Normoglycemia In Patients Research Articles

Impaired glucose metabolism and the risk of vascular events and mortality after ischemic stroke: A systematic review and meta-analysis

BackgroundDiabetes mellitus (DM), prediabetes, and insulin resistance are highly prevalent in patients with ischemic stroke (IS). DM is associated with higher risk for poor outcomes after IS.ObjectiveInvestigate the risk of recurrent vascular events and mortality associated with impaired glucose metabolism compared to normoglycemia in patients with IS and transient ischemic attack (TIA).MethodsSystematic literature search was performed in PubMed, Embase, Cochrane Library on 21st March 2024 and via citation searching. Studies that comprised IS or TIA patients and exposures of impaired glucose metabolism were eligible. Study Quality Assessment Tool was used for risk of bias assessment. Covariate adjusted outcomes were pooled using random-effects meta-analysis.Main outcomesRecurrent stroke, cardiac events, cardiovascular and all-cause mortality and composite of vascular outcomes.ResultsOf 10,974 identified studies 159 were eligible. 67% had low risk of bias. DM was associated with an increased risk for composite events (pooled HR (pHR) including 445,808 patients: 1.58, 95% CI 1.34–1.85, I2 = 88%), recurrent stroke (pHR including 1.161.527 patients: 1.42 (1.29–1.56, I2 = 92%), cardiac events (pHR including 443,863 patients: 1.55, 1.50–1.61, I2 = 0%), and all-cause mortality (pHR including 1.031.472 patients: 1.56, 1.34–1.82, I2 = 99%). Prediabetes was associated with an increased risk for composite events (pHR including 8,262 patients: 1.50, 1.15–1.96, I2 = 0%) and recurrent stroke (pHR including 10,429 patients: 1.50, 1.18–1.91, I2 = 0), however, not with mortality (pHR including 9,378 patients, 1.82, 0.73–4.57, I2 = 78%). Insulin resistance was associated with recurrent stroke (pHR including 21,363 patients: 1.56, 1.19–2.05, I2 = 55%), but not with mortality (pHR including 21,363 patients: 1.31, 0.66–2.59, I2 = 85%).DiscussionDM is associated with a 56% increased relative risk of death after IS and TIA. Risk estimates regarding recurrent events are similarly high between prediabetes and DM, indicating high cardiovascular risk burden already in precursor stages of DM. There was a high heterogeneity across most outcomes.

Comprehensive review of imaging in pancreas transplantation: a primer for radiologists.

Pancreas transplantation is a complex surgical procedure performed to restore normoglycemia in patients with type 1 diabetes and includes whole/segmental organ transplant and islet cell transplantation (ICT). In the United States, simultaneous pancreas-kidney transplant (SPK) is most commonly performed due to the higher occurrence of end-stage renal disease in diabetic patients. Understanding the surgical technique and postoperative anatomy is imperative for effective and accurate surveillance following transplantation. Imaging plays an essential role in patients with pancreatic transplants and is often used to evaluate viability, vascular and parenchymal anatomy, and identify potential complications. Imaging techniques such as ultrasound, color and spectral Doppler, computed tomography (CT), magnetic resonance imaging (MRI), and angiography have a complementary role in the postoperative evaluation following a pancreas transplant. The common complications after a whole organ pancreas transplant include vascular thrombosis, graft rejection, pancreatitis, and infections. Complications can be classified into vascular (partial or complete venous thrombosis, arterial thrombosis, stenosis or pseudoaneurysm), parenchymal (pancreatitis, graft rejection), and bowel-related or miscellaneous causes (bowel obstruction, anastomotic leak, and peripancreatic fluid collections). Islet cell transplantation is an innovative therapy for patients with type 1 diabetes. It involves isolating insulin-producing islet cells from donor pancreas and transplanting into recipients, to provide long-term insulin independence or significantly reduce insulin requirements. In recent years, isolation techniques, immunosuppressive regimens, and post-transplant monitoring advancements have propelled ICT as a viable therapeutic option. This comprehensive review aims to provide insights into the current state-of-the-art imaging techniques discussing both normal and abnormal features following pancreas transplantation.

