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F. C. Howarth - One of the best experts on this subject based on the ideXlab platform.
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P400Effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in Goto-Kakizaki type 2 diabetic rat heart
Cardiovascular Research, 2014Co-Authors: F. C. Howarth, K. Parekh, M. A. Qureshi, E El Nebrisi, Petrilla Jayaprakash, Thomas E. AdrianAbstract:There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity which in turn is a risk factor for development of type 2 diabetes mellitus. The effects of a sucrose-enriched diet on the pattern of gene expression, contraction and calcium transport in the Goto-Kakizaki (GK) type 2 diabetic rat heart have been investigated. Genes encoding cardiac muscle proteins (Myh7, Mybpc3, Myl1, Myl3, Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g, Cacnb1), potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared to Control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3, Tnn2), intercellular proteins (Gja1, Gja4), intracellular calcium transport (Atp2a1, Ryr2), cell membrane transport (Atp1a2, Atp1b1), potassium channel (Kcnj2, Kcnj8) proteins were upregulated and genes encoding cardiac muscle proteins (Myh7) were downregulated in Control/Sucrose compared to Control rats. Genes encoding cardiac muscle proteins (Myh7), potassium channel (Kcnj11) proteins were downregulated in GK/Sucrose compared to Control rats. Amplitude of shortening was reduced in myocytes from Control/Sucrose compared to Control and in GK/Sucrose compared to GK rats. Amplitude of the calcium transient was increased in myocytes from Control/Sucrose compared to Control and decreased in GK/Sucrose compared to GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular calcium transport in ventricular myocytes from GK type 2 diabetic and Control rats fed a sucrose-enriched diet.
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effects of a sucrose enriched diet on the pattern of gene expression contraction and ca2 transport in goto kakizaki type 2 diabetic rat heart
Experimental Physiology, 2014Co-Authors: E M Gaber, K. Parekh, M. A. Qureshi, Petrilla Jayaprakash, Thomas E. Adrian, F. C. HowarthAbstract:New Findings What is the central question of this study? Poor diet is a risk factor for development of type 2 diabetes mellitus and its associated complications. In this study, the effects of sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in type 2 diabetic heart are explored. What is the main finding and its importance? The altered pattern of gene expression in type 2 diabetic hearts was further altered in diabetic and control rats that received a sucrose-enriched diet, and these alterations were associated with changes in ventricular myocyte shortening and Ca2+ transport. There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM), and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity, which in turn is a risk factor for development of T2DM. In this study, the effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in the Goto–Kakizaki T2DM rat heart were investigated. Genes encoding cardiac muscle proteins (Myh7, Mybpc3, Myl1, Myl3 and Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g and Cacnb1) and potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared with control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3 and Tnn2), intercellular proteins (Gja1 and Gja4), intracellular Ca2+ transport (Atp2a1 and Ryr2), cell membrane transport (Atp1a2 and Atp1b1) and potassium channel proteins (Kcnj2 and Kcnj8) were upregulated and genes encoding cardiac muscle proteins (Myh7) were downregulated in control rats fed sucrose compared with control rats. Genes encoding cardiac muscle proteins (Myh7) and potassium channel proteins (Kcnj11) were downregulated in control and GK rats fed sucrose compared with control and GK rats, respectively. The amplitude of shortening was reduced in myocytes from the control–sucrose group compared with control rats and in the GK–sucrose group compared with GK rats. The amplitude of the Ca2+ transient was increased in myocytes from control–sucrose compared with control rats and decreased in GK–sucrose compared with GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular Ca2+ transport in ventricular myocytes from GK T2DM and control rats fed a sucrose-enriched diet.
Thomas E. Adrian - One of the best experts on this subject based on the ideXlab platform.
