Eprints.soton.ac.uk



Sulfonylurea Treatment of Chromosome 6q24-related Transient Neonatal Diabetes (6q24-TND)David Carmody, MB BCh1, Flavius A Beca1, Charles D. Bell, BS1, Jessica L. Hwang, MD1, Jazzmyne T Dickens1, BS, Deborah JG Mackay, PhD2,3, I Karen I Temple, MB ChB2,4, Lisa R Hays, MD5, Rochelle N Naylor, MD1, Louis H Philipson, MD, PhD1 and Siri Atma W Greeley, MD, PhD1.?1 Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA;2 Faculty of Medicine, University of Southampton, Southampton, UK;3 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK;4 Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK;5 Shawnee Mission Endocrinology and Diabetes, Shawnee Mission Medical Center , Kansas.Abbreviated Title: Sulfonylurea use in 6q24-related Transient Neonatal DMKeyterms: Neonatal Diabetes, Genetics, SulfonylureaWord Count:1621 Number of figures and tables: 2Corresponding author and person to whom reprint requests should be addressed: Siri Atma Greeley, MD, PhDDepartment of Pediatrics, The University of Chicago, 5841 S Maryland Ave, MC 1027, Chicago, Illinois 60637, USAPhone: +1-773-702-0829Fax: +1-773-702-9237e-mail: sgreeley@peds.bsd.uchicago.eduDisclosure Statement: The authors report no conflicts of interest and have no disclosures. The University of Chicago receives royalties from Athena Diagnostics for genetic testing for mutations in HNF1A, HNF4A and HNF1B.Funding source: This work was supported by the University of Chicago Diabetes Research and Training Center (DRTC), which along with Dr. Greeley’s K Award, was funded by grants from National Institute of Diabetes and Digestive and Kidney Diseases (DK020595 and K23 DK094866) of the National Institutes of Health, as well as by a grant from the American Diabetes Association (1-11-CT-41), and gifts from the Kovler Family Foundation and Lewis-Sebring Foundation. Conflict of Interest Statement: The authors report no conflicts of interest. AbstractContext: 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI. Sulfonylurea (SU) therapy is highly effective in the treatment of KATP channelopathies.Objective: We sought to characterize the insulin secreting potential and response to SU therapy in adults with 6q24-TND identified through the University of Chicago Monogenic Diabetes Registry (). Design: Three patients had a mixed meal test (MMT) and arginine stimulation test (AST), with all insulin products withheld on the morning of testing. A five-day course of glyburide (glibenclamide) was then initiated and insulin steadily withdrawn. A maximum target dose of 1mg/kg of glyburide was used to achieve euglycemia. A repeat MMTs and AST were performed on day five. Results: C-peptide values were significantly higher in patients follow a course of SU (p<0.05 by repeated measures ANOVA) when both MMT were compared. The C-peptide response was again higher following a course of SU (p<0.05) during the AST. Patients were discharged on glyburide therapy alone or in combination with other oral agents. A fourth patient was also successfully transitioned off insulin in lieu of oral agents. All patients remained off insulin therapy with good diabetes control at re-evaluation at least 3 months after transition.Conclusions: The best treatment for 6q24-TND following recurrence of hyperglycemia later in life is uncertain. Our data demonstrates that SU therapy can be effective as monotherapy or in combination with other oral medications.Introduction6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes with an estimated incidence of 1 in 200,000-500,000 live births ADDIN PAPERS2_CITATIONS <citation><uuid>3AF1E3E4-BFBF-4FE3-805A-D9FDF5BF07BA</uuid><priority>0</priority><publications><publication><uuid>6D1F5F7C-D653-4562-9EAF-5253165E40AF</uuid><volume>75</volume><doi>10.1111/j.1365-2265.2011.04049.x</doi><startpage>422</startpage><publication_date>99201110001200000000220000</publication_date><url> should have genetic testing for maturity-onset diabetes of the young?</title><location>602,0,0,0</location><institution>Department of Medicine, The Kovler Diabetes Center, The University of Chicago, Chicago, IL 606037, USA.</institution><number>4</number><subtype>400</subtype><endpage>426</endpage><bundle><publication><title>Clinical endocrinology</title><type>-100</type><subtype>-100</subtype><uuid>23E4FEAF-30FB-4DFA-BC8D-4C24FBFA274B</uuid></publication></bundle><authors><author><firstName>Rochelle</firstName><lastName>Naylor</lastName></author><author><firstName>Louis</firstName><middleNames>H</middleNames><lastName>Philipson</lastName></author></authors></publication><publication><uuid>711AC631-95C6-4856-AECA-593A07C18C6F</uuid><volume>76</volume><startpage>F39</startpage><publication_date>99199701001200000000220000</publication_date><url> and genetic basis of neonatal diabetes.</title><location>200,6,51.4595650,-2.6006343</location><institution>Institute of Child Health, St Michael's Hill, Bristol.</institution><number>1</number><subtype>400</subtype><endpage>42</endpage><bundle><publication><title>Archives of disease in childhood. Fetal and neonatal edition</title><type>-100</type><subtype>-100</subtype><uuid>B6DAB976-111F-453D-8668-CB5FA6A09DCA</uuid></publication></bundle><authors><author><firstName>J</firstName><middleNames>P</middleNames><lastName>Shield</lastName></author><author><firstName>R</firstName><middleNames>J</middleNames><lastName>Gardner</lastName></author><author><firstName>E</firstName><middleNames>J</middleNames><lastName>Wadsworth</lastName></author><author><firstName>M</firstName><middleNames>L</middleNames><lastName>Whiteford</lastName></author><author><firstName>R</firstName><middleNames>S</middleNames><lastName>James</lastName></author><author><firstName>D</firstName><middleNames>O</middleNames><lastName>Robinson</lastName></author><author><firstName>J</firstName><middleNames>D</middleNames><lastName>Baum</lastName></author><author><firstName>I</firstName><middleNames>K</middleNames><lastName>Temple</lastName></author></authors></publication><publication><uuid>17854D1E-705D-47F6-8939-1A201D01BE44</uuid><volume>49</volume><accepted_date>99201108251200000000222000</accepted_date><doi>10.1007/s00592-011-0331-8</doi><startpage>405</startpage><publication_date>99201210001200000000220000</publication_date><url> incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births.</title><submission_date>99201108081200000000222000</submission_date><number>5</number><institution>Department of Pediatrics, Second University of Naples, Italy.