Autologous intraarterial pancreatic bone-marrow mononuclear cells infusion in T2D patients: Changes on beta-cells function, insulin resistance, and inflammatory marker.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease. Many drugs currently being used for the management of T2D have minimal effect on pancreatic beta cells regeneration. Cell-based therapies might provide potential benefits in this aspect. METHODS: A pilot study in five T2D patients with 12 months follow-up was performed to evaluate the effect of autologous bone marrow mononuclear stem cells (BM-MNCs) infusion into pancreatic arteries on the insulin requirement, beta-cell function, insulin resistance, and systemic inflammatory marker (CRP). RESULTS: The primary endpoint, a 50 % reduction of total insulin doses from baseline, was not achieved in this study. However, a trend of increasing fasting C-peptide (p = 0.07) and C-peptide 60' (p = 0.07) and 90' (p = 0.07) after a mixed-meal tolerance test was observed 12 months post-infusion compared to baseline levels. A similar result was observed for the homeostatic model assessment of beta cell function (HOMA1-B), an index for beta cell function. No improvement was observed for insulin resistance measured by homeostasis model assessment of insulin resistance (HOMA1-IR) and systemic inflammatory parameter. CONCLUSION: Intraarterial pancreatic autologous BM-MNCs infusion might potentially improve beta cell function in T2D patients, although further study is needed to confirm this finding.

Relationship Between Remnant Pancreatic Volume and Endocrine Function After Pancreaticoduodenectomy.

BACKGROUND: Decreased pancreatic volume (PV) is a predictive factor for diabetes mellitus (DM) after surgery. There are few reports on PV and endocrine function pre- and post-surgery. We investigated the correlation between PV and insulin secretion. METHODS: Seventeen patients underwent pancreaticoduodenectomy (PD) Pre- and post-surgery PV and C-peptide index (CPI) measurements were performed. Additionally, the correlation between PV and CPI was analyzed. RESULTS: The mean preoperative PV (PPV) was 55.1 ± 31.6 mL, postoperative remnant PV (RPV) was 25.3±17.3 mL, and PV reduction was 53%. The mean preoperative C-peptide immunoreactivity (CPR) was 1.39 ± .51 and postoperative CPR was .85±.51. The mean preoperative CPI was 1.29±.72 and postoperative CPI was .73 ± .48. Significant correlations were observed between RPV and post CPR (ρ = .507, P = .03) and post CPI (ρ = .619, P = .008). DISCUSSION: There was a significant correlation between RPV and CPI after PD. A smaller RPV resulted in lower insulin secretion ability, increasing the potential risk of new-onset DM after PD.

Análisis comparativo de respuesta glicémica y de péptido C, tras la ingesta de estevia y D-tagatosa, según habitualidad de consumo de edulcorantes no nutritivos y preferencias alimentarias reportadas por mujeres con resistencia a la insulina / Comparative analysis of glicemic response and c peptide, after comsumption of stevia and d tagatosa, according to regular compsumtion of not nutritive sweeteners andnourish preferences reported by woman with insuline resistance

INTRODUCCIÓN: El consumo de edulcorantes no nutritivos (ENN) ha ido en aumento. A pesar de ello, se desconoce el efecto entre el consumo habitual de ENN y las preferencias alimentarias con parámetros bioquímicos en pacientes con resistencia a la insulina. OBJETIVO: Comparar la respuesta glicémica y de péptido C, según habitualidad de consumo de edulcorantes y preferencias alimentarias reportados por mujeres con resistencia a la insulina tras la ingesta de estevia y D-tagatosa. MÉTODOS: Treinta y tres mujeres con RI se sometieron a una encuesta de opción múltiple sobre preferencias alimentarias y ETCC modificada de edulcorantes. Aleatoriamente recibieron una precarga de control o experimental (estevia y D-tagatosa) donde se midió glicemia y péptido C en los tiempos -10, 30, 60, 90, 120, 180. RESULTADOS: Se encontró un ABC de péptido C más alto después de la ingesta de D-tagatosa (p = 0,02) en pacientes que prefieren alimentos ricos en proteínas en comparación con aquellos que prefieren alimentos ricos en grasas o en carbohidratos simples. Se observó un mayor ABC de péptido C (p = 0,04) para la prueba control en quienes prefieren el sabor salado y consumen menor cantidad de ENN, sin diferencias significativas entre quienes prefirieron sabor dulce. CONCLUSIONES: Al comparar las respuestas glicémicas e insulinémicas entre habitualidad de consumo de edulcorantes y preferencias alimentarias reportados por las pacientes tras la ingesta de agua, estevia y D-Tagatosa, no se obtuvieron diferencias significativas. Salvo en quienes preferían alimentos ricos en proteínas tras la ingesta de D- tagatosa y quienes preferían sabor salado con menor consumo habitual de ENN tras ingesta control.

