- Email: [email protected]
Hyperglycaemia and β-cell antibodies: Is it always pre-type 1 diabetes?
DIAB-5707; No. of Pages 3 diabetes research and clinical practice xxx (2013) xxx–xxx
Contents available at Sciverse ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Brief report
Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes? Giuseppe d’Annunzio a,*, Marta Marchi a, Concetta Aloi a, Alessandro Salina a, Francesca Lugani a,b, Renata Lorini a a b
Pediatric Clinic, IRCCS Giannina Gaslini Institute, Genoa, Italy Laboratory on Pathophysiology of Uremia, IRCCS G. Gaslini Institute, Genoa, Italy
article info
abstract
Article history:
We describe 10-year-old girl with mild incidental hyperglycaemia, impaired glucose toler-
Received 20 June 2012
ance and GADA positivity. Family history for mild hyperglycaemia and GADA fluctuation
Received in revised form
alerted us to a possible MODY diagnosis which was confirmed by detection of GCK mutation
15 November 2012
c.626C>T; p.T209M. Weak or transient b-cell autoimmunity should not preclude genetic
Accepted 3 January 2013
testing for MODY when the clinical features are suggestive. # 2013 Published by Elsevier Ireland Ltd.
Keywords: Hyperglycaemia MODY b-Cell antibodies Pre-type 1 diabetes
1.
Introduction
In type 1 diabetes mellitus (T1DM) genetic, environmental and immunological factors exert a T-cell mediated autoimmune process [1]. The immune-mediated b-cell destruction occurs over years with progressive insulin deficiency and varying degrees of hyperglycaemia ranging up to severe metabolic derangement. Immunological markers of b-cell destruction are detectable before clinical diagnosis in subjects at risk of T1DM, predict the future development of the disease and characterize the ‘‘pre-type 1 diabetes’’ condition [1]. Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of non-autoimmune diabetes resulting from a primary defect of insulin secretion characterized by
autosomal dominant inheritance, genetic heterogeneity, early onset of hyperglycaemia/diabetes, presence of obesity is variable and there is a lack of insulin dependence [2]. Currently many genetic defects are known. Several studies have highlighted that MODY may be misdiagnosed as type 1 diabetes or type 2 diabetes and has potential implications in susceptibility to adulthood diabetes [3].
2.
History and examination
A 10-year-old girl was admitted for incidental hyperglycaemia. There was a family history of diabetes (mother and grandmother) and celiac disease (mother and sister). The mother had been treated with oral hypoglycaemic agents and reported
* Corresponding author at: Pediatric Clinic, University of Genoa, IRCCS G. Gaslini Institute, Largo G. Gaslini, 5, 16147 Genova, Italy. Tel.: +39 0105636528; fax: +39 0103773210. E-mail address: [email protected] (G. d’Annunzio). 0168-8227/$ – see front matter # 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.diabres.2013.01.003 Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
DIAB-5707; No. of Pages 3
2
diabetes research and clinical practice xxx (2013) xxx–xxx
Fig. 1 – Electropherogram of GCK mutation c.626C>T; p.T209M in exon 6, found both in the proband and in her mother.
good metabolic control with no diabetic complications. The girl is the second child and was born at 36 weeks gestation by caesarean delivery because of gestational hypertension. Her birth weight was 2070 g and length 46 cm. The neonatal period, growth and neurological development were normal. At first evaluation she was in good general health, height 130.6 cm, weight 28.6 kg and BMI 16.9 kg/m2. Clinical history was negative for polyuria, polydipsia, and weight loss. Acanthosis nigricans was absent and eye examination was normal.
3.
Investigation
Laboratory examination revealed fasting hyperglycaemia (6.2 mmol/L) and HbA1c 6.5% (normal 4–6%). Testing for bcell auto-antibodies (GADA and IAA) was performed with 100% specificity and 100% sensitivity radioligand assay CentAK Anti-GAD65 and CentAK IAA RT (Medipan, Germany). GADA was weakly positive (1 U/mL, normal < 0.9) and IAA was negative. Oral glucose tolerance test (OGTT) showed impaired glucose tolerance (2 h plasma glucose 10.7 mmol/L). Intravenous glucose tolerance test (IVGTT) showed a First Phase Insulin Response (FPIR) of 49 mU/mL, less than 1st centile for pubertal stage [4]. Based on a slow increase in capillary glucose levels and elevated HbA1c levels, low dose insulin was prescribed (long-acting insulin analogue 0.2 U/ kg/day) which was followed by improvement of capillary glucose levels. Subsequent disappearance of GADA and stability of glycaemic levels, together with family history for mild hyperglycaemia lead us to consider a clinical diagnosis of MODY. Genetic analysis performed by direct sequencing showed a GCK mutation c.626C>T; p.T209M compatible with MODY2, also found in the patient’s mother (Fig. 1). Interestingly, GADA follow-up testing was again mildly positivity (1.7 U/mL), in the absence of signs and symptoms of metabolic decompensation.