</institution><subtype>400</subtype><endpage>408</endpage><bundle><publication><title>Acta diabetologica</title><type>-100</type><subtype>-100</subtype><uuid>1AD18002-AF0A-4295-99B6-807101C54048</uuid></publication></bundle><authors><author><firstName>D</firstName><lastName>Iafusco</lastName></author><author><firstName>O</firstName><lastName>Massa</lastName></author><author><firstName>B</firstName><lastName>Pasquino</lastName></author><author><firstName>C</firstName><lastName>Colombo</lastName></author><author><firstName>L</firstName><lastName>Iughetti</lastName></author><author><firstName>C</firstName><lastName>Bizzarri</lastName></author><author><firstName>C</firstName><lastName>Mammì</lastName></author><author><firstName>D</firstName><droppingParticle>Lo</droppingParticle><lastName>Presti</lastName></author><author><firstName>T</firstName><lastName>Suprani</lastName></author><author><firstName>R</firstName><lastName>Schiaffini</lastName></author><author><firstName>Colin</firstName><middleNames>G</middleNames><lastName>Nichols</lastName></author><author><firstName>L</firstName><lastName>Russo</lastName></author><author><firstName>V</firstName><lastName>Grasso</lastName></author><author><firstName>F</firstName><lastName>Meschi</lastName></author><author><firstName>R</firstName><lastName>Bonfanti</lastName></author><author><firstName>S</firstName><lastName>Brescianini</lastName></author><author><firstName>F</firstName><lastName>Barbetti</lastName></author><author><lastName>Early Diabetes Study Group of ISPED</lastName></author></authors></publication></publications><cites></cites></citation>(1-3). It is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI. It has been suggested that defects of the 6q24 locus are responsible for 70% of all cases of transient neonatal diabetes mellitus ADDIN PAPERS2_CITATIONS <citation><uuid>E545C226-23D1-42BA-9E13-36D82BE29FEE</uuid><priority>1</priority><publications><publication><uuid>8657EDDA-07BD-4B83-9965-6C4A2E2125FE</uuid><volume>5</volume><startpage>879</startpage><publication_date>99201107001200000000220000</publication_date><url> of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes.</title><location>200,9,41.7891322,-87.6001222</location><institution>Department of Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA. sgreeley@peds.bsd.uchicago.edu</institution><number>4</number><subtype>400</subtype><endpage>886</endpage><bundle><publication><title>Journal of diabetes science and technology</title><type>-100</type><subtype>-100</subtype><uuid>FF8EA4AB-97D5-4A4A-BDC3-00BD87E27CB5</uuid></publication></bundle><authors><author><firstName>Siri</firstName><middleNames>Atma W</middleNames><lastName>Greeley</lastName></author><author><firstName>Rochelle</firstName><middleNames>N</middleNames><lastName>Naylor</lastName></author><author><firstName>Lindsay</firstName><middleNames>S</middleNames><lastName>Cook</lastName></author><author><firstName>Susan</firstName><middleNames>E</middleNames><lastName>Tucker</lastName></author><author><firstName>Rebecca</firstName><middleNames>B</middleNames><lastName>Lipton</lastName></author><author><firstName>Louis</firstName><middleNames>H</middleNames><lastName>Philipson</lastName></author></authors></publication><publication><uuid>041A2883-137B-42E3-A695-AE49FD6669A2</uuid><volume>56</volume><doi>10.2337/db07-0043</doi><startpage>1930</startpage><publication_date>99200707001200000000220000</publication_date><url> in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.</title><location>200,9,50.7234642,-3.5164400</location><institution>Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.</institution><number>7</number><subtype>400</subtype><endpage>1937</endpage><bundle><publication><url> G</middleNames><lastName>Mackay</lastName></author><author><firstName>Emma</firstName><middleNames>L</middleNames><lastName>Edghill</lastName></author><author><firstName>Anna</firstName><middleNames>L</middleNames><lastName>Gloyn</lastName></author><author><firstName>David</firstName><lastName>Robinson</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author><author><firstName>Karen</firstName><lastName>Temple</lastName></author><author><firstName>Sian</firstName><lastName>Ellard</lastName></author><author><firstName>Andrew</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author></authors></publication></publications><cites></cites></citation>(4,5) and that 50-60% of neonatal diabetes is transient ADDIN PAPERS2_CITATIONS <citation><uuid>5A5A85C3-916E-4E1D-A72D-01798C5D40E5</uuid><priority>2</priority><publications><publication><uuid>9B4A8EE2-0D20-46C9-8CA7-6AAFC9E3E0B5</uuid><volume>356</volume><doi>10.1038/356721a0</doi><startpage>721</startpage><publication_date>99199204231200000000222000</publication_date><url> mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.</title><institution>Howard Hughes Medical Institute, Department of Biochemistry, University of Chicago, Illinois 60637.</institution><number>6371</number><subtype>400</subtype><endpage>722</endpage><bundle><publication><url> diabetes mellitus: chromosomal analysis in transient and permanent cases.</title><location>200,4,48.3903940,-4.4860760</location><institution>Department of Pediatrics, H?pital Morvan, Brest.</institution><number>4</number><subtype>400</subtype><endpage>489</endpage><bundle><publication><publisher>Mosby, Inc.</publisher><title>The Journal of pediatrics</title><type>-100</type><subtype>-100</subtype><uuid>78F6C31E-2742-4E9F-B671-F6F312A68826</uuid></publication></bundle><authors><author><firstName>Chantal</firstName><lastName>Metz</lastName></author><author><firstName>Hélène</firstName><lastName>Cavé</lastName></author><author><firstName>Anne</firstName><middleNames>Marie</middleNames><lastName>Bertrand</lastName></author><author><firstName>Christine</firstName><lastName>Deffert</lastName></author><author><firstName>Béatrice</firstName><lastName>Gueguen-Giroux</lastName></author><author><firstName>Paul</firstName><lastName>Czernichow</lastName></author><author><firstName>Michel</firstName><lastName>Polak</lastName></author><author><lastName>NDM French Study Group. Neonatal diabetes mellitus</lastName></author></authors></publication></publications><cites></cites></citation>(6). The term transient neonatal diabetes can be misleading as most many patients develop permanent hyperglycemia later in life ADDIN PAPERS2_CITATIONS <citation><uuid>4D0341B8-BFB7-4481-B609-831FA8E9D360</uuid><priority>3</priority><publications><publication><publication_date>99201402181200000000222000</publication_date><doi>10.2337/dc13-2248</doi><institution>University of Exeter Medical School, Exeter, Exeter, U.K.</institution><title>The 0.1% of the Population With Glucokinase Monogenic Diabetes Can be Recognized by Clinical Characteristics in Pregnancy: The Atlantic Diabetes in Pregnancy Cohort.