INTRODUCTION: The consumption of non-nutritive sweeteners (NNS) has been increasing. Despite this, the effect between the habitual consumption of ENN and food preferences with biochemical parameters in patients with insulin resistance is unknown. OBJECTIVE: To compare the glycemic and C-peptide response, according to the habitual consumption of sweeteners and food preferences reported by women with insulin resistance after ingesting stevia and D-tagatose. METHODS: Thirty-three women with IR underwent a multiple choice survey on food preferences and modified ETCC for sweeteners. They randomly received a control or experimental preload (stevia and D-tagatose) where glycemia and peptide C were measured at times -10, 30, 60, 90, 120, 180. RESULTS: A higher C-peptide AUC was found after ingestion of D-tagatose (p = 0.02) in patients who prefer foods rich in protein compared to those who prefer foods rich in fat or simple carbohydrates. A higher AUC of peptide C (p = 0.04) is performed for the control test in those who prefer a salty taste and consume a lower amount of ENN, without significant differences between those who prefer a sweet taste. CONCLUSION: When comparing the glycerol and insulin responses between the habitual consumption of sweeteners and the food preferences reported by the patients after the ingestion of water, stevia and D-Tagatose, no significant differences were obtained. Except in those who prefer foods rich in protein after ingesting D-tagatose and those who prefer salty taste with less habitual consumption of NNS after control intake.

Novel Human Insulin Isoforms and Cα-Peptide Product in Islets of Langerhans and Choroid Plexus.

Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains ß-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.

Hsa_circ_0054633 association of C peptide is related to IL-17 and TNF-α in patients with diabetes mellitus receiving insulin treatment.

BACKGROUND: Chronic inflammation damaged the islet and resulted in dysfunction of T2D. Circular RNA is stable and better for biomarker in many diseases. Here, we aimed to identify potential circular RNA hsa_circ_0054633 that can be a biomarkers for the effects of insulin therapy in T2D. METHODS: In this retrospective case-control study, patients were from Li Huili Hospital, Ningbo, China, from February 10, 2019, to August 15, 2019. We included 47 healthy adults, 46 new-onset T2D with insulin resistance, and 51 patients with insulin therapy. Serum inflammation factors were tested by ELISA assays. We selected hsa_circ_0054633 as a candidate biomarker and measured its concentration in serum by qRT-PCR. The Pearson correlation test was used to evaluate the correlation between this circRNA and clinical variables. RESULTS: Clinical data indicated that serum C peptide was increased in T2D treatment with insulin. Serum hsa_circ_0054633 was decreased in insulin treatment group. Hsa_circ_0054633 was negative correlated with C peptide (r = -0.2841, p = 0.0433,). IL-1 and IL-6, IL-17, and TNF-α were higher in T2D patients and decreased after insulin treatment, only IL-17 and TNF-α showed a positive correlation to hsa_circ_0054633 (r = 0.4825, p < 0.0001, and r = 0.6190, p < 0.0001). The area under ROC curve was 0.7432, 0.5839, and 0.7573 for Hsa_circ_0054633, C peptide, and their combination. CONCLUSION: Hsa_circ_0054633 level was lower in T2D with insulin treatment than untreated and was a negative correlation with C peptide, and positively correlated with IL-17 and TNF-α, suggesting that hsa_circ_0054633 may be a potential early indicator of insulin treatment effect to improve inflammation condition.

Model-Based Assessment of C-Peptide Secretion and Kinetics in Post Gastric Bypass Individuals Experiencing Postprandial Hyperinsulinemic Hypoglycemia.