4.
Conclusion
GCK/MODY is the most common form of MODY in Caucasians [2]. The enzymatic activity of GCK is linked with insulin secretion and GCK acts as the main glucosensor of b-cells. GCK/MODY phenotype ranges from fasting hyperglycaemia with small increases in HbA1c to mild clinical diabetes. Severe ketoacidosis and complications are extremely rare [5]. Diet
and exercise are the best initial treatment options. With more severe hyperglycemia, insulin therapy can be started followed by clinical re-evaluation. By contrast classic type 1 diabetes is preceded by a long prodromic, asymptomatic period characterized by b-cell autoimmunity and clinical diagnosis coincides with up to 90% b-cell mass destruction. Initial hyperglycaemia may evolve rapidly to severe metabolic decompensation [6]. Morbidity and mortality are still reported if the diagnosis is delayed [7], while early diagnosis positively influences partial remission and better metabolic outcomes [8]. Improvements in glycaemic control achieved initially correlate with long-term glycaemic control [9], while glycaemic instability may have negative consequences through a ‘‘metabolic memory’’ despite future improvements [10]. Incidental hyperglycaemia in children and adolescents represents a diagnostic challenge, since it can indicate a number of possibilities including pre-type 1 diabetes and monogenic forms of diabetes [11]. The search for immunological markers of b-cell autoimmunity and clinical follow-up may help for discriminate MODY from type 1 diabetes [12]. In our patient the lack of obesity and acanthosis nigricans together with hyperglycaemia and GADA positivity initially lead us to suspect a pre-type 1 diabetes. Subsequently temporary GADA disappearance, lack of progression of symptoms together with a family history of mild diabetes alerted us to the possibility of MODY. A recent survey in children and adolescents on phenotypic aspects of MODY reported a 17% prevalence of b-cell autoimmunity in genetically diagnosed MODY probands [13]. The coexistence of different form of MODY with type 1 diabetes has been reported in four cases [14–16]. Bowden described the first case, an overweight adolescent female who was firstly diagnosed as type 2 diabetes and was treated with oral agents. Worsening of metabolic control during treatment lead to suspecting type 1 diabetes, which was confirmed by positive b-cells auto-antibodies and recovery after insulin therapy. The strong family history of diabetes and the lack of acanthosis nigricans raised the suspicion of a monogenic form of diabetes and a HNF1a/MODY mutation was found. This resulted in the description of a new phenotype of ‘‘triple diabetes’’ [14]. Calcaterra et al reported the second case, a 13 years old girl with GCK/MODY diagnosed at seven years who developed clinical signs of metabolic syndrome followed by overt type 1 diabetes with b-cell autoimmunity [15]. Recently, Zucchini et al. reported worsening metabolic control in two different MODY patients (GCK/MODY and HNF1a/MODY, respectively) associated with detection of b-cell autoimmunity and insulin requiring type 1 diabetes [16]. In our case the detection of b-cells autoimmunity required us to continue careful metabolic follow-up to avoid missing severe metabolic decompensation and missing a diagnosis of type 1 diabetes. On the other hand, weak b-cells autoimmunity should not preclude genetic testing for MODY if clinical circumstances are suspicious.
Conflict of interest The authors declare that they have no conflict of interest.
Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
DIAB-5707; No. of Pages 3 diabetes research and clinical practice xxx (2013) xxx–xxx
references [10] [1] Daneman D. Type 1 diabetes. Lancet 2006;11:847–58. [2] Lorini R, Klersy C, d’Annunzio G, Massa O, Minuto N, Iafusco D, et al. Study Group. Maturity-onset diabetes of the young in children with incidental hyperglycaemia: a multi center Italian study of 172 families. Diabetes Care 2009;32:1864–6. [3] Barrett TG. Differential diagnosis of Type 1 diabetes, Which genetic syndromes need to be considered? Pediatr Diabetes 2007;8:15–23. [4] Lorini R, Vanelli M. Normal values of first-phase insulin response to intravenous glucose in healthy Italian children and adolescents. Diabetologia 1996;39:370–1. [5] Thanabalasingham G, Katharine R. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ 2011;343:6004. [6] Neu A, Hofer SE, Karges B, Oeverink R, Rosenbauer J, Holl RW. Ketoacidosis at diabetes onset is still frequent in children and adolescents: a multicenter analysis of 14,664 patients from 106 institutions. Diabetes Care 2009;32: 1647–8. [7] Szypowska A, Sko`rka A. The risk factor of ketoacidosis in children with newly diagnosed type 1 diabetes mellitus. Pediatr Diabetes 2011;12:302–6. [8] Bowden SA, Duck MM, Hoffman RP. Young children (<5 yr) and adolescents (>12 yr) with type 1 diabetes mellitus low rate of partial remission: diabetic ketoacidosis is an important risk factor. Pediatr Diabetes 2008;9:197–201. [9] Kordonouri O, Pankowska E, Rami B, Kapellen T, Coutant R, Hartmann. et al. Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: result of the
[11]
[12]
[13]
[14]
[15]
[16]
Pediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia 2010;53:2487–95. Ce` GV, Rohde LE, da Silva AM, Punales MK, de Castro AC, Bertolucci MC. Endothelial dysfunction is relegate to poor glycemic control in adolescents with type 1 diabetes under 5 years of disease: evidence of metabolic memory. J Clin Endocrinol Metab 2011;96:1493–9. Lorini R, Alibrandi A, Vitali L, Klersy C, Martinetti M, Betterle C, et al. Risk of Type 1 diabetes development in children with incidental hyperglycemia. Diabetes Care 2001;24:1210–6. McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, et al. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from type 1 diabetes. Diabet Med 2011;9:1028–33. Shober E, Rami B, Grabert M, Grabert M, Thon A, Kapellen. et al. Phenotypical aspects of maturity onset diabet of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicenter database. Diabet Med 2009;26: 466–73. Bowden SA, Hoffman RP. Triple diabetes: coexistence of type 1 diabetes mellitus and a novel mutation in gene responsible for MODY 3 in an overweight adolescent. Pediatr Diabetes 2008;9:162–4. Calcaterra V, Martinetti M, Salina A, Aloi C, Larizza D. The coexistence of type 1 diabetes, MODY2 and metabolic syndrome in a young girl. Acta Diabetol 2011. http:// dx.doi.org/10.1007/s00592-011-0300-2. Maltoni M, Zucchini S, Scipione M, Salardi S, Cicognani A. Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young. Pediatr Diabetes 2012;13:208–12.
Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
3
Contents available at Sciverse ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Brief report
Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes? Giuseppe d’Annunzio a,*, Marta Marchi a, Concetta Aloi a, Alessandro Salina a, Francesca Lugani a,b, Renata Lorini a a b
Pediatric Clinic, IRCCS Giannina Gaslini Institute, Genoa, Italy Laboratory on Pathophysiology of Uremia, IRCCS G. Gaslini Institute, Genoa, Italy
article info
abstract
Article history:
We describe 10-year-old girl with mild incidental hyperglycaemia, impaired glucose toler-
Received 20 June 2012
ance and GADA positivity. Family history for mild hyperglycaemia and GADA fluctuation
Received in revised form
alerted us to a possible MODY diagnosis which was confirmed by detection of GCK mutation
15 November 2012
c.626C>T; p.T209M. Weak or transient b-cell autoimmunity should not preclude genetic
Accepted 3 January 2013
testing for MODY when the clinical features are suggestive. # 2013 Published by Elsevier Ireland Ltd.
Keywords: Hyperglycaemia MODY b-Cell antibodies Pre-type 1 diabetes
1.
Introduction
In type 1 diabetes mellitus (T1DM) genetic, environmental and immunological factors exert a T-cell mediated autoimmune process [1]. The immune-mediated b-cell destruction occurs over years with progressive insulin deficiency and varying degrees of hyperglycaemia ranging up to severe metabolic derangement. Immunological markers of b-cell destruction are detectable before clinical diagnosis in subjects at risk of T1DM, predict the future development of the disease and characterize the ‘‘pre-type 1 diabetes’’ condition [1]. Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of non-autoimmune diabetes resulting from a primary defect of insulin secretion characterized by
autosomal dominant inheritance, genetic heterogeneity, early onset of hyperglycaemia/diabetes, presence of obesity is variable and there is a lack of insulin dependence [2]. Currently many genetic defects are known. Several studies have highlighted that MODY may be misdiagnosed as type 1 diabetes or type 2 diabetes and has potential implications in susceptibility to adulthood diabetes [3].
2.
