Pancreas transplantation and islet transplantation are now established in the treatment of IDDM. Several trials of stem cell‐derived cell transplantation therapy are underway and may offer an ...alternative to the limited supply of donor islets in the near future. This article summarizes recent developments in transplantation therapy for diabetes as well as research on the use of stem cells for complications of diabetes.
Abstract
Specifying the exact localization of insulinoma remains challenging due to the lack of insulinoma-specific imaging methods. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted ...imaging, especially positron emission tomography (PET), has emerged. Although various radiolabeled GLP-1R agonist exendin-4-based probes with chemical modifications for PET imaging have been investigated, an optimal candidate probe and its scanning protocol remain a necessity. Thus, we investigated the utility of a novel exendin-4-based probe conjugated with polyethylene glycol (PEG) for
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FFB(ePEG12)12-exendin-4 PET imaging for insulinoma detection. We utilized
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FFB(ePEG12)12-exendin-4 PET/CT to visualize mouse tumor models, which were generated using rat insulinoma cell xenografts. The probe demonstrated high uptake value on the tumor as 37.1 ± 0.4%ID/g, with rapid kidney clearance. Additionally, we used
Pdx1-Cre;Trp53
R172H
;Rb
f/f
mice, which developed endogenous insulinoma and glucagonoma, since they enabled differential imaging evaluation of our probe in functional pancreatic neuroendocrine neoplasms. In this model, our
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FFB(ePEG12)12-exendin-4 PET/CT yielded favorable sensitivity and specificity for insulinoma detection. Sensitivity: 30-min post-injection 66.7%, 60-min post-injection 83.3%, combined 100% and specificity: 30-min post-injection 100%, 60-min post-injection 100%, combined 100%, which was corroborated by the results of in vitro time-based analysis of internalized probe accumulation. Accordingly,
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FFB(ePEG12)12-exendin-4 is a promising PET imaging probe for visualizing insulinoma.
Aims/Introduction
To investigate the long‐term efficacy and safety of islet transplantation (ITx) compared with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII).
...Materials and Methods
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.
This study focuses on the efficacy, possible adverse events and effects on major organ function of islet transplantation during 10‐year follow up, in comparison with conventional insulin therapy. Islet transplantation achieved an improvement in glycemic control corresponding to graft function and a tendency to reduction of severe hypoglycemia, with tolerable, but attention‐requiring, risks, such as transient elevation of transaminase, infectious disease, digestive symptoms and malignancy, and with no mortality.
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.
ABSTRACT
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.
There has not been a detailed case study of the association between islet transplantation (ITx) and insulin antibody (IA) levels. Here we identified a unique profile of IA titers, which differed from glutamic acid decarboxylase antibody (GADA) titers, in four ITx patients. IA levels decreased with intensified immunosuppressive therapy, while GADAs increased transiently after ITx. The unique feature is suggestive of immunological pathogenesis and has implications for the treatment of IA‐causing disease conditions.
Bariatric surgery has been shown to have a variety of metabolically beneficial effects for patients with type 2 diabetes (T2D), and is now also called metabolic surgery. At the 2nd Diabetes Surgery ...Summit held in 2015 in London, the indication for bariatric and metabolic surgery was included in the “algorithm for patients with type T2D”. With this background, the Japanese Society for Treatment of Obesity (JSTO), the Japan Diabetes Society (JDS) and the Japan Society for the Study of Obesity (JASSO) have formed a joint committee to develop a consensus statement regarding bariatric and metabolic surgery for the treatment of Japanese patients with T2D. Eventually, the consensus statement was announced at the joint meeting of the 38th Annual Meeting of JSTO and the 41st Annual Meeting of JASSO convened in Toyama on March 21, 2021. In preparing the consensus statement, we used Japanese data as much as possible as scientific evidence to consider the indication criteria, and set two types of recommendation grades, “recommendation” and “consideration”, for items for which recommendations are possible. We hope that this statement will be helpful in providing evidence-based high-quality care through bariatric and metabolic surgery for the treatment of obese Japanese patients with T2D.
Abstract
Background
Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This ...disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology.
Methods
We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists.
Results
There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted.
Conclusions
Low circularity, which indicates an irregular islet shape, referred to as “irregular shape and occasional enlargement of islets” and “lobulated islet structure” in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to “macronucleoli in β-cells,“ has potential diagnostic value.
It is crucial to develop practical and noninvasive methods to assess the functional beta-cell mass in a donor pancreas, in which monitoring and precise evaluation is challenging. A patient with type ...1 diabetes underwent noninvasive imaging following simultaneous kidney-pancreas transplantation with positron emission tomography/computed tomography (PET/CT) using an exendin-based probe,
FFB(ePEG12)12-exendin-4. Following transplantation, PET imaging with
FFB(ePEG12)12-exendin-4 revealed simultaneous and distinct accumulations in the donor and native pancreases. The pancreases were outlined at a reasonable distance from the surrounding organs using
FFB(ePEG12)12-exendin-4 whole-body maximum intensity projection and axial PET images. At 1 and 2 h after
FFB(ePEG12)12-exendin-4 administration, the mean standardized uptake values were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas.
FFB(ePEG12)12-exendin-4 positron emission tomography imaging allowed repeatable and quantitative assessment of beta-cell mass following simultaneous kidney-pancreas transplantation.
Extraembryonic endoderm (ExE) is differentiated from the inner cell mass of the late blastocyst-stage embryo to form visceral and parietal endoderm, both of which have an important role in early ...embryogenesis. The essential roles of Gata-6 and Gata-4 on differentiation of visceral endoderm have been identified by analyses of knockout mice. Here we report that forced expression of either Gata-6 or Gata-4 in embryonic stem (ES) cells is sufficient to induce the proper differentiation program towards ExE. We believe that this is the first report of a physiological differentiation event induced by the ectopic expression of a transcription factor in ES cells.
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.
Our study shows that intermittently scanned continuous glucose monitoring can be useful for monitoring the reduction of glycemic variability after islet transplantation, and suggests the appropriate regulation of insulin secretion from graft islets during mixed‐meal test by using different doses of exogenous insulin administration. During the 2‐year observation period, glucagon elevation was detected only at hypoglycemia, whereas the level was within the normal range at normoglycemia or hyperglycemia.
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