ISPAD Clinical Practice Consensus Guidelines

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1 Peiatric Diabetes 2006: 7: All rights reserve Copyright # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Introuction With this issue of Peiatric Diabetes, the first chapters of the Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD) are publishe. Sequential chapters will be publishe in subsequent issues of Peiatric Diabetes. Finally, the complete set of these guielines will be publishe as a future compenium. In 2003, the total chil population of the worl (0 14 yr) was estimate to be 1.8 billion, of whom 0.024% have iabetes. This means that chilren aroun the worl have iabetes, with new cases iagnose each year (1). This very large number of chilren nee help with injections of insulin in orer to survive an live a full life without restrictions or isabling complications an without being stigmatize for their iabetes. In 1993, members of ISPAD formulate the Declaration of Kos, proclaiming their commitment to Ôpromote optimal health, social welfare, an quality of life for all chilren with iabetes aroun the worl by the year Although all the aims an ieals of the Declaration of Kos were not reache by 2000, we believe that slowly, by small steps, the worlwie care of chilren with iabetes mellitus is improving. ISPAD publishe its first set of guielines in 1995 (2) an its secon in 2000 (3). Since then, the acceptance of intensive therapy for chilren, even for very young chilren, has increase worlwie. Insulin pump usage has risen in all age groups in countries where this treatment moality can be affore. However, intensive therapy requires an investment in better an more comprehensive eucation for the caregivers in orer for it to be successful. The ISPAD Consensus Guielines 2000 have been translate into 11 languages, inicating the nee for a truly international ocument. In , national guielines for chilhoo iabetes were release: the Australian Clinical Practice Guielines from the National Health an Meical Research Council (writing committee chair, Martin Silink)(4) an in the Unite Kingom, the National Institute for Clinical Excellence Clinical Guielines (group leaer, Stephen Greene) (5). Both these publications are truly evience-base in that they eal with the boy of evience in a systematic approach, graing each reference, an builing the case for each recommenation. In 2003, the Canaian Diabetes Association publishe Clinical Practice Guielines with chapters both on type 1 iabetes mellitus (T1DM) an type 2 iabetes mellitus (T2DM) in chilren an aolescents (6). In 2005, the American Diabetes Association (ADA) publishe their statement on the care of chilren an aolescents with T1DM (7). This thir eition of ISPAD s Consensus Guielines, now entitle ÔClinical Practice Consensus Guielines, is much larger an has been enriche by reference to an resources in the above-mentione national guielines. In the Introuction to previous ISPAD Guielines, the acknowlege intention was for the next version of our guielines to be reference. We have use the ADA system for graing eviences (Table 1) (8). Whenever possible, the reference for a statement or recommenation has been inclue, but as reaers will note, a vast majority of the recommenations an suggestions will have the grae E (expert consensus or clinical experience). The Guielines are base on a wie consensus of clinical practice. They were rafte by international writing teams, moifie by experts in ifferent specialties from many countries, ebate at the annual ISPAD meeting in 2005 by the members, an reviewe by members via the internet an the ISPAD website. As far as possible, significant input by iniviuals has been acknowlege. Many thanks to those numerous iniviuals who have contribute but whose names coul not be inclue. As was the same in the 2000 Guielines, the eition places eucation at the center of clinical management. Eucation is the vehicle for optimal self-management, the key to success. New chapters have been ae on T2DM in chilren an aolescents, monogenic iabetes, an exercise. We hope, therefore, that the Guielines will be wiely consulte an will be use to improve awareness among governments, state healthcare proviers, an the general public of the serious long-term implications of poorly manage iabetes an of the essential resources neee for optimal care assist iniviual caregivers in managing chilren an aolescents with iabetes in a prompt, safe, consistent, equitable, an stanarize manner in accorance with the current views of experts in the fiel. 341

2 Hanas et al. Table 1. The evience graing system for Clinical Practice Recommenations of the American Diabetes Association (ADA) (8) Level of evience A B C E Description Clear evience from well-conucte, generalizable, ranomize, controlle trials that are aequately powere, incluing: Evience from a multicenter trial Evience from a meta-analysis incorporating quality ratings Compelling non-experimental evience (i.e., Ôall or none rule) evelope by the Center for Evience-Base Meicine at Oxfor* Supportive evience from well-conucte, ranomize, controlle trials that are aequately powere, incluing: Evience from a well-conucte trial at one or more institutions Evience from a meta-analysis that incorporate quality ratings in the analysis Supportive evience from well-conucte cohort stuies incluing: Evience from a well-conucte prospective cohort stuy or registry Evience from a well-conucte meta-analysis of cohort stuies Supportive evience from a well-conucte case control stuy Supportive evience from poorly controlle or uncontrolle stuies incluing: Evience from ranomize clinical trials with 1 major or 3 minor methoological flaws that coul invaliate the results Evience from observational stuies with high potential for bias (such as case series with comparison with historical controls) Evience from case series or case reports Conflicting evience with the weight of evience supporting the recommenation Expert consensus or clinical experience *Either all patients ie before therapy, at least some survive with therapy, or some patients ie without therapy, an none ie with therapy (e.g., the use of insulin in the treatment of iabetic ketoaciosis). As in 2000, Ôthese Guielines are not strict protocols nor are they the final wor. Iniviual clinical jugment an ecision making also require the family s values an expectations to be consiere, with the best outcomes being reache by consensus. Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith, Peter GF Swift Eitors of the ISPAD Clinical Practice Consensus Guielines Ragnar Hanas, MD, PhD Department of Peiatrics Uevalla Hospital S Uevalla, Sween References 1. IDF. Incience of iabetes. Diabetes Atlas 2006: LARON Z. Consensus Guielines for the Management of Insulin-Depenent (Type 1)Diabetes (IDDM) in Chilhoo an Aolescence. Lonon: Freun Publishing House, SWIFT PGF. (e.). ISPAD (International Society for Peiatric an Aolescent Diabetes) Consensus Guielines for the Management of Type 1 Diabetes Mellitus in Chilren an Aolescents. Zeist, Netherlans: Meforum, APEG. (Australasian Paeiatric Enocrine Group). Australian Clinical Practice Guielines: Type 1 Diabetes in Chilren an Aolescents. Australia: Australia Government, National Health an Meical Research Council, National Collaborating Centre for Women s an Chilren s Health. Type 1 Diabetes: Diagnosis an Management of Type 1 Diabetes in Chilren an Young People. Lonon: RCOG Press, CANADIAN DIABETES ASSOCIATION. Clinical Practice Guielines for the prevention an management of iabetes in Canaa. Can J Diab 2003: 27(Suppl. 2): S84 S SILVERSTEIN J, KLINGENSMITH G, COPELAND K et al. Care of chilren an aolescents with type 1 iabetes: a statement of the American Diabetes Association. Diabetes Care 2005: 28: AMERICAN DIABETES ASSOCIATION. Summary of revisions for the 2006 Clinical Practice Recommenations. Diabetes Care 2006: 29(Suppl. 1): S Peiatric Diabetes 2006: 7:

3 Peiatric Diabetes 2006: 7: All rights reserve # 2006 The Authors Journal compilation # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Definition, epiemiology an classification Authors: Maria E. Craig, University of NSW, University of Syney, The Chilren s Hospital at Westmea, Australia Anrew Hattersley, Institute of Biomeical an Clinical Sciences, Peninsula Meical School, Exeter, UK Kim Donaghue, University of Syney, The Chilren s Hospital at Westmea, NSW, Australia Acknowlegements: Denis Daneman, Zvi Laron, Shin Amemiya, Shigetaka Sugihara, Tatsuhiko Urakami, Gun Forsaner Eitors: Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Definition Diabetes mellitus (DM) is a group of metabolic iseases characterize by chronic hyperglycaemia resulting from efects in insulin secretion, insulin action, or both. The abnormalities in carbohyrate, fat, an protein metabolism that are foun in iabetes are ue to eficient action of insulin on target tissues. If ketones are present in the bloo or urine, treatment is urgent because ketoaciosis can evolve rapily. Diagnostic criteria for iabetes in chilhoo an aolescence Diagnostic criteria for iabetes are base on bloo glucose measurements an thepresenceorabsence of symptoms (E) (1, 2). Three ways to iagnose iabetes are possible an each, in the absence of unequivocal hyperglycaemia, must be confirme, on a subsequent ay, by any one of the three methos givenintable1. Diabetes in chilren usually presents with characteristic symptoms such as polyuria, polyipsia, blurring of vision, an weight loss, in association with glycosuria an ketonuria. In its most severe form, ketoaciosis, or rarely a non-ketotic hyperosmolar state, may evelop an lea to stupor, coma, an in absence of effective treatment, eath. The iagnosis is usually confirme quickly by measurement of a marke elevation of the bloo glucose level. In this situation, if ketones are present in the bloo or urine, treatment is urgent. Waiting another ay to confirm the hyperglycaemia may be angerous in allowing ketoaciosis to evolve rapily. In the absence of symptoms or presence of mil symptoms of iabetes, hyperglycaemia etecte incientally or uner conitions of acute infective, traumatic, circulatory, or other stress may be transitory an shoul not in itself be regare as iagnostic of iabetes. The iagnosis of iabetes shoul not be base on a single plasma glucose concentration. Diagnosis may require continue observation with fasting an/or 2-h postpranial bloo glucose levels an/or an oral glucose tolerance test (OGTT). An OGTT shoul not be performe if iabetes can be iagnose using fasting, ranom, or postpranial criteria, as excessive hyperglycaemia can result using a fasting OGTT in these circumstances. It is rarely inicate in making the iagnosis of type 1 DM (T1DM) in chilhoo an aolescence (E) (2). If oubt remains, perioic re-testing shoul be unertaken until the iagnosis is establishe or refute. Impaire glucose tolerance an impaire fasting glycaemia Impaire glucose tolerance (IGT) an impaire fasting glycaemia (IFG) are intermeiate stages in the natural history of isorere carbohyrate metabolism between normal glucose homeostasis an iabetes (E) (3, 4). IFG an IGT are not interchangeable an represent ifferent abnormalities of glucose regulation. IFG is a measure of isturbe carbohyrate metabolism in the basal state, while IGT is a ynamic measure of carbohyrate intolerance after a stanarize glucose loa. Patients with IFG an/or IGT are now referre to as having pre-iabetes, inicating the relatively high risk for evelopment of iabetes in these patients (A) (5, 6). They can be observe as intermeiate stages in any of the isease processes liste in Table 2. IFG an IGT may be associate with the metabolic synrome (MS), which inclues obesity (especially abominal or visceral obesity), yslipiaemia of the high-triglycerie an/or low-high ensity lipoprotein (HDL) type, an hypertension. 343

