et al. Sequence variants in the pancreatic islet beta-cell inwardly rectifying K channel Kir6.2(Bir) gene. Diabetes 1997;46:502-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9032109" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Alberti KG, Zimmet PZ. 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| Year/Month | Html | Total | |
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| 2024 October | 36 | 32 | 68 |
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| 2023 September | 29 | 24 | 53 |
| 2023 August | 42 | 23 | 65 |
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| 2023 June | 92 | 19 | 111 |
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| 2021 April | 81 | 85 | 166 |
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| 2020 December | 47 | 31 | 78 |
| 2020 November | 48 | 14 | 62 |
| 2020 October | 34 | 11 | 45 |
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| 2020 August | 45 | 16 | 61 |
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| 2020 May | 52 | 12 | 64 |
| 2020 April | 29 | 16 | 45 |
| 2020 March | 50 | 21 | 71 |
| 2020 February | 33 | 16 | 49 |
| 2020 January | 56 | 16 | 72 |
| 2019 December | 46 | 24 | 70 |
| 2019 November | 47 | 20 | 67 |
| 2019 October | 23 | 10 | 33 |
| 2019 September | 34 | 18 | 52 |
| 2019 August | 23 | 17 | 40 |
| 2019 July | 34 | 22 | 56 |
| 2019 June | 38 | 12 | 50 |
| 2019 May | 28 | 15 | 43 |
| 2019 April | 78 | 30 | 108 |
| 2019 March | 26 | 20 | 46 |
| 2019 February | 16 | 11 | 27 |
| 2019 January | 30 | 15 | 45 |
| 2018 December | 86 | 35 | 121 |
| 2018 November | 135 | 13 | 148 |
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| 2018 September | 79 | 21 | 100 |
| 2018 August | 129 | 14 | 143 |
| 2018 July | 53 | 23 | 76 |
| 2018 June | 59 | 11 | 70 |
| 2018 May | 47 | 15 | 62 |
| 2018 April | 68 | 7 | 75 |
| 2018 March | 76 | 7 | 83 |
| 2018 February | 102 | 3 | 105 |
| 2018 January | 85 | 9 | 94 |
| 2017 December | 82 | 9 | 91 |
| 2017 November | 40 | 9 | 49 |
| 2017 October | 29 | 6 | 35 |
| 2017 September | 30 | 12 | 42 |
| 2017 August | 32 | 9 | 41 |
| 2017 July | 29 | 6 | 35 |
| 2017 June | 42 | 9 | 51 |
| 2017 May | 33 | 10 | 43 |
| 2017 April | 31 | 6 | 37 |
| 2017 March | 28 | 2 | 30 |
| 2017 February | 12 | 6 | 18 |
| 2017 January | 23 | 5 | 28 |
| 2016 December | 53 | 7 | 60 |
| 2016 November | 57 | 8 | 65 |
| 2016 October | 90 | 7 | 97 |
| 2016 September | 90 | 5 | 95 |
| 2016 August | 175 | 14 | 189 |
| 2016 July | 161 | 10 | 171 |
| 2016 June | 118 | 0 | 118 |
| 2016 May | 131 | 0 | 131 |
| 2016 April | 104 | 0 | 104 |
| 2016 March | 81 | 0 | 81 |
| 2016 February | 102 | 0 | 102 |
| 2016 January | 91 | 0 | 91 |
| 2015 December | 95 | 0 | 95 |
| 2015 November | 63 | 0 | 63 |
| 2015 October | 86 | 0 | 86 |
| 2015 September | 71 | 0 | 71 |
| 2015 August | 65 | 0 | 65 |
| 2015 July | 49 | 0 | 49 |
| 2015 June | 38 | 0 | 38 |
| 2015 May | 40 | 0 | 40 |
| 2015 April | 5 | 0 | 5 |
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