Younger patients and low c-peptide immunoreactivity index but not nutritional states affect fasting blood ketone levels in Japanese with type 1 diabetes after sodium-glucose cotransporter 2 inhibitor administration.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c-peptide immunoreactivity (CPR) index and body composition. MATERIALS AND METHODS: In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated. RESULTS: All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = -0.514, p < .001) and the CPR index (r = -0.523, p = .038) after taking SGLT2is. Using a mixed-effects model based on the results before starting the inhibitors, it was noted that both patient-to-patient and age, or patient-to-patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (ß = -0.504, p = .003) and a low ratio of basal to bolus insulin (ß = -0.420, p = .005). CONCLUSIONS: When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given.

Insulin dose reduction in dapagliflozin combination therapy for type 1 diabetes mellitus: the RISING-STAR study.

To clarify the frequency of hypoglycemia in patients with type 1 diabetes mellitus receiving dapagliflozin combination therapy to reduce their basal insulin dose. Sixty subjects were assigned to two groups according to their basal insulin-to-total daily dose (TDD) ratio: group A (basal insulin/TDD <40%) and group B (≥40%). Reduction of the basal insulin dose was instituted in group B, but not in group A. The number of hypoglycemic events per day and ketosis frequency were the primary and secondary endpoints, respectively. The hypoglycemia frequency before and after the intervention was 0.23 and 0.26 times/day in group A and 0.19 and 0.23 times/day in group B, respectively, with no significant difference between the groups. The total insulin dose reduction was approximately 10% in both groups. Ketosis frequency increased significantly after the intervention (from 0.013 to 0.086 times/day in group A and 0.013 to 0.059 times/day in group B). Time-in-range, mean amplitude of glycemic excursion, and glycated hemoglobin A1c improved in both groups. No significant difference in hypoglycemia frequency was observed between patients with and without reduction of the basal insulin dose. The combination therapy improved glycemic control and patient satisfaction regarding hyperglycemia. Nevertheless, adequate attention to ketosis is crucial.

Multicenter, Open-Label, 2-Arm, Pilot Trial for Safe Reduction of Basal Insulin Dose Combined with SGLT2 Inhibitor in Type 1 Diabetes Mellitus: Study Protocol for a RISING-STAR Trial.

BACKGROUND: The safe method of instructing insulin dose reduction in combination with SGLT2 inhibitors, dapagliflozin for patients with type 1 diabetes mellitus has not been clarified. In this study, we conducted a stratified, 2-arm, parallel comparative study with the primary endpoint of decreasing the frequency of hypoglycemia by instructing basal insulin dose reduction. METHODS: The study has a multicenter, open-label, 2-arm design; 60 type 1 diabetes mellitus patients are being recruited from 7 hospitals. Study subjects have been stratified into 2 groups based on the ratio of basal insulin daily dose (Basal) to total daily insulin dose (TDD). The subjects whose Basal/TDD ratio is <0.4 are instructed not to reduce Basal but to reduce bolus insulin dose by 10% (group A), and subjects with a Basal/TDD ratio >0.4 will be instructed to reduce Basal by 10% (group B). The primary outcome is the daily frequency of hypoglycemia during the intervention period (SGLT2 inhibitor administration), as determined by self-monitoring of blood glucose. We aimed to confirm a greater reduction in frequency of hypoglycemia in group B (reduced Basal), than in group A (non-reduction of Basal and reduced insulin effect levels by 10%). Baseline hypoglycemia was set at 7 ± 6 times/month. The minimum sample size required to achieve a significance of .05 for a 1-sided t-test with a statistical power at 80% is determined. When the sample size is 26 patients in 1 group, the percentage increase in hypoglycemia exceeds 60%, and the sample size is considered sufficient. DISCUSSION: In this pilot study, we assumed that, given a sufficient Basal, hypoglycemia would be more frequent in patients with type 1 diabetes when combined with SGLT2 inhibitors, provided the Basal was not reduced.

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study.

