Basal insulin secretion capacity predicts the initial response and maximum levels of beta-hydroxybutyrate during therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin, in relation to weight loss.

AIMS: To investigate predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. METHODS: We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max-BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. RESULTS: Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2 , respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* µmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max-BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C-peptide levels compared with the lower three quartiles. CONCLUSIONS: Lower basal insulin secretion capacity might predict greater initial BHB elevations and max-BHB levels during long-term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.

Development of the Daily Time Management Scale for Use by Working People with Type 2 Diabetes.

AIM: The purpose of this study was to develop a scale to assess daily time management capabilities among working patients with diabetes and to test this scale's reliability and validity. METHODS: A self-administered questionnaire survey was conducted among 277 diabetes outpatients, and data from 220 participants (mean age = 54.3 ± 10.2 years, 76.8% male) were analyzed. Questionnaire items were selected through exploratory factor analysis. During the process of developing the questionnaire, opinions were solicited from experts on education for patients with diabetes, and Cronbach's α was calculated as a coefficient of reliability. Correlations with the Instrument of Diabetes Self-Care Agency (IDSCA) were examined and confirmatory factor analysis was performed to check for validity. RESULTS: Adequacy of a 4-factor, 16-item scale was confirmed. Cronbach's α coefficient was ≥.7 for the entire scale and for the subscale items. There was a significant correlation between total IDSCA scores and various factors (r = .280-.469). However, there was no correlation between the "adjustment of life rhythms" and parts of the IDSCA subscale. CONCLUSION: Although some aspects warrant further investigation, the developed scale provides a reliable and valid means of assessing daily time management capabilities among working patients with diabetes, and can thus be applied to help diabetes patients to manage their daily lives.

Renal effects of a sodium-glucose cotransporter 2 inhibitor, tofogliflozin, in relation to sodium intake and glycaemic status.

AIMS: Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however, SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D). METHODS: Individual-level data on 775 T2D patients in TOFO Phase 3 trials were analysed. Adjusted changes in variables during 52 weeks of TOFO therapy were compared according to basal daily salt intake (DSI), which was measured based on estimated daily urinary sodium excretion using the Tanaka formula. Multivariable analysis was used to investigate the impact of basal DSI on changes in eGFR at Weeks 4 and 52. RESULTS: Sixty-six percent of participants were men; mean age, HbA1c, body mass index, eGFRMDRD and median DSI were 58.5 years, 8.0%, 25.6 kg/m2 , 83.9 mL/min/1.73 m2 and 9.3 g/d, respectively. In all participants, eGFRMDRD sharply dipped during Week 4, and gradually increased by Week 52, showing a significant increase overall from baseline to Week 52. Multivariable analysis showed that basal DSI and HbA1c levels were independently correlated with eGFRMDRD changes at Weeks 4 and 52. Additionally, lower baseline HbA1c and DSI levels were significantly correlated with a greater increase in eGFRMDRD at Week 52. CONCLUSIONS: Dietary salt intake, in addition to glycaemic control, correlates with changed eGFRMDRD via TOFO. Thus, an appropriate dietary approach to therapy should be considered before treatment of T2D patients with an SGLT2i.

Effects of sodium-glucose cotransporter 2 inhibitor, tofogliflozin, on the indices of renal tubular function in patients with type 2 diabetes.

AIMS: Little is known of the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the renal tubules. We investigated the effect of the SGLT2 inhibitor, tofogliflozin (TOFO) on renal tubular indices, according to the degree of albuminuria, in type 2 diabetes mellitus (T2DM) patients with preserved renal function. MATERIALS AND METHODS: A total of 988 patients, receiving TOFO, were enroled and divided into 3 groups, based on the urine albumin-to-creatinine ratio (UACR). The tubular indices (urinary N-acetyl-beta-d-glucosaminidase [NAG]-to-creatinine and urinary beta-2 microglobulin [beta2MG]-to-creatinine ratios) and UACR were log-transformed in the correlation analysis. RESULTS: Treatment with TOFO led to similar reductions in glycated haemoglobin (HbA1c) levels, from baseline to week 24, across all groups. The NAG level increased in the normoalbuminuria group and decreased in the macroalbuminuria group significantly (P < .001, both), but did not change in the microalbuminuria group. Significant reductions in the UACR were observed in both microalbuminuria and macroalbuminuria groups (P < .001, both). Significant negative correlations between changes in the NAG and beta2MG levels and their corresponding baseline values were observed in all participants. The reduction in the UACR was negatively correlated with baseline levels. The changes in the tubular indices were positively correlated with reductions in the UACR across groups. CONCLUSIONS: Logarithmic reductions in the renal tubular indices, via SGLT2 inhibition, were observed in patients with T2DM. TOFO may not only improve the degree of albuminuria but may also have protective effects on the tubules.

