Long-term outcome of islet transplantation on insulin-dependent diabetes mellitus: An observational cohort study

Aims/Introduction: Among 619 patients diagnosed as insulin‐dependent diabetes mellitus or type 1 diabetes at Kyoto University, Kyoto, Japan, seven patients were selected as the ITx group and 26 age‐matched patients with no endogenous insulin secretion were selected as the MDI/CSII group. Hemoglobin A1c, aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine were assessed retrospectively at 1, 2, 5 and 10 years for both groups; serum C‐peptide immunoreactivity was assessed for the ITx group. Major clinical events were also assessed. Results: Hemoglobin A1c improvement in ITx was significant at 1 year (8.4% [7.8–9.9%] at baseline to 7.1% [6.3–7.4%] in ITx vs 8.2% [7.4–9.8%] at baseline to 8.1% [7.3–9.5%] in MDI/CSII, P < 0.01 between groups), and was maintained at 2 years (7.4% [6.3–8.2%] vs 8.4% [7.4–9.6%], P = 0.11). The increase of stimulated C‐peptide immunoreactivity was significant at 1 year (0.57 ng/mL [0.26–0.99 ng/mL], P < 0.05 from baseline) and 2 years (0.43 ng/mL [0.19–0.67 ng/mL], P < 0.05), although it became insignificant thereafter. There was no significant difference in AST/ALT or creatinine at 10 years, although a transient AST/ALT elevation was observed in ITx. In regard to clinical events, the occurrence of severe hypoglycemia was 14% vs 31% (relative risk 0.46, P = 0.64), that of infectious disease was 43% vs 12% (relative risk 3.71, P = 0.09) and digestive symptoms was 43% vs 7.7% (relative risk 5.57, P = 0.05) in ITx vs MDI/CSII, respectively. No patient died in either group. Conclusions: The present findings showed that ITx was considered to contribute to the reduction of hypoglycemia and better glycemic control with tolerable, but attention‐requiring, risks over a period of 10 years compared with MDI/CSII

A unique profile of insulin antibody titer in islet‐transplanted patients

Insulin antibodies (IAs) can cause glycemic variability. Islet transplantation (ITx) is a treatment for insulin-deficient diabetes that aims to establish on-target glycemic control in the absence of hypoglycemia. To date, there has not been a detailed case study of the association between ITx and IA levels. In this study, we identified a unique profile of IA titers, which differed from glutamic acid decarboxylase antibody titers, in four ITx patients. IA levels decreased with intensified immunosuppressive therapy, whereas glutamic acid decarboxylase antibodies increased transiently after ITx. These data suggest the possibility that IAs, unlike other islet autoantibodies, were eliminated due to immunosuppression after transplantation therapy. The disappearance of IAs, as well as the restoration of regulated insulin secretion after ITx, might have a positive effect on glycemic control in recipients with diabetes. Furthermore, this unique feature is suggestive of immunological pathogenesis and has implications for the treatment of IA-causing disease conditions

Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic β cells: a simulation study

To clarify the mechanisms underlying the pancreatic β-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca2+ dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst–interburst electrical events accompanied by Ca2+ transients, and continuous firing of action potentials over [G] ranges of 0–6, 7–18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca2+ transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst–interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate–sensitive K+ current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca2+- or Na+-dependent currents, which were generated by the plasma membrane Ca2+ pump, Na+/K+ pump, Na+/Ca2+ exchanger, and TRPM channel. Accumulation and release of Ca2+ by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings

Reduced glycemic variability and flexible graft function after islet transplantation: A case report

To date, studies of patients with islet transplantation addressing intermittently scanned continuous glucose monitoring profile and the flexibility of the graft islet function under different doses of insulin administration, both of which reflect the real daily life of patients, are quite limited. Here, we report a case of a 46‐year‐old woman who received islet transplantation after kidney transplantation. The patient was followed up over a period of 2 years after initial islet transplantation. Our results show that intermittently scanned continuous glucose monitoring can be useful for monitoring the reduction of glycemic variability, and suggest the appropriate regulation of insulin secretion from graft islets during mixed‐meal test by using different doses of exogenous insulin administration. Additionally, during the 2‐year observational period, glucagon elevation was detected only at hypoglycemia, whereas the level was within the normal range at normoglycemia or hyperglycemia