</title><uuid>7AAB84F5-1520-4734-AE31-64DB3C70C8DF</uuid><subtype>400</subtype><type>400</type><url> care</title><type>-100</type><subtype>-100</subtype><uuid>F15BF67E-35A3-41B0-8445-41E14E665D7A</uuid></publication></bundle><authors><author><firstName>Ali</firstName><middleNames>J</middleNames><lastName>Chakera</lastName></author><author><firstName>Gill</firstName><lastName>Spyer</lastName></author><author><firstName>Nicola</firstName><lastName>Vincent</lastName></author><author><firstName>Sian</firstName><lastName>Ellard</lastName></author><author><firstName>Andrew</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author><author><firstName>Fidelma</firstName><middleNames>P</middleNames><lastName>Dunne</lastName></author></authors></publication><publication><uuid>798DCC2C-6E3E-450F-A8EF-19197BF0C275</uuid><volume>11</volume><doi>10.1007/s11154-010-9150-4</doi><startpage>199</startpage><publication_date>99201009001200000000220000</publication_date><url> transient neonatal diabetes.</title><location>200,6,50.9375721,-1.4299327</location><institution>Academic Unit of Genetic Medicine, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK. ikt@soton.ac.uk</institution><number>3</number><subtype>400</subtype><endpage>204</endpage><bundle><publication><title>Reviews in endocrine &amp; metabolic disorders</title><type>-100</type><subtype>-100</subtype><uuid>480AFB77-B45F-4ADC-80F4-0A3658691B63</uuid></publication></bundle><authors><author><firstName>I</firstName><middleNames>Karen</middleNames><lastName>Temple</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author></authors></publication></publications><cites></cites></citation>(7).In the neonatal period patients are typically treated with insulin therapy. While treatment options of 6q24-TND in later life is less certain, insulin therapy is often needed ADDIN PAPERS2_CITATIONS <citation><uuid>971CA722-1B70-4BF4-8746-7D285BABC5B7</uuid><priority>4</priority><publications><publication><uuid>6D1F5F7C-D653-4562-9EAF-5253165E40AF</uuid><volume>75</volume><doi>10.1111/j.1365-2265.2011.04049.x</doi><startpage>422</startpage><publication_date>99201110001200000000220000</publication_date><url> should have genetic testing for maturity-onset diabetes of the young?</title><location>602,0,0,0</location><institution>Department of Medicine, The Kovler Diabetes Center, The University of Chicago, Chicago, IL 606037, USA.</institution><number>4</number><subtype>400</subtype><endpage>426</endpage><bundle><publication><title>Clinical endocrinology</title><type>-100</type><subtype>-100</subtype><uuid>23E4FEAF-30FB-4DFA-BC8D-4C24FBFA274B</uuid></publication></bundle><authors><author><firstName>Rochelle</firstName><lastName>Naylor</lastName></author><author><firstName>Louis</firstName><middleNames>H</middleNames><lastName>Philipson</lastName></author></authors></publication><publication><uuid>798DCC2C-6E3E-450F-A8EF-19197BF0C275</uuid><volume>11</volume><doi>10.1007/s11154-010-9150-4</doi><startpage>199</startpage><publication_date>99201009001200000000220000</publication_date><url> transient neonatal diabetes.</title><location>200,6,50.9375721,-1.4299327</location><institution>Academic Unit of Genetic Medicine, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK. ikt@soton.ac.uk</institution><number>3</number><subtype>400</subtype><endpage>204</endpage><bundle><publication><title>Reviews in endocrine &amp; metabolic disorders</title><type>-100</type><subtype>-100</subtype><uuid>480AFB77-B45F-4ADC-80F4-0A3658691B63</uuid></publication></bundle><authors><author><firstName>I</firstName><middleNames>Karen</middleNames><lastName>Temple</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author></authors></publication></publications><cites></cites></citation>(1,7). There is a paucity of data on the use of other glucose lowering agents in the treatment of this condition. We sought to characterize the beta cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy. We also aimed to safely transition patients off insulin therapy if possible.SubjectsIndividuals with suspected or established monogenic forms of diabetes were consented for participation through the University of Chicago Monogenic Diabetes Registry () through which longitudinal information regarding the diagnosis and treatment of diabetes, diabetes complications, other medical problems, family history and genetic testing results, is collected through surveys and medical records ADDIN PAPERS2_CITATIONS <citation><uuid>ED0C93F6-525D-4D6E-AD8C-5B3B142B8516</uuid><priority>5</priority><publications><publication><uuid>8657EDDA-07BD-4B83-9965-6C4A2E2125FE</uuid><volume>5</volume><startpage>879</startpage><publication_date>99201107001200000000220000</publication_date><url> of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes.</title><location>200,9,41.7891322,-87.6001222</location><institution>Department of Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA. sgreeley@peds.bsd.uchicago.edu</institution><number>4</number><subtype>400</subtype><endpage>886</endpage><bundle><publication><title>Journal of diabetes science and technology</title><type>-100</type><subtype>-100</subtype><uuid>FF8EA4AB-97D5-4A4A-BDC3-00BD87E27CB5</uuid></publication></bundle><authors><author><firstName>Siri</firstName><middleNames>Atma W</middleNames><lastName>Greeley</lastName></author><author><firstName>Rochelle</firstName><middleNames>N</middleNames><lastName>Naylor</lastName></author><author><firstName>Lindsay</firstName><middleNames>S</middleNames><lastName>Cook</lastName></author><author><firstName>Susan</firstName><middleNames>E</middleNames><lastName>Tucker</lastName></author><author><firstName>Rebecca</firstName><middleNames>B</middleNames><lastName>Lipton</lastName></author><author><firstName>Louis</firstName><middleNames>H</middleNames><lastName>Philipson</lastName></author></authors></publication></publications><cites></cites></citation>(4). Those adults with 6q24-TND leading to transient neonatal diabetes and recurrence of hyperglycemia requiring insulin therapy later in life were invited to participate in a trial of SU therapy.6q24-TND was diagnosed using methylation sensitive PCR ADDIN PAPERS2_CITATIONS <citation><uuid>4CDE6799-CC96-4865-8CC4-B3C9B9A12722</uuid><priority>6</priority><publications><publication><uuid>B917F910-89AD-4B90-AADB-1AA3DD5E67D4</uuid><volume>53</volume><accepted_date>99201004261200000000222000</accepted_date><doi>10.1007/s00125-010-1799-4</doi><startpage>2504</startpage><publication_date>99201012001200000000220000</publication_date><url> diabetes of the young (MODY): how many cases are we missing?</title><location>200,9,50.7362336,-3.5362751</location><submission_date>99201001271200000000222000</submission_date><number>12</number><institution>Peninsula Medical School, University of Exeter, Exeter, UK.</institution><subtype>400</subtype><endpage>2508</endpage><bundle><publication><url> sequencing of the transient neonatal diabetes mellitus DMR facilitates a novel diagnostic test but reveals no methylation anomalies in patients of unknown aetiology.