Abstract. In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K + (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS. Key words: GPCR, Pancreatic β-cells, TRP channel, Insulin secretionTHE CONCEPT that glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is initiated by closure of the ATP-sensitive K + (KATP) channel as a result of an increase in the intracellular ATP/ADP ratio induced by glucose metabolism upon elevation of glucose concentration in the blood ( Fig. 1; the triggering pathway), was proposed a long time ago [1][2][3]. Inhibition of the KATP channel is followed by membrane depolarization and activation of voltage-dependent Ca 2+ channels (VDCCs) [4,5]. Opening of the VDCCs brings about firing of action potential, cytosolic Ca 2+ increase and initiation of GSIS [6,7]. The triggering pathway is followed by time-dependent increase in insulin secretion that is potentiated by glucose exposure (the second phase, potentiating pathway or KATP-independent pathway) [3,8] However, closure of the KATP channel alone is not sufficient to induce a shift in the membrane potential towards the threshold level and for the triggering pathway that can activate VDCCs, since membrane potential is theoretically determined by the overall balance of outward and inward currents. Modest background inward currents through opening of nonselective cation channels (NSCCs) are crucial for induction of membrane depolarization following KATP channel closure [9,10]. This idea further suggests that regulation of a class of NSCCs may play an important role in producing effective depolarization of the membrane. Several types of NSCCs have been reported to be expressed in pancreatic β-cells, which, in terms of ion selectivity, are permeable to Na + , K + , and Ca 2+ . In contrast to these ion channels, which have not been well studied, the classic-type ion channels; i.e., the voltage-dependent Na + channel, the voltage-dependent K + channel [11,12], the voltage-dependent Ca 2+ channel [13,14] and the KATP channel have attracted a large amount of interest for a long time, because the first three types of these ion channels play an important role in membrane excitability and the KATP

Aims/Introduction Studies have shown that sodium–glucose cotransporter 2 (SGLT2) inhibitors increased time‐in‐range (TIR; percentage of time glucose level remains between 3.9 and 10.0 mmol/L [70–180 mg/dL]) and decreased glycemic variability in patients with type 1 diabetes. The aim of this study was to investigate the effects of SGLT2 inhibitors on TIR, glycemic variability and glucose control in Japanese patients with type 1 diabetes in a real clinical setting. Materials and Methods We designed a single‐arm, retrospective cohort study to analyze data from patients starting to use ipragliflozin or dapagliflozin and who used a sensor‐based flash glucose monitoring system between February 2019 and August 2019. We measured TIR, time above range >180 mg/dL (percentage of time with glucose level of >180 mg/dL or >10.0 mmol/L), time below range <70 mg/dL (percentage of time with glucose level of <70 mg/dL or <3.9 mmol/L), mean glucose and standard deviation, and coefficient of variation for glycemic variability, and then compared the data before and after SGLT2 inhibitors treatments. Results We enrolled 15 patients in the study. The total dosages of basal insulin decreased significantly, but the total doses of bolus insulin did not change significantly. TIR increased significantly by approximately 11.6%; the time below range <70 mg/dL remained unchanged; and the mean glucose and standard deviation decreased significantly, whereas the coefficients of variation did not. Conclusions SGLT2 inhibitors improved TIR and the mean glucose level and standard deviation without increasing the time below range <70 mg/dL in patients with type 1 diabetes.

These findings indicated that serum CPP Fetuin-A were affected by food intake and may contribute to the pathophysiology of mineral metabolism in subjects with normal and moderately impaired renal function.

Aims/Introduction: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in b-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in b-cells. Materials and Methods: Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD + ) production in islets were measured under static incubation. NSCC currents in mouse single b-cells were measured by patch-clamp experiments. Results: Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD + , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in b-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. Conclusions: Imeglimin may activate TRPM2 channels in b-cells via the production of NAD + /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.