Assessment of insulin secretion is key to diagnose postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized complication following bariatric surgery. To this end, the Oral C-peptide Minimal Model (OCMM) can be used. This usually requires fixing C-peptide (CP) kinetics to the ones derived from the Van Cauter population model (VCPM), which has never been validated in PHH individuals. The objective of this work was to test the validity of the OCMM coupled with the VCPM in PHH subjects and propose a method to overcome the observed limitations. Two cohorts of adults with PHH after gastric bypass (GB) underwent either a 75 g oral glucose (9F/3M; age=42±9 y; BMI=28.3±6.9 kg/m2) or a 60 g mixed-meal (7F/3M; age = 43 ± 11 y; BMI=27.5±4.2 kg/m2) tolerance test. The OCMM was identified on CP concentration data with CP kinetics fixed to VCPM (VC approach). In both groups, the VC approach underestimated CP-peak and overestimated CP-tail suggesting CP kinetics predicted by VCPM to be inaccurate in this population. Thus, the OCMM was identified using CP kinetics estimated from the data (DB approach) using a Bayesian Maximum a Posteriori estimator. CP data were well predicted in all the subjects using the DB approach, highlighting a significantly faster CP kinetics in patients with PHH compared to the one predicted by VCPM. Finally, a simulation study was used to validate the proposed approach. The present findings question the applicability of the VCPM in patients with PHH after GB and call for CP bolus experiments to develop a reliable CP kinetic model in this population.

False Laboratory Test Result Through Colistin Interference in an Intensive Care Patient: Case Report.

BACKGROUND: In blood samples taken for testing purposes during drug infusion in the intensive care unit, there is a risk of interference due to drug-reactive interaction during the analysis. CASE REPORT: A 19-year-old female patient had undergone surgery for intracranial astrocytoma, 12 years ago. Acinetobacter baumannii was found in the blood culture and deep tracheal aspiration fluid of the patient who had a fever (39.2 °C) with a body temperature during the follow-up. The patient was started on colistin 2 * 4.5 million IU. After the colistin infusion, biochemical tests were requested to control the patient's clinical situation. CK-MB mass and ProBNP values were measured in high concentrations. Cardiology consultation was requested to evaluate the increase in the CK-MB mass and ProBNP values. The patient's ECG and echocardiography showed no abnormality. The increase in cardiac markers was neither clinically acceptable nor insignificant. There was no hemolysis in the sample or analytical error in the device. Variability in the tests was thought to be due to the interference. As the bloodletting time was questioned, it was determined that it was taken during colistin treatment. In order to determine the effect of colistin-related interference on the other tests, the laboratory was contacted and additional tests (TSH, FT4, Anti- TPO, B-HCG, Estradiol, Prolactin, CA 125, CA 15-3, CA 19-9, Vitamin B12, C-Peptide, DDimer, PTH, 25 hydroxy vitamin D, PT, INR, APTT) were conducted. During colistin treatment, in many tests, bias was detected between -75 and + 268.80%. CONCLUSION: Clinicians should consider suspicious test results that are incompatible with the diagnosis for the possibility of erroneous measurements due to colistin interference and review the sampling processes.

Elevated C-peptide Levels Are Associated With Acute Rejection in Kidney Pancreas Transplantation.

BACKGROUND: We assessed whether allograft rejection or failure can be predicted by an acute increase in C-peptide production from the transplanted pancreas. METHODS: Patients with a minimum of 5 years of follow-up post simultaneous pancreas-kidney transplant were identified. C-peptide levels were obtained during clinic visits routinely. Graft failure was defined as return to dependence on insulin therapy or return to dialysis for pancreas and kidney grafts, respectively. Protocol kidney allograft biopsies were performed at 3 and 12 months. For-cause biopsies were also performed. RESULTS: Acute rejections were detected in 11 patients on biopsy results of the renal allograft. C-peptide levels drawn prior to documented rejections were significantly higher in patients with acute rejection than patients with borderline or no rejection (P = .006). Receiver operating characteristics curves for C-peptide indicated greater accuracy in predicting rejection than simultaneously drawn serum creatinine or lipase. CONCLUSIONS: Higher C-peptide levels in simultaneous pancreas-kidney recipients is associated with acute rejection vs nonrejection.