</title><location>200,5,51.0439553,-1.7898225</location><submission_date>99200404221200000000222000</submission_date><number>4</number><institution>Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK. djgm@soton.ac.uk</institution><subtype>400</subtype><endpage>261</endpage><bundle><publication><title>Human genetics</title><type>-100</type><subtype>-100</subtype><uuid>50F519F9-783D-4DBD-A932-832E50A7E36B</uuid></publication></bundle><authors><author><firstName>Deborah</firstName><middleNames>J G</middleNames><lastName>Mackay</lastName></author><author><firstName>I</firstName><middleNames>Karen</middleNames><lastName>Temple</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author><author><firstName>David</firstName><middleNames>O</middleNames><lastName>Robinson</lastName></author></authors></publication></publications><cites></cites></citation>(8). Duplication was confirmed using microsatellite analysis using standard methods and published microsatellite markers ADDIN PAPERS2_CITATIONS <citation><uuid>36C68F35-09ED-40C7-82F9-9F8733B300ED</uuid><priority>7</priority><publications><publication><publication_date>99201406181200000000222000</publication_date><startpage>jc20142257</startpage><doi>10.1210/jc.2014-2257</doi><institution>Diabetes Institute, Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD, 20889;</institution><title>The Clinical Endocrinology Workforce: Current Status and Future Projections of Supply and Demand.</title><uuid>BCFFC1D1-99B7-4B38-84BC-3421F41A7F12</uuid><subtype>400</subtype><type>400</type><url> Journal of clinical endocrinology and metabolism</title><type>-100</type><subtype>-100</subtype><uuid>58578023-B24F-4B74-909B-A21E236FE68D</uuid></publication></bundle><authors><author><firstName>Robert</firstName><middleNames>A</middleNames><lastName>Vigersky</lastName></author><author><firstName>Lisa</firstName><lastName>Fish</lastName></author><author><firstName>Paul</firstName><lastName>Hogan</lastName></author><author><firstName>Andrew</firstName><lastName>Stewart</lastName></author><author><firstName>Stephanie</firstName><lastName>Kutler</lastName></author><author><firstName>Paul</firstName><middleNames>W</middleNames><lastName>Ladenson</lastName></author><author><firstName>Michael</firstName><lastName>McDermott</lastName></author><author><firstName>Kenneth</firstName><middleNames>H</middleNames><lastName>Hupart</lastName></author></authors></publication><publication><uuid>E09ED2AB-5D5D-496E-A6E6-996079BBE88E</uuid><volume>53</volume><accepted_date>99201006241200000000222000</accepted_date><doi>10.1007/s00125-010-1853-2</doi><startpage>2347</startpage><publication_date>99201011001200000000220000</publication_date><url> refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes.</title><location>200,5,51.0439553,-1.7898225</location><submission_date>99201004301200000000222000</submission_date><number>11</number><institution>Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, SP2 8BJ, UK. l.e.docherty@soton.ac.uk</institution><subtype>400</subtype><endpage>2351</endpage><bundle><publication><url> G</middleNames><lastName>Mackay</lastName></author></authors></publication></publications><cites></cites></citation>(9). Diagnostic genetic testing was performed by the division of human genetics, University of Southampton (UK) or department of human genetics, University of Chicago. MethodsAll subjects were consented for participation through protocols approved by the institutional review board at the University of Chicago. Subjects over 18 years of age with 6q24-TND treated with insulin therapy and agreeable to a trial of SU were invited to participate. We sought to characterize the insulin secreting potential and also the response to SU therapy in adults with 6q24-TND. A mixed meal test (MMT) and arginine stimulation test (AST) were performed on day one and day five. All insulin products were withheld on the morning of day one. Metabolic testing was performed in the morning (between 7 and 10 A.M.) after an eight-hour overnight fast, without food or drink (with the exception of water). Subjects ingested 12 oz. of BOOST? High Protein (calories 360, total fat 9g, total carbohydrate 49.5g, total protein 22.5g) over one minute. Samples for glucose and C-peptide were obtained at 0, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180 minutes.Each AST was performed following the MMT. Arginine was infused 185 minutes after commencing the MMT. A single dose of 5g of arginine hydrochloride was infused over thirty seconds. Glucose and C-peptide samples will be obtained at 184, 187, 188, 189, 190, 192, and 195 minutes. A five-day course of glyburide (glibenclamide) was initiated aiming to achieve euglycemia with a maximum target dose of 1 mg/kg using a published protocol used successfully for those with mutations affecting the KATP channel ADDIN PAPERS2_CITATIONS <citation><uuid>0A3A9527-1121-4657-A6C0-122A1E2F6861</uuid><priority>8</priority><publications><publication><publication_date>99201310041200000000222000</publication_date><doi>10.1007/s00125-013-3075-x</doi><institution>MacLeod Diabetes and Endocrine Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.</institution><accepted_date>99201309111200000000222000</accepted_date><title>Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia.</title><uuid>39508C76-B2B9-49BB-80BE-3A80009B23B4</uuid><subtype>400</subtype><submission_date>99201308071200000000222000</submission_date><type>400</type><url> from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.</title><location>200,9,50.7234642,-3.5164400</location><institution>Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.</institution><number>5</number><subtype>400</subtype><endpage>477</endpage><bundle><publication><url> New England journal of medicine</title><type>-100</type><subtype>-100</subtype><uuid>2122C342-742A-495E-9D39-8D3E98EB5DC7</uuid></publication></bundle><authors><author><firstName>Ewan</firstName><middleNames>R</middleNames><lastName>Pearson</lastName></author><author><firstName>Isabelle</firstName><lastName>Flechtner</lastName></author><author><firstName>P?l</firstName><middleNames>R</middleNames><lastName>Nj?lstad</lastName></author><author><firstName>Maciej</firstName><middleNames>T</middleNames><lastName>Malecki</lastName></author><author><firstName>Sarah</firstName><middleNames>E</middleNames><lastName>Flanagan</lastName></author><author><firstName>Brian</firstName><lastName>Larkin</lastName></author><author><firstName>Frances</firstName><middleNames>M</middleNames><lastName>Ashcroft</lastName></author><author><firstName>Iwar</firstName><lastName>Klimes</lastName></author><author><firstName>Ethel</firstName><lastName>Codner</lastName></author><author><firstName>Violeta</firstName><lastName>Iotova</lastName></author><author><firstName>Annabelle</firstName><middleNames>S</middleNames><lastName>Slingerland</lastName></author><author><firstName>Julian</firstName><lastName>Shield</lastName></author><author><firstName>Jean-Jacques</firstName><lastName>Robert</lastName></author><author><firstName>Jens</firstName><middleNames>J</middleNames><lastName>Holst</lastName></author><author><firstName>Penny</firstName><middleNames>M</middleNames><lastName>Clark</lastName></author><author><firstName>Sian</firstName><lastName>Ellard</lastName></author><author><firstName>Oddmund</firstName><lastName>S?vik</lastName></author><author><firstName>Michel</firstName><lastName>Polak</lastName></author><author><firstName>Andrew</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author><author><lastName>Neonatal Diabetes International Collaborative Group</lastName></author></authors></publication></publications><cites></cites></citation>(10). All insulin was steadily withdrawn before a repeat MMT and AST performed on day five. Plasma glucose concentrations were determined by the hexokinase method. Plasma C-peptide was measured by double antibody radioimmunoassay. Patients were discharged on glyburide therapy alone or in combination with other oral agents. HbA1c was recorded prior to metabolic testing and at least 3 months following cessation of insulin therapy. HbA1c was measured by high performance liquid chromatography.Statistical analysisData was analyzed using Graphpad Prism 6 (GraphPad Software Inc. Ca, USA). Repeated measures analysis of variance (ANOVA) was used to identify differences in metabolic variables between treatment conditions. Statistical significance was considered at p < 0.05.Results166 individuals with an established monogenic cause of neonatal diabetes were identified within the monogenic diabetes registry. The majority of patients had mutations within the KCNJ11 (48.8%), ABCC8 (13.3%) or INS (15.7%) gene. Of 21 (12.7%) subjects with 6q24-TND, all 6 who are currently over 18 years of age reported recurrence of hyperglycemia requiring insulin therapy. 3 adults (UC153A, UC90A and UC277A) were available for dynamic studies while a fourth patient (UC702A) was transitioned to oral SU therapy as an outpatient. Their clinical details are outlined in table 1. None of the available patients were on SU therapy in the six-month period prior to the study and all had uniparental disomy of chromosome 6 (UPD6) as the underlying genetic cause of 6q24-TND. When comparing MMT off SU with those after a five-day course of SU, there was no difference in the serum glucose. C-peptide values were significantly higher in patients following a course of SU (p<0.05 by repeated measures ANOVA). When comparing AST off SU with those after a five-day course of SU, there was no significant difference in the serum glucose. The C-peptide response was again higher following a course of SU (p<0.01 by repeated measures ANOVA). The results of the MMT and AST are displayed in figure 1. All four subjects successfully transition off insulin therapy in lieu of oral medications. Patients had their glycemic control assessed at varying times after transitioning. Subjects’ insulin doses immediately prior to transition medications and medications at reassessment are outlined in table 1. Two patients required metformin and sitagliptin combination therapy in addition to an SU to achieve adequate glucose control. Another patient required metformin in addition to SU therapy.Discussion6q24-TND can be caused by a number of genetic and epigenetic changes at the 6q24 locus. Overexpression of the PLAGL1 (also known as ZAC) and HYMAI can result from uniparental disomy of chromosome 6, submicroscopic duplication of the paternal 6q24 allele or isolated loss of maternal methylation at the differentially methylated region at 6q24. Uniparental disomy of chromosome 6 is a sporadic event in embryonic development without an increased risk of recurrence in future offspring. In patients with submicroscopic duplication of the paternal 6q24 allele, there is a 50% chance of offspring inheriting the duplication. Isolated loss of maternal methylation is a poorly understood phenomenon with an unknown etiology and uncertain recurrence and inheritance risk. There are also rare autosomal recessive conditions which give rise to multiple loci with loss of methylation ADDIN PAPERS2_CITATIONS <citation><uuid>65778EBC-752E-47DF-8C2A-7A747706B790</uuid><priority>9</priority><publications><publication><uuid>5B0958FD-5BA8-4645-B42B-24EE5DCA2952</uuid><volume>116</volume><accepted_date>99200411041200000000222000</accepted_date><doi>10.1007/s00439-004-1236-1</doi><startpage>255</startpage><publication_date>99200503001200000000220000</publication_date><url> sequencing of the transient neonatal diabetes mellitus DMR facilitates a novel diagnostic test but reveals no methylation anomalies in patients of unknown aetiology.</title><location>200,5,51.0439553,-1.7898225</location><submission_date>99200404221200000000222000</submission_date><number>4</number><institution>Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK. djgm@soton.ac.uk</institution><subtype>400</subtype><endpage>261</endpage><bundle><publication><title>Human genetics</title><type>-100</type><subtype>-100</subtype><uuid>50F519F9-783D-4DBD-A932-832E50A7E36B</uuid></publication></bundle><authors><author><firstName>Deborah</firstName><middleNames>J G</middleNames><lastName>Mackay</lastName></author><author><firstName>I</firstName><middleNames>Karen</middleNames><lastName>Temple</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author><author><firstName>David</firstName><middleNames>O</middleNames><lastName>Robinson</lastName></author></authors></publication><publication><uuid>19EEAAAD-278B-4CBF-9089-25C14A87C4C2</uuid><volume>40</volume><accepted_date>99200805211200000000222000</accepted_date><doi>10.1038/ng.187</doi><startpage>949</startpage><publication_date>99200808001200000000220000</publication_date><url> of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57.