Pulmonary Tumor Thrombotic Microangiopathy Induced by Prostate Cancer

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal, malignancy-related respiratory complication; we herein report a PTTM case induced by metastatic prostate cancer. An 81-year-old Japanese man developed dyspnea. High-resolution computed tomography (HRCT) revealed ground-glass opacities spread across bilateral lung fields. Pulmonary microvascular aspiration cytology detected prostate cancer cells. As PTTM was highly suspected, docetaxel chemotherapy was performed immediately. His respiratory condition and HRCT findings improved temporarily, but he died approx. 6 weeks after admission. Autopsy showed fibrocellular intimal proliferation of small pulmonary arterioles, which confirmed the diagnosis of PTTM induced by prostate cancer. As in the present case, it is often difficult to confirm the presence of not only tumor embolization but also fibrocellular intimal proliferation before the patient’s death

A case of sarcoidosis associated with chronic eosinophilic pneumonia

A 38-year-old man was hospitalized in our university hospital because of pulmonary opacities with bilateral hilar and mediastinal lymphadenopathy seen on chest radiograph. Eosinophilia was observed in the circulation and bronchoalveolar lavage (BAL) fluid. Histological examination revealed noncaseating epithelioid granulomas and eosinophilic infiltration in the lung. Based on these findings, a diagnosis of sarcoidosis combined with chronic eosinophilic pneumonia was made. The infiltrates on chest radiograph and BAL eosinophilia were promptly reduced with corticosteroid therapy, but only mild reduction was observed in diffuse nodular shadows and hilar and mediastinal lymphadenopathy, and high amounts of lymphocytes in BAL fluid remained. Increased IFN-γ, IL-4 and IL-5 were detected in the BAL fluid, and corticosteroid therapy reduced IL-4 and IL-5 (Th-2 cytokines) but not IFN-γ(Th-1 cytokine). These cytokine levels in BAL fluid were intimately correlated with the clinical course of sarcoidosis and chronic eosinophilic pneumonia

Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model

ヒトiPS細胞分化モデルを用いた膵内胚葉分化におけるHHEXの役割の解明. 京都大学プレスリリース. 2023-06-09.Identification of HHEX as a crucial factor in pancreatic endoderm differentiation using a human iPS cell differentiation model. 京都大学プレスリリース. 2023-06-15.For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreatic endoderm differentiation by searching for factors that regulate a crucial pancreatic endoderm marker gene, NKX6.1. Unbiasedly screening an siRNA knockdown library, we identified a candidate transcription factor, HHEX. HHEX knockdown suppressed the expression of another pancreatic endoderm marker gene, PTF1A, as well as NKX6.1, independently of PDX1, a known regulator of NKX6.1 expression. In contrast, the overexpression of HHEX upregulated the expressions of NKX6.1 and PTF1A. RNA-seq analysis showed decreased expressions of several genes related to pancreatic development, such as NKX6.1, PTF1A, ONECUT1 and ONECUT3, in HHEX knockdown pancreatic endoderm. These results suggest that HHEX plays a key role in pancreatic endoderm differentiation

Plasma pharmacokinetics after combined therapy of gemcitabine and oral S-1 for unresectable pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The combination of gemcitabine (GEM) and S-1, an oral 5-fluorouracil (5-FU) derivative, has been shown to be a promising regimen for patients with unresectable pancreatic cancer.</p> <p>Methods</p> <p>Six patients with advanced pancreatic cancer were enrolled in this pharmacokinetics (PK) study. These patients were treated by oral administration of S-1 30 mg/m²twice daily for 28 consecutive days, followed by a 14-day rest period and intravenous administration of GEM 800 mg/m²on days 1, 15 and 29 of each course. The PK parameters of GEM and/or 5-FU after GEM single-administration, S-1 single-administration, and co-administration of GEM with pre-administration of S-1 at 2-h intervals were analyzed.</p> <p>Results</p> <p>The maximum concentration (Cmax), the area under the curve from the drug administration to the infinite time (AUCinf), and the elimination half-life (T1/2) of GEM were not significantly different between GEM administration with and without S-1. The Cmax, AUCinf, T1/2, and the time required to reach Cmax (Tmax) were not significantly different between S-1 administration with and without GEM.</p> <p>Conclusion</p> <p>There were no interactions between GEM and S-1 regarding plasma PK of GEM and 5-FU.</p

Antiferromagnetic Zigzag Spin Chain in Magnetic Fields at Finite Temperatures

We study thermodynamic behaviors of the antiferromagnetic zigzag spin chain in magnetic fields, using the density-matrix renormalization group method for the quantum transfer matrix. We focus on the thermodynamics of the system near the critical fields in the ground-state magnetization process($M$-$H$ curve): the saturation field, the lower critical field associated with excitation gap, and the field at the middle-field cusp singularity. We calculate magnetization, susceptibility and specific heat of the zigzag chain in magnetic fields at finite temperatures, and then discuss how the calculated quantities reflect the low-lying excitations of the system related with the critical behaviors in the $M$-$H$ curve.Comment: accepted for publication in Physical Review