Clinical characteristics of HNF1B-related disorders in a Japanese population.

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Evaluation of metabolic parameters and body composition in Japanese patients with type 2 diabetes mellitus who were administered tofogliflozin for 48 weeks.

Sodium glucose cotransporter 2 inhibitors are unique antihyperglycemic agents that cause osmotic diuresis and calorie loss to urine. We previously reported that administration of tofogliflozin, a sodium glucose cotransporter 2 inhibitor, for 8 weeks decreased fat-free mass without affecting fat mass. We thus investigated the impact of tofogliflozin on metabolic parameters and body composition for 48 weeks in Japanese patients with type 2 diabetes mellitus. This single-arm open-label study enrolled 20 patients. Patients received tofogliflozin 20 mg once daily for 48 weeks. At week 48, changes in metabolic parameters and body composition from baseline were evaluated. Two patients discontinued administration due to adverse events during the first 8 weeks; however, no other adverse events occurred after that period. Seventeen patients completed the 48 weeks of administration of tofogliflodin. Body weight and body mass index decreased during the treatment period. Hemoglobin A1c decreased from 7.8% to 7.1%. The degree of improvement in hemoglobin A1c was correlated with body mass index, fat mass, and plasma glucose level at baseline. As for body composition, fat mass decreased without any change in fat-free mass (including total body water, extracellular water, and intracellular water). Red blood cell count and hematocrit increased, while the estimated glomerular filtration rate decreased. ALT and γ-GTP decreased and the decrease in γ-GTP was correlated with the loss of fat mass. In conclusion, our study clearly suggests that the body weight reduction caused by tofogliflozin administration for 48 weeks was almost entirely due to fat mass dissipation.

Concurrent Therapy with a Low-carbohydrate Diet and Miglitol Remarkably Improved the Postprandial Blood Glucose and Insulin Levels in a Patient with Reactive Hypoglycemia due to Late Dumping Syndrome.

Reactive hypoglycemia induced by late dumping syndrome is often observed after gastrectomy. However, no effective therapy has yet been fully established. We herein describe a case in which concurrent therapy with a low-carbohydrate diet using low-glycemic-index food and an alpha-glucosidase inhibitor, miglitol, very effectively ameliorated the postprandial fluctuations in the blood glucose and plasma insulin levels in a patient with reactive hypoglycemia due to late dumping syndrome following total gastrectomy. The administration of miglitol under a low-carbohydrate diet using low-glycemic-index food may therefore be an ideal treatment for reactive hypoglycemia due to late dumping syndrome.

Impact of the 8-week Administration of Tofogliflozin for Glycemic Control and Body Composition in Japanese Patients with Type 2 Diabetes Mellitus.

Objective The adverse effects of selective sodium-glucose co-transporter 2 (SGLT2) inhibitors generally appear within about two or three months after treatment initiation in Japan. Therefore, we investigated the impact of tofogliflozin, a class of SGLT2 inhibitors, on glycemic control and body composition during this period in Japanese patients with type 2 diabetes mellitus. Methods This single-arm open-label study enrolled 20 patients. Patients received tofogliflozin 20 mg once daily for 8 weeks. At week 8, changes from baseline in body weight, serum metabolic markers, and body composition were evaluated. Results A total of 17 patients completed the 8-week administration of tofogliflodin. No serious adverse events were noted. Hemoglobin A1c (HbA1c) decreased significantly, from 7.8% to 7.3% with 8-week administration of tofogliflozin. Both the body weight and body mass index (BMI) also decreased. In addition, a decreased renal function of the boundary zone and hemoconcentration were detected. As for body composition, the free fat mass, total body water, extracellular water and intracellular water were all decreased significantly. Interestingly, the amount of fat mass did not change. The degree of improvement in HbA1c was correlated with the baseline fat mass and BMI. Conclusion An eight-week administration of tofogliflozin improved glycemic control and reduced the body weight and free fat mass in type 2 diabetic patients without affecting the fat mass. In this period, the hematocrit level and renal function should be monitored to guard against hemoconcentration and renal impairment, respectively.