Fatty liver disease and metabolic syndrome (MetS) are both shown to increase the risk of type 2 diabetes. The aim of this study was to investigate the combined effect of fatty liver and MetS on incident diabetes. In this cohort study of 17,810 participants, fatty liver was diagnosed by abdominal ultrasonography and MetS was defined by a joint interim statement. We divided the participants into four groups according to the presence of fatty liver and/or MetS. Type 2 diabetes was defined as HbA1c ≥6.5%, fasting plasma glucose ≥7.0 mmol/L or treatment for diabetes. During the follow up examination (median 5.1 years), 804 participants developed diabetes. Compared with non-MetS without fatty liver, hazard ratios (HR) for incident diabetes after adjusting for age, body mass index, smoking status, exercise habit, alcohol consumption, family history of diabetes logarithm of alanine aminotransferase and fasting plasma glucose, were as follow: 2.35 (95 % CI 1.91-2.89, p<0.001) in non-MetS with fatty liver, 1.70 (95% CI 1.30-2.20, p<0.001) in MetS without fatty liver, and 2.33 (95% CI 1.85-2.94, p<0.001) in MetS with fatty liver. In addition, adjusted HRs for incident diabetes compared with MetS without fatty liver were 1.39 (95% CI 1.07-1.80, p=0.012) in non-MetS with fatty liver and 1.38 (95% CI 1.07-1.79, p=0.013) in MetS with fatty liver. Fatty liver affects more on the risk of incident diabetes than MetS. To prevent the further risk of diabetes, we should pay more attention to fatty liver.

Home Blood Pressure Variability From the Stored Memory Is Correlated With Albuminuria, but From the Logbook Is not.

BACKGROUND: The aim of this study was to evaluate whether the mean and the variability of home blood pressure (HBP) from the logbook correlate with albuminuria as well as HBP from the stored memory in patients with type 2 diabetes. METHODS: This study is a post hoc analysis of a cross-sectional multicenter study. HBP measurements were performed for 14 consecutive days in 276 patients with type 2 diabetes. Patients were requested to write down their HBP values in logbooks and were not informed about the memory function of their BP monitoring devices. RESULTS: HBP values from the logbook were significantly lower and less variable than those from the stored memory. The mean of morning systolic BP (SBP) from the logbook (adjusted ß = 0.326, P < 0.001) as well as that from the stored memory (adjusted ß = 0.336, P < 0.0001) was significantly associated with logarithm of urinary albumin excretion (UAE). The SD of morning SBP (adjusted ß = 0.134, P = 0.017) from the stored memory was significantly associated with logarithm of UAE, in contrast, the SD of morning SBP (adjusted ß = 0.104, P = 0.057) from the logbook was not associated with logarithm of UAE. CONCLUSIONS: Patients with type 2 diabetes might report inaccurate HBP measurements and, as a result, the variability of HBP from the logbook is underestimated and poorly correlates with albuminuria. The use of stored BP measurements is recommended to accurately evaluate the relationship with diabetic nephropathy.

Combined effect of body mass index and waist-height ratio on incident diabetes; a population based cohort study.

We investigated the impact of combined effect of body mass index and waist-to-height ratio on risk of diabetes. Overweight and abdominal obesity were defined as body mass index ≥23 kg/m2 and waist-to-height ratio ≥0.5, respectively. We divided participants into four groups according to presence of overweight and/or abdominal obesity. About 20% individuals with overweight did not complicated with an abdominal obesity. Among 3,737 participants, 286 participants had diabetes at baseline-examination. Adjusted odds ratios for prevalence of diabetes compared with non-overweight participants without abdominal obesity were as follow: 1.87 (95% confidence interval 1.09-3.14, p = 0.024) in non-overweight participants with abdominal obesity, 1.51 (0.87-2.55, p = 0.141) in overweight participants without abdominal obesity and 3.25 (2.37-4.52, p<0.001) in overweight participants with abdominal obesity. In the follow-up examination, 86 participants were diagnosed as diabetes among 2,263 participants. Adjusted odds ratios for incident diabetes were as follow: 2.59 (0.98-6.44, p = 0.056) in non-overweight participants with abdominal obesity, 1.65 (0.64-4.00, p = 0.288) in overweight participants without abdominal obesity and 2.77 (1.55-5.15, p<0.001) in overweight participants with abdominal obesity. Non-overweight individuals with abdominal obesity as well as overweight individuals with abdominal obesity was associated with diabetes compared with non-overweight individuals without abdominal obesity.

Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice.

Sex steroid hormones, such as estrogen and testosterone, are believed to play important roles in lipid metabolism. To elucidate the effects of estrogen depletion on lipid metabolism in male and female mice, we used aromatase-knockout (ArKO) mice, in which Cyp19 gene disruption prevented estrogen synthesis in vivo. These mice were divided into the following 4 groups: male and female ArKO mice and male and female wild-type (WT) mice. These mice were fed a normal-fat diet (13.6% fat) ad libitum. At 159 days after birth, the mice were tested for liver and plasma lipid content and hepatic hormone receptor- and lipid/lipoprotein metabolism-related gene expression. Interestingly, we found that hepatic steatosis was accompanied by markedly elevated plasma testosterone levels in male ArKO mice but not in female ArKO mice. Plasma lipoprotein profiles exhibited concurrent decreases in LDL- and small dense LDL-triglyceride (TG) levels in male ArKO mice. Moreover, male mice, but not female mice, exhibited marked elevations in androgen receptor (AR), sterol regulatory element-binding protein 1 (SREBP1), and CD36 expression. These results strongly suggest that Cyp19 gene disruption, which induces a sexually dimorphic response and high plasma testosterone levels in male mice, also induces hepatic steatosis.

Transient remission of nonalcoholic fatty liver disease decreases the risk of incident type 2 diabetes mellitus in Japanese men.

INTRODUCTION: It is unclear how the transient remission of nonalcoholic fatty liver disease (NAFLD) affects incident type 2 diabetes mellitus (T2DM). Here, we sought to determine the effect of the transient remission of NAFLD on incident T2DM in Japanese men. MATERIALS AND METHODS: We used a population-based health check-up program. The primary outcome was set as incident T2DM. We divided the participants who showed NAFLD at the time of enrollment into three groups according to their clinical course of NAFLD: the Regression group, in which the participants showed a regression of NAFLD and no relapse during the follow-up period; the Transient Remission group, in which participants achieved a transient remission of NAFLD, but had a relapse of NAFLD; and the Persistent group, in which participants showed NAFLD throughout the follow-up. The Never group of participants who did not show NAFLD throughout the follow-up served as a reference. RESULTS: The incidence rates of T2DM in the Never group, the Regression group, the Transient Remission group, and the Persistent group were 4.7% (62/1306), 9.2% (14/153), 18.0% (25/139), and 35.1% (120/342), respectively. In a multivariate Cox regression analysis with covariates, the adjusted hazard ratios for incident T2DM compared with the Never group were as follows: Regression group: 1.08 [95% confidence interval (CI) 0.53-2.04, P=0.81], Transient Remission group: 2.12 (95% CI 1.22-3.57, P<0.01), and Persistent group: 3.44 (95% CI 2.29-5.21, P<0.001). The adjusted hazard ratio of the Transient Remission group was significantly lower than that of the Persistent group (P<0.05). CONCLUSION: Transient remission of NAFLD significantly decreased the risk of developing T2DM.

Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes.

Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2-[(3)H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100 nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes by inducing the LKB1/AMPK signaling pathway.

Effect of repaglinide versus glimepiride on daily blood glucose variability and changes in blood inflammatory and oxidative stress markers.