Triglyceride to high-density lipoprotein cholesterol ratio is associated with regression to normoglycemia from prediabetes in adults: a 5-year cohort study in China

ObjectiveThe current body of evidence on the association between the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-c) and the reversal of prediabetes to normoglycemia remains limited. The aim of this study is to investigate the association between TG/HDL-c and the reversion to normoglycemia in patients with prediabetes.MethodsThis retrospective cohort study included 15,107 individuals with prediabetes from 32 Chinese districts and 11 cities who completed health checks from 2010 to 2016. The Cox proportional-hazards regression model examined baseline TG/HDL-c and reversion to normoglycemia from prediabetes. Cox proportional hazards regression with cubic spline functions and smooth curve fitting determined the non-linear connection between TG/HDL-c and reversion to normoglycemia. We also ran sensitivity and subgroup analysis. By characterizing progression to diabetes as a competing risk for the reversal of prediabetes to normoglycemic event, a multivariate Cox proportional hazards regression model with competing risks was created.ResultsUpon adjusting for covariates, the findings indicate a negative association between TG/HDL-c and the likelihood of returning to normoglycemia (HR = 0.869, 95%CI:0.842–0.897). Additionally, a non-linear relationship between TG/HDL-c and the probability of reversion to normoglycemia was observed, with an inflection point of 1.675. The HR on the left side of the inflection point was 0.748 (95%CI:0.699, 0.801). The robustness of our results was confirmed through competing risks multivariate Cox's regression and a series of sensitivity analyses.ConclusionThe present study reveals a negative and non-linear correlation between TG/HDL-c and the reversion to normoglycemia among Chinese individuals with prediabetes. The findings of this study are anticipated to serve as a valuable resource for clinicians in managing dyslipidemia in prediabetic patients. Interventions aimed at reducing the TG/HDL-c ratio through the reduction of TG or elevation of HDL-c levels may substantially enhance the likelihood of achieving normoglycemia in individuals with prediabetes.

Association between body mass index and reversion to normoglycemia from impaired fasting glucose among Chinese adults: a 5-year cohort study.

Evidence regarding the relationship between body mass index (BMI) and reversion to normoglycemia from prediabetes is still limited. The purpose of our study is to survey the link of BMI on reversion to normoglycemia among patients with impaired fasting glucose (IFG). This study, a retrospective cohort, covered 32 regions and 11 cities in China and collected 258,74 IFG patients who underwent a health check from 2010 to 2016. We investigated the association between baseline BMI and reversion to normoglycemia in patients with IFG using the Cox proportional-hazards regression model. The nonlinear relationship between BMI and reversion to normoglycemia was determined using a Cox proportional hazards regression with cubic spline functions and smooth curve fitting. In addition, we also performed a series of sensitivity analyses and subgroup analyses. A competing risk multivariate Cox regression was performed using progression to diabetes as a competing risk for reversal of normoglycemic events. After adjusting covariates, the results showed that BMI was negatively related to the probability of reversion to normoglycemia (HR=0.977, 95%CI:0.971-0.984). Compared with participants with normal BMI(<24kg/m2), overweight (BMI:24-28kg/m2) participants with IFG had a 9.9% lower probability of returning to normoglycemia (HR=0.901,95%CI:0.863-0.939), while obese patients (BMI ≥ 28kg/m2) had a 16.9% decreased probability of reverting from IFG to normoglycemia (HR=0.831,95%CI:0.780-0.886). There was also a nonlinear relationship between them, and the inflection point of BMI was 21.7kg/m2. The effect sizes (HR) on the left sides of the inflection point were 0.972(95%CI:0.964-0.980). The competing risks multivariate Cox's regression and sensitivity analysis demonstrated the robustness of our results. This study demonstrates a negative and nonlinear relationship between BMI and reversion to normoglycemia in Chinese patients with IFG. Minimizing BMI to 21.7 kg/m2 in patients with IFG through aggressive intervention may significantly increase the probability of returning to normoglycemia.

Perioperative variable rate intravenous insulin infusion: a quality improvement project on a vascular surgery ward

AimsVariable rate intravenous insulin infusion (VRIII) is used perioperatively to maintain normoglycaemia in patients with diabetes who are undergoing surgery. The aims of this project were as follows: (1) to...