</title><submission_date>99200802051200000000222000</submission_date><number>8</number><institution>Division of Human Genetics, University of Southampton, Southampton SO16 6YD, UK. djgm@soton.ac.uk</institution><subtype>400</subtype><endpage>951</endpage><bundle><publication><title>Nature genetics</title><type>-100</type><subtype>-100</subtype><uuid>68E9C2A7-7CA5-4285-B203-0D40DADE5364</uuid></publication></bundle><authors><author><firstName>Deborah</firstName><middleNames>J G</middleNames><lastName>Mackay</lastName></author><author><firstName>Jonathan</firstName><middleNames>L A</middleNames><lastName>Callaway</lastName></author><author><firstName>Sophie</firstName><middleNames>M</middleNames><lastName>Marks</lastName></author><author><firstName>Helen</firstName><middleNames>E</middleNames><lastName>White</lastName></author><author><firstName>Carlo</firstName><middleNames>L</middleNames><lastName>Acerini</lastName></author><author><firstName>Susanne</firstName><middleNames>E</middleNames><lastName>Boonen</lastName></author><author><firstName>Pinar</firstName><lastName>Dayanikli</lastName></author><author><firstName>Helen</firstName><middleNames>V</middleNames><lastName>Firth</lastName></author><author><firstName>Judith</firstName><middleNames>A</middleNames><lastName>Goodship</lastName></author><author><firstName>Andreas</firstName><middleNames>P</middleNames><lastName>Haemers</lastName></author><author><firstName>Johanne</firstName><middleNames>M D</middleNames><lastName>Hahnemann</lastName></author><author><firstName>Olga</firstName><lastName>Kordonouri</lastName></author><author><firstName>Ahmed</firstName><middleNames>F</middleNames><lastName>Masoud</lastName></author><author><firstName>Elsebet</firstName><lastName>Oestergaard</lastName></author><author><firstName>John</firstName><lastName>Storr</lastName></author><author><firstName>Sian</firstName><lastName>Ellard</lastName></author><author><firstName>Andrew</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author><author><firstName>David</firstName><middleNames>O</middleNames><lastName>Robinson</lastName></author><author><firstName>I</firstName><middleNames>Karen</middleNames><lastName>Temple</lastName></author></authors></publication></publications><cites></cites></citation>(8,11). The pathogenesis of hyperglycemia 6q24-TND is uncertain with a variable course of DM in the neonatal period and later life. The true incidence of relapse is also unclear. The TNDM29 transgenic mouse uses the human PLAGL1 and HYMAI gene locus to mimic the genotype seen in humans. This model suggests decreased levels of transcription factors (PDX1, NGN3, PAX6) and a reduction in beta cell mass at birth ADDIN PAPERS2_CITATIONS <citation><uuid>779FAB4F-5CF2-45A1-8A78-354B5FAC01E7</uuid><priority>10</priority><publications><publication><uuid>A22187C1-1C7D-4282-9C09-A4221DB0E72A</uuid><volume>114</volume><doi>10.1172/JCI22506</doi><startpage>314</startpage><publication_date>99200408001200000000220000</publication_date><url> the secrets of the pancreatic beta cell: man and mouse provide the key.</title><location>200,9,50.7234642,-3.5164400</location><institution>Diabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom. A.T.Hattersley@ex.ac.uk</institution><number>3</number><subtype>400</subtype><endpage>316</endpage><bundle><publication><title>The Journal of clinical investigation</title><type>-100</type><subtype>-100</subtype><uuid>FA7EDCEE-5CD0-40C4-A5BD-C06B5029EB2D</uuid></publication></bundle><authors><author><firstName>Andrew</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author></authors></publication></publications><cites></cites></citation>(12). There appears to be a compensatory increase in beta cell number but is inadequate to maintain euglycemia later in life in the mouse model ADDIN PAPERS2_CITATIONS <citation><uuid>585D1D2A-6292-432A-9941-6CDB5F90833D</uuid><priority>11</priority><publications><publication><uuid>AC09E021-1EB8-409F-9D6B-2E47EBBBFECA</uuid><volume>114</volume><accepted_date>99200405251200000000222000</accepted_date><doi>10.1172/JCI19876</doi><startpage>339</startpage><publication_date>99200408001200000000220000</publication_date><url> glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.</title><location>602,0,0,0</location><submission_date>99200308221200000000222000</submission_date><number>3</number><institution>Developmental Genetics Programme, The Babraham Institute, Cambridge, United Kingdom.</institution><subtype>400</subtype><endpage>348</endpage><bundle><publication><title>The Journal of clinical investigation</title><type>-100</type><subtype>-100</subtype><uuid>FA7EDCEE-5CD0-40C4-A5BD-C06B5029EB2D</uuid></publication></bundle><authors><author><firstName>Dan</firstName><lastName>Ma</lastName></author><author><firstName>Julian</firstName><middleNames>P H</middleNames><lastName>Shield</lastName></author><author><firstName>Wendy</firstName><lastName>Dean</lastName></author><author><firstName>Isabelle</firstName><lastName>Leclerc</lastName></author><author><firstName>Claude</firstName><lastName>Knauf</lastName></author><author><firstName>R</firstName><middleNames>éMy</middleNames><lastName>Burcelin R</lastName></author><author><firstName>Guy</firstName><middleNames>A</middleNames><lastName>Rutter</lastName></author><author><firstName>Gavin</firstName><lastName>Kelsey</lastName></author></authors></publication></publications><cites></cites></citation>(13). Recent data in humans would also suggest that some patients may be at risk of significant hypoglycemia during the remission period ADDIN PAPERS2_CITATIONS <citation><uuid>7453DE2B-7CD3-4374-AC5C-A3663C76F543</uuid><priority>12</priority><publications><publication><location>200,6,50.7164616,-3.5100833</location><publication_date>99201210311200000000222000</publication_date><doi>10.1007/s00125-012-2766-z</doi><institution>University of Exeter Medical School, Barrack Road, Exeter, Devon, EX2 5DW, UK, sarah.flanagan@pms.ac.uk.</institution><accepted_date>99201210121200000000222000</accepted_date><title>Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype.</title><uuid>3159ED64-F523-4AC0-B69C-779F02BE1B9A</uuid><subtype>400</subtype><submission_date>99201208031200000000222000</submission_date><type>400</type><url> G</middleNames><lastName>Mackay</lastName></author><author><firstName>S</firstName><middleNames>A W</middleNames><lastName>Greeley</lastName></author><author><firstName>T</firstName><middleNames>J</middleNames><lastName>McDonald</lastName></author><author><firstName>V</firstName><lastName>Mericq</lastName></author><author><firstName>J</firstName><lastName>Hassing</lastName></author><author><firstName>E</firstName><middleNames>J</middleNames><lastName>Richmond</lastName></author><author><firstName>W</firstName><middleNames>R</middleNames><lastName>Martin</lastName></author><author><firstName>C</firstName><lastName>Acerini</lastName></author><author><firstName>A</firstName><middleNames>M</middleNames><lastName>Kaulfers</lastName></author><author><firstName>D</firstName><middleNames>P</middleNames><lastName>Flynn</lastName></author><author><firstName>J</firstName><lastName>Popovic</lastName></author><author><firstName>M</firstName><middleNames>A</middleNames><lastName>Sperling</lastName></author><author><firstName>K</firstName><lastName>Hussain</lastName></author><author><firstName>S</firstName><lastName>Ellard</lastName></author><author><firstName>A</firstName><middleNames>T</middleNames><lastName>Hattersley</lastName></author></authors></publication></publications><cites></cites></citation>(14) and point toward some element of beta cell dysfunction rather than simply an overall reduction in cell number. Other groups have demonstrated abnormal insulin response to hyperglycemia but a normal response to glucagon use ADDIN PAPERS2_CITATIONS <citation><uuid>45405621-4353-40C7-B042-A02F011FC053</uuid><priority>13</priority><publications><publication><uuid>552E540B-725D-4C2E-AA15-4A9BC87359E0</uuid><volume>27</volume><startpage>2405</startpage><publication_date>99200410001200000000220000</publication_date><url> dysfunction in classic transient neonatal diabetes is characterized by impaired insulin response to glucose but normal response to glucagon.