1. Metformin treatment in a boy with HNF-1A mutation and criteria of T2DM
P01-185
45th ESPE Annual Meeting Rotterdam, June 30 – July 3, 2006
Metformin treatment in a boy with HNF-1A mutation and criteria of T2DM
Ralph Decker (1), Jens Jacobeit (2), Per Ivar Brekke (1)
(1) Division of Paediatric Endocrinology, Children’s Hospital, Molde, Norway, (2) Endokrinologikum Hamburg, Germany
Correspondence:
Introduction
Oral hypoglycemic agents are widely used for treatment of type 2 diabetes mellitus (T2DM) in children and adolescents. In a trial almost half of these patients were treated with insulin and the other half with oral hypoglycemic agents (1). Among the latter metformin is most used. 71% were treated with metformin, 46% with sulfonylureas, 9% with thiazolidinediones and 4% with meglitinide (1). Metformin is functioning as a insulin sensitizer. It increases insulin-stimulated uptake of glucose in peripheral tissues, decreases gluconeogenesis and has an anorectic effect.
Severe hyperglycemia in type 3 maturity-onset diabetes of the young (MODY3) usually occurs after puberty(2). It is caused by mutations in the hepatocyte nuclear factor-1A (HNF-1α) gene, which is essential for the signal transduction in the β-cell and in turn for an adequate insulin secretion (3). Prepubertal children are usually asymptomatic.
Patient
We present a 10 year old prepubertal caucasian boy with a positive family history of diabetes mellitus, obesity, hyperglycemia and a pathologic oral glucose tolerance test (o-GTT). However he did not have any clinical sign of diabetes. A deficit in insulin secretion was not present. In contrast, insulin resistance and high insulin response to o-GTT was diagnosed. He fulfils the criteria of diabetes mellitus of the World Health Organization (WHO) (4). In addition a mutation in the HNF-1α (P291fsinsC) gene was diagnosed.
Treatment
A low carbohydrate diet was performed due to his severe obesity two years prior diabetes was diagnosed. He also underwent an intensive exercise programme before he came to us. Despite these measures BMI increased dramatically.
Our patient is now treated with metformin in a dose of 750 mg per day for 1.5 years. The indication for this treatment is his diabetes mellitus type 2 in combination with insulin resistance and obesity.
Outcome
Fasting S-glucose before treatment mmol/l
Fasting S-glucose during treatment mmol/l
Oral glucose tolerance test (75 g glucose)
S-glucose after 2 hours before treatment mmol/l *
S-glucose after 2 hours during treatment mmol/l *
Body mass index (BMI) before treatment kg/m2
BMI SDS SDS LMS
Body mass index (BMI) during treatment kg/m2
BMI SDS SDS LMS
* WHO criteria: Reference Range [< 11.1]
Fig.2 Model of a pancreatic β-cell.
The MODY-associated transcription factors regulate the transcription of the insulin gene either directly, as in the case of HNF-4α (hepatocyte nuclear factor-4α) [MODY1] or indirectly, as in the case of HNF-1α [MODY3], IPF1 (insulin promotor factor-1) [MODY4], HNF-1β [MODY5], and BETA-2 (β-cell E-box transactivator 2) [MODY6].
With friendly permission of Matthias Epe, MD, Endokrinologikum Hamburg.
Fig.1 Body mass index
(percentiles for boys) Kromeyer Hauschild K, Wabitsch M, Kunze D et al: Monatsschr. Kinderheilk. 149 (2001)
Discussion
The concerning upswing in the prevalence of T2DM in children and adolescents has continued, parellel to the increasing rates of obesity (5). The conventional classification of MODY comprises age of onset beneath 25 years, dominant pattern of inheritance (which is present in our patient), and presence of β-cell dysfunction. These criteria do not allow the distinction of MODY from T2DM in young adults or even in children (6). Nevertheless in our patient a mutation in the HNF-1α gene was found.
The patient presented does not yet suffer from insufficiency in insulin secretion as this is the mechanism of MODY3. In contrast the pathophysiology of his current type of diabetes, which is classified as T2DM, is insulin resistance. It can be speculated that this boy is too young to develop hyperglycemia related to MODY. In a recent study variation in the HNF-4α enhancer element, which is characterized containing binding sites for HNF-1α, is not a common cause of susceptibility to T2DM (7).
However, it can be suspected that in this patient the mechanism of impaired insulin secretion will become the main factor after puberty. Therefore it is of fundamental importance to reduce weight and to treat impaired glucose tolerance due to insulin resistance and obesity by using a modern anti-obesity drug (8). Metformin is widely used in paediatric patients and is considered to be the most effective oral agent (9).
The synergism of metformin both on insulin sensitizing and its anorectic effect has been used in our patient. A success is already seen during 1.5 years of treatment. Both fasting glucose and o-GTT has been normalized and BMI decreased markedly from 31.1 to 24.6 kg/m2. The treatment has been shown to be safe and no side effects have been noted.
(1) Silverstein JH, Rosenboom AL, Treatment of type 2 diabetes mellitus in children and adolescents. J Pediatr Endocrinol Metab 2000; 13 suppl 6: (2) Timsit J, Bellanne-Chantelot C, Dubois-Laforgue D, Velho G, Diagnosis and management of maturity-onset diabetes of the young. Treat Endocrinol 2005; 4(1): (3) Fajans S, Bell GI, Polonsky KS, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001; 345(13): (4) World Health Organization: Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO consultation. Part 1. Diagnosis and classification of diabetes mellitus. Geneve, World Health Organization, (5) Gungor N, Arslanian S, Pathophysiology of type 2 diabetes mellitus in children and adolescents: treatment implications. Treat Endocrinol 2002;1(6): (6) Owen KR, Shepherd M, Stride A, Ellard S, Hattersley AT. Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristics. Diabet Med 2002 Sep;19(9): (7) Mitchell SM, Gloyn AL, Owen KR, Hattersley AT, Frayling TM. The role of the HNF4alpha enhancer in type 2 diabetes. Mol Genet Metab 2002 Jun;76(2): (8) Svacina S, Owen K, Obesity, type 2 diabets and their relation. Vnitr Lek; 2002 Jun 48(6): (9) Urakami T. How should we treat type 2 diabetes in youth? Pediatr Endokrinol Revn 2005 Sep 3(1):33-39
References