4 Craig et al. Table 1. Criteria for the iagnosis of iabetes mellitus (1, 2) (E) Symptoms of iabetes plus casual plasma glucose concentration 11.1 mmol/l (200 mg/l).* Casual is efine as any time of ay without regar to time since the last meal. or Fasting plasma glucose 7.0 mmol/l (126 mg/l). Fasting is efine as no caloric intake for at least 8 h. or 2-h postloa glucose 11.1 mmol/l (200 mg/l) uring an oral glucose tolerance test (OGTT). The test shoul be performe as escribe by the Worl Health Organization (WHO) (2), using a glucose loa containing the equivalent of 75 g anhyrous glucose issolve in water or 1.75 g/kg of boy weight to a maximum of 75 g (3). *Corresponing values (mmol/l) are 10.0 for venous whole bloo an 11.1 for capillary whole bloo. Corresponing values are 6.3 mg/l for both venous an capillary whole bloo. Iniviuals who meet the criteria for IGT or IFG may be euglycaemic in their aily lives as shown by normal or near-normal glycate haemoglobin levels, an those with IGT may manifest hyperglycaemia only when challenge with an OGTT. Categories of fasting plasma glucose (FPG) are efine as follows: FPG, 5.6 mmol/l (100 mg/l) ¼ normal fasting glucose. FPG mmol/l ( mg/l) ¼ IFG. FPG 7.0 mmol/l (126 mg/l) ¼ provisional iagnosis of iabetes (the iagnosis must be confirme, as escribe above uner Diagnostic criteria ). The corresponing categories when the OGTT is use are as follows: 2-h postloa glucose, 7.8 mmol/l (140 mg/l) ¼ normal glucose tolerance. 2-h postloa glucose mmol/l ( mg/ L) ¼ IGT. 2-h postloa glucose mmol/l (200 mg/l) ¼ provisional iagnosis of iabetes (the iagnosis must be confirme, as escribe above). Pathogenesis of T1DM Iniviuals have an absolute eficiency of insulin secretion an are prone to ketoaciosis. Most cases are primarily ue to T-cell meiate pancreatic islet b-cell estruction, which occurs at a variable rate an becomes clinically symptomatic when approximately 90% of pancreatic b-cells are estroye (C) (7). Serological markers of an autoimmune pathologic process, incluing islet cell, glutamic aci ecarboxylase (GAD), islet antigen (IA)-2, IA-2b, or insulin autoantiboies (IAAs), are present in 85 90% of iniviuals when fasting hyperglycaemia is etecte (B) (8, 9). Susceptibility to autoimmune T1DM is etermine by the interaction of multiple genes. Human leucocyte antigen (HLA) genes having the strongest known association, with linkage to DQA an DQB genes, which can be either preisposing or protective (B) (10 12). Iniviuals at increase risk of eveloping T1DM can often be ientifie by measurement of iabetes-associate autoantiboies, genetic markers, an intravenous glucose tolerance testing (B) (13 16). The environmental triggers (chemical an/or viral) which initiate pancreatic b-cell estruction remain largely unknown, but the process usually begins months to years before the manifestation of clinical symptoms (B) (15, 16). In geographical areas where T1DM occurs with lower incience, there is a higher rate of iabetic ketoaciosis (DKA) at presentation (17, 18) When the clinical presentation is typical of T1DM (often associate with DKA) but antiboies are absent, then the iabetes is classifie as T1B (iiopathic). Other forms of iabetes shoul also be consiere as shown in Table 2. Epiemiology of T1DM More than half of iniviuals with T1DM are iagnose before the age of 15 yr (B) (19). In most western countries, T1DM accounts for more than 90% of chilhoo an aolescent iabetes. Type 2 DM (T2DM) is becoming more common an accounts for a significant proportion of youthonset iabetes in certain at-risk populations (B) (20). Epiemiological incience stuies efine the onset of T1DM by the ate of the first insulin injection because of the variable time between the onset of symptoms an iagnosis (B) (21). The incience of T1DM varies greatly between ifferent countries, within countries, an between ifferent ethnic populations (B). Annual incience rates for chilhoo T1DM (0 14 yr age group) comparing ifferent countries of the worl are shown in Figure 1 ( per ) (21, 22). 344 Peiatric Diabetes 2006: 7:

5 Consensus Guielines Table 2. Aetiological classification of isorers of glycaemia I. Type 1 b-cell estruction, usually leaing to absolute insulin eficiency A. Autoimmune B. Iiopathic II. Type 2 May range from preominantly insulin resistance with relative insulin eficiency to a preominantly secretory efect with or without insulin resistance III. Other specific types A. Genetic efects of b-cell function E. Drug or chemical inuce Chromosome 12, HNF-1a (MODY3) Vacor Chromosome 7, glucokinase (MODY2) Pentamiine Chromosome 20, HNF-4a (MODY1) Nicotinic aci Chromosome 13, insulin promoter factor (IPF)-1 (MODY4) Glucocorticois Thyroi hormone Chromosome 17, HNF-1b (MODY5) Diazoxie Chromosome 2, NeuroD1 (MODY6) b-arenergic agonists Mitochonrial DNA mutation Thiazies Chromosome 11, KCNJ11 (Kir6.2), ABCC8 [sulphonylurea receptor 1 (SUR1)] Dilantin a-interferon Others Others B. Genetic efects in insulin action F. Infections Type A insulin resistance Congenital rubella Leprechaunism Cytomegalovirus Rabson Menenhall synrome Coxsackie B4 Lipoatrophic iabetes Others Others G. Uncommon forms of immune-meiate iabetes C. Diseases of the exocrine pancreas Stiff-man synrome Pancreatitis Anti-insulin receptor antiboies Trauma/pancreatectomy Autoimmune polyenocrine synrome eficiencies Neoplasia I an II Cystic fibrosis Others Haemochromatosis H. Other genetic synromes sometimes Fibrocalculous pancreatopathy associate with iabetes Others Down s synrome D. Enocrinopathies Klinefelter s synrome Acromegaly Turner s synrome Cushing synrome Wolfram s synrome Glucagonoma Friereich s ataxia Phaeochromocytoma Huntington s chorea Hyperthyroiism Laurence Moon Biel synrome Somatostatinoma Myotonic ystrophy Alosteronoma Others IV. Gestational iabetes Porphyria Praer Willi synrome Others HNF, hepatocyte nuclear factor; MODY, maturity-onset iabetes of the young. In Europe, incience rates show a close correlation with the frequency of HLA susceptibility genes in increase in those younger than the age of 5 yr (B) (33 35). the general population (B) (23 26). A seasonal variation in the presentation of new In Japan, the incience of T1DM is extremely low at per an has a ifferent an unique cases is well escribe, with the peak being in the winter months (B) (32, 36, 37). HLA association compare with Caucasians (27). In aition, a slowly progressive form of T1DM is common (28). Gener ifferences in incience are foun in some, but not all, populations (B) (21, 29 32). A well-ocumente rise in the incience has been note in many countries, an in some reports, Despite familial aggregation, there is no recognizable pattern of inheritance. The risk of iabetes to an ientical twin of a patient with T1DM is about 36% (B) (38); for a sibling, the risk is approximately 4% by the age of 20 yr (B) (39, 40) an 9.6% by the age of 60 yr (B) (41), compare with 0.5% for the general population. The risk is higher in siblings of there has been a isproportionately greater probans iagnose at a younger age (B) (40, 42). Peiatric Diabetes 2006: 7:

6 Craig et al. Finlan Sarinia Canaa Sween UK (Scotlan) New Zealan Kuwait Australia UK (Northern Irelan) Norway Canaa (Calgary) UK (Oxfor) USA (White) USA (African-American) Puerto Rico (USA) Denmark Spain Malta Germany Icelan Netherlans Italy (Liguria) Belgium Estonia USA (Hispanic) Luxembourg Cyprus Bulgaria Greece Austria Czech Republic Slovak Republic Hungary Portugal Libya Slovenia Algeria France Suan Lithuania Polan Latvia Brazil Russia Croatia Argentina Israel Romania Chile Maceonia Cuba Japan Korea China (H.K.) Paraguay Pakistan Columbia Thailan China (Zunyi) Fiji Fig. 1. Annual incience rates for type 1 iabetes mellitus (T1DM) (0 14 yr age group) comparing ifferent countries in the worl [moifie from the International Diabetes Feeration Atlas (80)]. 346 Peiatric Diabetes 2006: 7:

7 Consensus Guielines T1DM is two to three times more common in the offspring of iabetic men ( %) compare with iabetic women ( %) (B) (40, 42 47). Classification The etiological classification recommene by the American Diabetes Association (ADA) (E) (1) an the Worl Health Organization (WHO) expert committee on the classification an iagnosis of iabetes (E) (2) is shown in Table 2 with minor moification. Classifying types of iabetes The ifferentiation between T1DM, T2DM, an monogenic iabetes has important implications for both therapeutic ecisions an eucational approaches. Regarless of the type of iabetes, however, the chil who presents with severe fasting hyperglycaemia, metabolic erangements, an ketonaemia will require insulin therapy initially to reverse the metabolic abnormalities (48). The possibility of other types of iabetes shoul be consiere in the chil who has the following: An autosomal ominant family history of iabetes. Associate conitions such as eafness, optic atrophy, or synromic features. Marke insulin resistance or requires little or no insulin outsie the partial remission phase. A history of exposure to rugs known to be toxic to b-cells or cause insulin resistance. Measurement of fasting insulin or C-peptie is useful in the iagnosis of T2DM in chilren. Fasting insulin an C-peptie levels are usually normal or elevate, although not as elevate as might be expecte for the egree of hyperglycaemia (E) (49). If patients are treate with insulin, measuring C-peptie when the glucose is sufficiently high (.8 mmol/l) to stimulate C-peptie will etect if enogenous insulin secretion is still occurring. This is rare outsie the honeymoon perio (2 3 yr) in chilren with T1DM (E). T2DM is more completely iscusse in a later chapter. Characteristic features of youth-onset T1DM in comparison with T2DM an monogenic iabetes are shown in Table 3. Maturity-onset iabetes of the young Maturity-onset iabetes of the young (MODY) was escribe as a isorer with the following characteristics: onset before 25 yr of age, autosomal ominant inheritance, non-ketotic DM (50, 51). These classical efinitions given to MODY are no longer very helpful, as T2DM occurs in chilren an will often meet all these criteria (B, C) (52). In aition, efining the molecular genetics has shown that there are marke ifferences between genetic subgroups within these ol, broa categories, making it much more appropriate to use the genetic subgroups, an approach that has been supporte by the ADA an WHO in their guielines on classification (E) (Table 2). There is great variation in the egree of hyperglycaemia, nee for insulin, an risk for future complications (B) (53), see chapter, The iagnosis an management of monogenic iabetes in chilren. Table 3. Clinical characteristics of T1DM, T2DM an monogenic iabetes in chilren an aolescents T1DM T2DM Monogenic Characteristics Genetics Polygenic Polygenic Monogenic Age Throughout chilhoo Usually pubertal (or later) Often postpubertal except MODY2 an neonatal Onset Most often acute, rapi Variable; from slow, mil (often insiious) to severe iabetes Variable Associations Autoimmunity Yes No No Ketosis Common Rare Rare in MODY, common in neonatal iabetes Obesity Reflects the backgroun risk Very common Acanthosis nigricans No Yes No Frequency (% of all Usually 90%1 Most countries,10%?1 3% iabetes in young people) (Japan 60 80%) Parent with iabetes 2 4% 80% 90% Reflects the backgroun risk MODY, maturity-onset iabetes of the young; T1DM, type 1 iabetes mellitus; T2DM, type 2 iabetes mellitus. Peiatric Diabetes 2006: 7:

8 Craig et al. Neonatal iabetes Insulin-requiring hyperglycaemia in the first 3 6 months of life is known as neonatal DM. This rare conition (1 in births) may be associate with intra-uterine growth retaration (C) (54, 55). Approximately half of the cases are transient an have been associate with paternal isoisomy an other imprinting efects of chromosome 6 (B, C) (55, 56), see chapter, The iagnosis an management of monogenic iabetes in chilren. In patients with transient neonatal DM, permanent iabetes may appear later in life (C) (57). Permanent cases have been associate with pancreatic aplasia, activating mutations of KCNJ11, which is the gene encoing the aenosine-triphosphatesensitive potassium channel subunit Kir6.2 (7p15- p13), as well as ABCC8 [sulphonylurea receptor 1 (SUR1)], also in the same chromosome region (57, 58); mutations of the insulin promoter factor-1 (IPF-1) (chromosome 7) in which there is pancreatic aplasia; complete glucokinase eficiency (chromosome 7) (C) (59); mutations of the FOXP3 gene (Tcell regulatory gene) as part of the IPEX synrome (C) (60). Mitochonrial iabetes Mitochonrial iabetes is commonly associate with sensorineural eafness an is characterize by progressive non-autoimmune b-cell failure. Maternal transmission of mutate mitochonrial DNA can result in maternally inherite iabetes. Although several mutations have been implicate, the strongest evience relates to a point substitution at nucleotie position 3243 (A to G) in the mitochonrial trna [leu (UUR)] gene (B) (61, 62). Cystic fibrosis an iabetes Cystic fibrosis (CF)-relate iabetes (CFRD) is primarily ue to insulin eficiency, but insulin resistance uring acute illness, seconary to infections an meications (bronchoilators an glucocorticois), may also contribute to IGT an iabetes. Screening recommenations vary from testing a ranom bloo glucose level annually in all chilren with cystic fibrosis 14 yr ol to performing an OGTT annually in all those.10 yr ol (63, 64), but conventional measures such as FPG, OGTT, an haemoglobin A1c (HbA1c) may not be appropriate tools for the iagnosis of iabetes in patients with CF (B) (65). Insulin therapy initially may only be neee uring respiratory infections ue to acute or chronic infective episoes, but eventually, insulin therapy is frequently necessary. Initially, insulin oses are small (supplemental rather than total insulin replacement). In some patients, early insulin therapy prior to symptoms of hyperglycaemia may provie metabolic effects beneficial to growth, weight, an pulmonary function (66, 67) (B). Drug-inuce iabetes In neurosurgery, large oses of examethasone are frequently use to prevent cerebral oeema (e.g., examethasone 24 mg/). The aitional stress of the surgery may a to the rug-inuce insulin resistance an cause a relative insulin eficiency, sufficient to cause a transient form of iabetes. This will be exacerbate if large volumes of intravenous extrose are given for iabetes insipius. An intravenous insulin infusion is the optimal way to control the hyperglycaemia, which is usually transient. In oncology, protocols which use L-asparaginase, high-ose glucocorticois, cyclosporin, or tacrolimus (FK506) may be associate with iabetes. L-Asparaginase usually causes a reversible form of iabetes (B) (68). Tacrolimus an cyclosporin may cause a permanent form of iabetes, possibly ue to islet cell estruction (C) (69). Often the iabetes is cyclical an associate with the chemotherapy cycles, especially if associate with large oses of glucocorticois. Following transplantation, iabetes most frequently occurs with the use of high-ose sterois an tacrolimus; the risk is increase in patients with pre-existing obesity (B) (70, 71). Diabetes can also be inuce by the use of atypical antipsychotics incluing olanzapine, risperiol, quetiapine, an ziprasione, in association with weight gain (72). CFRD tens to occur late in the isease, typically in aolescence an early aulthoo. Cirrhosis, if present, may contribute to insulin resistance. The onset of CFRD is a poor prognostic sign an is associate with increase morbiity an mortality. Poorly controlle iabetes will interfere with immune responses to infection an promote catabolism (E) (63, 64). Stress hyperglycaemia Stress hyperglycaemia has been reporte in up to 5% of chilren presenting to an emergency epartment. Acute illness or injury, traumatic injuries, febrile seizures, an elevate boy temperature (.39 C) were ientifie as the most common associate features (73). 348 Peiatric Diabetes 2006: 7:

9 Consensus Guielines The reporte incience of progression to overt iabetes varies from 0 to 32% (B, C) (74 79). Chilren with inciental hyperglycaemia without a serious concomitant illness were more likely to evelop iabetes than those with a serious illness (77). Islet cell antiboies (ICAs) an IAAs testing ha a high positive an negative preictive value for T1DM in chilren with stress hyperglycaemia (77). Recommenations Diagnostic criteria for iabetes are base on bloo glucose measurements an the presence or absence of symptoms (E) (1, 2). The iagnosis is usually confirme quickly by measurement of a marke elevation of the bloo glucose level. In this situation, if ketones are present in the bloo or urine, treatment is urgent. Waiting another ay to confirm the hyperglycaemia may be angerous in allowing ketoaciosis to evolve rapily (E). An OGTT shoul not be performe if iabetes can be iagnose using fasting, ranom or postpranial criteria, as excessive hyperglycaemia can result. It is rarely inicate in making the iagnosis of T1DM in chilhoo an aolescence (E) (2). Severe hyperglycaemia etecte uner conitions of acute infection, trauma, surgery, respiratory istress, circulatory, or other stress may be transitory an require treatment but shoul not in itself be regare as iagnostic of iabetes (E). Measurement of iabetes-associate autoantiboy markers, e.g., ICAs, GAD, IA-2, IAAs an/or HbA1c may be helpful in some situations. There is currently insufficient evience to support the routine use of the HbA1c for the iagnosis of iabetes (E) (1). Measurement of fasting insulin or C-peptie is useful in the iagnosis of T2DM in chilren. Fasting insulin an C-peptie levels are usually normal or elevate, although not as elevate as might be expecte for the egree of hyperglycaemia (E) (49). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications or corrections shoul be irecte to the Corresponing Author. References 1. AMERICAN DIABETES ASSOCIATION. Diagnosis an Classification of Diabetes Mellitus. Diabetes Care 2005: 28: S37 S WORLD HEALTH ORGANIZATION. Definition, Diagnosis an Classification of Diabetes Mellitus an its Complications. Part 1: Diagnosis an Classification of Diabetes Mellitus. Geneva: WHO/NCD/NCS/99.2, RASILAINEN S, YLIPAASTO P, ROIVAINEN M et al. Mechanisms of beta cell eath uring restricte an unrestricte enterovirus infection. J Me Virol 2004: 72: DAHLQUIST GG, FORSBERG J, HAGENFELDT L, BOMAN J, JUTO P. Increase prevalence of enteroviral RNA in bloo spots from newborn chilren who later evelope type 1 iabetes: a population-base case-control stuy. Diabetes Care : HARRIS R, DONAHUE K, RATHORE SS, FRAME P, WOOLF SH, LOHR KN. Screening aults for type 2 iabetes: a review of the evience for the U.S. Preventive Services Task Force. Ann Intern Me 2003: 138: HOERGER TJ, HARRIS R, HICKS KA, DONAHUE K, SORENSEN S, ENGELGAU M. Screening for type 2 iabetes mellitus: a cost-effectiveness analysis. Ann Intern Me 2004: 140: GEPTS W. Pathologic anatomy of the pancreas in juvenile iabetes mellitus. Diabetes 1965: 14: SABBAH E, SAVOLA K, EBELING T et al. Genetic, autoimmune, an clinical characteristics of chilhooan ault-onset type 1 iabetes. Diabetes Care 2000: 23: VERGE CF, STENGER D, BONIFACIO E et al. Combine use of autoantiboies (IA-2 autoantiboy, GAD autoantiboy, insulin autoantiboy, cytoplasmic islet cell antiboies) in type 1 iabetes: Combinatorial Islet Autoantiboy Workshop. Diabetes 1998: 47: LAMBERT AP, GILLESPIE KM, THOMSON G et al. Absolute risk of chilhoo-onset type 1 iabetes efine by human leukocyte antigen class II genotype: a population-base stuy in the Unite Kingom. J Clin Enocrinol Metab 2004: 89: NOBLE JA, VALDES AM, COOK M, KLITZ W, THOMSON G, ERLICH HA. The role of HLA class II genes in insulin-epenent iabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet 1996: 59: PUGLIESE A, KAWASAKI E, ZELLER M et al. Sequence analysis of the iabetes-protective human leukocyte antigen-dqb1*0602 allele in unaffecte, islet cell antiboy-positive first egree relatives an in rare patients with type 1 iabetes. J Clin Enocrinol Metab 1999: 84: KULMALA P, SAVOLA K, REIJONEN H et al. Genetic markers, humoral autoimmunity, an preiction of type 1 iabetes in siblings of affecte chilren. Chilhoo Diabetes in Finlan Stuy Group. Diabetes 2000: 49: MACLAREN N, LAN M, COUTANT R et al. 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10 Craig et al. 18. LEVY-MARCHAL C, PATTERSON CC, GREEN A. Geographical variation of presentation at iagnosis of type I iabetes in chilren: the EURODIAB stuy. European an Diabetes. Diabetologia 2001: 44(Suppl. 3): B75 B VANDEWALLE CL, COECKELBERGHS MI, DE L et al. Epiemiology, clinical aspects, an biology of IDDM patients uner age 40 years. Comparison of ata from Antwerp with complete ascertainment with ata from Belgium with 40% ascertainment. The Belgian Diabetes Registry. Diabetes Care 1997: 20: PINHAS-HAMIEL O, ZEITLER P. The global sprea of type 2 iabetes mellitus in chilren an aolescents. J Peiatr 2005: 146: KARVONEN M, VIIK-KAJANDER M, MOLTCHANOVA E, LIBMAN I, LAPORTE R, TUOMILEHTO J. Incience of chilhoo type 1 iabetes worlwie. Diabetes Moniale (DiaMon) Project Group. Diabetes Care 2000: 23: INTERNATIONAL DIABETES FEDERATION. Diabetes Atlas. Secon En, Brussels: IDF DORMAN JS, BUNKER CH. HLA-DQ locus of the human leukocyte antigen complex an type 1 iabetes mellitus: a HuGE review. Epiemiol Rev 2000: 22: GILLESPIE KM, BAIN SC, BARNETT AH et al. The rising incience of chilhoo type 1 iabetes an reuce contribution of high-risk HLA haplotypes. Lancet 2004: 364: ILONEN J, REIJONEN H, GREEN A et al. Geographical ifferences within Finlan in the frequency of HLA-DQ genotypes associate with type 1 iabetes susceptibility. Eur J Immunogenet 2000: 27: KUKKO M, VIRTANEN SM, TOIVONEN A et al. Geographical variation in risk HLA-DQB1 genotypes for type 1 iabetes an signs of beta-cell autoimmunity in a highincience country. Diabetes Care 2004: 27: SUGIHARA S, SAKAMAKI T, KONDA S et al. Association of HLA-DR, DQ genotype with ifferent beta-cell functions at IDDM iagnosis in Japanese chilren. Diabetes 1997: 46: OHTSU S, TAKUBO N, KAZAHARI M et al. Slowly progressing form of type 1 iabetes mellitus in chilren: genetic analysis compare with other forms of iabetes mellitus in Japanese chilren. Peiatr Diabetes 2005: 6: KARVONEN M, PITKANIEMI M, PITKANIEMI J, KOHTAMAKI K, TAJIMA N, TUOMILEHTO J. Sex ifferences in the incience of insulin-epenent iabetes mellitus: an analysis of the recent epiemiological ata. Worl Health Organization DIAMOND Project Group. Diabetes Metab Rev 1997: 13: GALE EA, GILLESPIE KM. Diabetes an gener. Diabetologia 2001: 44: CUCCA F, GOY JV, KAWAGUCHI Y et al. A male-female bias in type 1 iabetes an linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nat Genet 1998: 19: WEETS I, KAUFMAN L, VAN er AB et al. Seasonality in clinical onset of type 1 iabetes in Belgian patients above the age of 10 is restricte to HLA-DQ2/DQ8- negative males, which explains the male to female excess in incience. Diabetologia 2004: 47: EURODIAB ACE STUDY GROUP. Variation an trens in incience of chilhoo iabetes in Europe. Lancet 2000: 355: KARVONEN M, PITKANIEMI J, TUOMILEHTO J. The onset age of type 1 iabetes in Finnish chilren has become younger. Diabetes Care 1999: 22: ONKAMO P, VAANANEN S, KARVONEN M, TUOMILEHTO J. Worlwie increase in incience of type I iabetes the analysis of the ata on publishe incience trens. Diabetologia 1999: 42: GREEN A, BRUTTI G, PATTERSON CC et al. Variation an trens in incience of chilhoo iabetes in Europe. Lancet 2000: 355: LEVY-MARCHAL C, PATTERSON C, GREEN A. Variation by age group an seasonality at iagnosis of chilhoo IDDM in Europe. The EURODIAB ACE Stuy Group. Diabetologia 1995: 38: OLMOS P, A HERN R, HEATON DA et al. The significance of the concorance rate for type 1 (insulin-epenent) iabetes in ientical twins. Diabetologia 1988: 31: HARJUTSALO V, PODAR T, TUOMILEHTO J. Cumulative incience of type 1 iabetes in 10,168 siblings of Finnish young-onset type 1 iabetic patients. Diabetes 2005: 54: STECK AK, BARRIGA KJ, EMERY LM, FIALLO-SCHARER RV, GOTTLIEB PA, REWERS MJ. Seconary attack rate of type 1 iabetes in Colorao families. Diabetes Care 2005: 28: LORENZEN T, POCIOT F, HOUGAARD P, NERUP J. Longterm risk of IDDM in first-egree relatives of patients with IDDM. Diabetologia 1994: 37: GILLESPIE KM, GALE EA, BINGLEY PJ. High familial risk an genetic susceptibility in early onset chilhoo iabetes. Diabetes 2002: 51: Anon. Familial risk of type I iabetes in European chilren. The Euroiab Ace Stuy Group an The Euroiab Ace Substuy 2 Stuy Group. Diabetologia 1998: 41: DORMAN JS, STEENKISTE AR, O LEARY LA, MCCARTHY BJ, LORENZEN T, FOLEY TP. Type 1 iabetes in offspring of parents with type 1 iabetes: the tip of an autoimmune iceberg? Peiatr Diabetes 2000: 1: EL HASHIMY M, ANGELICO MC, MARTIN BC, KROLEWSKI AS, WARRAM JH. Factors moifying the risk of IDDM in offspring of an IDDM parent. Diabetes 1995: 44: LORENZEN T, POCIOT F, STILGREN L et al. Preictors of IDDM recurrence risk in offspring of Danish IDDM patients. Danish IDDM Epiemiology an Genetics Group. Diabetologia 1998: 41: WARRAM JH, KROLEWSKI AS, GOTTLIEB MS, KAHN CR. Differences in risk of insulin-epenent iabetes in offspring of iabetic mothers an iabetic fathers. N Engl J Me 1984: 311: SILVERSTEIN J, KLINGENSMITH G, COPELAND K et al. Care of chilren an aolescents with type 1 iabetes: a statement of the American Diabetes Association. Diabetes Care 2005: 28: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. Peiatrics 2000: 105: FAJANS SS, BELL GI, POLONSKY KS. Molecular mechanisms an clinical pathophysiology of maturity-onset iabetes of the young. N Engl J Me 2001: 345: OWEN K, HATTERSLEY AT. Maturity-onset iabetes of the young: from clinical escription to molecular genetic characterization. Best Pract Res Clin Enocrinol Metab 2001: 15: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. American Diabetes Association. Diabetes Care 2000: 23: EHTISHAM S, HATTERSLEY AT, DUNGER DB, BARRETT TG. 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11 Consensus Guielines 55. METZ C, CAVE H, BERTRAND AM et al. Neonatal iabetes mellitus: chromosomal analysis in transient an permanent cases. J Peiatr 2002: 141: HERMANN R, LAINE AP, JOHANSSON C et al. Transient but not permanent neonatal iabetes mellitus is associate with paternal uniparental isoisomy of chromosome 6. Peiatrics 2000: 105: GLOYN AL, PEARSON ER, ANTCLIFF JF et al. Activating mutations in the gene encoing the ATP-sensitive potassium-channel subunit Kir6.2 an permanent neonatal iabetes. N Engl J Me 2004: 350: MASSA O, IAFUSCO D, D AMATO E et al. KCNJ11 activating mutations in Italian patients with permanent neonatal iabetes. Hum Mutat 2005: 25: NJOLSTAD PR, SOVIK O, CUESTA-MUNOZ A et al. Neonatal iabetes mellitus ue to complete glucokinase eficiency. N Engl J Me 2001: 344: BENNETT CL, CHRISTIE J, RAMSDELL F et al. The immune ysregulation, polyenocrinopathy, enteropathy, X- linke synrome (IPEX) is cause by mutations of FOXP3. Nat Genet 2001: 27: VAN DEN OUWELAND JM, LEMKES HH, RUITENBEEK W et al. Mutation in mitochonrial trna(leu)(uur) gene in a large peigree with maternally transmitte type II iabetes mellitus an eafness. Nat Genet 1992: 1: REARDON W, ROSS RJ, SWEENEY MG et al. Diabetes mellitus associate with a pathogenic point mutation in mitochonrial DNA. Lancet 1992: 340: YANKASKAS JR, MARSHALL BC, SUFIAN B, SIMON RH, RODMAN D. Cystic fibrosis ault care: consensus conference report. Chest 2004: 125: 1S 39S. 64. MORAN A, HARDIN D, RODMAN D et al. Diagnosis, screening an management of cystic fibrosis relate iabetes mellitus: a consensus conference report. Diabetes Res Clin Pract 1999: 45: DOBSON L, SHELDON CD, HATTERSLEY AT. Conventional measures unerestimate glycaemia in cystic fibrosis patients. Diabet Me 2004: 21: DOBSON L, HATTERSLEY AT, TILEY S, ELWORTHY S, OADES PJ, SHELDON CD. Clinical improvement in cystic fibrosis with early insulin treatment. Arch Dis Chil 2002: 87: NOUSIA-ARVANITAKIS S, GALLI-TSINOPOULOU A, KARA- MOUZIS M. Insulin improves clinical status of patients with cystic-fibrosis-relate iabetes mellitus. Acta Paeiatr 2001: 90: PUI CH, BURGHEN GA, BOWMAN WP, AUR RJ. Risk factors for hyperglycemia in chilren with leukemia receiving L-asparaginase an prenisone. J Peiatr 1981: 99: DRACHENBERG CB, KLASSEN DK, WEIR MR et al. Islet cell amage associate with tacrolimus an cyclosporine: morphological features in pancreas allograft biopsies an clinical correlation. Transplantation 1999: 68: MAES BD, KUYPERS D, MESSIAEN T et al. Posttransplantation iabetes mellitus in FK-506-treate renal transplant recipients: analysis of incience an risk factors. Transplantation 2001: 72: AL UZRI A, STABLEIN DM, COHN A. Posttransplant iabetes mellitus in peiatric renal transplant recipients: a report of the North American Peiatric Renal Transplant Cooperative Stuy (NAPRTCS). Transplantation 2001: 72: LEVITT KATZ LE, SWAMI S, ABRAHAM M et al. Neuropsychiatric isorers at the presentation of type 2 iabetes mellitus in chilren. Peiatr Diabetes 2005: 6: VALERIO G, FRANZESE A, CARLIN E, PECILE P, PERINI R, TENORE A. High prevalence of stress hyperglycaemia in chilren with febrile seizures an traumatic injuries. Acta Paeiatr 2001: 90: SHEHADEH N, ON A, KESSEL I et al. Stress hyperglycemia an the risk for the evelopment of type 1 iabetes. J Peiatr Enocrinol Metab 1997: 10: BHISITKUL DM, VINIK AI, MORROW AL et al. Preiabetic markers in chilren with stress hyperglycemia. Arch Peiatr Aolesc Me 1996: 150: VARDI P, SHEHADE N, ETZIONI A et al. Stress hyperglycemia in chilhoo: a very high risk group for the evelopment of type I iabetes. J Peiatr 1990: 117: HERSKOWITZ-DUMONT R, WOLFSDORF JI, JACKSON RA, EISENBARTH GS. Distinction between transient hyperglycemia an early insulin-epenent iabetes mellitus in chilhoo: a prospective stuy of incience an prognostic factors. J Peiatr 1993: 123: SCHATZ DA, KOWA H, WINTER WE, RILEY WJ. Natural history of inciental hyperglycemia an glycosuria of chilhoo. J Peiatr 1989: 115: HERSKOWITZ RD, WOLFSDORF JI, RICKER AT et al. Transient hyperglycemia in chilhoo: ientification of a subgroup with imminent iabetes mellitus. Diabetes Res 1988: 9: Incience an trens of chilhoo Type 1 iabetes worlwie Diabet Me 2006: 23: Peiatric Diabetes 2006: 7:

12 Peiatric Diabetes 2007: 8: All rights reserve # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaar Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines Phases of iabetes Couper JJ, Donaghue KC. Phases of iabetes. Peiatric Diabetes 2007: 8: Jennifer Couper a Kim Donaghue b a University of Aelaie, South Australia, Australia b University of Syney, The Chilren s Hospital at Westmea, NSW, Australia Corresponing author: Kim Donaghue, The Chilren s Hospital at Westmea, Locke Bag 4001, Westmea, NSW 2145, Australia The Chilren s Hospital at Westmea, Australia. Tel: ; Acknowlegments: Denis Daneman, Desmon Schatz Eitors of the ISPAD Clinical Practice Consensus Guielines ; Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Type 1 iabetes mellitus (T1DM) is characterize by Preclinical iabetes. Presentation of iabetes. Partial remission or honeymoon phase. Chronic phase of lifelong epenency on aministere insulin. Preclinical iabetes Preclinical iabetes refers to the months or years preceing the clinical presentationoft1dmwhenantiboies can be etecte as markers of beta-cell autoimmunity: Islet cell autoantiboies. Glutamic aci ecarboxylase autoantiboies (65K isoform). IA2 (also known as ICA512 or tyrosine phosphatase) autoantiboies. Insulin autoantiboies. In aition to these immunological an genetic markers [human leukocyte antigen (HLA) genotype an INS genotype], the risk of T1DM can be further refine by measurement of insulin release in response to an intravenous glucose loa [intravenous glucose tolerance test (IVGTT)]. Risks of progression to iabetes Genetic markers conferring increase or ecrease risk inclue: a) HLA DR3-DQA1*0501-DQB1* 0201 (susceptible genotype). 44 b) HLA DR4-DQA1*0301-DQB1* 0302 (susceptible genotype). c) HLA DR2-DQA1*0102-DQB1* 0602 (protective genotype). Islet autoimmunity can be transient an one raise islet antiboy alone has little prognostic value (1 3). If an iniviual is uner 45 yr an oes not have HLA DR2-DQA1*0102-DQB1* 0602 then: Impaire first phase insulin release on IVGTT (efine as an insulin response less than the 10th percentile for age an sex-matche controls) confers a 60% risk over the next 5 yr (4). Two or more islet antiboies raise without impaire first phase insulin release confer a 25 50% risk over the next 5 yr (5, 6). Neither screening of any population nor intervention in the preclinical phase shoul occur outsie the context of efine clinical stuies (7). Iniviuals who screen positive for genetic or immunological markers of T1DM shoul have access to appropriate counselling an to centres participating in intervention an other efine stuies. Intervention stuies shoul be registere as part of an international network of investigation an information about ongoing stuies shoul be reaily available (7, 8). The one proven environmental trigger of T1DM is congenital rubella (9, 10). Other potential environmental triggers are enteroviral infections (11), casein (12), an cereals (gluten or non gluten) (13, 14). Low levels of intercurrent infection an improve hygiene may be associate with increase risk (15). The hypothesis of acceleration (rather than triggering) of beta-cell

13 Phases of iabetes estruction because of overloa of the beta-cell with risk factors such as rapi growth an weight gain in early life can explain the increasing incience of chilhoo iabetes an the younger age of onset (16). International networks following chilren at increase genetic risk from birth are investigating potential trigger an protective factors (8). Presentation of T1DM Prospective follow-up of high-risk subjects shows that iagnosis of T1DM can be mae in asymptomatic iniviuals in the majority of cases (4). In the Diabetes Prevention Trial Type 1 (DPT-1), when high-risk iniviuals were followe, 73% of participants who were iagnose with iabetes were asymptomatic (4). A chil presenting with a classical history of increasing polyuria, polyipsia, an weight loss over 2 6 wk presents a straightforwar iagnosis. However, failure to consier the possibility of iabetes or atypical presentations may result in late iagnosis. Some chilren have a rapi onset of symptoms an present within ays in iabetic ketoaciosis (DKA); others have a slow onset over several months. Urinary Ôipstick testing for glycosuria an ketonuria provies a simple an sensitive tool for excluing iabetes with less typical presentation. A bloo glucose measurement (plasma glucose.11.1 mmol/l) confirms the iagnosis. The bloo glucose measurement shoul be a laboratory estimation rather than a home glucose monitor or besie reaing. Clinical presentation of iabetes can vary from nonemergency presentations (e.g., polyipsia, polyuria, weight loss, enuresis) to severe ehyration, shock an DKA (17, 18) (E). Non-emergency presentations Non-emergency presentations of iabetes inclue: Recent onset of enuresis in a previously toilet-traine chil, which may be misiagnose as a urinary tract infection or the result of excessive flui ingestion. Vaginal caniiasis, especially in prepubertal girls. Vomiting, which may be misiagnose as gastroenteritis. Chronic weight loss or failure to gain weight in a growing chil. Irritability an ecreasing school performance. Recurrent skin infections. Emergency presentations The usual emergency presentation of DKA in a chil or aolescent inclues: Severe ehyration. Frequent vomiting. Continuing polyuria espite the presence of ehyration. Weight loss because of flui loss an loss of muscle an fat. Flushe cheeks because of the ketoaciosis. Acetone etecte on the breath. Hyperventilation of DKA (Kussmaul respiration) is characterize by a high respiratory rate an large tial volume of each breath, which gives it a sighing quality. Disorere sensorium (isoriente, semicomatose or rarely comatose). Shock (rapi pulse rate, poor peripheral circulation with peripheral cyanosis). Hypotension (a late sign an rare in chilren with DKA). Diagnostic ifficulties leaing to late iagnosis The following situations may result in a late iagnosis of DKA: Very young chilren may present in severe ketoaciosis because of a more rapi onset of severe insulin eficiency (19) an because the iagnosis was not consiere early. Hyperventilation of ketoaciosis may be misiagnose as pneumonia or asthma (cough an breathlessness istinguish these conitions from DKA). Abominal pain associate with ketoaciosis may simulate an acute abomen an lea to referral to a surgeon. Polyuria an enuresis may be misiagnose as a urinary tract infection. Polyipsia may be thought to be psychogenic. Vomiting may be misiagnose as gastroenteritis or sepsis. If a chil is iagnose with iabetes in the presence of symptoms immeiate referral to a centre with expertise in the care of such chilren is manatory, because prompt iagnosis of iabetes in chilren is important in preventing rapi eterioration into ketoaciosis. Severe ketoaciosis, if untreate, is fatal. Therapy is urgent an referral to specialize services is essential (E). Differentiating between T1DM an type 2 iabetes mellitus (T2DM) at iagnosis Features suggesting the iagnosis of type 2 iabetes mellitus (T2DM) rather than T1DM at iagnosis are (20, 21): Obesity. Age greater than 10 yr. Strong family history of T2DM. Acanthosis nigricans. High-risk racial or ethnic group. Unetectable pancreatic autoantiboies. Normal to high C-Peptie levels. Peiatric Diabetes 2007: 8:

14 Couper an Donaghue Partial remission or honeymoon phase in T1DM In approximately 80 percent of chilren an aolescents, insulin requirements ecrease transiently following initiation of insulin treatment (22). The efinition of the partial remission phase has been uncertain but a recent efinition is when the patient requires less than 0.5 units of insulin per kg of boy weight per ay an has an HbA1c,7% (22). The partial remission phase commences within ays or weeks of the start of insulin therapy an may last for weeks to months. During this phase bloo glucose levels are frequently stable within the normal range, espite fluctuations in iet an exercise. It is important for the families to be avise of the transient nature of the partial remission phase so as to avoi the false hope that the iabetes is spontaneously isappearing. Several stuies have shown intensive therapy preserves c-peptie, leas to better control (measure by A1c), an often a ecrease in insulin ose (18, 23). Intervention trials from iagnosis are in progress as part of an international network of intervention trials to preserve beta-cell function either in the preclinical phase or from iagnosis (8). In a few chilren an aolescents, requirements for insulin may ecrease to the point of being able to withraw insulin therapy temporarily an still maintain normoglycaemia. As low ose subcutaneous insulin therapy oes not prolong resiual beta-cell function in the preclinical phase, continuing insulin seems unlikely to provie any other avantage other than maintaining establishe iabetes routines for the chil. Ketoaciosis at presentation (17) an young age (14) reuce the likelihoo of a remission phase. Parents an chilren with T1DM shoul be informe that the remission phase of iabetes is transient an oes not inicate total remission of iabetes (18) (E). Chronic phase of lifelong epenence on insulin The progression from the partial remission phase into the chronic phase of lifelong epenence on insulin is usually a graual ecrease in resiual beta-cell function but clinically seems to be accelerate by an intercurrent illness. At present, exogenous insulin replacement remains the only form of replacement therapy for chilren an aolescents with T1DM, although some other experimental treatments are uner investigation. Transplantation Islet transplantation has become more successful since the introuction of less beta-cell toxic immunosuppressive agents an refine techniques to harvest aequate numbers of viable beta-cells (24). The numbers of subjects who remain insulin-inepenent fall with follow-up an several onor pancreases are require for aequate beta-cell numbers in the transplant (25). The Emonton protocol, which is a glucocorticoi-free immunosuppressant regimen, has been use in several centres with goo clinical outcomes in those with full an partial graft function, namely, protection from severe hypoglycaemia an less labile bloo glucose levels (26) The inuction of immunologic tolerance without the nee for chronic immunosuppressive therapy is a major goal an the potential use of haematopoietic stem cell therapy for inuction of tolerance an islet cell regeneration in vivo an neogenesis in vitro are rapily expaning research irections. Pancreas transplantation provies high rates of graft survival at 1 yr but there are significant surgical risks an the requirement for long-term immunosuppression preclues its use in chilren an aolescents (26, 27). Prevention of iabetes the evience The evience on intervention trials to elay or prevent the onset of T1DM is liste in: European Nicotinamie Diabetes Intervention Trial, a multinational quasiranomize placebo-controlle, ouble-bline intervention stuy, emonstrate that nicotinamie i not elay or prevent the onset of T1DM in high-risk, first-egree relatives (27, 28) (A). The National Institutes of Health DPT-1 emonstrate in a ranomize controlle trial that low ose subcutaneous insulin therapy i not elay or prevent the onset of clinical iabetes in high-risk, first-egree relatives (4) (A). Prevention recommenations an principles Health care professionals shoul be aware that there are no interventions shown to elay or prevent the onset of T1DM. Neither screening of any population nor intervention in the preclinical phase shoul occur outsie the context of efine clinical stuies (7) (E). This article is a Chapter in the ISPAD Clinical Practice Consensus Guielines of the International Society for Peiatric an Aolescent Diabetes (ISPAD, The complete set of these Guielines will later be publishe as a compenium. Aitional comments, clarifications or corrections shoul be irecte to the Corresponing Author. The evience graing system use in the ISPAD Guielines is the same as that use by the American 46 Peiatric Diabetes 2007: 8: 44 47

15 Phases of iabetes Diabetes Association. See the Introuction of the ISPAD Clinical Practice Consensus Guielines in Peiatric Diabetes 2006: 7: References 1. COLMAN PG, STEELE C, COUPER JJ et al. Islet autoimmunity in infants with a Type I iabetic relative is common but is frequently restricte to one autoantiboy. Diabetologia 2000: 43: KIMPIMAKI T, KULMALA P, SAVOLA K et al. Natural history of beta-cell autoimmunity in young chilren with increase genetic susceptibility to type 1 iabetes recruite from the general population. J Clin Enocrinol Metab 2002: 87: KNIP M. Natural course of preclinical type 1 iabetes. Horm Res 2002: 57: DIABETES PREVENTION TRIAL-TYPE 1 DIABETES STUDY GROUP. Effects of insulin in relatives of patients with type 1 iabetes mellitus. N Engl J Me 2002: 346: BINGLEY PJ, CHRISTIE MR, BONIFACIO E et al. Combine analysis of autoantiboies improves preiction of IDDM in islet cell antiboy-positive relatives. Diabetes 1994: 43: VERGE CF, GIANANI R, KAWASAKI E et al. Preiction of type I iabetes in first-egree relatives using a combination of insulin, GAD, an ICA512bc/IA-2 autoantiboies. Diabetes 1996: 45: AMERICAN DIABETES ASSOCIATION. Prevention of type 1 iabetes mellitus. Diabetes Care 2003: 26: GINSBERG-FELLNER F, WITT ME, FEDUN B et al. Diabetes mellitus an autoimmunity in patients with the congenital rubella synrome. Rev Infect Dis 1985: 7(Suppl. 1): S170 S MCINTOSH ED, MENSER MA. A fifty-year follow-up of congenital rubella. Lancet 1992: 340: HYOTY H, HILTUNEN M, KNIP M et al. A prospective stuy of the role of coxsackie B an other enterovirus infections in the pathogenesis of IDDM. Chilhoo Diabetes in Finlan (DiMe) Stuy Group. Diabetes 1995: 44: AKERBLOM HK, VIRTANEN SM, ILONEN J et al. Dietary manipulation of beta cell autoimmunity in infants at increase risk of type 1 iabetes: a pilot stuy. Diabetologia 2005: 48: NORRIS JM, BARRIGA K, KLINGENSMITH G et al. Timing of initial cereal exposure in infancy an risk of islet autoimmunity. JAMA 2003: 290: ZIEGLER AG, SCHMID S, HUBER D, HUMMEL M, BONIFACIO E. Early infant feeing an risk of eveloping type 1 iabetes-associate autoantiboies. JAMA 2003: 290: FILIPPI C, VON HERRATH M. How viral infections affect the autoimmune process leaing to type 1 iabetes. Cell Immunol 2005: 233: DAHLQUIST G. Can we slow the rising incience of chilhoo-onset autoimmune iabetes? The overloa hypothesis. Diabetologia 2006: 49: BOBER E, DUNDAR B, BUYUKGEBIZ A. Partial remission phase an metabolic control in type 1 iabetes mellitus in chilren an aolescents. J Peiatr Enocrinol Metab 2001: 14: THE DIABETES CONTROL AND COMPLICATIONS TRIAL RESEARCH GROUP. Effect of intensive therapy on resiual beta-cell function in patients with type 1 iabetes in the iabetes control an complications trial. A ranomize, controlle trial. Ann Intern Me 1998: 128: KESKINEN PK. First-phase insulin response in young healthy chilren at genetic an immunological risk for type I iabetes. Diabetologia 2002: 45: AMERICAN DIABETES ASSOCIATION. Type 2 iabetes in chilren an aolescents. Peiatrics 2000: 105: AMERICAN DIABETES ASSOCIATION. Screening for type 2 iabetes. Diabetes Care 2003: 26: LOMBARDO F, VALENZISE M, WASNIEWSKA M et al. Twoyear prospective evaluation of the factors affecting honeymoon frequency an uration in chilren with insulin epenent iabetes mellitus: the key-role of age at iagnosis. Diabetes Nutr Metab Clin Exp 2002: 15: DE BEAUFORT CE, HOUTZAGERS CM, BRUINING GJ et al. Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly iagnose iabetic chilren: two-year follow-up of a ranomize, prospective trial. Diabet Me 1989: 6: SHAPIRO AM, LAKEY JR, RYAN EA et al. Islet transplantation in seven patients with type 1 iabetes mellitus using a glucocorticoi-free immunosuppressive regimen. N Engl J Me 2000: 343: RYAN EA, LAKEY JR, PATY BW et al. Successful islet transplantation: continue insulin reserve provies longterm glycemic control. Diabetes 2002: 51: SHAPIRO AM, RICORDI C, HERING BJ et al. International trial of the Emonton protocol for islet transplantation. N Engl J Me 2006: 255: ODORICO JS, SOLLINGER HW. Technical an immunosuppressive avances in transplantation for insulinepenent iabetes mellitus. Worl J Surg 2002: 26: GALE EA, BINGLEY PJ, EMMETT CL, COLLIER T. European Nicotinamie Diabetes Intervention Trial (ENDIT) Group. European Nicotinamie Diabetes Intervention Trial (ENDIT): a ranomise controlle trial of intervention before the onset of type 1 iabetes. Lancet 2004: 363: Peiatric Diabetes 2007: 8:

16 Peiatric Diabetes 2006: 7: All rights reserve # 2006 The Authors Journal compilation # Blackwell Munksgaar 2006 Peiatric Diabetes ISPAD Clinical Practice Consensus Guielines The iagnosis an management of monogenic iabetes in chilren Authors: Anrew Hattersley, Institute of Biomeical an Clinical Sciences, Peninsula Meical School, Exeter, UK Jan Bruining, Sophia Chilren s Hospital, Rotteram, the Netherlans Julian Shiel, Department of Chil Health, University of Bristol, Bristol, UK Pal Njolsta, Department of Chil Health, University of Bergen, Bergen, Norway Kim Donaghue, The Chilren s Hospital at Westmea, University of Syney, NSW, Australia Eitors: Kim Donaghue, Ragnar Hanas, Georgeanna Klingensmith, Peter Swift Definition Monogenic iabetes results from the inheritance of mutation or mutations in a single gene. It may be ominantly or recessively inherite or may be a e novo mutation an, hence, a spontaneous case. In chilren, almost all monogenic iabetes results from mutations in genes that regulate b-cell function, although iabetes can rarely occur from mutations resulting in very severe insulin resistance (C) (1). Diagnosis Why iagnose monogenic iabetes? The majority of patients with genetically proven monogenic iabetes are initially incorrectly iagnose as having type 1 iabetes mellitus (T1DM) or type 2 iabetes mellitus (T2DM) (2) (C). It is important to correctly iagnose monogenic iabetes as it can preict the clinical course of the patient, explain other associate clinical features, an, very important, guie the most appropriate treatment. In aition, making a iagnosis will have implications for other family members often correcting the iagnosis an treatment for other iabetic family members, as well as allowing appropriate genetic counseling. Clinical presentation of monogenic iabetes Clinical presentations in chilren when a iagnosis of monogenic iabetes shoul be consiere are iscusse below an inclue the following: 352 (i) Neonatal iabetes an iabetes iagnose within the first 6 months of life. (ii) Familial iabetes with an affecte parent. (iii) Mil ( mmol/l) fasting hyperglycemia, especially if young or familial. (iv) Diabetes associate with extra pancreatic features. When to suspect a iagnosis of T1DM in chilren may not be correct? Features in chilren initially thought to have T1DM that shoul suggest a possible iagnosis of monogenic iabetes are shown below. None of these are absolute an shoul be consiere as together, rather than in isolation (C) (3). (i) A iagnosis of iabetes before 6 months (B) [in T1DM:,1% (4)]. (ii) Family history of iabetes with a parent affecte (C) [in T1DM: 2 4% (5)]. (iii) Evience of enogenous insulin prouction outsie the Ôhoneymoon phase (after 3 yr of iabetes), with etectable C-peptie (.200 nmol/l) when glucose level is.8 mmol/l (E) (in T1DM: 1 5%). (iv) When pancreatic islet autoantiboies are absent, especially if measure at iagnosis (C) [in T1DM: 3 30% (6 8)]. The great variation in antiboy prevalence in series probably represents ifferences in assays an means it is har to apply publishe series irectly into clinical practice. Absent antiboies shoul lea to other investigation/consieration rather than leaing irectly to genetic tests (E). When to suspect a iagnosis of T2DM in chilren may not be correct? Features in chilren initially thought to have T2DM that shoul suggest a possible iagnosis of monogenic iabetes are shown below. It shoul be note that most T2DM in youth will meet the former classification for maturity-onset iabetes of the young (MODY) [iagnose,25, autosomal ominant inheritance an non-insulin epenent (C) (9 12)]. (i) Not markely obese or iabetic family members who are of normal weight [in T2DM: 20% (12)].

17 Consensus Guielines (ii) Acanthosis nigricans not etecte [in T2DM: 10% (9)]. (iii) Ethnic backgroun with a low prevalence of T2DM, e.g., European Caucasian (in T2DM: 0 45%). (iv) No evience of insulin resistance with fasting C-peptie within the normal range [in T2DM: 0 20% (9 12)]. Making a iagnosis of monogenic iabetes As well as having clinical features that are unusual for T1DM an T2DM, a patient on whom a iagnosis of monogenic iabetes is mae shoul also have the features of a specific genetic subtype of monogenic iabetes (E). The features of the more common monogenic iabetes are given below. While in T1DM an T2DM iabetes there is no single iagnostic test, this is not the case in monogenic iabetes where in.80% of cases, a molecular genetic iagnosis can be mae by DNA testing (C). Molecular genetic testing is offere in most European countries an the USA, but many labs will test patients from other countries (for example, www. iabetesgenes.org an These tests are expensive (up to V500/$600) but can have a big impact on management of the proban an other family members, for whom it will be cheaper, as the mutation is known (V100/$120). Some recently escribe monogenic iabetes genes like Kir6.2 testing in patients iagnose less than 6 months may be available as research tests for no charge (see Approval from the patient s insurance company shoul be sought prior to sening DNA when applicable. Given the limite resources available, it is vital that these tests are use in situations where they are likely to be positive an will alter clinical care. This will involve careful clinical selection an performing physiological tests like C-peptie an autoantiboy measurement, as well as testing other family members before performing molecular genetic tests (E). Specific subtypes of monogenic iabetes an their management Neonatal iabetes an iabetes iagnose within the first 6 months of life There is goo evience that iabetes iagnose in the first 6 months is not T1DM, as autoantiboies are rare an human leukocyte antigen (HLA) genotyping shows HLA haplotypes actually protective for T1DM in these patients (B) (4). Neonatal iabetes is another area which has rapily move from a clinical to a molecular genetic classification (13, 14). Neonatal iabetes is insulin-requiring iabetes, which is usually iagnose in the first 3 months of life. Clinically, two subgroups have been recognize: transient neonatal iabetes mellitus (TNDM) that resolve at a meian of 12 wk an then i not require any treatment, although as many as 50% of cases woul ultimately relapse (B) (15, 16); in contrast to permanent neonatal iabetes mellitus (PNDM), which require continual insulin treatment from iagnosis onwar. For most patients with both types of neonatal iabetes, the molecular etiology can now be efine. The majority of patients with TNDM have an abnormality of imprinting of the ZAC an HYMAI genes on chromosome 6q (B) (14, 15), while the most common known cause of PNDM are mutations in the KCNJ11 gene encoing the Kir6.2 subunit of the b-cell K ATP channel (B) (17, 18). However, TNDM an PNDM are foun with activating mutations in KCNJ11 (Kir 6.2) an ABCC8 [sulfonylurea receptor (SUR) 1]; some of these are amenable to treatment with sulfonylurea rugs which stimulate enogenous insulin secretion (19). If both parents are glucose intolerant, homozygous or compoun heterozygous mutations in glucokinase are most frequent (20, 21). Differential iagnosis. When iabetes is iagnose in the neonatal perio, it is ifficult to tell if it is likely to be transient or permanent, although the features in Table 1 can help ifferentiate the possible ifferent subtypes an can be use to guie molecular genetic testing. TNDM from imprinting anomalies on 6q24. Imprinte anomalies of the 6q24 locus involving the ZAC an HYAMI genes are the most common cause of neonatal iabetes an result in TNDM (B) (14, 15, 22). The commonest 6q24anomalies are inherite paternal uplications or paternal uniparental isomy, although methylation anomalies are being more frequently ientifie (E) (16). Diabetes associate with this is typically iagnose within the first week an resolves aroun 12 wk (B) (15). In approximately 50% of cases, iabetes will reoccur uring the peiatric agerange(b)(15).apart from macroglossia, seen in 23%, there are no nonpancreatic features (B) (15). Initial glucose values can be very high (range: mmol/l) an, therefore, insulin is use initially, although the ose can rapily be reuce. Once patients have relapse, they shoul remain uner annual follow up ue to the risk of iabetes relapsing. On relapse, patients are not insulin epenent an can be treate with iet initially, although subsequently, they often nee insulin (E) (14). The response to oral treatments such as sulfonylureas or metformin is uncertain. PNDM, TNDM an iabetes iagnose in the first 6 months of life ue to Kir6.2 mutations. Kir6.2 mutations are the secon most common cause of Peiatric Diabetes 2006: 7:

18 Hattersley et al. Table 1. Characteristics of iabetes presenting in the first 6 months of life [moifie from reference (13)] Gene, clinical synrome, inheritance PNDM/TNDM Number of cases escribe (% in consanguineous or isolate populations) Meian birth weight in grams (SDS) Age of iagnosis in weeks, meian (range) Pancreatic appearance Other features ZAC/HYAMI, imprinting efect on 6q24 Kir6.2 (KCNJ11), spontaneous ominant (10%) EIF2AK3, Wolcott Rallison synrome, recessive FOXP3, IPEX synrome, X linke TNDM ffi150, rare 2100 (22.94) 0.5 (0 4) Normal Macroglossia (23%) PNDM, TNDM (10%) ffi100, rare (21.73) 6 (0 260) Normal Developmental elay (20%), epilepsy (6%), DKA (30%) PNDM 30 (90)? 13 (6 65) Atrophy of pancreas (?), exocrine ysfunction (25%) Epiphyseal ysplasia (90%), osteopenia (50%), acute liver failure (75%), evelopmental elay (80%), hypothyroiism (25%) PNDM 14, rare 2860 (21.2) 6 (0 30)? Only boys affecte, chronic iarrhea with villous atrophy (95%); pancreatic an thyroi autoantiboies (75%), thyroiitis (20%), eczema (50%); anemia (30%) an often ie young (1 yr) GCK (glucokinase), recessive PNDM 6 (85) 1720 (22.75) Normal Parents have fasting hyperglycemia, as heterozygotes IPF1, recessive PNDM 2 (50) 2140 (22.97) Absent Parents may have early-onset iabetes, as heterozygotes TNDM 2, rare 1900 (23.21) Atrophy Renal evelopmental isorers HNF-1b, ominant (60%) spontaneous PTF1A, recessive PNDM 3 (100) 1390 (23.8) Atrophy Severe neurological ysfunction an cerebellar hypoplasia DKA, iabetic ketoaciosis; HNF, hepatocyte nuclear factor; IPEX, immunoysregulation, polyenocrinopathy, enteropathy, X-linke; IPF1, insulin promoter factor 1; PNDM, permanent neonatal iabetes mellitus; SDS, stanar eviation score; TNDM, transient neonatal iabetes mellitus. 354 Peiatric Diabetes 2006: 7:

19 Consensus Guielines mutations in patients with iabetes iagnose in the first 6 months of life (B) (17, 18). While some (10%) have a remitting form of iabetes that may later relapse, the majority have PNDM (C) (23). Most patients have isolate iabetes, although neurological features are seen in 20% of patients. Despite being a heterozygous mutation, most have no family history, as 90% of cases are spontaneous mutations. The most severe efect is very marke evelopmental elay of motor an social function an generalize epilepsy often with hypsarrhythmia, as seen in West synrome (C) (17). This has been calle the evelopmental elay, epilepsy, an neonatal iabetes (DEND) synrome (18). More common is the intermeiate DEND synrome where patients have less severe evelopmental elay an o not have epilepsy (18). Patients with Kir6.2 mutations have all the clinical features of insulin epenency, as 30% of them present with ketoaciosis, an they usually o not have etectable C-peptie an, thus, are treate with insulin (C) (18). It has recently been shown that these patients can not only be successfully treate with oral sulfonylureas but can also get better glycemic control without an increase in hypoglycemia. The oses neee are high when calculate on a per kg boy weight basis compare with aults, with patients typically neeing 0.5 mg/kg/glibenclamie/, although some may nee as much as 1 mg/kg/ (C) (24 29). With time, many patients have been able to reuce their oses of sulfonylureas but maintain excellent glycemic control (E). Wolcott Rallison synrome. Wolcott Rallison synrome is a rare autosomal recessive conition characterize by early-onset iabetes, epiphyseal ysplasia, renal impairment, acute hepatic failure, an evelopmental elay (B) (30, 31). It is associate with mutations in EIF2AK3 (32). Diabetes usually presents in infancy but may appear later. It is associate with ß-cell loss, leaing to insulin eficiency without autoimmune pathology. Insulin treatment is require. Wolcott Rallison synrome shoul be consiere in any patient with iabetes in the first 3 yr who has epiphyseal ysplasia or acute severe hepatic failure (C, E) (30). Other causes of neonatal iabetes. In Table 1, the clinical features of other causes of neonatal iabetes are outline. Scanning the pancreas to assess if it is present an its size, checking for exocrine pancreatic function an pancreatic autoantiboies [foun in the immunoysregulation, polyenocrinopathy, enteropathy, X-linke (IPEX) synrome] are the most useful iagnostic tests before proceeing to molecular genetic testing (E). All other causes nee to be treate with insulin. Some peiatricians consier that these patients are easiest to manage on subcutaneous insulin pumps. In patients with pancreatic aplasia, exocrine pancreatic supplements will be require. Familial iabetes The most common causes of familial iabetes or familial hyperglycemia are shown in Table 2. Chilren an young aults with iabetes an a strong family history of iabetes: hepatocyte nuclear factor 1 alpha gene mutations (MODY3). The possibility of monogenic iabetes shoul be consiere whenever a parent has iabetes, even if he/she is thought to have T1DM or T2DM (E). The most common form of monogenic iabetes which results in familial iabetes (known in the past as MODY) are hepatocyte nuclear Table 2. Characteristics of common forms of monogenic iabetes an hyperglycemia Inheritance Number of families ientifie in UK Typical age of presentation in peiatric clinic (range) Typical glucose level at presentation (range) mmol/l Other clinical features HNF-1a (MODY3) HNF-4a (MODY1) Glucokinase (MODY2) Dominant (4 18) 17 (11 26) Large increment in an OGTT (at 2 0 h usually.5 mmol/l), low renal threshol, progressive hyperglycemia with age, sensitive to sulfonylureas Dominant (5 18) 15 (9 20) Similar to HNF-1a but renal Dominant (may not be iagnose in parents as mil) threshol normal (0 18) 11 (5.5 16) Usually inciental fining at iagnosis, fasting glucose in the range of mmol/l, small increment in an OGTT (at 2 0 h usually,3.5 mmol/l), little eterioration in glycemia with age HNF, hepatocyte nuclear factor; MODY, maturity-onset iabetes of the young; OGTT, oral glucose tolerance test. Peiatric Diabetes 2006: 7:

20 Hattersley et al. factor (HNF)-1a mutations (B) (33). The clinical characteristics of patients with HNF-1a mutations are as follows: (i) Young-onset iabetes that shows characteristics of not being insulin epenent, e.g., not eveloping ketoaciosis in the absence of insulin, goo glycemic control on a small ose of insulin, or etectable C-peptie measure when on insulin, with glucose.8 mmol/l outsie a normally expecte honeymoon perio (3 yr) (E). (ii) Family history of iabetes. This may be treate with insulin an consiere to be ÔT1DM. This woul typically be iagnose in the age of 20, 30, or 40 yr. There may also be an affecte granparent although often they are iagnose after 45 yr (C). (iii) Oral glucose tolerance tests (OGTTs) in early stages ten to show a very large glucose increment, usually.5 mmol/l (34). Some subjects may have a normal fasting value but still rise into the iabetic range at 2 h (34) (B). (iv) Glycosuria at relatively normal bloo glucose levels is often seen, as these patients have a low renal threshol (B) (34). (v) Marke sensitivity to sulfonylureas resulting in hypoglycemia, espite poor glycemic control before starting sulfonylureas (C) (35, 36). Treatment. Patients with HNF-1a gene mutations can initially be treate with iet although they will have marke postpranial hyperglycemia following a high carbohyrate meal, as the b-cell efect results in insufficient increase in insulin secretion with hyperglycemia (37). Most patients will nee pharmacological treatment, as they show progressive eterioration in glycemic control throughout life an are at risk of consierable microvascular an macrovascular complications (B,C) (38). The first treatment to be use in chilren who are not controlle on insulin shoul be low-ose sulfonylureas, which results in a four-fol greater lowering of glucose than metformin (A) (39). These patients are extremely sensitive to sulfonylureas, an as long as they o not have problems with hypoglycemia, they can be maintaine on these for many ecaes (C) (35). Glycemic control by sulfonylureas is often better than that achieve by insulin, especially in chilren an young aults (40). The ose of sulfonylureas shoul initially be low (one-quarter of the normal starting ose in aults) to avoi hypoglycemia (E). If there is hypoglycemia espite ose titration of a once- or twice-aily sulfonylurea preparation such as gliclazie, a slowrelease preparation or meal time oses with a shortacting agent like nateglinie may be consiere (C) (41). Chilren an young aults with iabetes an a strong family history of iabetes: HNF-4a gene mutations (MODY1). Diabetes ue to mutations of the HNF-4a gene are consierably less common (Table 2) than iabetes ue to mutations of the HNF-1a gene but has similar characteristics, except that there is no low renal threshol an the age of iagnosis may be later (C) (42). HNF-4a mutations shoul be consierewhenhnf-1a sequencing is negative but the clinical features were strongly suggestive of HNF-1a (42). Patients are often sensitive to sulfonylureas (C) (43). Other causes of familial iabetes. A hanful of families with autosomal ominant non-insulinepenent iabetes have been escribe with mutations in insulin promoter factor 1 (IPF1) (MODY4) (44), NeuroD1 (MODY6) (45, 46) an, recently, the carboxyl ester lipase (CEL) gene (MODY7) (47), but these are so unusual, they o not nee to be teste for in chilren with iabetes except in a research setting (E) or when there are aitional phenotypes, such as pancreatic exocrine ysfunction (47). Mil fasting hyperglycemia: ue to glucokinase mutations (MODY2) The fining of raise fasting bloo glucose in the range of mmol/l is unusual in chilren an young aults. This always raises concern that they may be about to evelop T1DM or that the patient has T2DM. However, a consierable proportion of these patients with persistent mil fasting hyperglycemia will have a heterozygous mutation in the glucokinase gene. The phenotype associate with glucokinase mutations is remarkably similar for all mutations. The following features suggest a iagnosis of a glucokinase mutation: (i) The fasting hyperglycemia is persistent an stable over a perio of months or years (34). (ii) Hemoglobin A1c is typically just below or just above the upper limit of normal range ( %). (iii) In an OGTT, the increment (2-h glucose fasting glucose) is small (typically,3.5 mmol/l), although because of the variability of the OGTT, this shoul not be consiere an absolute criterion (34). (iv) Parents may have ÔT2DM or may not be iabetic. On testing, one parent will have a milly raise fasting bloo glucose, in the range of mmol/ L, as this is an autosomal ominant conition (C) (34). Testing of apparently unaffecte parents fasting glucose is important when consiering a iagnosis of a glucokinase mutation (E). Treatment. The fasting hyperglycemia oes not eteriorate significantly an the glucose is regulate at the higher set point (34). This is rarely associate with 356 Peiatric Diabetes 2006: 7:

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