BACKGROUND: Hemoglobin A1c is the main treatment target for patients with type 2 diabetes. It has also been shown recently that postprandial glucose and daily glucose fluctuations affect the progression of diabetic complications and atherosclerotic damages. METHODS: Continuous glucose monitoring was performed in patients with type 2 diabetes to evaluate the efficacy of repaglinide vs. glimepiride on postprandial glucose spikes and fluctuations. A total of 10 Japanese patients with type 2 diabetes treated with glimepiride monotherapy were enrolled. After observation period for 8 weeks, glimepiride was changed to repaglinide. Continuous glucose monitoring was performed whilst consuming calorie-restricted diets for two days at baseline and at the end of the 12-week trial. Blood and urine samples were collected for measurement of glucose control parameters and inflammatory and oxidative stress markers on the last day of taking either glimepiride or repaglinide. RESULTS: Nine patients completed the trial. Although the glucose control parameters were not significantly different between glimepiride and repaglinide, the mean amplitude of glycemic excursions measured by continuous glucose monitoring was significantly reduced by changing treatment from glimepiride to repaglinide. The levels of plasminogen activator inhibitor-1, high sensitivity C-reactive protein, and urinary 8-hydoroxydeoxyguanosine were reduced significantly by repaglinide treatment. CONCLUSION: These results suggest that repaglinide may decrease the risk of cardiovascular disease in type 2 diabetes by minimizing glucose fluctuations thereby reducing inflammation and oxidative stress.

Is home blood pressure reporting in patients with type 2 diabetes reliable?

The aim of this study was to evaluate the reliability of self-reported home blood pressure (HBP) in patients with type 2 diabetes by comparing the self-reported values with HBP measurements stored in the memory of the blood pressure (BP) monitor. We also examined what factors affect the reliability of HBP measurements. A cross-sectional study was conducted in 280 patients with type 2 diabetes. Patients were requested to perform triplicate morning and evening measurements over a span of 2 weeks and to enter their HBP values into logbooks. Patients were not informed about the memory function of their BP monitoring devices. The concordance rate of HBP reporting was 78.6%. A total of 51.4% of patients (n=144) had >90% concordant data, and 15.7% of patients (n=44) had ⩽50% concordant data. In general, HBP values from the logbook were significantly lower and less variable than those from the stored memory (P<0.05). The most common type of incorrect data was selected data that were reported in the logbooks that were randomly selected from multiple readings by the HBP monitors (55.8%). The concordance rate of HBP reporting significantly correlated with hemoglobin A1c levels (ß=-0.156; P=0.0149) and with smoking status (current vs. never, ß=-0.165; P=0.0184). In conclusion, HBP measurements from the patients' logbooks were lower and less variable than those from the stored memory in the BP monitors of patients with type 2 diabetes, and the reliability of HBP reporting was affected by glycemic control and smoking status. Repeated instructions regarding HBP measurement to the patients or the use of stored BP measurements is recommended to ensure accurate HBP measurements in patients with type 2 diabetes.

The inter-arm difference in systolic blood pressure is a novel risk marker for subclinical atherosclerosis in patients with type 2 diabetes.

Recent studies have suggested that the inter-arm blood pressure difference (IAD) is associated with cardiovascular events and mortality. The aim of this study was to assess whether the IAD could be a marker for subclinical atherosclerosis in patients with type 2 diabetes who are at high risk of cardiovascular disease (CVD). In a cross-sectional retrospective study of 206 Japanese patients with type 2 diabetes aged 49-76 years, we examined the correlation of the IAD with the carotid intima-media thickness (IMT), ankle-brachial index (ABI) or cardio ankle vascular index (CAVI). The IAD was positively correlated with the maximum IMT (r=0.266, P<0.0001), mean IMT (r=0.209, P=0.00726) or CAVI (r=0.240, P=0.0005). The IAD was higher in patients with CVD than in those without (P=0.0020). A multiple linear regression analysis demonstrated that the IAD was an independent determinant of maximum IMT (ß=0.169, P=0.0167), mean IMT (ß=0.178, P=0.0153), ABI (ß=-0.222, P=0.0033) or CAVI (ß=0.213, P=0.0011) after adjusting for known risk factors. The area under the receiver operating characteristic curve (AUC) of the IAD as a predictor of subclinical atherosclerosis was similar to the AUC of the Framingham 10-year coronary heart disease risk score. In conclusion, the IAD could be a novel risk marker for subclinical atherosclerosis in patients with type 2 diabetes.