Childhood trauma and glucose metabolism in patients with first-episode psychosis.

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.

Coenzyme Q10 does not improve peripheral insulin sensitivity in statin-treated men and women: the LIFESTAT study.

Simvastatin is a cholesterol-lowering drug that is prescribed to lower the risk of cardiovascular disease following high levels of blood cholesterol. There is a possible risk of new-onset diabetes mellitus with statin treatment but the mechanisms behind are unknown. Coenzyme Q10 (CoQ10) supplementation has been found to improve glucose homeostasis in various patient populations and may increase muscle glucose transporter type 4 content. Our aim was to investigate if 8 weeks of CoQ10 supplementation can improve glucose homeostasis in simvastatin-treated subjects. Thirty-five men and women in treatment with a minimum of 40 mg of simvastatin daily were randomized to receive either 2 × 200 mg/day of CoQ10 supplementation or placebo for 8 weeks. Glucose homeostasis was investigated with fasting blood samples, oral glucose tolerance test (OGTT) and intravenous glucose tolerance test. Insulin sensitivity was assessed with the hyperinsulinemic-euglycemic clamp. Different indices were calculated from fasting samples and OGTT as secondary measures of insulin sensitivity. A muscle biopsy was obtained from the vastus lateralis muscle for muscle protein analyzes. There were no changes in body composition, fasting plasma insulin, fasting plasma glucose, or 3-h glucose with intervention, but glycated hemoglobin decreased with time. Glucose homeostasis measured as the area under the curve for glucose, insulin, and C-peptide during OGTT was unchanged after intervention. Insulin secretory capacity was also unaltered after CoQ10 supplementation. Insulin sensitivity was unchanged but hepatic insulin sensitivity increased. No changes in muscle GLUT4 content was observed after intervention. CoQ10 supplementation does not change muscle GLUT4 content, insulin sensitivity, or secretory capacity, but hepatic insulin sensitivity may improve.

Postoperative insulin secretion is decreased in patients with preoperative insulin resistance.

BACKGROUND: Postoperative hyperglycemia is associated with increased rate of surgical site infection, renal failure, and cardiovascular events. The study of insulin sensitivity state before surgery could help in treating postoperative hyperglycemia and preventing iatrogenic hypoglycemia. We studied the postoperative insulin secretion in patients who have a low insulin sensitivity (IR) before surgery compared to patients with normal preoperative insulin sensitivity (IS). MATERIALS AND METHODS: Forty-two consecutive patients, undergoing abdominal surgery, underwent preoperative sequential hyperglycemic-euglycemic clamp (SHEC) in order to measure insulin secretion and to screen patients with low insulin sensitivity (IR) or with normal insulin sensitivity (IS). Patients had been randomized to receive either general anesthesia with epidural or PCA. RESULTS: Postoperative insulin secretion in IR patients is decreased compared to IS (P = 0.059) and to IR before surgery regardless to the type of analgesia (P < 0.001). In the IS group, postoperative insulin secretion depends on type of analgesia. It is increased when using PCA and decreased when using epidural (P < 0.05). Blood glucose increased after surgery in both IS an IR (P < 0.001). Patients with preoperative insulin resistance had a higher glycemia before and after surgery (P < 0.001). Blood glucose levels were comparable between PCA and epidural patients (P = 0.450). CONCLUSION: Insulin secretion is reduced in IR regardless the type of anesthesia. PCA increases insulin secretion, whereas epidural decreases it in patients with normal insulin sensitivity. These findings implicate that after surgery insulin administration is advisable in patients with preoperative insulin resistance while it should be given cautiously in those with normal preoperative insulin sensitivity.

Intrinsic insulin secretion capacity might be preserved by discontinuing anti-programmed cell death protein 1 antibody treatment in 'anti-programmed cell death protein 1 antibody-induced' fulminant type 1 diabetes.

Intrinsic insulin secretion capacity may be preserved by discontinuing anti-PD-1 antibody treatment in 'anti-PD-1 antibody-induced'fulminant type 1 diabetes.

Insulinoma: A retrospective study analyzing the differences between benign and malignant tumors.