Onset of reversible flaccid quadriplegia during treatment of thyrotoxic crisis.

Two unrelated women were hospitalized for thyrotoxic crisis complicated by multiple organ failure. Both patients were treated with antithyroid drugs and hydrocortisone, as well as insulin for hyperglycemia, and underwent mechanical ventilation with sedation. Flaccid quadriplegia became apparent after each patient completely recovered their level of consciousness once sedation was discontinued on days 6 and 15, respectively. Three to six months of rehabilitation was required for the muscle strength to fully improve in both cases. Thyrotoxicosis in addition to critical illness polyneuromyopathy and the administration of glucocorticoid therapy may have contributed to the onset of quadriplegia in these two cases. Flaccid quadriplegia is one of the serious neuromuscular conditions experienced during the treatment of thyrotoxic crisis.

Simultaneous occurrence of type 1 diabetes mellitus and Graves' disease: a report of two cases and a review of the literature.

Two unrelated Japanese women, 41 and 27 years of age, were admitted with histories of thirst, weight loss and palpitations of a few weeks' duration. Both were diagnosed to have diabetic ketosis or ketoacidosis with acute-onset type 1 diabetes (T1D) and Graves' disease (GD) (autoimmune polyglandular syndrome type 3 variant; APS3v), and were treated with intensive insulin therapy and anti-thyroid drugs. Human leukocyte antigen examinations showed that both cases had the HLA-A2, A24, B54, and DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which made them susceptible not only to APS3v, but also to both acute-onset T1D and GD. The genetic background of patients strongly contributes to the simultaneous occurrence of T1D and GD.

Isolated adrenocorticotropin deficiency associated with painless thyroiditis: a case report and review of the literature.

A 53-year-old Japanese man was admitted with a 3-month history of transient headache followed by general fatigue and weight loss. He had a history of ocular myasthenia gravis which had been in remission following thymectomy 30 years ago. He had a small diffuse goiter without tenderness, and was diagnosed as having painless thyroiditis with mild thyrotoxicosis on admission. Endocrinological studies showed he had isolated adrenocorticotropin deficiency. Magnetic resonance imaging of the pituitary gland revealed no abnormalities. His symptoms improved soon after replacement of glucocorticoid. After an episode of hypothyroidism, he spontaneously became euthyroid. It is likely that thyrotoxicosis uncovered adrenal insufficiency that had developed insidiously, and hypoadrenocorticism-induced immunological changes may have triggered the development of painless thyroiditis. Moreover, thymectomy might have facilitated the development of pituitary and thyroid autoimmunity.

Randomized controlled trial of single-agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes: A comparative study.

