Ipragliflozin and sitagliptin differentially affect lipid and apolipoprotein profiles in type 2 diabetes: the SUCRE study.

BACKGROUND: SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters. METHODS: This is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20-74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120-399 mg/dL (1.35-4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment. RESULTS: Ipragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin. CONCLUSIONS: While ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.

Crucial role of iron in epigenetic rewriting during adipocyte differentiation mediated by JMJD1A and TET2 activity.

Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, 　including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.

Fasting plasma glucose level-based formula for estimating starting daily dose in basal-bolus insulin therapy.

There is no standard formula for estimating the starting daily dose (SDD) of basal-bolus insulin therapy (BBT). We aimed to develop a formula for estimating SDD and evaluate its efficacy and safety in patients with type 2 diabetes hospitalized for BBT. In the first study (n = 104), we retrospectively analyzed the relationship between peak daily dose (PDD) during hospitalization and clinical parameters. The PDD was significantly associated with fasting plasma glucose (FPG) (R = 0.449, P < 0.0001) and HbA1c levels (R = 0.384, P < 0.0001) but not body weight, body mass index, body surface area, or serum C-peptide levels. Based on the results, we developed a formula for estimating SDD using FPG levels: SDD (U/day) = 0.08 × FPG (mg/dL). In the second study (n = 405), we assessed efficacy and safety of the formula by evaluating the M-value from the daily glucose profile and assessing the frequency of hypoglycemia (blood glucose level < 70 mg/dL). When BBT was initiated using the FPG level-based formula, the M-values decreased from 61.0 ± 52.8 to 12.8 ± 10.8 (P < 0.0001), and hypoglycemia was observed in only 3/405 cases (0.74%) under the SDD. The FPG level-based formula is useful for estimating SDD in BBT and is safe for clinical use.

Efficacy and safety of sitagliptin treatment in older adults with moderately controlled type 2 diabetes: the STREAM study.

Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65-80 years with moderately controlled glycemic levels (HbA1c 7.4-10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were - 27.2 mg/dL, - 0.61%, and - 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, - 0.29%, and - 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients.Trial registration number: UMIN000010376.

Perioperative glycemic status is linked to postoperative complications in non-intensive care unit patients with type-2 diabetes: a retrospective study.

Background: Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D. Materials and Methods: Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis. Results: Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85-0.98), P = 0.01) and mean postoperative BG (1.11 (1.05-1.18), P < 0.001) were independently associated with postoperative complications. Conclusion: Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

Measurement of the nuclear concentration of α-ketoglutarate during adipocyte differentiation by using a fluorescence resonance energy transfer-based biosensor with nuclear localization signals.

α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2-oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KG-binding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time- and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.

Irrational Responses to Risk Preference Questionnaires by Patients with Diabetes with or without Retinopathy and Comparison with Those without Diabetes.

PURPOSE: The risk preferences of patients with diabetes have profound effects on the progression of complications. The present study aimed to clarify whether the preferences of patients with diabetes and retinopathy are deliberately risk-seeking or irrational and whether this propensity is specific to those with retinopathy or is also found in patients without retinopathy compared with those without diabetes. PATIENTS AND METHODS: A total of 394 patients with diabetes (264 without retinopathy and 130 with retinopathy) and 198 patients without diabetes agreed to participate in this survey. The questions were modified versions of those from the Japan Household Survey on Consumer Preferences and Satisfaction, which sought to determine the participants' personal socioeconomic status and risk preferences. In the questionnaires, responses were analyzed by determining the participants' willingness to pay for a lottery ticket and for an insurance policy. Irrational responses were defined as violations of two axioms of the Expected Utility Theory: completeness and transitivity. RESULTS: The incidence of irrational responses increased with age and was associated with educational level. The incidence of irrational responses was significantly higher in patients with retinopathy than in those without retinopathy after adjusting for age and educational level. There was no significant difference in the incidence of irrational responses between patients with diabetes but without retinopathy and those without diabetes. CONCLUSION: The risk-seeking behavior of patients with diabetes and retinopathy was not deliberate but was irrational under uncertainty. Medical professionals should be aware of their patients' propensity to make irrational decisions, which is an important risk factor for the progression of retinopathy in patients with diabetes regardless of age and educational level.

Sitagliptin improves plasma apolipoprotein profile in type 2 diabetes: A randomized clinical trial of sitagliptin effect on lipid and glucose metabolism (SLIM) study.

AIM: This study aims to evaluate the effect of dipeptidyl peptidase-4 inhibitors on lipid metabolism in patients with type 2 diabetes mellitus (T2D). METHODS: This is a multicenter, open-labeled, randomized controlled study. T2D patients with HbA1c 6.9-8.9% (52-74 mmol/mol) who were under treatment with sulfonylurea were randomly allocated to either the sitagliptin group or the non-sitagliptin group. Glucose and lipid metabolism parameters including apolipoproteins (apo), sterols, and urinary albumin were assessed at baseline, 3, and 6 months of the treatment. RESULTS: A total of 164 patients completed the 6-month observation (n = 81 for sitagliptin and n = 83 for non-sitagliptin). HbA1c decreased in the sitagliptin group but not in the non-sitagliptin group. Serum TG and total, LDL and HDL cholesterol levels did not change in either group. Apo B-48, apo CII, and apo CIII levels decreased in the sitagliptin group, but not in the non-sitagliptin group. The change in urinary albumin was significantly different between the groups with a preferable change in the sitagliptin group. There were no changes in serum sterols levels in the two groups. CONCLUSIONS: The treatment of sitagliptin for 6 months improves the metabolism of glucose and chylomicron and reduces plasma levels of atherogenic lipoproteins in patients with T2D.

Levels of glucose-regulatory hormones in patients with non-islet cell tumor hypoglycemia: including a review of the literature.

Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 µIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 µg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.

ACTH stimulation test and computed tomography are useful for differentiating the subtype of primary aldosteronism.

The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.

JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis.

Histone 3 lysine 9 (H3K9) demethylase JMJD1A regulates ß-adrenergic-induced systemic metabolism and body weight control. Here we show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate the ß1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1 in brown adipocytes (BATs). Phosphorylation of JMJD1A by PKA increases its interaction with the SWI/SNF nucleosome remodelling complex and DNA-bound PPARγ. This complex confers ß-adrenergic-induced rapid JMJD1A recruitment to target sites and facilitates long-range chromatin interactions and target gene activation. This rapid gene induction is dependent on S265 phosphorylation but not on demethylation activity. Our results show that JMJD1A has two important roles in regulating hormone-stimulated chromatin dynamics that modulate thermogenesis in BATs. In one role, JMJD1A is recruited to target sites and functions as a cAMP-responsive scaffold that facilitates long-range chromatin interactions, and in the second role, JMJD1A demethylates H3K9 di-methylation.

Comparison of three α-glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes.

AIMS/INTRODUCTION: α-Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes. MATERIALS AND METHODS: Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m(2)) were enrolled in this multicenter, open-label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low-density lipoprotein and high-density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks. RESULTS: In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups. CONCLUSIONS: αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).

Association of glycated albumin with the presence of carotid plaque in patients with type 2 diabetes.

AIMS/INTRODUCTION: Postprandial hyperglycemia is a potent risk factor for cardiovascular disease. Serum glycated albumin (GA) has been reported to reflect postprandial blood glucose fluctuations. In the present study, we assessed the possible correlation of GA with the presence of carotid plaque to evaluate the potential clinical usefulness of GA for predicting atherosclerotic cardiovascular complications in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes (n = 236) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control (aged 19-86 years, 81 females and 155 males) were examined. Clinical measurements were taken on admission. The presence of carotid plaque was assessed by ultrasonography. RESULTS: In patients with carotid plaque (n = 154), GA (P = 0.023) was higher than those without carotid plaque (n = 82). In contrast, neither fasting plasma glucose (P = 0.48) nor glycated hemoglobin (P = 0.41) was significantly different between the groups. The results of logistic regression analysis showed that GA (age- and sex-adjusted odds ratio [95% confidence interval], 1.05 [1.01-1.09]; P = 0.017) and glycated hemoglobin (1.17 [1.01-1.37]; P = 0.036) were significantly associated with the presence of carotid plaque. CONCLUSIONS: The positive correlation of serum GA with the presence of carotid plaque in type 2 diabetes suggests that GA will serve as a useful clinical marker for predicting diabetic cardiovascular complications.