Applications of bile acids as biomaterials-based modulators, in biomedical science and microfluidics.

Chronic disorders such as diabetes mellitus are associated with multiple organ dysfunction, including retinopathy, neuropathy, nephropathy, peripheral vascular disease, and vascular disease. Lifelong subcutaneous insulin injections are currently the only treatment option for patients with Type 1diabetes mellitus, and it poses numerous challenges. Since the breakthrough achieved from the Edmonton protocol in the year 2000, there has been important research to investigate whether islet cell transplantation can achieve long-term normoglycemia in patients without the need for insulin. The use of biopolymeric scaffold to enclose islet cells has also been explored to improve survivability and viability of islet cells. This review paper summarizes the latest research in using biopolymeric scaffolds in islet transplantation and how microfluidic devices can assist.

Intelligent Control with Artificial Neural Networks for Automated Insulin Delivery Systems.

Type 1 diabetes mellitus is a disease that affects millions of people around the world. Recent progress in embedded devices has allowed the development of artificial pancreas that can pump insulin subcutaneously to automatically regulate blood glucose levels in diabetic patients. In this work, a Lyapunov-based intelligent controller using artificial neural networks is proposed for application in automated insulin delivery systems. The adoption of an adaptive radial basis function network within the control scheme allows regulation of blood glucose levels without the need for a dynamic model of the system. The proposed model-free approach does not require the patient to inform when they are going to have a meal and is able to deal with inter- and intrapatient variability. To ensure safe operating conditions, the stability of the control law is rigorously addressed through a Lyapunov-like analysis. In silico analysis using virtual patients are provided to demonstrate the effectiveness of the proposed control scheme, showing its ability to maintain normoglycemia in patients with type 1 diabetes mellitus. Three different scenarios were considered: one long- and two short-term simulation studies. In the short-term analyses, 20 virtual patients were simulated for a period of 7 days, with and without prior basal therapy, while in the long-term simulation, 1 virtual patient was assessed over 63 days. The results show that the proposed approach was able to guarantee a time in the range above 95% for the target glycemia in all scenarios studied, which is in fact well above the desirable 70%. Even in the long-term analysis, the intelligent control scheme was able to keep blood glucose metrics within clinical care standards: mean blood glucose of 119.59 mg/dL with standard deviation of 32.02 mg/dL and coefficient of variation of 26.78%, all below the respective reference values.

Pancreatic β-Cell Development and Regeneration.

The pancreatic β-cells are essential for regulating glucose homeostasis through the coordinated release of the insulin hormone. Dysfunction of the highly specialized β-cells results in diabetes mellitus, a growing global health epidemic. In this review, we describe the development and function of β-cells the emerging concept of heterogeneity within insulin-producing cells, and the potential of other cell types to assume β-cell functionality via transdifferentiation. We also discuss emerging routes to design cells with minimal β-cell properties and human stem cell differentiation efforts that carry the promise to restore normoglycemia in patients suffering from diabetes.

Pharmacotherapy weight-loss interventions to prevent type 2 diabetes in overweight or obese adults and older adults: A protocol for systematic review and network meta-analysis.

Background:Obesity is a worldwide problem and is associated with multiple negative health effects. Obesity also has a direct relationship with risk of diabetes. Several pharmacotherapy weight-reducing interventions have been employed to prevent type 2 diabetes (T2D) in overweight or obese adults and older adults. However, data with respect to comparative effectiveness are limited. To address this gap, in this study, evidence on benefits of anti-obesity agents for preventing diabetes will be systematically reviewed using a network meta-analysis.Methods:We will perform an online systematic search for randomized controlled trials (RCTs) investigating 5 FDA-approved anti-obesity agents for preventing T2D in obese or overweight adults and older adults through electronic databases of PubMed, Embase, and the Cochrane Library from inception until December 31, 2020. Two independent reviewers will screen titles, abstracts, and full-texts of all potentially eligible trials. Two authors working independently will abstract data on trial-, participant- and intervention-related characteristics. The primary outcome will be incidence of T2D. Secondary outcomes will be achievement of normoglycaemia in patients with prediabetes, percentage of individuals achieving at least 5% or 10% weight loss of their baseline weight. We will conduct pairwise meta-analyses for all outcomes included in this study. To determine comparative efficacy of multiple interventions, network meta-analysis with a frequentist random-effects model will be performed. Moreover, subgroup analyses and sensitivity analyses will be performed to assess the robustness of our findings. To evaluate publication bias, the comparison-adjusted funnel plot will be utilized. Stata version 14.0 and RevMan version 5.3.3 will be used to perform all statistical analyses.Results:This study will evaluate the effectiveness of weight-loss medications on T2D prevention in overweight or obese people.Conclusions:This study will generate meaningful findings for overweight or obese adults and older adults, clinicians, and policy-makers concerning the optimal anti-obesity pharmacotherapy to decrease risk of T2D.Study registration number:INPLASY202110104.