UNLABELLED: Aims/Introduction: To compare first-line, single-agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes uncontrolled by diet and exercise with respect to glycemic control, safety and metabolic changes. MATERIALS AND METHODS: Patients with previously untreated type 2 diabetes were enrolled in a multicenter, randomized, non-blind, parallel-group trial of glimepiride (0.5-6 mg/day) or pioglitazone (15-45 mg/day) for 6 months. RESULTS: A total of 191 patients aged 30-75 years were randomized. Similar percentages of patients attained the primary end-point, with glycated hemoglobin < 6.9% at month 6 with glimepiride and pioglitazone, respectively (61.2 vs 56.8%, P = 0.64). At month 6, the following significant (P < 0.05) intragroup changes in mean plasma lipid concentrations were noted as compared with baseline: total cholesterol decreased from 203.5 to 195.5 mg/dL and low-density lipoprotein (LDL)-cholesterol decreased from 124.5 to 116.3 mg/dL in the glimepiride group, whereas high-density lipoprotein (HDL)-cholesterol increased from 51.6 to 56.0 mg/dL and triglycerides decreased from 167.6 to 143.6 mg/dL in the pioglitazone group. The only symptomatic adverse events were mild-to-moderate in four patients receiving pioglitazone, and constipation in one patient receiving glimepiride. Similar numbers of patients experienced asymptomatic hypoglycemia (<60 mg/dL) in the glimepiride and pioglitazone groups (n = 7 and 5, respectively). CONCLUSIONS: There was no statistically significant difference between glimepiride and pioglitazone with respect to glycemic control, and both agents were well tolerated. Glimepiride significantly lowered total cholesterol and LDL-cholesterol, whereas pioglitazone increased HDL-cholesterol. This trial was registered with University Hospital Medical Information Network (UMIN), Japan, UMIN000004582. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00115.x, 2011).

Usability of a microtapered needle (TN3305) for insulin treatment in japanese patients with diabetes mellitus: a comparative clinical study with a standard thin wall needle.

BACKGROUND: We evaluated the clinical usability of a microtapered needle (TN3305, "Needle T," Terumo Corp., Tokyo, Japan) by comparing it with a standard needle (Micro-Fine +, 31 gauge, 5 mm, thin wall, "Needle B," Nippon Becton Dickinson Co., Ltd., Tokyo) in a multicenter study. METHODS: Ninety-nine patients with diabetes mellitus being treated in 11 Japanese hospitals were enrolled in the study. Written consent was obtained from all patients. They were allocated randomly to two groups by an envelope (crossover) method. Injections were performed using one needle first, followed by the other needle 4 or 5 days later. Pain caused by injection was evaluated using a visual analogue scale (VAS). RESULTS: In the overall evaluation, Needle T was chosen by 40 patients (44.4%) and Needle B by 17 (18.8%); 33 patients (36.7%) expressed no preference. VAS scores for Needles T and B were 1.48 +/- 0.18 and 2.47 +/- 0.24 cm, respectively (P < 0.001). In this study, lower VAS indicated less pain. CONCLUSIONS: The preferences and VAS scores suggested that Needle T caused less pain than Needle B. The incidence of adverse events and safety were equivalent for both needles. We believe that usability of Needle T by patients for self-injection is better.

Intermittent and recurrent hepatomegaly due to glycogen storage in a patient with type 1 diabetes: genetic analysis of the liver glycogen phosphorylase gene (PYGL).

We report a 19-year-old woman who had a history of type 1 diabetes with recurrent glycogen accumulation in the liver. During her infantile period she presented with no hepatomegaly nor growth retardation. On admission she was diagnosed with diabetic ketoacidosis (DKA). She also had hepatomegaly and elevated transaminase levels, but these abnormalities had resolved after administration of insulin. However, 4 weeks after DKA marked hepatomegaly and elevated transaminases were reappeared with simultaneous hypoglycemia which suggested an impaired glycogenolysis in the extraordinary conditions. We supposed the partial deficiency of liver glycogen phosphorylase activity in this patient and analyzed the liver glycogen phosphorylase gene (PYGL). Deduced amino acid sequence of the PYGL in this patient was completely identical to that reported by Burwinkel et al. (Y15233), however, the nucleotide sequence of PYGL cDNA was heterozygous for substitutions at positions Asp339 (GAT to GAC) on exon 9 and Ala703 (GCT to GCC on exon 17, respectively. These SNPs were also screened in 51 Japanese normal subjects by PCR-based direct sequencing or PCR-RFLP method. The same genotype observed in this patient was detected in 2 of 51(3.9%) normal subjects. These results suggest that the structure of PYGL coding sequence in this patient is unlikely to account for her excessive liver glycogen accumulation. Further studies including genetic analysis on the promoter region of the gene are necessary to clarify the etiology of susceptibility to excessive liver glycogen storage in patients with type 1 diabetes.