History and examination
A 10-year-old girl was admitted for incidental hyperglycaemia. There was a family history of diabetes (mother and grandmother) and celiac disease (mother and sister). The mother had been treated with oral hypoglycaemic agents and reported
* Corresponding author at: Pediatric Clinic, University of Genoa, IRCCS G. Gaslini Institute, Largo G. Gaslini, 5, 16147 Genova, Italy. Tel.: +39 0105636528; fax: +39 0103773210. E-mail address: [email protected] (G. d’Annunzio). 0168-8227/$ – see front matter # 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.diabres.2013.01.003 Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
DIAB-5707; No. of Pages 3
2
diabetes research and clinical practice xxx (2013) xxx–xxx
Fig. 1 – Electropherogram of GCK mutation c.626C>T; p.T209M in exon 6, found both in the proband and in her mother.
good metabolic control with no diabetic complications. The girl is the second child and was born at 36 weeks gestation by caesarean delivery because of gestational hypertension. Her birth weight was 2070 g and length 46 cm. The neonatal period, growth and neurological development were normal. At first evaluation she was in good general health, height 130.6 cm, weight 28.6 kg and BMI 16.9 kg/m2. Clinical history was negative for polyuria, polydipsia, and weight loss. Acanthosis nigricans was absent and eye examination was normal.
3.
Investigation
Laboratory examination revealed fasting hyperglycaemia (6.2 mmol/L) and HbA1c 6.5% (normal 4–6%). Testing for bcell auto-antibodies (GADA and IAA) was performed with 100% specificity and 100% sensitivity radioligand assay CentAK Anti-GAD65 and CentAK IAA RT (Medipan, Germany). GADA was weakly positive (1 U/mL, normal < 0.9) and IAA was negative. Oral glucose tolerance test (OGTT) showed impaired glucose tolerance (2 h plasma glucose 10.7 mmol/L). Intravenous glucose tolerance test (IVGTT) showed a First Phase Insulin Response (FPIR) of 49 mU/mL, less than 1st centile for pubertal stage [4]. Based on a slow increase in capillary glucose levels and elevated HbA1c levels, low dose insulin was prescribed (long-acting insulin analogue 0.2 U/ kg/day) which was followed by improvement of capillary glucose levels. Subsequent disappearance of GADA and stability of glycaemic levels, together with family history for mild hyperglycaemia lead us to consider a clinical diagnosis of MODY. Genetic analysis performed by direct sequencing showed a GCK mutation c.626C>T; p.T209M compatible with MODY2, also found in the patient’s mother (Fig. 1). Interestingly, GADA follow-up testing was again mildly positivity (1.7 U/mL), in the absence of signs and symptoms of metabolic decompensation.
4.
Conclusion
GCK/MODY is the most common form of MODY in Caucasians [2]. The enzymatic activity of GCK is linked with insulin secretion and GCK acts as the main glucosensor of b-cells. GCK/MODY phenotype ranges from fasting hyperglycaemia with small increases in HbA1c to mild clinical diabetes. Severe ketoacidosis and complications are extremely rare [5]. Diet
and exercise are the best initial treatment options. With more severe hyperglycemia, insulin therapy can be started followed by clinical re-evaluation. By contrast classic type 1 diabetes is preceded by a long prodromic, asymptomatic period characterized by b-cell autoimmunity and clinical diagnosis coincides with up to 90% b-cell mass destruction. Initial hyperglycaemia may evolve rapidly to severe metabolic decompensation [6]. Morbidity and mortality are still reported if the diagnosis is delayed [7], while early diagnosis positively influences partial remission and better metabolic outcomes [8]. Improvements in glycaemic control achieved initially correlate with long-term glycaemic control [9], while glycaemic instability may have negative consequences through a ‘‘metabolic memory’’ despite future improvements [10]. Incidental hyperglycaemia in children and adolescents represents a diagnostic challenge, since it can indicate a number of possibilities including pre-type 1 diabetes and monogenic forms of diabetes [11]. The search for immunological markers of b-cell autoimmunity and clinical follow-up may help for discriminate MODY from type 1 diabetes [12]. In our patient the lack of obesity and acanthosis nigricans together with hyperglycaemia and GADA positivity initially lead us to suspect a pre-type 1 diabetes. Subsequently temporary GADA disappearance, lack of progression of symptoms together with a family history of mild diabetes alerted us to the possibility of MODY. A recent survey in children and adolescents on phenotypic aspects of MODY reported a 17% prevalence of b-cell autoimmunity in genetically diagnosed MODY probands [13]. The coexistence of different form of MODY with type 1 diabetes has been reported in four cases [14–16]. Bowden described the first case, an overweight adolescent female who was firstly diagnosed as type 2 diabetes and was treated with oral agents. Worsening of metabolic control during treatment lead to suspecting type 1 diabetes, which was confirmed by positive b-cells auto-antibodies and recovery after insulin therapy. The strong family history of diabetes and the lack of acanthosis nigricans raised the suspicion of a monogenic form of diabetes and a HNF1a/MODY mutation was found. This resulted in the description of a new phenotype of ‘‘triple diabetes’’ [14]. Calcaterra et al reported the second case, a 13 years old girl with GCK/MODY diagnosed at seven years who developed clinical signs of metabolic syndrome followed by overt type 1 diabetes with b-cell autoimmunity [15]. Recently, Zucchini et al. reported worsening metabolic control in two different MODY patients (GCK/MODY and HNF1a/MODY, respectively) associated with detection of b-cell autoimmunity and insulin requiring type 1 diabetes [16]. In our case the detection of b-cells autoimmunity required us to continue careful metabolic follow-up to avoid missing severe metabolic decompensation and missing a diagnosis of type 1 diabetes. On the other hand, weak b-cells autoimmunity should not preclude genetic testing for MODY if clinical circumstances are suspicious.
