Yuki Hosokawa

Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus

Yorifuji T, Fujimaru R, Hosokawa Y, Tamagawa N, Shiozaki M, Aizu K, Jinno K, Maruo Y, Nagasaka H, Tajima T, Kobayashi K, Urakami T. Comprehensive molecular analysis of Japanese patients with pediatric‐onset MODY‐type diabetes mellitus.

Efficacy and safety of long-term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP-channel hyperinsulinism.

To evaluate the efficacy of long‐term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP‐channel genes, KCNJ11 and ABCC8.

Dominantly inherited diabetes mellitus caused by GATA6 haploinsufficiency: variable intrafamilial presentation

GATA6 haploinsufficiency has recently been reported as the most frequent cause of neonatal diabetes with pancreatic agenesis. Although all previously reported cases represented a de novo mutation with complete agenesis or pronounced hypoplasia of the pancreas, in this study we identified a family with a dominantly inherited mutation. Unlike previously reported cases, the degree of pancreatic hypoplasia and the severity of diabetes varied among members of the family, ranging from neonatally lethal diabetes with only a remnant of pancreatic tissue to adult-onset diabetes associated with dorsal agenesis of the pancreas. These observations further broaden the clinical spectrum of diabetes associated with GATA6 haploinsufficiency.

Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients.

To investigate the molecular and clinical characteristics of the largest series of Japanese patients with glucokinase maturity‐onset diabetes of the young (GCK‐MODY), and to find any features specific to Asian people.

Lasting 18F-DOPA PET Uptake after Clinical Remission of the Focal Form of Congenital Hyperinsulinism

Background: Positron emission tomography (PET) using 18F-DOPA is a useful tool for detecting the focal forms of congenital hyperinsulinism. 18F-DOPA is taken up by aromatic L-amino acid decarboxylase in pancreatic β-cells. However, the role of this enzyme in insulin secretion is unknown. Subjects and Methods: A Japanese boy who presented with symptomatic hyperinsulinemic hypoglycemia at the age of 2 days and spontaneous resolution at 1 year and 10 months was subjected to mutational analysis and repeated 18F-DOPA PET scans. Results: Mutational analysis revealed a paternally inherited monoallelic mutation, c.4186G>T (p.D1396Y), in the ABCC8 gene, and an 18F-DOPA PET scan revealed focal uptake in the body of the pancreas. The patient was successfully treated with frequent feeding. A follow-up PET scan revealed virtually identical uptake to that observed previously. However, in the arterial stimulation-venous sampling procedure, no significant insulin release was observed. He was placed on a normal diet, and no hypoglycemia recurrence was observed. Conclusion: This case demonstrates two important findings. Firstly, the uptake of 18F-DOPA does not correlate with the insulin-secreting capacity of the lesion. Secondly, clinical remission could be a functional process not necessarily accompanied by the apoptotic death of abnormal β-cells.

Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report

The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24‐related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene‐like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase‐4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0–7.5% (52–58 mmol/mol) to 6.0–6.5% (41–47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24‐related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the β cell mass and responsiveness through G protein‐coupled pathways.

Abnormalities in chromosome 6q24 as a cause of early‐onset, non‐obese, non‐autoimmune diabetes mellitus without history of neonatal diabetes

Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24‐related transient neonatal diabetes). 6q24‐Related transient neonatal diabetes is characterized by the patient being small‐for‐gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early‐onset, non‐autoimmune diabetes without transient neonatal diabetes.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia

To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays.

Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance

Causative mutations cannot be identified in the majority of Asian patients with suspected maturity‐onset diabetes of the young (MODY).

Chromosome 6q24-related diabetes mellitus

Abstract. Chromosome 6q24-related diabetes mellitus is the most common cause of transient neonatal diabetes (TNDM), accounting for approximately two-thirds of all TNDM cases. Patients with 6q24-TNDM develop insulin-requiring diabetes soon after birth, followed by the gradual improvement and eventual remission of the disorder by 18 mo of age. The most important clinical feature of affected patients is a small-for-gestational age (SGA) birth weight, which reflects the lack of insulin in utero. It is believed that 6q24-TNDM is caused by the overexpression of the paternal allele of the imprinted locus in chromosome 6q24, which contains only two expressed genes, PLAGL1 and HYMAI. Identified mechanisms include: (1) duplication of the paternal allele, (2) paternal uniparental disomy, and (3) hypomethylation of the maternal allele. Many patients with TNDM relapse after puberty. Relapsed 6q24-related diabetes is no longer transient and typically occurs in non-obese patients who are autoantibody negative. Thus, these patients possess features indistinguishable from those of maturity-onset diabetes of the young (MODY). Conversely, it has been shown that not all patients with 6q24-related diabetes have a history of TNDM. 6q24-related diabetes should therefore be considered as one of the differential diagnoses for patients with MODY-like diabetes, especially when they are SGA at birth.