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The hypothalamus is a center of food intake and energy metabolism regulation. Information signals from peripheral organs are mediated through the circulation or the vagal afferent pathway and input into the hypothalamus, where signals are integrated to determine various behaviors, such as eating. Numerous appetite‐regulating peptides are expressed in the central nervous system and the peripheral organs, and interact in a complex manner. Of such peptides, gut peptides are known to bind to receptors at the vagal afferent pathway terminal that extend into the mucosal layer of the digestive tract, modulate the electrical activity of the vagus nerve, and subsequently send signals to the solitary nucleus and furthermore to the hypothalamus. All peripheral peptides other than ghrelin suppress appetite, and they synergistically suppress appetite through the vagus nerve. In contrast, the appetite‐enhancing peptide, ghrelin, antagonizes the actions of appetite‐suppressing peptides through the vagus nerve, and appetite‐suppressing peptides have attenuated effects in obesity as a result of inflammation in the vagus nerve. With greater understanding of the mechanism for food intake and energy metabolism regulation, medications that apply the effects of appetite‐regulating peptides or implantable devices that electrically stimulate the vagus nerve are being investigated as novel treatments for obesity in basic and clinical studies. The hypothalamus is a center of food intake. Numerous appetite‐regulating peptides are expressed in the central nervous system and the peripheral organs and interact in a complex manner. The appetite‐enhancing peptide ghrelin antagonizes the actions of appetite‐suppressing peptides via the vagus nerve, and appetite‐suppressing peptides have attenuated effects in obesity due to inflammation in the vagus nerve.

Liver-expressed antimicrobial peptide 2 (LEAP2) is a peptide that counteracts the hunger hormone ghrelin-induced functions. Recently, we showed that vertical sleeve gastrectomy (VSG) did not alter the serum LEAP2 concentration in individuals with obesity. Here, we investigated the effects of VSG in both chow diet (CD)-fed and high-fat diet (HFD)-fed mice. In CD-fed mice, VSG increased plasma LEAP2 levels and hepatic Leap2 mRNA levels while decreasing body weight, blood glucose levels, and ghrelin levels. Intraperitoneal (ip) administration of ghrelin reversed these changes. These effects were found in both male and female mice. In contrast, VSG or weight loss in HFD-induced obese mice decreased LEAP2 levels. After fasting, the plasma LEAP2 concentration was in the following order: hepatic vein > abdominal aorta > portal vein. A high glucose concentration robustly increased the plasma LEAP2 concentration in the hepatic vein and abdominal aorta but not in the portal vein. In addition, corn oil or palmitate increased LEAP2 expression and secretion. The increase in LEAP2 levels after the meal tolerance test was delayed in the human subjects with diabetes. Our data suggest that various factors (metabolic, hormonal, and nutritional) regulate LEAP2, and the liver is the predominant site for the production and secretion of LEAP2. Furthermore, the interaction between ghrelin and LEAP2 is involved in the pathogenesis of obesity and diabetes.

Background/Objectives: While sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated additional non-glycemic benefits for renal protection in individuals with type 2 diabetes, less evidence is available for those with type 1 diabetes (T1D). To determine whether the adjunctive use of the SGLT2 inhibitor ipragliflozin confers kidney protection in individuals with T1D, we retrospectively analyzed data from a real-world cohort examined at 25 centers in Japan. Methods: We enrolled 359 subjects aged 20–74 years with T1D (IPRA group: 159 ipragliflozin users; control [CTRL] group: 200 non-users). The primary outcome was changes in the estimated glomerular filtration rate (eGFR) from baseline to 24 months after the initiation of ipragliflozin. The secondary outcomes were all other changes, including the urinary albumin–creatinine ratio (UACR) and urinary protein–creatinine ratio (UPCR). Results: The IPRA group’s eGFR decline slopes were 0.79 mL/min/1.73 m2/year milder than the CTRL group’s after propensity score matching, but this difference was not significant. The subjects complicated by chronic kidney disease (CKD) defined as UACR ≥ 30 mg/g and/or UPCR ≥ 0.5 g/g and/or eGFR < 60 mL/min/1.73 m2 showed changes in UPCR (g/g) from baseline to 24 months that were significantly lower in the IPRA group (−0.27 ± 1.63) versus the CTRL group (0.18 ± 0.36) (p = 0.016). No significant increase in adverse events (including severe hypoglycemia and hospitalization due to ketosis/ketoacidosis or cardiovascular diseases) was observed in the IPRA group. Conclusions: Adjunctive treatment with ipragliflozin exerted potential renal benefits by decreasing proteinuria in T1D subjects with CKD. Further investigations are required to determine whether its additional benefits exceed the increased risk of ketoacidosis.

Introduction Endothelial dysfunction is a risk factor for cardiovascular disease in patients with diabetes. We hypothesized that imeglimin, a novel oral hypoglycemic agent, would improve endothelial function. Methods In this study, imeglimin was administered to patients with type 2 diabetes and HbA1c ≥ 6.5% who were not receiving insulin therapy. A meal tolerance test (592 kcal, glucose 75.0 g, fat 28.5 g) was performed before and 3 months after administration, and endothelial function, blood glucose, insulin, glucagon, and triglycerides were evaluated. Endothelial function was assessed by flow-mediated dilation (FMD). Results Twelve patients (50% male) with a median age of 55.5 years old (interquartile range [IQR] 51.3–66.0) were enrolled. Fasting FMD did not differ before or 3 months after imeglimin administration (from 6.1 [3.9–8.5] to 6.6 [3.9–9.0], p  = 0.092), but 2 h postprandial FMD was significantly improved 3 months after imeglimin administration (from 2.3 [1.9–3.4] to 2.9 [2.4–4.7], p  = 0.013). In terms of the glucose profile, imeglimin administration significantly improved HbA1c (from 7.2 ± 0.6% to 6.9 ± 0.6%, p  = 0.007), fasting glucose (from 138 ± 19 mg/dL to 128 ± 20 mg/dL, p  = 0.020), and 2 h postprandial glucose (from 251 ± 47 mg/dL to 215 ± 68 mg/dL, p  = 0.035). The change in 2 h postprandial FMD between before and 3 months after imeglimin administration (Δ2 h postprandial FMD) was negatively correlated with Δ2 h postprandial glucose ( r  = − 0.653, p  = 0.021) in a univariate correlation coefficient analysis. Both patients with and without decreased postprandial glucose 3 months after imeglimin administration had improved postprandial FMD. Conclusion In this small study, imeglimin administration improved 2 h postprandial FMD. Both glycemic control-dependent and -independent mechanisms might contribute to improved endothelial function. Trial Registration This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000046311).

Aims/Introduction The Japanese diabetes treatment guidelines do not specify the first choice of hypoglycemic agents, unlike those of Western countries. Furthermore, the current situation in diabetes treatment is that the choice of hypoglycemic agents is determined by each physician. Therefore, we aimed to determine the current situation in Miyazaki Prefecture, Japan, in this context. For this, we carried out a questionnaire survey among physicians twice regarding the target value of glycated hemoglobin and the choice of hypoglycemic agents in various cases. Materials and Methods We administered an unsigned questionnaire to physicians in Miyazaki Prefecture, Japan, in July 2016 and March 2020. We divided responses into those of diabetologists and those of non‐diabetologists, and analyzed each response. We then compared the results between both years. Results In total, 18 diabetologists and 142 non‐diabetologists responded in 2016, and 21 diabetologists and 134 non‐diabetologists responded in 2020. Many diabetologists chose biguanide as the first‐line drug for obese type 2 diabetes patients. In addition, the rate of choice of sodium–glucose cotransporter 2 inhibitor (SGLT2i) among physicians almost increased in 2020. Some non‐diabetologists, and even a few diabetologists, inappropriately chose SGLT2i and biguanide for patients with severe renal dysfunction. Conclusions Because SGLT2i became available in 2016 and a few years have passed, both diabetologists and non‐diabetologists seemed to refrain from prescribing SGLT2i. However, with the emergence of various lines of firm evidence regarding the use of SGLT2i, physicians started to prescribe it. However, some diabetologists and non‐diabetologists chose hypoglycemic agents inadequately; therefore, there is a need for novel and precise information. We carried out a questionnaire survey among physicians twice regarding the target value of glycated hemoglobin and the choice of hypoglycemic agents in various cases, and divided the responses into those of diabetologists and those of non‐diabetologists. We analyzed each response and compared the results between both years.