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P400Effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in Goto-Kakizaki type 2 diabetic rat heart
Cardiovascular Research, 2014Co-Authors: F. C. Howarth, K. Parekh, M. A. Qureshi, E El Nebrisi, Petrilla Jayaprakash, Thomas E. AdrianAbstract:There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity which in turn is a risk factor for development of type 2 diabetes mellitus. The effects of a sucrose-enriched diet on the pattern of gene expression, contraction and calcium transport in the Goto-Kakizaki (GK) type 2 diabetic rat heart have been investigated. Genes encoding cardiac muscle proteins (Myh7, Mybpc3, Myl1, Myl3, Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g, Cacnb1), potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared to Control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3, Tnn2), intercellular proteins (Gja1, Gja4), intracellular calcium transport (Atp2a1, Ryr2), cell membrane transport (Atp1a2, Atp1b1), potassium channel (Kcnj2, Kcnj8) proteins were upregulated and genes encoding cardiac muscle proteins (Myh7) were downregulated in Control/Sucrose compared to Control rats. Genes encoding cardiac muscle proteins (Myh7), potassium channel (Kcnj11) proteins were downregulated in GK/Sucrose compared to Control rats. Amplitude of shortening was reduced in myocytes from Control/Sucrose compared to Control and in GK/Sucrose compared to GK rats. Amplitude of the calcium transient was increased in myocytes from Control/Sucrose compared to Control and decreased in GK/Sucrose compared to GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular calcium transport in ventricular myocytes from GK type 2 diabetic and Control rats fed a sucrose-enriched diet.
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effects of a sucrose enriched diet on the pattern of gene expression contraction and ca2 transport in goto kakizaki type 2 diabetic rat heart
Experimental Physiology, 2014Co-Authors: E M Gaber, K. Parekh, M. A. Qureshi, Petrilla Jayaprakash, Thomas E. Adrian, F. C. HowarthAbstract:New Findings What is the central question of this study? Poor diet is a risk factor for development of type 2 diabetes mellitus and its associated complications. In this study, the effects of sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in type 2 diabetic heart are explored. What is the main finding and its importance? The altered pattern of gene expression in type 2 diabetic hearts was further altered in diabetic and control rats that received a sucrose-enriched diet, and these alterations were associated with changes in ventricular myocyte shortening and Ca2+ transport. There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM), and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity, which in turn is a risk factor for development of T2DM. In this study, the effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in the Goto–Kakizaki T2DM rat heart were investigated. Genes encoding cardiac muscle proteins (Myh7, Mybpc3, Myl1, Myl3 and Mylpf), intercellular proteins (Gja4), cell membrane transport (Atp1b1), calcium channels (Cacna1c, Cacna1g and Cacnb1) and potassium channels (Kcnj11) were upregulated and genes encoding potassium channels (Kcnb1) were downregulated in GK compared with control rats. Genes encoding cardiac muscle proteins (Myh6, Mybpc3 and Tnn2), intercellular proteins (Gja1 and Gja4), intracellular Ca2+ transport (Atp2a1 and Ryr2), cell membrane transport (Atp1a2 and Atp1b1) and potassium channel proteins (Kcnj2 and Kcnj8) were upregulated and genes encoding cardiac muscle proteins (Myh7) were downregulated in control rats fed sucrose compared with control rats. Genes encoding cardiac muscle proteins (Myh7) and potassium channel proteins (Kcnj11) were downregulated in control and GK rats fed sucrose compared with control and GK rats, respectively. The amplitude of shortening was reduced in myocytes from the control–sucrose group compared with control rats and in the GK–sucrose group compared with GK rats. The amplitude of the Ca2+ transient was increased in myocytes from control–sucrose compared with control rats and decreased in GK–sucrose compared with GK rats. Subtle alterations in the pattern of expression of genes encoding a variety of cardiac muscle proteins are associated with changes in shortening and intracellular Ca2+ transport in ventricular myocytes from GK T2DM and control rats fed a sucrose-enriched diet.
Wenhui Wang - One of the best experts on this subject based on the ideXlab platform.