</title><location>200,4,40.8517746,14.2681244</location><institution>Faculty of Movement Sciences, Parthenope University, Napoli, Italy. giuliana.valerio@uniparthenope.it</institution><number>10</number><subtype>400</subtype><endpage>2408</endpage><bundle><publication><title>Diabetes care</title><type>-100</type><subtype>-100</subtype><uuid>F15BF67E-35A3-41B0-8445-41E14E665D7A</uuid></publication></bundle><authors><author><firstName>Giuliana</firstName><lastName>Valerio</lastName></author><author><firstName>Adriana</firstName><lastName>Franzese</lastName></author><author><firstName>Mariacarolina</firstName><lastName>Salerno</lastName></author><author><firstName>Gianluca</firstName><lastName>Muzzi</lastName></author><author><firstName>Gaetano</firstName><lastName>Cecere</lastName></author><author><firstName>Karen</firstName><middleNames>I</middleNames><lastName>Temple</lastName></author><author><firstName>Julian</firstName><middleNames>P</middleNames><lastName>Shield</lastName></author></authors></publication></publications><cites></cites></citation>(15) in patients with 6q24 methylation defects. Our data suggests that agents that promote non-glucose dependent insulin release may represent treatment alternatives to insulin therapy. All four of our patients were successfully transitioned off insulin therapy in lieu of SU therapy alone or a combination of multiple oral agents. There are reports of successful treatment with SU therapy for over 10 years following relapse ADDIN PAPERS2_CITATIONS <citation><uuid>73947410-BA03-4E79-A421-28AB85FF191A</uuid><priority>14</priority><publications><publication><volume>32</volume><publication_date>99200901001200000000220000</publication_date><number>1</number><doi>10.2337/dc08-1813</doi><startpage>e9</startpage><title>Long-standing sulfonylurea therapy after pubertal relapse of neonatal diabetes in a case of uniparental paternal isodisomy of chromosome 6.</title><uuid>FED588FA-49D5-46BC-9E18-24749DF767F3</uuid><subtype>400</subtype><type>400</type><url> care</title><type>-100</type><subtype>-100</subtype><uuid>F15BF67E-35A3-41B0-8445-41E14E665D7A</uuid></publication></bundle><authors><author><firstName>Ulf</firstName><lastName>Schimmel</lastName></author></authors></publication></publications><cites></cites></citation>(16). SU therapy has been successfully used for the treatment of KATP channelopathies, which make up the majority of permanent neonatal DM. While the pathogenesis of hyperglycemia in 6q24-TND is less well characterized, there are some anecdotal reports of SU use in the neonatal period. SU therapy in type 2 diabetes can result in hastening of beta cell failure ADDIN PAPERS2_CITATIONS <citation><uuid>D27845B2-4E88-48B1-A9EC-65F774D58909</uuid><priority>15</priority><publications><publication><uuid>916C33A8-C31F-4168-A7A0-0CAAB5EFBEC1</uuid><volume>355</volume><doi>10.1056/NEJMoa066224</doi><startpage>2427</startpage><publication_date>99200612071200000000222000</publication_date><url> durability of rosiglitazone, metformin, or glyburide monotherapy.</title><institution>Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle 98108, USA. skahn@u.washington.edu</institution><number>23</number><subtype>400</subtype><endpage>2443</endpage><bundle><publication><url> New England journal of medicine</title><type>-100</type><subtype>-100</subtype><uuid>2122C342-742A-495E-9D39-8D3E98EB5DC7</uuid></publication></bundle><authors><author><firstName>Steven</firstName><middleNames>E</middleNames><lastName>Kahn</lastName></author><author><firstName>Steven</firstName><middleNames>M</middleNames><lastName>Haffner</lastName></author><author><firstName>Mark</firstName><middleNames>A</middleNames><lastName>Heise</lastName></author><author><firstName>William</firstName><middleNames>H</middleNames><lastName>Herman</lastName></author><author><firstName>Rury</firstName><middleNames>R</middleNames><lastName>Holman</lastName></author><author><firstName>Nigel</firstName><middleNames>P</middleNames><lastName>Jones</lastName></author><author><firstName>Barbara</firstName><middleNames>G</middleNames><lastName>Kravitz</lastName></author><author><firstName>John</firstName><middleNames>M</middleNames><lastName>Lachin</lastName></author><author><firstName>M</firstName><middleNames>Colleen</middleNames><lastName>O'Neill</lastName></author><author><firstName>Bernard</firstName><lastName>Zinman</lastName></author><author><firstName>Giancarlo</firstName><lastName>Viberti</lastName></author><author><lastName>ADOPT Study Group</lastName></author></authors></publication></publications><cites></cites></citation>(17). However our data and other reports would suggest that insulin therapy may not be required for many years after relapse of diabetes in these patients ADDIN PAPERS2_CITATIONS <citation><uuid>1E906599-C258-44B3-BBBD-A8226C516564</uuid><priority>16</priority><publications><publication><uuid>0E8ABB53-C50B-46A2-8CF5-05CA1AE6971B</uuid><volume>13</volume><doi>10.1111/j.1399-5448.2011.00776.x</doi><startpage>155</startpage><publication_date>99201203001200000000220000</publication_date><url> occurrence of neonatal diabetes with duplications in chromosome 6q24: treatment with sulfonylurea and 40-yr follow-up.</title><location>200,9,60.3880754,5.3228542</location><institution>Department of Clinical Medicine, University of Bergen, Bergen, Norway. oddmund.sovik@pedi.uib.no</institution><number>2</number><subtype>400</subtype><endpage>162</endpage><bundle><publication><title>Pediatric diabetes</title><type>-100</type><subtype>-100</subtype><uuid>BC72F0CA-CA7D-48ED-B39E-0C26A5436867</uuid></publication></bundle><authors><author><firstName>Oddmund</firstName><lastName>S?vik</lastName></author><author><firstName>Oystein</firstName><lastName>Aagenaes</lastName></author><author><firstName>Stig</firstName><middleNames>?