Background Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. Methods To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. Results We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p  < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p  < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. Conclusions The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.

In terms of cardiac indices of atherosclerosis, Nishikawa and colleagues suggested that we not only focus on the cardio–ankle vascular index (CAVI) and the ankle–brachial index (ABI), but also on the systolic time interval (STI). [...]we used the CAVI and ABI data to perform an additional analysis of the STI, calculated as the ratio of the pre-ejection period to the left ventricular ejection time. The results of that analysis showed that the STI did not differ significantly before and 3 months after imeglimin administration (median 0.30, interquartile range [IQR] 0.27–0.35 and median 0.33, IQR 0.31–0.36, respectively; p = 0.266); however, our patient population was small and there may have been too few participants to enable an adequate evaluation of the STI. The research was registered in the University Hospital Medical Information Network (UMIN:

Glucagon‐like peptide‐1 (GLP‐1), a 30‐amino acid peptide processed from proglucagon protein by prohormone convertase 1/3, plays important roles in glucose and energy metabolism, including glucose‐stimulated insulin secretion, inhibition of glucagon secretion and gut motility, and reduction of appetite. [...]insulin secretion is generally increased by obesity, thus hyperinsulinemia cannot be explained only by ghrelin's enhancing effect on GLP‐1 secretion. Because the dose of ghrelin used in the report nu Gagnon et al. was pharmacological, it is uncertain whether physiological differences in plasma ghrelin levels influence human postprandial GLP‐1 secretion in individuals with obesity or diabetes, or who are in the postprandial state. [...]administration of ghrelin or growth hormone secretagogues under fasting conditions will increase appetite. [...]both therapies might be less than ideal for the treatment of type 2 diabetes in patients who are obese.

Aim Education on insulin self-injection techniques is important for good glycemic control, but its effectiveness in some elderly patients is limited due to loss of cognitive function and impaired activities of daily living. We hypothesized that classification using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) would help identify elderly patients with diabetes who effectively learn self-injection techniques. Methods Diabetes patients aged ≥ 65 years who used a self-injection insulin pen were administered the DASC-8 and a questionnaire to evaluate insulin self-injection techniques, and then received technical education. The questionnaire was administered again 4 months later, and patients were classified into the education-effective and education-ineffective groups. The achievement of HbA1c targets defined for each patient according to guidelines based on DASC-8 category was examined over 12 months. Results 76 Japanese patients (median age 72.0 years and 53.9% female) with DASC-8 categories I (n = 55), II (n = 13), and III (n = 8) were enrolled. In the education-effective group, the percentage of patients in category I was significantly higher than that of patients in category II or III (92.0% to 23.8%, P < 0.001). Category I was independently associated with education effectiveness (odds ratio 14.50, 95% confidence interval: 2.110–100.0, P = 0.007). Category I patients in the education-effective group showed significantly improved achievement of target HbA1c from baseline to the 12th month (from 27.6% to 62.1%, P = 0.008). Conclusions The DASC-8 was a useful indicator for identifying elderly patients who would benefit from education on self-injection techniques.

Although cAMP is well known to regulate exocytosis in many secretory cells, its direct target in the exocytotic machinery is not known. Here we show that cAMP-GEFII, a cAMP sensor, binds to Rim (Rab3-interacting molecule, Rab3 being a small G protein) and to a new isoform, Rim2, both of which are putative regulators of fusion of vesicles to the plasma membrane. We also show that cAMP-GEFII, through its interaction with Rim2, mediates cAMP-induced, Ca 2+ -dependent secretion that is not blocked by an inhibitor of cAMP-dependent protein kinase (PKA). Accordingly, cAMP-GEFII is a direct target of cAMP in regulated exocytosis and is responsible for cAMP-dependent, PKA-independent exocytosis.