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Deletion of Kir5.1 Impairs Renal Ability to Excrete Potassium During Increased Dietary Potassium Intake
Journal of The American Society of Nephrology, 2019Co-Authors: Peng Wu, Xiao-tong Su, Dan-dan Zhang, Wenhui WangAbstract:Background The basolateral potassium channel in the distal convoluted tubule (DCT), comprising the inwardly rectifying potassium channel Kir4.1/Kir5.1 heterotetramer, plays a key role in mediating the effect of dietary potassium intake on the thiazide-sensitive NaCl cotransporter (NCC). The role of Kir5.1 (encoded by Kcnj16) in mediating effects of dietary potassium intake on the NCC and renal potassium excretion is unknown. Methods We used electrophysiology, renal clearance, and immunoblotting to study Kir4.1 in the DCT and NCC in Kir5.1 knockout (Kcnj16-/- ) and wild-type (Kcnj16+/+ ) mice fed with normal, high, or low potassium diets. Results We detected a 40-pS and 20-pS potassium channel in the basolateral membrane of the DCT in wild-type and knockout mice, respectively. Compared with wild-type, Kcnj16-/- mice fed a normal potassium diet had higher basolateral potassium conductance, a more negative DCT membrane potential, higher expression of phosphorylated NCC (pNCC) and total NCC (tNCC), and augmented thiazide-induced natriuresis. Neither high- nor low-potassium diets affected the basolateral DCT's potassium conductance and membrane potential in Kcnj16-/- mice. Although high potassium reduced and low potassium increased the expression of pNCC and tNCC in wild-type mice, these effects were absent in Kcnj16-/- mice. High potassium intake inhibited and low intake augmented thiazide-induced natriuresis in wild-type but not in Kcnj16-/- mice. Compared with wild-type, Kcnj16-/- mice with normal potassium intake had slightly lower plasma potassium but were more hyperkalemic with prolonged high potassium intake and more hypokalemic during potassium restriction. Conclusions Kir5.1 is essential for dietary potassium's effect on NCC and for maintaining potassium homeostasis.
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kcnj10 kir4 1 is expressed in the basolateral membrane of the cortical thick ascending limb
American Journal of Physiology-renal Physiology, 2015Co-Authors: Dao Hong Lin, Lijun Wang, Chengbiao Zhang, Wenhui WangAbstract:The aim of the present study is to examine the role of Kcnj10 (Kir.4.1) in contributing to the basolateral K conductance in the cortical thick ascending limb (cTAL) using Kcnj10+/+ wild-type (WT) a...
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caveolin 1 deficiency inhibits the basolateral k channels in the distal convoluted tubule and impairs renal k and mg2 transport
Journal of The American Society of Nephrology, 2015Co-Authors: Dao Hong Lin, Lijun Wang, Chengbiao Zhang, Wenhui WangAbstract:Kcnj10 encodes the inwardly rectifying K + channel Kir4.1 in the basolateral membrane of the distal convoluted tubule (DCT) and is activated by c-Src. However, the regulation and function of this K + channel are incompletely characterized. Here, patch-clamp experiments in Kcnj10-transfected HEK293 cells demonstrated that c-Src–induced stimulation of Kcnj10 requires coexpression of caveolin-1 (cav-1), and immunostaining showed expression of cav-1 in the basolateral membrane of parvalbumin-positive DCT. Patch-clamp experiments detected a 40-pS inwardly rectifying K + channel, a heterotetramer of Kir4.1/Kir5.1, in the basolateral membrane of the early DCT (DCT1) in both wild-type (WT) and cav-1-knockout (KO) mice. However, the activity of this basolateral 40-pS K + channel was lower in KO mice than in WT mice. Moreover, the K + reversal potential (an indication of membrane potential) was less negative in the DCT1 of KO mice than in the DCT1 of WT mice. Western blot analysis demonstrated that cav-1 deficiency decreased the expression of the Na + /Cl – cotransporter and Ste20-proline-alanine-rich kinase (SPAK) but increased the expression of epithelial Na + channel- α . Furthermore, the urinary excretion of Mg 2+ and K + was significantly higher in KO mice than in WT mice, and KO mice developed hypomagnesemia, hypocalcemia, and hypokalemia. We conclude that disruption of cav-1 decreases basolateral K + channel activity and depolarizes the cell membrane potential in the DCT1 at least in part by suppressing the stimulatory effect of c-Src on Kcnj10. Furthermore, the decrease in Kcnj10 and Na + /Cl – cotransporter expression induced by cav-1 deficiency may underlie the compromised renal transport of Mg 2+ , Ca 2+ , and K + .
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KCNJ10 determines the expression of the apical Na-Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1)
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Chengbiao Zhang, Ute I Scholl, Richard P Lifton, Lijun Wang, Dao Hong Lin, Junhui Zhang, Gerhard Giebisch, Wenhui WangAbstract:The renal phenotype induced by loss-of-function mutations of inwardly rectifying potassium channel (Kir), Kcnj10 (Kir4.1), includes salt wasting, hypomagnesemia, metabolic alkalosis and hypokalemia. However, the mechanism by which Kir.4.1 mutations cause the tubulopathy is not completely understood. Here we demonstrate that Kcnj10 is a main contributor to the basolateral K conductance in the early distal convoluted tubule (DCT1) and determines the expression of the apical Na-Cl cotransporter (NCC) in the DCT. Immunostaining demonstrated Kcnj10 and Kcnj16 were expressed in the basolateral membrane of DCT, and patch-clamp studies detected a 40-pS K channel in the basolateral membrane of the DCT1 of p8/p10 wild-type Kcnj10+/+ mice (WT). This 40-pS K channel is absent in homozygous Kcnj10−/− (knockout) mice. The disruption of Kcnj10 almost completely eliminated the basolateral K conductance and decreased the negativity of the cell membrane potential in DCT1. Moreover, the lack of Kcnj10 decreased the basolateral Cl conductance, inhibited the expression of Ste20-related proline–alanine-rich kinase and diminished the apical NCC expression in DCT. We conclude that Kcnj10 plays a dominant role in determining the basolateral K conductance and membrane potential of DCT1 and that the basolateral K channel activity in the DCT determines the apical NCC expression possibly through a Ste20-related proline–alanine-rich kinase-dependent mechanism.
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src family protein tyrosine kinase regulates the basolateral k channel in the distal convoluted tubule dct by phosphorylation of kcnj10 protein
Journal of Biological Chemistry, 2013Co-Authors: Lijun Wang, Dao Hong Lin, Chengbiao Zhang, Sherin Thomas, Kemeng Wang, Jesse Rinehart, Wenhui WangAbstract:Abstract The loss of function of the basolateral K channels in the distal nephron causes electrolyte imbalance. The aim of this study is to examine the role of Src family protein tyrosine kinase (SFK) in regulating K channels in the basolateral membrane of the mouse initial distal convoluted tubule (DCT1). Single-channel recordings confirmed that the 40-picosiemen (pS) K channel was the only type of K channel in the basolateral membrane of DCT1. The suppression of SFK reversibly inhibited the basolateral 40-pS K channel activity in cell-attached patches and decreased the Ba2+-sensitive whole-cell K currents in DCT1. Inhibition of SFK also shifted the K reversal potential from −65 to −43 mV, suggesting a role of SFK in determining the membrane potential in DCT1. Western blot analysis showed that KCNJ10 (Kir4.1), a key component of the basolateral 40-pS K channel in DCT1, was a tyrosine-phosphorylated protein. LC/MS analysis further confirmed that SFK phosphorylated KCNJ10 at Tyr8 and Tyr9. The single-channel recording detected the activity of a 19-pS K channel in KCNJ10-transfected HEK293T cells and a 40-pS K channel in the cells transfected with KCNJ10+KCNJ16 (Kir.5.1) that form a heterotetramer in the basolateral membrane of the DCT. Mutation of Tyr9 did not alter the channel conductance of the homotetramer and heterotetramer. However, it decreased the whole-cell K currents, the probability of finding K channels, and surface expression of KCNJ10 in comparison to WT KCNJ10. We conclude that SFK stimulates the basolateral K channel activity in DCT1, at least partially, by phosphorylating Tyr9 on KCNJ10. We speculate that the modulation of tyrosine phosphorylation of KCNJ10 should play a role in regulating membrane transport function in DCT1.
Yohan Bignon - One of the best experts on this subject based on the ideXlab platform.
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defective bicarbonate reabsorption in kir4 2 potassium channel deficient mice impairs acid base balance and ammonia excretion
Kidney International, 2020Co-Authors: Yohan Bignon, Laurent Pinelli, Nadia Frachon, Olivier Lahuna, Lucile Figueres, Pascal HouillierAbstract:The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood. Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process. In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction. Urinary ammonium excretion rates in Kcnj15- deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct. In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15-deleted mice. Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization. Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism. The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.
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defective bicarbonate reabsorption in kir4 2 potassium channel deficient mice impairs acid base balance and ammonia excretion
Kidney International, 2020Co-Authors: Yohan Bignon, Laurent Pinelli, Nadia Frachon, Olivier Lahuna, Lucile Figueres, Pascal HouillierAbstract:The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood. Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process. In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction. Urinary ammonium excretion rates in Kcnj15- deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct. In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15-deleted mice. Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization. Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism. The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.
Leslie P Plotnick - One of the best experts on this subject based on the ideXlab platform.
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medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15 yr old boy with neonatal diabetes mellitus and intermediate dend syndrome extending the age of kcnj11 mutation testing in neonatal dm
Pediatric Diabetes, 2009Co-Authors: Ali Mohamadi, Loretta M Clark, Paul H Lipkin, Mark E Mahone, Ericka L Wodka, Leslie P PlotnickAbstract:Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel, often result in neonatal diabetes. Patients with this mutation have been successfully transitioned from insulin to sulfonylurea (SU) therapy without compromise in their glycemic control. Among patients with neonatal diabetes due to KCNJ11 mutations, approximately 25% have neurological findings including developmental delay, motor dysfunction, and epilepsy, known as DEND syndrome. There have been rare cases of juvenile patients with intermediate DEND syndrome (iDEND) reporting variable improvement in neurological function following transition from insulin to SU treatment. We describe the response to glyburide in a 15-yr-old boy with severe global developmental delays resulting from the KCNJ11 mutation V59M. The patient was discovered to have diabetes mellitus at 11.5 months of age, making this the oldest age at diagnosis of a KCNJ11 mutation-related case of neonatal diabetes. Because consensus has been to screen patients for this mutation only if younger than 6 months at the time of diagnosis, we suggest that all patients under the age of 12 months at diagnosis should receive genetic testing for monogenic causes of diabetes.
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medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15 yr old boy with neonatal diabetes mellitus and intermediate dend syndrome extending the age of kcnj11 mutation testing in neonatal dm
Pediatric Diabetes, 2009Co-Authors: Ali Mohamadi, Loretta M Clark, Paul H Lipkin, Mark E Mahone, Ericka L Wodka, Leslie P PlotnickAbstract:Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel, often result in neonatal diabetes. Patients with this mutation have been successfully transitioned from insulin to sulfonylurea (SU) therapy without compromise in their glycemic control. Among patients with neonatal diabetes due to KCNJ11 mutations, approximately 25% have neurological findings including developmental delay, motor dysfunction, and epilepsy, known as DEND syndrome. There have been rare cases of juvenile patients with intermediate DEND syndrome (iDEND) reporting variable improvement in neurological function following transition from insulin to SU treatment. We describe the response to glyburide in a 15-yr-old boy with severe global developmental delays resulting from the KCNJ11 mutation V59M. The patient was discovered to have diabetes mellitus at 11.5 months of age, making this the oldest age at diagnosis of a KCNJ11 mutation-related case of neonatal diabetes. Because consensus has been to screen patients for this mutation only if younger than 6 months at the time of diagnosis, we suggest that all patients under the age of 12 months at diagnosis should receive genetic testing for monogenic causes of diabetes.