A multicenter, open-label, single-arm trial of the long-term safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE-02).

AIMS/INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS: The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS: Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS: Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.

Diabetes mellitus with severe insulin resistance in a young male patient with a heterozygous pathogenic IRS1 frameshift variant.

We present the case of a young male patient (height, 158.1 cm [+3.3 standard deviation (SD)]; weight, 63.7 kg [body mass index, 25.5]) with diabetes mellitus and severe insulin resistance associated with a heterozygous pathogenic insulin receptor substrate 1 (IRS1) frameshift mutation. The patient also had severe acanthosis nigricans. Notably, the patient's father was undergoing treatment with high doses of insulin for diabetes mellitus, and had been experiencing angina pectoris. Laboratory data showed a fasting plasma glucose level of 88 mg/dL, hemoglobin A1C (HbA1c) of 7.4%, fasting insulin level of 43.1 µg/mL, and a homeostasis model assessment-insulin resistance (HOMA-IR) score of 9.36, indicating hyperinsulinism. Oral glucose tolerance test revealed a diabetic pattern and insulin hypersecretion. In addition, the patient had hyperlipidemia. Genetic studies revealed a heterozygous frameshift variant of IRS1 [NM_005544.3:c.1791dupG:p.(His598Alafs*13)] in the patient and his father, which can impair the binding and activation of phosphoinositide 3 (PI-3) kinase and defectively mediate the translocation of glucose transporter type 4 (GLUT4) in adipose tissues, possibly leading to glucose intolerance. Therefore, this variant may be disease causing. After confirming IRS1 mutation, metformin was administered, and physical exercise and dietary management were initiated; metformin was well tolerated, and optimal glycemic control was maintained.

A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01).

INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.

Treatment strategy for children and adolescents with type 2 diabetes-based on ISPAD Clinical Practice Consensus Guidelines 2022.

The principles of treatment for children and adolescents with type 2 diabetes include dietary and exercise management. For dietary management, a relatively modest dietary regimen with an appropriate energy source composition is recommended. Moderate- to vigorous-intensity aerobic activity is recommended for at least 60 min/d. Family members are encouraged to modify their lifestyles. Some patients fail to improve hyperglycemia through dietary and exercise management and eventually require pharmacological treatment. If the patient is metabolically stable (HbA1c level < 8.5% [69 mmol/mol]), metformin is the first-line treatment of first choice. In a case with ketosis or HbA1c of more than 8.5% (69 mmol/mol), insulin will be required initially with once daily basal insulin (0.25-0.5 units/kg). The goal of the initial treatment is to attain an HbA1c level < 7.0% (53 mmol/mol). If the glycemic goal is not attained, the addition of a second agent should be considered. However, the use of antihyperglycemic drugs in pediatric patients is limited in most countries. Therefore, the efficacy and safety of these drugs used in adult patients, including GLP-1 receptor agonists and SGLT2 inhibitors, should be evaluated in pediatric patients worldwide.

Nighttime hypoglycemia in Japanese children with type 1 diabetes mellitus treated with multiple daily injection insulin therapy.

Prevention of hypoglycemia is an important strategy for glycemic management in patients with type 1 diabetes mellitus (T1D). Hypoglycemia is difficult to recognize at night while sleeping, particularly when using multiple daily injection (MDI) insulin therapy rather than sensor-augmented insulin-pump therapy. Therefore, it is possible that patients with T1D are at higher risk of nocturnal hypoglycemia when insulin is administered using an MDI regimen. We investigated nocturnal hypoglycemia in 50 pediatric patients with T1D on MDI insulin therapy using data from an intermittently scanned continuous glucose monitoring (isCGM) system. Hypoglycemia was observed on 446 of the 1,270 nights studied. Most of the hypoglycemic episodes were severe (blood glucose <54 mg/dL). On nights when hypoglycemia occurred, the blood glucose concentrations measured using finger-stick blood glucose monitoring (FSGM) before sleep and the next morning were lower than nights when hypoglycemia did not occur. However, few values were below the normal blood glucose range, suggesting that FSGM alone may be insufficient to detect nocturnal hypoglycemia. Approximately 7% of time was spent below the normal glucose range during the 10 hours from 21:00 to 7:00 the next morning. This result suggests that the patients on MDI insulin therapy could end up spending more time in hypoglycemia than is recommended by the American Diabetes Association (time below range <4.0% of time per day). Monitoring glucose levels overnight using an isCGM sensor may improve glycemic management via automatic detection of blood glucose peaks and troughs.

The Advanced Diabetes Technologies for Reduction of the Frequency of Hypoglycemia and Minimizing the Occurrence of Severe Hypoglycemia in Children and Adolescents with Type 1 Diabetes.

Hypoglycemia is an often-observed acute complication in the management of children and adolescents with type 1 diabetes. It causes inappropriate glycemic outcomes and may impair the quality of life in the patients. Severe hypoglycemia with cognitive impairment, such as a convulsion and coma, is a lethal condition and is associated with later-onset cognitive impairment and brain-structural abnormalities, especially in young children. Therefore, reducing the frequency of hypoglycemia and minimizing the occurrence of severe hypoglycemia are critical issues in the management of children and adolescents with type 1 diabetes. Advanced diabetes technologies, including continuous glucose monitoring and sensor-augmented insulin pumps with low-glucose suspension systems, can reduce the frequency of hypoglycemia and the occurrence of severe hypoglycemia without aggravating glycemic control. The hybrid closed-loop system, an automated insulin delivery system, must be the most promising means to achieve appropriate glycemic control with preventing severe hypoglycemia. The use of these advanced diabetes technologies could improve glycemic outcomes and the quality of life in children and adolescents with type 1 diabetes.

Pathophysiological significance in abdominal fat distribution in non-obese children with type 2 diabetes.

The aim of the study was to determine the pathogenesis of non-obese children with type 2 diabetes, and its relationship with fat distribution. The study participants included 36 obese children with type 2 diabetes (age: 13.5 years, BMI: 28.3, BMI percentile: 91.9) and 30 non-obese children with type 2 diabetes (age: 13.5 years, BMI: 23.1, BMI percentile: 74.0). The proportion of female participants was significantly higher in non-obese children than in obese children (73.3% vs. 41.7%, p < 0.001). Abdominal fat distribution, evaluated by subcutaneous fat (SF) area, visceral fat (VF) area, and the ratio of VF area to SF area (V/S ratio), measured using computed tomography, and serum lipid levels and liver function were compared between the two groups. Non-obese children with type 2 diabetes had significantly smaller SF area and also smaller VF area than obese children with type 2 diabetes (SF area: 158.3 m2 vs. 295.3 m2, p < 0.001, VF area: 71.0 m2 vs. 94.7 m2, p = 0.032). Whereas non-obese children with type 2 diabetes had significantly greater V/S ratio than obese children with type 2 diabetes (0.41 vs. 0.31, p = 0.007).The prevalence of dyslipidemia and liver dysfunction were similar in the two groups. In conclusion, non-obese children with type 2 diabetes had excess accumulation of VF despite a small amount of SF, which might be associated with glucose intolerance and other metabolic disorders.

Efficacy of Low-dose Dapagliflozin in Young People with Type 1 Diabetes.

Objective Young people with type 1 diabetes are likely to gain body weight and not achieve optimal glycemic control with only high doses of insulin. This study examined the efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin as an adjunct-to-insulin therapy in young Japanese subjects with type 1 diabetes who had been diagnosed before 15 years old, were overweight, and had inadequate control despitereceiving intensive insulin therapy. Methods Twenty-two patients with type 1 diabetes (12 boys and 10 girls 16.0-33.9 years old) were involved in the study. All patients had a body mass index (BMI) >25 kg/m2, glycated hemoglobin (HbA1c) level >7.0%, and daily insulin dose >0.5 units/kg. They were treated with a low dose of dapagliflozin (5.0 mg/day) as an adjunctive therapy to insulin. Fourteen patients were treated with multiple daily injections of insulin, while eight used an insulin pump. Results The body weights and BMIs were significantly reduced during the 12-month study period (change of -4.4 kg and -1.7 kg/m2, p<0.001, respectively). Their insulin dose was significantly decreased (-0.17 units/kg, P <0.001), and glycemic control was significantly improved (fasting plasma glucose: -18.7 mg/dL, HbA1c: -0.62%, p<0.001) during the study period. There was one episode of diabetic ketoacidosis, with no other problematic adverse events, including severe hypoglycemia, observed. Conclusion The use of low-dose dapagliflozin as an adjunct therapy may be beneficial in overweight young people with poorly controlled type 1 diabetes.

Difference in the early clinical course between children with type 1 diabetes having a single antibody and those having multiple antibodies against pancreatic ß-cells.

Islet-cell associated antibodies are predictive and diagnostic markers for type 1 diabetes. We studied the differences in the early clinical course of children with type 1 diabetes with a single antibody and those with multiple antibodies against pancreatic ß-cells. Sixty-seven children with type 1 diabetes aged less than 15 years diagnosed between 2010 and 2021 were included in the study and subdivided into two subgroups: children who were single positive for either glutamic acid decarboxylase (GAD) antibodies (n = 16) or insulinoma-associated antigen-2 (IA-2) antibodies (n = 13) and those positive for both antibodies (n = 38) at diagnosis. We compared the patients' clinical characteristics, pancreatic ß-cell function, and glycemic control during the 5 years after diagnosis. All clinical characteristics at diagnosis were similar between the two groups. One and two years after diagnosis, children who tested positive for both antibodies showed significantly lower postprandial serum C-peptide (CPR) levels than those who tested positive for either GAD or IA-2 antibodies (p < 0.05). In other periods, there was no significant difference in CPR levels between the two groups. There was a significant improvement in glycosylated hemoglobin (HbA1c) levels after starting insulin treatment in both groups (p < 0.05), but no significant difference in HbA1c levels between the groups. Residual endogenous insulin secretion may be predicted based on the number of positive islet-cell associated antibodies at diagnosis. Although there are differences in serum CPR levels, optimal glycemic control can be achieved by individualized appropriate insulin treatment, even in children with type 1 diabetes.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Association of Plasma Cortisol Levels with Gestational Age and Anthropometric Values at Birth in Preterm Infants.

There are no study reports to clarify the association between gestational age (GA) or anthropometric values at birth, and plasma cortisol levels in the blood of preterm infants at birth and at one month of age. This hospital-based retrospective cohort study included infants born at <37 weeks' gestation between 2019 and 2021. First, the association between plasma cortisol level and GA or anthropometric values at birth (birth weight standard deviation score [SDS], birth length SDS, and birth head circumference SDS) was identified by regression and multiple regression analyses. Second, plasma cortisol levels in the umbilical cord at birth and at one month of age were compared between small-for-gestational age (SGA) and non-SGA infants. Sixty-one preterm infants were enrolled (SGA: 24 and non-SGA: 37). Plasma cortisol levels at birth were significantly associated with GA. Plasma cortisol levels at one month of age were associated with GA and birth head circumference SDS. Plasma cortisol levels at birth were significantly higher in SGA than non-SGA (p = 0.010). GA was an independent determinant of plasma cortisol levels at birth. SGA infants had a high plasma cortisol level at birth; resulting in speculation that a high plasma cortisol level at birth may predict abnormal neurological outcomes.

Significance of the CGM metric of time in range in children and adolescents with type 1 diabetes.

Continuous glucose monitoring (CGM) has been widely used in children and adolescents as well as adults with type 1 diabetes. CGM metrics include three key measurements of target glucose: time in range (TIR: 70-180 mg/dL), time below range (TBR: <70 mg/dL), and time above range (TAR: >180 mg/dL). The primary goal of optimal glycemic control is to increase TIR to more than 70%, while simultaneously reducing TBR to less than 4%, while minimizing severe hypoglycemia to less than 1%, as proposed by the Advanced Technologies and Treatments for Diabetes (ATTD) panel. However, several studies have indicated that the TIR goal is quite difficult to achieve in pediatric patients who have remarkable interindividual and day-to-day glycemic variation due to their irregular lifestyles. Previous studies have demonstrated that patients without an automated insulin delivery system are unlikely to attain the recommended glycemic goals. On the other hand, reduction of hypoglycemia, particularly minimizing severe hypoglycemia, is a critical issue in the effective management of children with type 1 diabetes. Frequent episodes of severe hypoglycemia and hypoglycemia can cause lasting neurological damage. Accordingly, we propose reducing the TBR to less than 5%, rather than just targeting the TIR to more than 70%. In CGM metrics this should be the cardinal glycemic goal for pediatric patients who are either being treated with multiple daily injections of insulin or a conventional insulin pump, but who are not using an automated insulin delivery system.

Comparison of the clinical effects of intermittently scanned and real-time continuous glucose monitoring in children and adolescents with type 1 diabetes: A retrospective cohort study.

AIMS/INTRODUCTION: The aim of the study was to compare two continuous glucose monitoring (CGM) systems, intermittently scanned CGM (isCGM) and real-time CGM (rtCGM), to determine which system achieved better glycemic control in pediatric patients. MATERIALS AND METHODS: We carried out a retrospective cohort study of children and adolescents with type 1 diabetes, and compared the time in range (70-180 mg/dL), time below range (<70 mg/dL) and time above range (>180 mg/dL), and estimated glycated hemoglobin levels between patients on isCGM and rtCGM. RESULTS: Of the 112 participants, 76 (67.9%) used isCGM and 36 (32.1%) used rtCGM for glycemic management. Patients on rtCGM had significantly greater time in range (57.7 ± 12.3% vs 52.3 ± 12.3%, P = 0.0368), and had significantly lower time below range (4.3 ± 2.7% vs 10.2% ± 5.4%, P < 0.001) than those on isCGM, but there was no significant difference in the time above range (37.4 ± 12.9% vs 38.0% ± 12.5%, P = 0.881) or the glycosylated hemoglobin A1c levels (7.4 ± 0.9% vs 7.5 ± 0.8%, P = 0.734) between the two groups. CONCLUSIONS: Pediatric patients with type 1 diabetes on rtCGM also showed more beneficial effects for increase of time in range, with a notable reduction of time below range compared with those on isCGM. Real-time CGM might provide better glycemic control than isCGM in children with type 1 diabetes.

Epidemiology and phenotypes of diabetes in children and adolescents in non-European-origin populations in or from Western Pacific region.

BACKGROUND: Type 1 diabetes (T1D) incidence varies substantially between countries/ territories, with most studies indicating increasing incidence. In Western Pacific region (WPR), reported rates are much lower than European-origin populations. In contrast, there are reports of substantial numbers of young people with type 2 diabetes (T2D). A deeper understanding of T1D and T2D in the WPR may illuminate factors important in pathogenesis of these conditions. Furthermore, with varying resources and funding for diabetes treatment in this region, there is a need to more clearly determine the current burden of disease and also any gaps in knowledge. AIM: To compile and summarise published epidemiologic and phenotypic data on childhood diabetes in non-European populations in and from WPR. METHODS: Research articles were systematically searched from PubMed (MEDLINE), Embase, Cochrane library, and gray literature. Primary outcome measures were incidence and prevalence, with secondary measures including phenotypic descriptions of diabetes, including diabetes type categorization, presence of diabetic ketoacidosis (DKA) at onset, autoantibody positivity, C-peptide levels, and human leucocyte antigen phenotype. Extracted data were collected using a customized template. Three hundred and thirty relevant records were identified from 16 countries/territories, with analysis conducted on 265 (80.3%) records published from the year 2000. RESULTS: T1D incidence ranged from < 1-7.3/100000 individuals/year, rates were highest in emigrant/ mixed populations and lowest in South-East Asia, with most countries/territories (71.4%) having no data since 1999. Incidence was increasing in all six countries/territories with data (annual increases 0.5%-14.2%, highest in China). Peak age-of-onset was 10-14 years, with a female case excess. Rate of DKA at onset varied from 19.3%-70%. Pancreatic autoantibodies at diagnosis were similar to European-origin populations, with glutamic acid decarboxylase-65 autoantibody frequency of 44.1%-64.5%, insulinoma-associated 2 autoantibody 43.5%-70.7%, and zinc transporter-8 autoantibody frequency 54.3% (one study). Fulminant T1D also occurs. T2D was not uncommon, with incidence in Japan and one Chinese study exceeding T1D rates. Monogenic forms also occurred in a number of countries. CONCLUSION: T1D is less common, but generally has a classic phenotype. Some countries/ territories have rapidly increasing incidence. T2D is relatively common. Registries and studies are needed to fill many information gaps.

Adrenal cytomegaly with elevated serum androgen levels in a patient with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is infrequently associated with adrenocortical carcinoma (ACC) or non-hormone-producing adrenal cytomegaly, but we recently, encountered a single case of adrenal cytomegaly in a patient with BWS, which was difficult to distinguish from androgen-producing adrenocortical carcinoma (ACC). Here, we describe the case of a 4-month-old female who presented with clitoromegaly, hemihypertrophy, and an adrenal mass identified during the prenatal period. The mass was located in detected at the left suprarenal region and detected at 20 weeks of gestational age. At birth, she also presented with clitoromegaly and elevated serum levels of 17α-hydroxyprogesterone, dehydroepiandrosterone, and testosterone at birth and experienced hyper-insulinemic hypoglycemia, which improved following diazoxide therapy. We initially suspected androgen-producing ACC with metastasis and the left adrenal mass was resected accordingly when the patient reached 4 months of age. However, histological examination revealed adrenal cytomegaly. Genetic analysis revealed paternal uniparental disomy, and the patient was finally diagnosed as having BWS. Resection of the left adrenal gland restored the serum androgen levels to normal physiological levels without any recurrence. While it is reasonably well known that BWS is sometimes accompanied by virilization due to androgen-producing ACC, our findings are among the first to suggest that adrenal cytomegaly can also increase androgen hormone production. Thus, we propose that adrenal cytomegaly should be considered one of the differential diagnoses when accompanied with hyperandrogenism in BWS patients.

Frequent scanning using flash glucose monitoring contributes to better glycemic control in children and adolescents with type 1 diabetes.

AIMS/INTRODUCTION: We examined the impact of scanning frequency with flash glucose monitoring on glycemic control in children and adolescents with type 1 diabetes. MATERIALS AND METHODS: The study included 85 patients, aged 14.0 ± 0.5 years, with type 1 diabetes. The median time in the target glucose range (TIR) and glycosylated hemoglobin (HbA1c) values were 50.0 ± 1.4% and 7.5 ± 0.1%, respectively. RESULTS: The median scanning frequency using flash glucose monitoring was 12.0 ± 0.4 times/day. Scanning frequency showed a significant positive correlation with TIR and an inverse correlation with HbA1c. Scanning frequency was identified to be the determinant of TIR and HbA1c by using multivariate analysis. The participants whose scanning frequency was <12 times/day were categorized as the low-frequency group (n = 40), and those who carried out the scanning >12 times/day were categorized as the high-frequency group (n = 45). Patients in the high-frequency group were more likely to be treated with insulin pumps compared with those in the low-frequency group; however, this difference was not significant (21.3 vs 5.3%, P = 0.073). The high-frequency group showed significantly greater TIR than the low-frequency group (57 ± 1.6 vs 42 ± 1.7%, P = 0.002). Furthermore, the high-frequency group showed significantly lower HbA1c levels than the low-frequency group (6.8 ± 0.1 vs 8.0 ± 0.1%, P < 0.001). CONCLUSIONS: These findings showed that patients with a higher scanning frequency had better glycemic control, with greater TIRs and lower HbA1c levels, compared with those with a lower scanning frequency. Scanning frequency of >12 times/day might contribute to better glycemic outcomes in real-world practice in children with type 1 diabetes.

A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

Effectiveness of a smartphone application on medication adherence in children with short stature receiving GH therapy: A multicenter prospective cohort study (GTL-App).

This multicenter prospective cohort study followed up Japanese children who had just started GH therapy using a drug delivery device (GROWJECTOR® L) linked to a newly developed smartphone application and analyzed precise medication adherence data stored in GROWJECTOR® L to evaluate the usefulness of the application in improving GH therapy adherence over a 24-wk observation period. Moreover, a questionnaire survey on GH therapy and the smartphone application was conducted, and factors affecting adherence to GH therapy were assessed. This study enrolled 60 children with short stature who had GH deficiency or Turner syndrome or were small for gestational age from 28 Japanese medical institutions and analyzed 57 of them. The median and mean adherence rates after 24 wk of observation were 96% and 93%, respectively. Although adherence rates were significantly lower from wk 16 to wk 20 than from wk 1 to wk 4, cumulative adherence rates remained high throughout the observation period. The questionnaire analysis revealed that most patients actively used the application. Overall, our results suggest that active discussion regarding the development of healthcare systems that contribute toward improving the patient quality of life is warranted.

Nutrient management in the intrapartum period in maternal maple syrup urine disease.

Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.