Cell Replacement Therapy for Insulin-Dependent Diabetes: Maintaining Islet Architecture and Distribution After Graft

To survey current practices in clinical islet transplantation to identify the critical factors for designing a successful implant strategy for islets derived from pluripotent stem cells. Of particular importance is the volume of a therapeutic dose and the host sites capable of housing that volume. A calculated dose of surviving islets required for normoglycemia in patients is large, though less than the number of islets present in a healthy pancreas. Great strides have been made developing methods for delivery of a large dose of islets that maintain cell viability and potency. Although many of these endeavor to provide the islets close association to the host vasculature, only some of the strategies maintain the architecture and distribution of the individual islets. The trends in clinical research and in laboratory models suggest that strategies that maintain the architecture and distribution of the individual islets are the most successful. This requirement increases the volume required to deliver a therapeutic dose and limits the anatomical sites available for clinical transplant.

Сhronic kidney disease complications in patients with type 1 diabetes mellitus after simultaneous pancreas-kidney transplantation – potential role of oxidative stress and glycation end products

BACKGROUND: Normoglycaemia in patients with diabetes mellitus type 1 (T1DM) after simultaneous pancreas-kidney transplantation (SPKT) is very interesting in regards to chronic kidney disease (CKD) complications dynamics depending of posttransplantation period and possible targets of potential treatment from the point of view metabolic memory&#x0D; AIM: To evaluate the relationship between oxidative stress indicators and advanced glycation end products and complications of end-stage renal disease (ESRD) in patients with T1DM аnd a long-term history of diabetes decompensation, who reached stable euglycemia after SPKT.&#x0D; MATERIALS AND METHODS: The study included 20 patients with compensation of carbohydrate metabolism after SPKT performed from November 2011 to September 2018. Assessment included examination of complications of ESRD (arterial hypertension, dyslipidemia, anemia, mineral and bone disorder) and analysis of "metabolic memory" markers: 3-nitrothyrosine (3-NT), superoxide dismutase (SOD), advanced glycation end products (AGE) and AGE receptor (RAGE). We performed follow-up examination of patients included in the early postoperative period (1st day/week) in 6-12 months after SPKT.&#x0D; RESULTS: All patients with DM1 duration for 22 [19; 28] years, diabetic nephropathy (DN) 8 [6; 14] years and duration of renal replacement therapy (dialysis) for 3 [1.5; 4] years reached euglycemia (HbA1c 5,5 [5,1; 5,8] %; С-peptide 3,2 [2,45; 3,63] ng/ml) after 6 month of surgical treatment. Despite of stable graft function (estimated glomerular filtration rate (eGFR) CKD-EPI 84 [69; 95] ml/min/1.73m2) 35% of patients still needed antihypertensive therapy, 40% needed treatment with recombinant human erythropoietin (RHuEPO) and 15% ferrotherapy. With vitamin D deficiency, observed in 80% of cases (13.3 [9.3; 18.5] ng/ml), 55% of patients had secondary hyperparathyroidism, 45% osteoporosis. The results of the correlation analysis revealed the association of the state of ESRD target organs with the studied "metabolic memory" markers: oxidative stress and AGE-RAGE system.&#x0D; CONCLUSIONS: SPKT as the way to achieve compensation of carbohydrate metabolism and uremia does not provide regress of diabetes and complications of ESRD. Analysis of "metabolic memory" markers indicate their direct contribution to the persistence of metabolic consequences of diabetic nephropathy (DN). Found trends need more long-lasting observation and enlargement of study groups.

Thai CV Risk Score and Primary Prevention in Impaired Fasting Plasma Glucose or Diabetes Mellitus versus Normoglycemia in Patients with Metabolic Syndrome.

Background:Impaired fasting plasma glucose (IFG) as well as diabetes mellitus (DM) may influence the presence of another metabolic syndrome (MetS) components resulting in the different risk of cardiovascular (CV) morbidity and mortality. This study aimed to determine the impact of IFG as well as DM on the 10-year CV risk using Thai CV risk score and primary prevention in complying with CV risk score in these patients.Methods:This cross-sectional study was conducted at the internal medicine clinic, Pathum Thani Hospital, Thailand. The study was approved by the hospital ethics committee and written informed consent was obtained from all patients. Patients having MetS according to the criteria of the International Diabetes Federation were enrolled while those with a history of CVD were excluded. The 10-year CV risk was assessed using the Thai CV risk score.Results:The total of 112 patients were enrolled in the study. They were in old age and female sex was a significantly higher proportion (61.70% vs 35.50%, P = 0.013). Of these, 72.32% had IFG or DM. Proportions of patients with moderate and high CV risk score were significantly greater in IFG/DM group and only 34.48% and 79.31% of patients with moderate or high CV risk score received aspirin and statin. IFG or DM significantly elevated CV risk score (OR = 6.66, 95% CI = 2.29, 19.58).Conclusions:IFG/DM significantly elevated CV risk score in these patients with the strongest impact. The assessment of CV risk is highly recommended for primary prevention and long-term CVD benefit.

IPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets.

Islet transplantation is an effective therapy for achieving and maintaining normoglycemia in patients with type 1 diabetes mellitus. However, the supply of transplantable human islets is limited. Upon removal from the pancreas, islets rapidly disintegrate and lose function, resulting in a short interval for studies of islet biology and pretransplantation assessment. Here, we developed a biomimetic platform that can sustain human islet physiology for a prolonged period ex vivo. Our approach involved the creation of a multichannel perifusion system to monitor dynamic insulin secretion and intracellular calcium flux simultaneously, enabling the systematic evaluation of glucose-stimulated insulin secretion under multiple conditions. Using this tool, we developed a nanofibrillar cellulose hydrogel-based islet-preserving platform (iPreP) that can preserve islet viability, morphology, and function for nearly 12 weeks ex vivo, and with the ability to ameliorate glucose levels upon transplantation into diabetic hosts. Our platform has potential applications in the prolonged maintenance of human islets, providing an expanded time window for pretransplantation assessment and islet studies.

Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial

There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission. In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m2) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264. Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054). Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. Eisai.

Long-term Outcomes in Simultaneous Pancreas-Kidney Transplant Recipients: Single-center Experience From Poland

BackgroundSimultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with end-stage renal disease (ESRD) due to type 1 diabetes mellitus (DM1). Since the 1980s, pancreas transplantation has become the most effective strategy to restore normoglycemia in patients with DM1. The aim of this study was to present long-term outcomes data for SPKT. MethodsWe performed a retrospective analysis of 73 SPKT recipients followed in our outpatient center who underwent transplantation between 1988 and 2015. ResultsA total of 50.7% of the patients were male. At the time of surgery, patients' mean age was 37.38 ± 7.44 years. Patients were diagnosed with DM1 at an average of 25 ± 6.08 years before SPKT. For 21.9% of patients, the transplant was done preemptively. Most (91.8%) had enteric drainage. All patients received induction of immunosuppression (either polyclonal immunoglobulins anti-thymocyte globulin or thymoglobulin [64.4%] or monoclonal globulins daclizumab or basiliximab [35.6%]). Patient survival at 1, 5, 10, 15 years was 99%, 97%, 89%, and 75%; kidney survival was 99%, 96%, 84%, and 67%; and pancreas survival was 95%, 92%, 84%, and 64%, respectively. There was a notable tendency toward increased creatinine level (from 1.18 at 1 year to 1.78 at 15 years) and decreased hemoglobin level (from 13.84 at 1 year to 12.65 at 15 years). ConclusionDiabetic patients with ESRD have a poor prognosis without transplantation. SPKT provides marked prolongation of the patient's life and freedom from insulin injections. Enteric drainage is currently the surgical technique of choice. SPKT should remain as the treatment of choice in this patient population.

Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes

Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of β-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.

Use of RGD-Functionalized Sandwich Cultures to Promote Redifferentiation of Human Pancreatic Beta Cells After In Vitro Expansion.

Islet transplantation has provided proof of concept that cell therapy can restore normoglycemia in patients with diabetes. However, limited availability of islet tissue severely restricts the clinical use of the treatment. Thus, there is an urgent need to develop new strategies to generate an abundant source of insulin-producing cells that could be used to treat diabetes. A potential approach is the in vitro expansion of pancreatic beta cells obtained from cadaveric organ donors. However, when human beta cells are expanded in vitro, they dedifferentiate and lose the expression of insulin, probably as a consequence of pancreatic islet dissociation into single cells. We have studied whether reestablishment of cell-cell and cell-matrix relationships with a biomimetic synthetic scaffold could induce redifferentiation of expanded dedifferentiated beta cells. Cells isolated from human islet preparations were expanded in monolayer cultures and allowed to reaggregate into islet-like cell clusters (ICCs). Afterward, ICCs were embedded between two thin layers of the noninstructive self-assembling peptide (SAP), RAD16-I or RAD16-I functionalized with the integrin-binding motif RGD (RAD16-I/RGD) (R: arginine, G: glycine, D: aspartic acid), which was expected to promote cell-extracellular matrix interactions. ICCs cultured with RAD16-I were viable, maintained their cluster conformation, and increased in size by aggregation of ICCs, suggesting a self-organizing process. ICCs cultured in RAD16-I/RGD showed enhanced cell adhesion to RAD16-I matrix and reexpression of the beta cell-specific genes, Ins, Pdx1, Nkx6.1, and MafA. Redifferentiation was caused solely by bioactive cues introduced to the RAD16-I peptide since no differentiation factors were added to the culture medium. The results indicate that RGD-functionalized SAP in sandwich conformation is a promising three-dimensional platform to induce redifferentiation toward a beta cell phenotype and to generate insulin-expressing cells that could be used in diabetes therapy.

Long-term outcome after pancreas transplantation: a registry analysis.

Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the most important risk factors for short-term survival of a pancreas transplant, more information about factors that distinguish short-term from long-term graft function is needed. Analysis of 21 328 pancreas transplants from the International Pancreas Transplant Registry, performed from 1984 to 2009 (minimum 5-year follow-up), shows a significant improvement in long-term patient survival and pancreas graft function. Total 5-and 10-year pancreas graft function rates are 73 and 56%, respectively, for simultaneous pancreas-kidney transplants; 64 and 38%, respectively, for pancreas after kidney; and 53 and 36%, respectively, for pancreas transplants alone. The most influential period is the first year posttransplant. Recipients who reach this time point with a functioning graft have a much higher probability for excellent long-term graft function. Important factors influencing long-term function were features that described the quality of the deceased donor. Pancreas transplants in younger, high panel reactive antibody, or African-American recipients also showed an increased risk of early graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants. With careful recipient and donor selection and close follow-up in the first year posttransplant, not only good short-term but also long-term pancreas graft function and, therefore, durable metabolic control can be achieved for the diabetic patient.

Human pancreatic beta-like cells converted from fibroblasts.

Pancreatic beta cells are of great interest for biomedical research and regenerative medicine. Here we show the conversion of human fibroblasts towards an endodermal cell fate by employing non-integrative episomal reprogramming factors in combination with specific growth factors and chemical compounds. On initial culture, converted definitive endodermal progenitor cells (cDE cells) are specified into posterior foregut-like progenitor cells (cPF cells). The cPF cells and their derivatives, pancreatic endodermal progenitor cells (cPE cells), can be greatly expanded. A screening approach identified chemical compounds that promote the differentiation and maturation of cPE cells into functional pancreatic beta-like cells (cPB cells) in vitro. Transplanted cPB cells exhibit glucose-stimulated insulin secretion in vivo and protect mice from chemically induced diabetes. In summary, our study has important implications for future strategies aimed at generating high numbers of functional beta cells, which may help restoring normoglycemia in patients suffering from diabetes.

Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy

The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.