</middleNames><lastName>Eide</lastName></author><author><firstName>Deborah</firstName><lastName>Mackay</lastName></author><author><firstName>Isabel</firstName><middleNames>K</middleNames><lastName>Temple</lastName></author><author><firstName>Anders</firstName><lastName>Molven</lastName></author><author><firstName>P?l</firstName><middleNames>R</middleNames><lastName>Nj?lstad</lastName></author></authors></publication></publications><cites></cites></citation>(18). All participants diagnosed with 6q24-TND who are currently over 18 years of age reported recurrence of hyperglycemia and were treated with insulin. Each received a genetic diagnosis in adulthood despite the classical features seen in the neonatal period. Reports suggesting that 6q24-TND is responsible for 40-50% of all cases of neonatal diabetes ADDIN PAPERS2_CITATIONS <citation><uuid>E2EAA7EF-D1B3-4B69-8DEF-ADA343B2A633</uuid><priority>17</priority><publications><publication><uuid>DC2070A2-EB8E-4E96-8759-58FE22F6307D</uuid><volume>141</volume><doi>10.1067/mpd.2002.127089</doi><startpage>483</startpage><publication_date>99200210001200000000220000</publication_date><url> diabetes mellitus: chromosomal analysis in transient and permanent cases.</title><location>200,4,48.3903940,-4.4860760</location><institution>Department of Pediatrics, H?pital Morvan, Brest.</institution><number>4</number><subtype>400</subtype><endpage>489</endpage><bundle><publication><publisher>Mosby, Inc.</publisher><title>The Journal of pediatrics</title><type>-100</type><subtype>-100</subtype><uuid>78F6C31E-2742-4E9F-B671-F6F312A68826</uuid></publication></bundle><authors><author><firstName>Chantal</firstName><lastName>Metz</lastName></author><author><firstName>Hélène</firstName><lastName>Cavé</lastName></author><author><firstName>Anne</firstName><middleNames>Marie</middleNames><lastName>Bertrand</lastName></author><author><firstName>Christine</firstName><lastName>Deffert</lastName></author><author><firstName>Béatrice</firstName><lastName>Gueguen-Giroux</lastName></author><author><firstName>Paul</firstName><lastName>Czernichow</lastName></author><author><firstName>Michel</firstName><lastName>Polak</lastName></author><author><lastName>NDM French Study Group. Neonatal diabetes mellitus</lastName></author></authors></publication></publications><cites></cites></citation>(6). 6q24-TND is under represented in our registry (12.7% of cases) and remains an infrequently recognized form of diabetes despite the 6q24 locus being associated transient neonatal diabetes for almost 20 years ADDIN PAPERS2_CITATIONS <citation><uuid>F9CC5A10-01BE-45BF-B05E-894215690D2D</uuid><priority>18</priority><publications><publication><volume>9</volume><publication_date>99199502001200000000220000</publication_date><number>2</number><doi>10.1038/ng0295-110</doi><startpage>110</startpage><title>An imprinted gene(s) for diabetes?</title><uuid>39326BF9-DD72-40B3-916F-63CAA05CB85B</uuid><subtype>400</subtype><endpage>112</endpage><type>400</type><url> genetics</title><type>-100</type><subtype>-100</subtype><uuid>68E9C2A7-7CA5-4285-B203-0D40DADE5364</uuid></publication></bundle><authors><author><firstName>I</firstName><middleNames>K</middleNames><lastName>Temple</lastName></author><author><firstName>R</firstName><middleNames>S</middleNames><lastName>James</lastName></author><author><firstName>J</firstName><middleNames>A</middleNames><lastName>Crolla</lastName></author><author><firstName>F</firstName><middleNames>L</middleNames><lastName>Sitch</lastName></author><author><firstName>P</firstName><middleNames>A</middleNames><lastName>Jacobs</lastName></author><author><firstName>W</firstName><middleNames>M</middleNames><lastName>Howell</lastName></author><author><firstName>P</firstName><lastName>Betts</lastName></author><author><firstName>J</firstName><middleNames>D</middleNames><lastName>Baum</lastName></author><author><firstName>J</firstName><middleNames>P</middleNames><lastName>Shield</lastName></author></authors></publication></publications><cites></cites></citation>(19). Our data suggests that 6q24-TND may be mistaken for other forms of diabetes when hyperglycemia recurs outside the neonatal period. Failure to correctly identify the underlying genetic etiology results in a missed opportunity to offer individualized pharmacotherapy.Conclusions6q24-TND may be mistaken for other forms of diabetes when hyperglycemia recurs. A careful birth and neonatal history is important when assessing patients newly diagnosed with diabetes. The exact pathogenic mechanisms underlying this unusual type of diabetes remains incompletely understood. Correct identification of the underlying genetic diagnosis may impact clinical and therapeutic strategies. The role of non-insulin based therapies in 6q24-TND warrants further study and should be considered.AcknowledgementsWe would like to acknowledge the continued support of Dr. DJG Mackay (Division of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton School of Medicine, UK) for performing diagnosis of 6q24-TND (funded by Diabetes UK). This work was supported by USPHS grants P30-DK020595, K23-DK094866 and UL1 RR024999, the American Diabetes Association (1-11-CT-41), and gifts from the Kovler Family Foundation and Lewis-Sebring Foundation. We also thank Kristen Wroblewski for providing statistical support and all of the patients and families who participated in these studies. References ADDIN PAPERS2_CITATIONS <papers2_bibliography/>1.Naylor R, Philipson LH 2011 Who should have genetic testing for maturity-onset diabetes of the young? Clin. Endocrinol. (Oxf) 75:422–4262.Shield JP, Gardner RJ, Wadsworth EJ, Whiteford ML, James RS, Robinson DO, Baum JD, Temple IK 1997 Aetiopathology and genetic basis of neonatal diabetes. Arch. Dis. Child. Fetal Neonatal Ed. 76:F39–F423.Iafusco D, Massa O, Pasquino B, Colombo C, Iughetti L, Bizzarri C, Mammì C, Lo Presti D, Suprani T, Schiaffini R, Nichols CG, Russo L, Grasso V, Meschi F, Bonfanti R, Brescianini S, Barbetti F; Early Diabetes Study Group of ISPED 2012 Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births. Acta Diabetol 49:405–4084.Greeley SAW, Naylor RN, Cook LS, Tucker SE, Lipton RB, Philipson LH 2011 Creation of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes. 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UC90AUC153AUC277AUC702AGenetic defectUPD6UPD6UPD6UPD6SexFemaleMaleFemaleFemaleGestational age (weeks)33344038Birth weight (grams)1280247022401810Age at initial DM diagnosis (days)1111Age at DM remission (months)4763Age at DM recurrence (years)1312 2712 Age at cessation of insulin (years) 20232928BMI at cessation of insulin (kg/m2)26.2831.3821.6629.44Insulin dose at transition (units/kg)0.590.730.410.76Medications at reassessment -Glyburide 0.59 mg/kg0.53 mg/kg0.13 mg/kg0.23 mg/kg -Sitagliptin100 mg100mg---Metformin2g2g-1.5gHbA1c at cessation of insulin8.2%7.8%7.2% 9.9% HbA1c at Reassessment-Months off insulin therapy7.1%56.6%87.3%177.5%6UPD6- Uniparental disomy of chromosome 6 ABCDFigure 1. Metabolic testing. A-B) Mixed meal test glucose (A) and C-peptide (B) levels. C-D) Arginine stimulation test glucose (C) and C-peptide (D) levels. Values are expressed as mean ± SEM. * Repeated measures ANOVA used to identify differences in metabolic variables between treatment conditions. ................
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