Conflict of interest The authors declare that they have no conflict of interest.
Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
DIAB-5707; No. of Pages 3 diabetes research and clinical practice xxx (2013) xxx–xxx
references [10] [1] Daneman D. Type 1 diabetes. Lancet 2006;11:847–58. [2] Lorini R, Klersy C, d’Annunzio G, Massa O, Minuto N, Iafusco D, et al. Study Group. Maturity-onset diabetes of the young in children with incidental hyperglycaemia: a multi center Italian study of 172 families. Diabetes Care 2009;32:1864–6. [3] Barrett TG. Differential diagnosis of Type 1 diabetes, Which genetic syndromes need to be considered? Pediatr Diabetes 2007;8:15–23. [4] Lorini R, Vanelli M. Normal values of first-phase insulin response to intravenous glucose in healthy Italian children and adolescents. Diabetologia 1996;39:370–1. [5] Thanabalasingham G, Katharine R. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ 2011;343:6004. [6] Neu A, Hofer SE, Karges B, Oeverink R, Rosenbauer J, Holl RW. Ketoacidosis at diabetes onset is still frequent in children and adolescents: a multicenter analysis of 14,664 patients from 106 institutions. Diabetes Care 2009;32: 1647–8. [7] Szypowska A, Sko`rka A. The risk factor of ketoacidosis in children with newly diagnosed type 1 diabetes mellitus. Pediatr Diabetes 2011;12:302–6. [8] Bowden SA, Duck MM, Hoffman RP. Young children (<5 yr) and adolescents (>12 yr) with type 1 diabetes mellitus low rate of partial remission: diabetic ketoacidosis is an important risk factor. Pediatr Diabetes 2008;9:197–201. [9] Kordonouri O, Pankowska E, Rami B, Kapellen T, Coutant R, Hartmann. et al. Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: result of the
[11]
[12]
[13]
[14]
[15]
[16]
Pediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia 2010;53:2487–95. Ce` GV, Rohde LE, da Silva AM, Punales MK, de Castro AC, Bertolucci MC. Endothelial dysfunction is relegate to poor glycemic control in adolescents with type 1 diabetes under 5 years of disease: evidence of metabolic memory. J Clin Endocrinol Metab 2011;96:1493–9. Lorini R, Alibrandi A, Vitali L, Klersy C, Martinetti M, Betterle C, et al. Risk of Type 1 diabetes development in children with incidental hyperglycemia. Diabetes Care 2001;24:1210–6. McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, et al. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from type 1 diabetes. Diabet Med 2011;9:1028–33. Shober E, Rami B, Grabert M, Grabert M, Thon A, Kapellen. et al. Phenotypical aspects of maturity onset diabet of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicenter database. Diabet Med 2009;26: 466–73. Bowden SA, Hoffman RP. Triple diabetes: coexistence of type 1 diabetes mellitus and a novel mutation in gene responsible for MODY 3 in an overweight adolescent. Pediatr Diabetes 2008;9:162–4. Calcaterra V, Martinetti M, Salina A, Aloi C, Larizza D. The coexistence of type 1 diabetes, MODY2 and metabolic syndrome in a young girl. Acta Diabetol 2011. http:// dx.doi.org/10.1007/s00592-011-0300-2. Maltoni M, Zucchini S, Scipione M, Salardi S, Cicognani A. Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young. Pediatr Diabetes 2012;13:208–12.
Please cite this article in press as: d’Annunzio G, et al. Hyperglycaemia and b-cell antibodies: Is it always pre-type 1 diabetes?. Diabetes Res Clin Pract (2013), http://dx.doi.org/10.1016/j.diabres.2013.01.003
3