Introduction: Once-weekly (OW) glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide has been shown to have a more potent glycated hemoglobin (HbA1c)-lowering effect than other oral hypoglycemic agents and existing GLP-1RAs in global randomized controlled trials. The study aim was to evaluate the safety and effectiveness of OW semaglutide in Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify pre-and post-treatment predictors of good response. Methods: We investigated the change in HbA1c, percentage of patients achieving \ 7% HbA1c, and factors contributing to the effect 6 months after OW semaglutide use in Japanese patients with T2DM. We also examined differences in effectiveness between patients with different backgrounds. Results: At baseline, the 77 patients had a mean baseline HbA1c of 8.1% ± 1.23%, 74% of the patients were injecting another GLP-1RA, and 42.9% of the patients were being treated with insulin. HbA1c decreased by 0.89% and by 0.66% in the other GLP-1RA users. The rate of achievement of \ 7% HbA1c increased from 21% to 43%. There were no differences in effect by age, sex, or body mass index. Higher baseline HbA1c and shorter duration of diabetes were associated with greater HbA1c reduction. OW semaglutide was tolerable for the majority of our study population. Conclusion: This study provided real-world evidence showing that OW semaglutide significantly reduced HbA1c in Japanese patients with T2DM who had inadequate HbA1c control.

Urinary calcium excretion is not known to predict progression of renal dysfunction in patients with type 2 diabetes mellitus. This study aimed to investigate associations between urinary calcium excretion and progression of estimated glomerular filtration rate (eGFR) in type 2 diabetic patients. This study was a retrospective, single-center, observational cohort study. We enrolled a total of 89 patients with type 2 diabetes mellitus and the average follow-up period was 7.2 ± 1.0 years. We divided patients into two groups based on the median of annual decline in the slope of eGFR, then defined the over-median population as the progressed group and under-median population as the non-progressed group. Median of annual decline in the slope of eGFR was −1.1 mL/min/1.73 m2/year. Correlation coefficient analysis showed positive correlation of urinary calcium excretion with eGFR (r = 0.39, p < 0.001). Multivariate logistic analysis showed that baseline eGFR and urinary calcium excretion were independent variables for progression of eGFR decline. Urinary calcium excretion could be a useful metabolic parameter for predicting decline in slope of eGFR in patients with type 2 diabetes mellitus.

Background This study aimed to evaluate whether hypereosinophilia is a clinical biomarker of immune checkpoint inhibitor-induced hypopituitarism in patients with renal cell carcinoma treated with nivolumab plus ipilimumab. Methods This was a retrospective cohort study conducted at Jichi Medical University Saitama Medical Center between January 2018 and December 2020. In total, 12 patients with renal cell carcinoma who presented with immune checkpoint inhibitor-induced hypopituitarism were enrolled in this study. The clinical parameters and symptoms at baseline, last visit, and onset of hypopituitarism were analyzed. Results The median period from the initial treatment with immune checkpoint inhibitors to the onset of hypopituitarism was 82.5 (range: 56–196) days. Most patients developed hypopituitarism within 6 months. One patient presented with hypophysitis and 11 patients presented with isolated adrenocorticotropic hormone deficiency. The major symptoms noted at onset were fatigue (66.7%) and loss of appetite (41.7%). None of the patients had symptoms during the last visit. However, four developed hypereosinophilia. Eosinophil fraction (%) and eosinophil count (/µL) increased during the last visit and at the onset of hypopituitarism, respectively. The serum sodium and plasma glucose levels were similar. Conclusions The eosinophil count increased before the onset of hypopituitarism. Thus, hypereosinophilia can be an early predictor of hypopituitarism.

Background The aim of the study was to investigate risk factors of hypoglycemic encephalopathy (HE) in patients with severe hypoglycemia. Methods We retrospectively enrolled patients with severe hypoglycemia who were transported to the emergency department in an ambulance. We defined severe hypoglycemia as plasma glucose level < 60 mg/dL (or capillary levels < 50 mg/dL). HE was defined as severe hypoglycemia with altered level of consciousness (Glasgow coma scale < 12) and prolonged HE as coma or stupor lasting > 24 h after glucose administration. We compared several parameters between patients with and without HE and between prolonged and recovered patients. Results Included were 173 patients with severe hypoglycemia; of them, 94 were diagnosed with HE, with 12 of them prolonged HE. Glucose level in HE patients was lower than that in those without HE (P < 0.001). Moreover, we noted a significant difference in glucose levels between the prolonged and recovered groups. Furthermore, body temperature was higher in prolonged versus recovered patients (P = 0.0017). Conclusion Blood glucose level may be correlated with severity of altered level of consciousness. In addition, body temperature may be related to coma or prolonged stupor.