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Aims/hypothesisObesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa–Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.MethodsFood intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.ResultsON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.Conclusions/interpretationThe results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p  < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.

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.

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.

A number of epidemiological studies demonstrated that postprandial hyperglycemia is a risk factor for cardiovascular disease in individuals with impaired glucose tolerance. Although several laboratory studies have addressed the plausible causal role of postprandial acute hyperglycemia (glucose spikes) in the development of atherosclerosis, there is little convincing evidence in vivo whether the atherosclerotic lesion formation can be accelerated solely by glucose spikes. Here, we assessed the effect of repetitive glucose spikes on atherosclerotic lesion formation in mice. Female C57BL/6 mice were fed an atherogenic diet from 8 to 28 weeks of age. During the atherogenic diet feeding period, the mice orally received a glucose solution (50 mg glucose/mouse; G group) or water (W group) twice daily, 6 days a week. Atherosclerotic lesion formation in the aortic sinus was quantitatively analyzed in serial cross-sections by oil red O staining. G group mice showed transient increases in blood glucose level (~5 mmol/L above W group), and the levels returned to levels similar to those in W group mice within 60 min. No significant differences in glucose tolerance, insulin sensitivity, and plasma lipid profiles were observed after the 20-week repetitive administration between the 2 groups. G group mice showed an approximately 4-fold greater atherosclerotic lesion size in the aortic sinus than W group mice. Gene expression levels of Cd68 and Icam1 in the thoracic aorta were higher in G group mice than in W group mice. These results indicate that glucose spikes can accelerate atherosclerotic lesion formation, with little influence on other metabolic disorders. Repetitive glucose administration in wild-type mice may serve as a simple and useful approach to better understanding the causal role of glycemic spikes in the development of atherosclerosis.

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.

Background: The impact of Graves’ hyperthyroidism treatment on lipid metabolism remains unclear. This prospective observational study aimed to clarify the changes in lipid profiles and associated metabolic pathways, including cholesterol synthesis, absorption, and low-density lipoprotein (LDL) receptor regulation, following treatment. Methods: Seventeen patients newly diagnosed with Graves’ hyperthyroidism were enrolled and followed for 6 months after achieving euthyroid status. Serum lipids (total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides), apolipoproteins, non-cholesterol sterols (markers of cholesterol synthesis and absorption), proprotein convertase subtilisin/kexin type 9 (PCSK9), and lipoprotein lipase (LPL) levels were measured at baseline, at euthyroid status (Eu-0M), and 6 months after euthyroid status (Eu-6M). Results: After treatment, serum total cholesterol, LDL-C, and HDL-C levels increased rapidly compared to baseline, while triglyceride levels showed a delayed but significant increase at Eu-6M. Levels of apolipoprotein (apo) AI, AII, B, and CIII increased significantly after treatment, whereas apo B-48 increased only at Eu-6M, and apo CII and apo E remained unchanged. Markers of cholesterol synthesis (lathosterol) and absorption (sitosterol, campesterol, and cholestanol) increased significantly after treatment, indicating enhanced cholesterol metabolism. Circulating PCSK9 levels increased significantly and remained elevated, while LPL levels did not change significantly. Conclusion: Treatment of Graves’ hyperthyroidism rapidly increases cholesterol levels through enhanced cholesterol synthesis and absorption, possibly mediated by increased circulating PCSK9.

Aims/Introduction An increased risk of diabetes mellitus has been reported in primary aldosteronism, but the pathogenesis of glucose intolerance between the primary aldosteronism subtypes remains unclear. This study aimed to evaluate glucose metabolism in oral glucose tolerance test between aldosterone‐producing adenoma and idiopathic hyperaldosteronism, and characterize patients with improved glucose intolerance after primary aldosteronism treatment. Materials and Methods Oral glucose tolerance test was carried out in 116 patients who were diagnosed with primary aldosteronism and received adrenal venous sampling for subtyping. Oral glucose tolerance test was re‐evaluated after starting the treatment of primary aldosteronism for those who had glucose intolerance before the treatment. Results A total of 46.4% and 52.3% of patients with aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively, were diagnosed with impaired glucose tolerance or diabetes. The insulinogenic index was significantly lower in aldosterone‐producing adenoma than in idiopathic hyperaldosteronism (P = 0.045), whereas the Matsuda insulin sensitivity index was significantly higher in aldosterone‐producing adenoma than in idiopathic hyperaldosteronism (P = 0.022). After the treatment of primary aldosteronism, glucose intolerance was improved in 66.6% and 45.8% of aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. The presence of obesity and central obesity were significantly lower in patients who improved glucose intolerance after the treatment of primary aldosteronism as compared with those not improved (P = 0.013 and P = 0.033, respectively). Conclusions Insulin secretion impairment and insulin resistance play pathogenic roles for glucose intolerance in aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. In addition, primary aldosteronism treatments can ameliorate glucose intolerance more effectively in patients without obesity and/or central obesity. Insulin secretion impairment and insulin resistance play pathogenic roles for glucose intolerance in aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. Primary aldosteronism treatments can ameliorate glucose intolerance more effectively in idiopathic hyperaldosteronism patients without obesity.

Aims/Introduction A prolonged QT interval plays a causal role in life‐threatening arrhythmia, and becomes a risk factor for sudden cardiac death. Here, we assessed the association between microvascular complications and the QT interval in patients with type 2 diabetes. Materials and Methods Patients with type 2 diabetes (n = 219) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control were enrolled. QT interval was measured manually in lead II on the electrocardiogram, and corrected for heart rate using Bazett's formula (QTc). Diabetic neuropathy, retinopathy and nephropathy were assessed by neuropathic symptoms or Achilles tendon reflex, ophthalmoscopy and urinary albumin excretion, respectively. Results In univariate analyses, female sex (P = 0.025), duration of type 2 diabetes (P = 0.041), body mass index (P = 0.0008), systolic blood pressure (P = 0.0011) and receiving insulin therapy (P < 0.0001) were positively associated with QTc. Patients with each of the three microvascular complications had longer QTc than those without: neuropathy (P = 0.0005), retinopathy (P = 0.0019) and nephropathy (P = 0.0001). As retinopathy or nephropathy progressed, QTc became longer (P < 0.001 and P < 0.001 for trend in retinopathy and nephropathy, respectively). Furthermore, QTc was prolonged with the multiplicity of the microvascular complications (P < 0.001 for trend). Multiple regression analyses showed that neuropathy, nephropathy and the multiplicity of the microvascular complications were independently associated with QTc. Conclusions Patients with type 2 diabetes with severe microvascular complications might be at high risk for life‐threatening arrhythmia associated with QT interval prolongation. The severity and multiplicity of microvascular complications are associated with QT interval prolongation in patients with type 2 diabetes. Neuropathy, nephropathy, and the multiplicity of microvascular complications are independently associated with the QT interval. Patients with type 2 diabetes with severe microvascular complications may be at high risk for life‐threatening arrhythmia associated with QT interval prolongation.

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1–6.7 kPa) (p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.