BACKGROUND/OBJECTIVES: Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors. METHODS: Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease. RESULTS: Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 µU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm. CONCLUSIONS: Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases.

Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab.

Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute-onset insulin-dependent diabetes after anti-PD-1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti-PD-1 therapy. We describe an atypical case of hyperglycemia after anti-PD-1 antibody administration. A 68-year-old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA-A*24:02 and -DRB1*09:01) and resistant (HLA-DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti-PD-1 antibody-induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

[Recurrent seizures of unknown aetiology]. / Rezidivierende zerebrale Krampfanfälle unklarer Genese.

History and admission findings | A 41year old woman presented at our internistic clinic after treatment by an emergency doctor because of confusion and amnesia accompanied by a hypoglycaemic episode while driving her car. Only by giving continuous glucose intravenously a stable clinical state could be achieved. In her medical history she took Lamotrigin for 12 years since she had seizures of unknown aetiology. 16 years ago she had similar sudden attacks with confusion and hypoglycaemia. At that time thorough diagnostics at the clinic for internal medicine did not reveal any evidence for hyperinsulinaemia. While taking Lamotrigin the patient had no seizures or similar symptoms for 12 years. Treatment and course | In the present case we detected a tumor in the pancreas and a two-fold increased insulin secretion. Histopathological work-up of the removed tissue confirmed the suspected diagnosis of insulinoma. Postoperatively, Lamotrigin treatment was terminated. Since then the patient remained asymptomatic.

Modification of a traditional breakfast leads to increased satiety along with attenuated plasma increments of glucose, C-peptide, insulin, and glucose-dependent insulinotropic polypeptide in humans.

Our hypothesis was that carbohydrate, fat, and protein contents of meals affect satiety, glucose homeostasis, and hormone secretion. The objectives of this crossover trial were to examine satiety, glycemic-insulinemic response, and plasma peptide levels in response to 2 different recommended diabetes diets with equivalent energy content. One traditional reference breakfast and one test breakfast, with lower carbohydrate and higher fat and protein content, were randomly administered to healthy volunteers (8 men, 12 women). Blood samples were collected, and satiety was scored on a visual analog scale before and 3 hours after meals. Plasma glucose was measured, and levels of C-peptide, ghrelin, glucagon, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), insulin, plasminogen activator inhibitor-1, and adipokines were analyzed by Luminex. Greater satiety, visual analog scale, and total and delta area under the curve (P < .001), and lower glucose postprandial peak (max) and change from baseline (dmax; P < .001) were observed after test meal compared with reference meal. Postprandial increments of C-peptide, insulin, and GIP were suppressed after test meal compared with reference meal (total delta area under the curve [P = .03, .006, and .004], delta area under the curve [P = .006, .003, and .02], max [P = .01, .007, and .002], and dmax [P = .004, .008, and .007], respectively). Concentrations of other peptides were similar between meals. A lower carbohydrate and higher fat and protein content provides greater satiety and attenuation of C-peptide, glucose, insulin, and GIP responses compared with the reference breakfast but does not affect adipokines, ghrelin, glucagon, glucagon-like peptide-1, and plasminogen activator inhibitor-1.

Hypoglycemic Syndrome without Hyperinsulinemia. A Diagnostic Challenge.

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States.

We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.

Accelerated Maturation of Human Stem Cell-Derived Pancreatic Progenitor Cells into Insulin-Secreting Cells in Immunodeficient Rats Relative to Mice.

Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes. To investigate the impact of the host recipient on hESC-derived pancreatic progenitor cell maturation, cells were transplanted into immunodeficient SCID-beige mice or nude rats. Following the transplant, basal human C-peptide levels were consistently higher in mice compared with rats, but only rats showed robust meal- and glucose-responsive human C-peptide secretion by 19-21 weeks. Grafts from rats contained a higher proportion of insulin:glucagon immunoreactivity, fewer exocrine cells, and improved expression of mature ß cell markers compared with mice. Moreover, ECM-related genes were enriched, the collagen network was denser, and blood vessels were more intricately integrated into the engrafted endocrine tissue in rats relative to mice. Overall, hESC-derived pancreatic progenitor cells matured faster in nude rats compared with SCID-beige mice, indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation.