Insulin Independence Research Articles

Частота асимптоматической гиперурикемии среди взрослых больных сахарным диабетом 1-го и 2-го типа

Цель исследования — изучить частоту асимптоматической гиперурикемии у больных сахарным диабетом (СД) 1-го и 2-го типа в украинской популяции на примере жителей г. Харькова и области. Материалы и методы. Обследованы 316 больных СД: 81 больной СД 1-го типа (группа 1), 150 больных СД 2-го типа (группа 2) и 85 больных СД 2-го типа с абсолютной инсулинозависимостью (группа 3). Оценку состояния пуринового обмена проводили путем определения концентрации мочевой кислоты в сыворотке крови и моче. Уровни мочевой кислоты определяли колориметрическим методом с помощью набора реагентов «СпайнЛаб, UricasePOD» (Украина). Для оценки влияния возраста больного, возраста больного на момент манифестации заболевания, продолжительности заболевания и индекса массы тела группы обследуемых были разделены на две подгруппы (А и Б соответственно) с учетом уровня урикемии и урикурии. Подгруппу 1А составили 60 больных СД 1-го типа без гиперурикемии (ГУ) и/или гиперурикурии (ГУУ), подгруппу 1Б — 21 больной с ГУ и/или ГУУ, подгруппу 2А — 76 больных без ГУ и/или ГУУ, подгруппу 2Б — 74 больных с ГУ и/или ГУУ, подгруппу 3А — 57 больных без ГУ и/или ГУУ, подгруппу 3Б — 28 больных с ГУ и/или ГУУ. Результаты. Частота нарушений пуринового обмена среди взрослых больных СД 1-го и 2-го типа составляет 38,9 %. Самая высокая частота нарушений пуринового обмена наблюдается у больных СД 2-го типа (49,3 %). Возраст больного при проведении исследования и на момент манифестации СД, продолжительность заболевания и индекс массы тела не являются определяющими факторами, влияющими на формирование нарушений пуринового обмена у больных СД 1-го и 2-го типа; возрастной фактор и продолжительность заболевания являются факторами риска нарушений пуринового обмена у больных СД 2-го типа с абсолютной инсулинозависимостью. Выводы. Асимптоматическая гиперурикемия диагностирована у 27,8 % обследованных больных сахарным диабетом. Частота асимптоматической гиперурикемии значительно выше у больных сахарным диабетом 2-го типа, чем у больных сахарным диабетом 1-го типа (3,48 и 24,4 % соответственно); абсолютная инсулинозависимость у больных сахарным диабетом 2-го типа не влияет на частоту асимптоматической гиперурикемии.

Low C-peptide together with a high glutamic acid decarboxylase autoantibody level predicts progression to insulin dependence in latent autoimmune diabetes in adults: The HUNT study.

To search for risk factors that could predict progression in latent autoimmune diabetes in adults (LADA) and compare them with those for type 2 diabetes. This study included 175 participants with LADA (autoantibody positive, without insulin treatment ≥1year after diagnosis) and 2331 participants with type 2 diabetes (autoantibody negative, without insulin treatment ≥1year after diagnosis) from the HUNT2 and HUNT3 surveys. We used Cox regression models and receiver operating characteristic curve analysis to identify predictive factors for progression to insulin dependency within 10 years. Low C-peptide levels (<0.3nmol/L) predicted progression to insulin dependency within 10 years in both LADA (hazard ratio [HR] 6.40 [95% CI, 2.02-20.3]) and type 2 diabetes (HR 5.01 [95% CI, 3.53-7.10]). In addition, a high glutamic acid decarboxylase autoantibody (GADA) level (HR 5.37 [95% CI, 1.17-24.6]) predicted progression in LADA. Together, these two factors had a discriminatory power between non-progressors and progressors of area under the curve (AUC) of 0.86 (95% CI, 0.80-0.93). In type 2 diabetes, younger age at diagnosis (<50 years: HR 2.83 [95% CI, 1.56-5.15]; 50-69 years: HR 2.11 [95% CI, 1.19-3.74]), high HbA1c levels (≥53 mmol/mol, HR 2.44 [95% CI, 1.72-3.46]), central obesity (HR 1.65 [95% CI, 1.06-2.55]) and a body mass index of more than 30 kg/m2 (HR 1.73 [95% CI, 1.23-2.41]) were independent predictors. Together with C-peptide they reached an AUC of 0.79 (95% CI, 0.76-0.82). Factors predicting progression to insulin dependence are partly similar and partly dissimilar between LADA and type 2 diabetes. A constellation of low C-peptide and high GADA levels identifies LADA patients who are probable to progress to insulin dependence.

A comparative study of pancreas transplantation between type 1 and 2 diabetes mellitus.

Pancreas transplantation remains the best long-term treatment option to achieve physiological euglycemia and insulin independence in patients with labile diabetes mellitus (DM). It is widely accepted as an optimal procedure for type 1 DM (T1DM), but its application in type 2 DM (T2DM) is not unanimously acknowledged. In total, 146 diabetes patients undergoing pancreas transplantation were included in this study. Clinical data and outcomes were compared between the T1DM and T2DM groups. Majority (93%) of the pancreas transplantations in T2DM were for uremic recipients. Complications occurred in 106 (73%) patients, including 70 (48%) with early complications before discharge and 79 (54%) with late complications during follow-up period. Overall, rejection of pancreas graft occurred in 37 (25%) patients. Total rejection rate in T2DM recipients was significantly lower than that in T1DM. The short- and long-term outcomes for endocrine function in terms of fasting blood sugar and hemoglobin A1c levels and graft survival rates are comparable between the T2DM and T1DM groups. T2DM is not inferior to T1DM after pancreas transplantation in terms of surgical risks, immunological and endocrine outcomes, and graft survival rates. Therefore, pancreas transplantation could be an effective option to treat selected uremic T2DM patients without significant insulin resistance.

Association between Flash Glucose Monitors and A1C: A Retrospective Pre-Post Analysis.

Background: Randomized controlled trials have investigated the effect of continuous glucose monitors on hemoglobin A1C; however, more evidence is needed to justify their use and expand insurance coverage. Additionally, there are few published studies investigating the A1C lowering effect of flash glucose monitors (FGMs) in broad diabetes populations with varying insulin requirements. This analysis aimed to help fill this gap in medical literature and help clinicians evaluate costs/benefits when considering FGMs for their patients with diabetes. Objectives: To determine the association between FGM use and A1C reduction in patients with type 1 or type 2 diabetes mellitus regardless of insulin dependence. Methods: Pharmacy dispensing records were used to identify patients for inclusion. Patients who received a FGM from a University of Utah pharmacy between July 7, 2018 and July 7, 2020 were included. Patients who did not receive at least an 84-day supply of FGM sensors or did not have a baseline or follow-up A1C were excluded. Baseline and follow-up A1Cs, defined as A1Cs that are within one year before and 3-12 months after the FGM dispense date, were collected for each patient. New diabetes medications within a six-month window of the initial FGM dispense date were also recorded. Outcome variables were collected before and after patients received their first FGM (pre-FGM vs. post-FGM, respectively). The primary outcome was the difference between baseline and follow-up A1C for each patient. Secondary outcomes were the difference in baseline and follow-up A1C for various clinical subgroups within the overall sample. Descriptive statistics were used to summarize baseline characteristics and outcome data. Paired Student's t-tests were used to evaluate outcome differences (α=0.05). Results: Fifty-seven patients (50.8% male; mean age: 49 years) were included. For the primary outcome, the average baseline and follow-up A1Cs were 9.33% and 8.32%, respectively for a difference of -1.01% ([95%CI -1.31:-0.72]; p<0.0001). Conclusions: The use of FGMs is associated with decreases in A1C within a cohort of patients at one health system. Further effort to determine impact of FGM on clinical and economic outcomes is warranted.

Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus.

(1) Background: The correlation between titers of islet autoantibodies (IAbs) and the loss of transplanted islets remains controversial. We sought to evaluate the prognostic utility of monitoring IAbs in diabetic patients after islet transplantation (ITx); (2) Methods: Twelve patients with Type 1 diabetes mellitus and severe hypoglycemia underwent ITx. Serum concentration of glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), and zinc transport 8 (ZnT8) autoantibodies was assessed before ITx and 0, 7, and 75 days and every 3 months post-operatively; (3) Results: IA-2A (IA-2 antibody) and ZnT8A (ZnT8 antibody) levels were not detectable before or after ITx in all patients (median follow-up of 53 months (range 24–61)). Prior to ITx, GAD antibody (GADA) was undetectable in 67% (8/12) of patients. Of those, 75% (6/8) converted to GADA+ after ITx. In 67% (4/6) of patients with GADA+ seroconversion, GADA level peaked within 3 months after ITx and subsequently declined. All patients with GADA+ seroconversion maintained long-term partial or complete islet function (insulin independence) after 1 or 2 ITx. There was no correlation between the presence of IAb-associated HLA haplotypes and the presence of IAbs before or after ITx; (4) Conclusions: There is no association between serum GADA trends and ITx outcomes. IA-2A and ZnT8A were not detectable in any of our patients before or after ITx.

Update on islet cell transplantation.

Chronic diabetes-related complications continue to exert a rapidly growing and unsustainable pressure on healthcare systems worldwide. In type 1 diabetes, glycemic control is particularly challenging, as intensive management substantially increase the risk of severe hypoglycemic episodes. Alternative approaches to address this issue are required. Islet cell transplantation offers the best approach to reduce hypoglycemic risks and glycemic lability, while providing optimal glycemic control. Although ongoing efforts have improved clinical outcomes, the constraints in tissue sources and the need for chronic immunosuppression limit the application of islet cell transplantation as a curative therapy for diabetes. This review provides an update on islet cell transplantation, focusing on recent clinical experience, ongoing research, and future challenges. Current evidence demonstrates advances in terms of long-term glycemic control, improved insulin independence rates, and novel approaches to eliminate chronic immunosuppression requirements after islet cell transplantation. Advances in stem cell-based therapies provide a promising path towards truly personalized regenerative therapies, solving both tissue supply shortage and the need for lifelong immunosuppression, enabling widespread use of this potentially curative treatment. However, as these therapies enter the clinical realm, regional access variability and ethical questions regarding commercialization are becoming increasingly important and require a collaborative solution. In this state-of-the-art review, we discuss current clinical evidence and discuss key aspects on the present and future of islet cell transplantation.

Patient-reported Outcomes After Metabolic Surgery Versus Medical Therapy for Diabetes: Insights From the STAMPEDE Randomized Trial.

The aim of this study was to investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient-reported outcomes (PROs). Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. The Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that 5 years after randomization, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were superior to intensive medical therapy (IMT) alone in achieving glycemic control in patients with T2DM and obesity. A subset of 104 patients participating in the STAMPEDE trial were administered two generic health-related quality of life (QoL) questionnaires (RAND-36 and EQ-5D-3L) and a diabetes-specific instrument at baseline, and then on an annual basis up to 5 years after randomization. On longitudinal analysis, RYGB and SG significantly improved the domains of physical functioning, general health perception, energy/fatigue, and diabetes-related QoL compared with IMT group. In the IMT group, none of the QoL components in the generic questionnaires improved significantly from baseline. No significant long-term differences were observed among the study groups in measures of psychological and social aspects of QoL. On multivariable analysis, independent factors associated with improved general health perception at long-term included baseline general health (P < 0.001), insulin independence at 5 years (P = 0.005), RYGB versus IMT (P = 0.005), and SG versus IMT (P = 0.034). Favorable changes following RYGB and SG were comparable. In patients with T2DM, metabolic surgery is associated with long-term favorable changes in certain PROs compared with IMT, mainly on physical health and diabetes-related domains. Psychosocial well-being warrants greater attention after metabolic surgery.

One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study

BackgroundThe preservation or restoration of β cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D.MethodsThis was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. Fifty-three participants including 33 adult-onset (≥ 18 years) and 20 juvenile-onset T1D were enrolled. Twenty-seven subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n = 26) only received standard care based on intensive insulin therapy. Data at 1-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses.ResultsAfter 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide were not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed.ConclusionOne repeated intravenous dose of allogeneic UC-MSCs is safe in people with recent-onset T1D and may result in better islet β cell preservation during the first year after diagnosis compared to standard treatment alone.Trial registrationChiCTR2100045434. Registered on April 15, 2021—retrospectively registered, http://www.chictr.org.cn/

Insulin dependence increases the risk of postoperative complications and inferior outcome but not the survivorship of total joint arthroplasty among diabetic population: a systematic review and meta-analysis

Diabetes mellitus (DM) has been associated with poorer outcomes in total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, it is not clear if insulin-dependent diabetes mellitus (IDDM) patients display more perioperative complications and a worse clinical outcome compared to patients with non-insulin-dependent diabetes mellitus (NIDDM). Medline, Scopus, and the Cochrane library were systematically searched from inception to December 2020 to identify studies evaluating the results of THA and TKA in IDDM and NIDDM patients. The primary outcomes of the review were the surgical and systemic complications, 30-day mortality and readmission, and revision arthroplasty. Secondary outcomes were the survival of the prosthetic joints and the Knee Society Score (KSS). Thirteen studies with 54,215 patients were included in the review. IDDM patients showed a greater risk for developing periprosthetic joint infection (p = 0.02), wound complications (p = 0.01), 30-day readmission (p <0.01) and mortality (p <0.01), reoperation (p <0.01), revision joint surgery (p = 0.02), and systemic complications (p <0.01) than NIDDM patients. The KSS-knee score was similar in IDDM and NIDDM patients, but the KSS-function score was lower in IDDM patients (p = 0.002). The overall survival rates of the prosthetic joints were similar between the groups. Among diabetic population who undergo THA and TKA, insulin dependence is a risk factor for postoperative complications, and inferior functional outcome but not for shorter survivorship of the prosthetic joints.

630-P: Improved Glucose Control for People with Diabetes Who Enrolled in a Multi-Chronic Condition Remote Monitoring Platform

Background: Remote monitoring platforms (RMP) with personalized coaching continue to scale and have shown to be an effective tool for self-monitoring blood glucose (BG) and blood pressure (BP) for individuals with diabetes (DM) and hypertension (HTN). With HTN being a common risk factor for individuals with DM, it’s important to understand how RMPs can support individuals with both DM and HTN. Methods: Members were enrolled in a multi-chronic condition RMP with access to both DM and HTN programs. Using Propensity Score Matching to ensure no statistical differences in age, gender, race, DM type, insulin dependence, self-reported HbA1c, median zip code income, and zip code, two sample populations were constructed of those who were enrolled in DM only and DM+HTN between 1/1/2019 and 6/30/2019 and active on the platform for at least 1 year. For robust results, Bootstrapped Propensity Score Matching was used with 2,000 iterations. Paired t-test was used to compare reduction in estimated a1c at 6- and 9-months. Due to COVID-19, outcomes at 12-months were not evaluated. Results: No statistical differences between DM only (n=888) and DM+HTN (n=888) groups in age (56 vs. 56), gender (50% vs. 48% female), race (59% vs. 62% Caucasian), diabetes type (95% vs. 95% T2DM), insulin dependent (24% vs. 27%), started uncontrolled (49% vs. 50%), and self-reported HbA1c at time of registration (7.3% vs. 7.3%). Average estimated HbA1c reductions at 6 months were -0.46% for DM only and -0.65% for DM+HTN (p = 0.011). Reduction was similar at 9-month though no longer statistically different with values of -0.42% vs. -0.57%, respectively. Conclusions: Members enrolled in both DM+HTN versus DM only had improved glucose control within 6-months indicating RMPs that support multiple chronic conditions may have better outcomes. Future study is required to better understand the drivers of the clinical improvement for multiple conditions. Disclosure S. Liu: Employee; Self; Livongo, Teladoc Health. S. L. Painter: Employee; Self; Livongo. R. James: Employee; Self; Livongo, Teladoc Health, Stock/Shareholder; Self; Livongo, Teladoc Health. T. Kompala: Consultant; Self; Eli Lilly and Company, Employee; Self; Livongo. B. Shah: Employee; Self; Teladoc Health, Stock/Shareholder; Self; Teladoc Health.

168-OR: Five-Year Follow-up after Islet Transplantation in Nonuremic Patients with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness: Favorable Long-Term Outcomes of Multicenter Trial at University of Chicago

Introduction: Prospective randomized multicenter trial did not find advantage of CXCR1/2 blocker (Reparixin) over placebo in islet transplantation in patients with type 1 diabetes mellitus and problematic hypoglycemia at 1 year follow-up. We note favorable metabolic outcomes at 5-year follow-up in trial cohort from our center. Material and Methods: 12 patients with type 1 diabetes and problematic hypoglycemia received a total 19 islet transplants (max 2 per patient) within one year. Eight patients were randomly assigned and received Reparixin and 4 received placebo within first week after each transplant in addition to standard immunosuppression (anti-thymocyte globulin, tacrolimus, and mycophenolate). Results: 11/12 patients achieved insulin independence during the study period. At 5-year follow-up 4/8 (50%) remained insulin free with HbA1c &amp;lt;6.0 % in Reparixin group vs. 1/4 (25%) in placebo group. One patient had partial islet function without severe hypoglycemic episodes (SHE). Diabetic neuropathy and renal function remained unchanged while retinopathy improved in 3/6 (50%) patients. 6/12 (50%) patients left the study: 3/6 proceeded with pancreas transplant and remain off insulin, the remaining 3/6 stopped immunosuppression with decline of islet graft function, deterioration of glucose control (HbA1c &amp;gt; 7.0 %), and recurrence of SHE. No patients experienced any cardiovascular events nor became persistently sensitized (current PRA 0%). Conclusions: Repeat islet transplantation led to insulin independence in 91% of patients; 50% of patients in Reparixin group and 25% in placebo. Secondary diabetic complications did not progress. No patients became persistently sensitized. Subsequent pancreas transplantation was feasible and effective in patients with decline of islet graft function. Disclosure P. J. Bachul: None. A. Perez-gutierrez: None. A. C. Lucander: None. J. Fung: None. P. Witkowski: None. G. S. Generette: None. P. Borek: None. J. S. Pyda: None. R. Anteby: None. L. Basto: None. L. Perea: None. K. Golab: None. M. Tibudan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK02059); Kovler Family Fund; Dompé farmaceutici S.p.A.

1119-P: Improving Clinical Utility of GAD65 Autoantibodies by Electrochemiluminescence Assay When Identifying Autoimmune Adult-Onset Diabetes

Aims: It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes (T1D) and non-autoimmune type 2 diabetes (T2D). Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune T1D, but the clinical value of GADA by current standard radio-binding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes. Methods: Two cohorts of individuals recently diagnosed with diabetes at ≥20 years of age were analyzed including 771 patients 30-70 years olds from the Action LADA study and 2,063 patients 20-45 year olds from the Diabetes in Young Adults (DiYA) study. Clinical characteristics including requirement of early insulin treatment, BMI, and development of multiple islet autoantibodies were analyzed according to the status of RBA-GADA and ECL-GADA, respectively. Results: GADA was the most prevalent and predominant autoantibody, &amp;gt;90% in both cohorts with any positive autoantibody. GADA positivity by either RBA or ECL assay significantly discriminated clinical T1D from T2D. However, patients with ECL-GADA in both cohorts were at greatest risk of insulin treatment, multiple islet autoantibodies and lower BMI (all p&amp;lt;0.0001). Among patients GADA positive by RBA, 32.4% (90/278) in the Action LADA study and 25.6% (32/125) in the DiYA study were negative by ECL assay. Patients with GADA detectable by RBA, not confirmed by ECL, had a phenotype more similar to T2D and these RBA-GADA had lower affinity compared to GADA confirmed by ECL assay. Conclusion: The ECL-GADA assay offers advantages over the RBA-GADA in identification of adult-onset diabetes patients at higher risk of early insulin dependency. Disclosure X. Jia: None. L. Yu: None. R. D. Leslie: None. The action lada consortium: n/a. The diabetes in young adults (diya) study group: n/a. Y. Gu: None. T. Vartak: None. D. Miao: None. F. Dong: None. S. T. Jerram: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research &amp; Development, LLC, JDRF. A. Ferrara: None. J. M. Lawrence: None. Funding JDRF (2-SRA-2019-695-S-B); National Institutes of Health (DK32083); 5th Framework Program of the European Union; Centers for Disease Control and Prevention (1U18DP006289)

What Is New with Total Pancreatectomy and Autologous Islet Cell Transplantation? Review of Current Progress in the Field.

Patients with chronic pancreatitis have benefited from total pancreatectomy and autologous islet cell transplantation (TPAIT) since the 1970s. Over the past few decades, improvements have been made in surgical technique and perioperative management that have led to improved success of islet cell function, insulin independence and patient survival. This article focuses on recent updates and advances for the TPAIT procedure that continue to expand and innovate the impact on patients with debilitating disease.

Pre-operative glycaemic control and long-term survival in diabetic patients after coronary artery bypass grafting.

We analysed the Veteran Affairs data to evaluate the association of pre-operative glycated haemoglobin (HbA1c) and long-term outcome after isolated coronary artery bypass grafting (CABG). Veterans with diabetes mellitus and isolated CABG (2006-2018) were divided into 4 groups (I: HbA1c <6.5%, II: HbA1c 6.5-8, III 8-10% and IV: HbA1c >10%). The relationship of pre-operative HbA1c and long-term survival was evaluated with a multivariable Cox proportional hazards model and reported as hazard ratios (HR). The cumulative incidence of secondary end-points [myocardial infarction (MI) and repeat revascularization (percutaneous intervention)] for each group was modelled as competing events with cause-specific Cox proportional hazards models. Overall, 16190 patients (mean age 64.9 years, male 98%; insulin dependent 53%) with diabetes mellitus underwent isolated CABG. We observed 19.4%, 45.4%, 27% and 8.2% patients in groups I, II, III and IV, respectively. Patients with HbA1c >10% were the youngest (mean age 60.9 years) and had high rates of Insulin dependence (78%). In patients with HbA1c >10%, improvement in levels was observed in 76%. The median follow-up observed was 5.8 (3.2-8.8) years. Compared to the study mean HbA1c (7.3%), mortality rate increased with HbA1c levels >8%, and especially with pre-operative HbA1c levels >9%. Compared to patients with HbA1c <8%, HbA1c 8-10% and >10% were associated with increased MI (HR 1.24 and HR 1.39, respectively) and need for reintervention (HR 1.20 and HR 1.24, respectively). In patients undergoing CABG, pre-operative HbA1c >8% is associated with the increased risk of mortality and adverse cardiac events.

Australian experience with total pancreatectomy with islet autotransplantation to treat chronic pancreatitis.

This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P< 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.

Effects of islet transplantation on microvascular and macrovascular complications in type 1 diabetes.

Type 1 diabetes is associated with high morbidity and mortality from microvascular and macrovascular disease with considerable economic cost to society. Islet cell transplantation (ICT) is a treatment option recommended by National Institute for Health and Care Excellence (NICE) for people with debilitating hypoglycaemia due to type 1 diabetes, including those with renal failure where kidney transplantation may also be indicated. The primary aim of ICT is to improve glycaemic control, reduce severe hypoglycaemia, stabilise glycaemic variability and restore awareness of hypoglycaemia where this is compromised. Insulin independence, although not a primary aim, should also be considered a therapeutic goal. The impact ICT has on the progression of microvascular and macrovascular diabetes complications is derived from small studies and has not been examined in large clinical trials. Lifelong immunosuppression, which is necessary to avoid transplant rejection, has adverse effects on lipid metabolism, hypertension and renal function, which must also be considered. In this review, we discuss the role of ICT in type 1 diabetes management and the available evidence with respect to microvascular and macrovascular disease progression post-transplantation. We conclude that, following ICT, microvascular complications including retinopathy and neuropathy are stabilised or improved. Effects on nephropathy can be complicated by coexisting kidney transplantation and the impact of immunosuppression, the latter leading to an early decline in renal function; however, there is evidence to suggest stable renal outcomes in the long term. Short-term studies have demonstrated a positive impact of ICT on surrogate markers of macrovascular disease; however, long-term studies and trials in this area are lacking.

Clozapine Induced Insulin Dependence

Background: Antipsychotic medications come with an array of potential side effects in a difficult-to-treat population, particularly if management of other comorbidities is required. A review of the literature shows some studies have discussed the possibility of antipsychotic medication inducing hyperglycemia by blocking pancreatic M3 receptors. Other studies have shown dramatic worsening of metabolic parameters in patients who already have Type 2 Diabetes Mellitus after starting Clozapine. Clinical Case: A 23 year old African American Male with a past history of treatment resistant Schizophrenia presented to the ED with hyperglycemia and altered mental status. Blood sugar 489 mg/dL, anion gap 28 mmol/L, bicarb 13 mmol/L, white Blood Cell count 9.0 x10^3/cmm. Urine positive for Ketones. Chest Xray and EKG were normal, there were no obvious signs of infection. This was the sixth admission for Diabetic Ketoacidosis (DKA) in the past 10 months. Antibodies obtained showed negative Glutamic Acid Decarboxylase Autoantibodies (<5 IU/mL), Islet Cell Antibody IgG, Zinc Transporter 8 Antibody (<10 U/mL), IA-2 (<5.4 U/mL). C-peptide levels were in the low normal range (1.12 ng/mL) with a blood sugar 204 mg/dL. Prior to 10 months ago, the patient did not have a diagnosis of diabetes, with labs showing expected normal fasting blood sugar levels (90s mg/dL) and triglyceride levels of 150 - 200 mg/dL. One month after starting Clozapine for treatment resistant Schizophrenia, A1c doubled to 12.3%, Triglycerides increased to 1,378 mg/dL. The patient had been insulin dependent since the time of starting Clozapine. On this admission, Clozapine was held, DKA resolved with intravenous fluid, potassium replacement, and insulin drip. Repeat testing of c-peptide with blood glucose levels analyzed with the Homeostasis Model Assessment (HOMA) showed increasing HOMA%S (from 93% to 174%) and decreasing HOMA-IR with stopping Clozapine. Psychiatry recommended Clozapine as required treatment of his Schizophrenia, therefore the patient required chronic insulin. Conclusion: This case study shows Clozapine as the only major change in medications or lifestyle in this patient’s case. He demonstrated severe hyperglycemia and development of Diabetes Mellitus within a 4-week period of medication initiation as evidenced by multiple admissions for DKA, with low/normal C-peptide levels and insulin resistance. He has since been managed as a patient with Type 1 Diabetes. Clinicians should take a multidisciplinary approach to clinical surveillance during changes in schizophrenia treatment, particularly with second generation antipsychotics such as Clozapine, with attention to metabolic derangements including DKA.

Features of Slowly Progressive Type 1 Diabetes Mellitus in Overweight Adolescents

Background: he obesity epidemic has led to an increase in the incidence of type 1 diabetes mellitus (T1DM) on the background of overweight. The combination of T1DM and obesity can lead to an erroneous diagnosis of type 2 diabetes (T2DM). Methods: The study included 35 adolescents with T1DM. Inclusion criteria were obesity at onset, high titer of diabetes-associated autoantibodies, and insulin requirement less than 0.5 U/kg with a diabetes duration of more than 6 months. We assessed the level of HbA1c, fasting level of insulin and c-peptide, and level during the Mixed-Meal Tolerance Test, the immunological status of GADA, IA-2, ZnT8, ICA. Results: The age of onset was 12.7 years [10.6; 14.5], the tanner stage of puberty was 4 [3; 5]. Sex distribution: boys (n = 25) - 71.5%, girls (n = 10) - 28.5%. HbA1c at the time of onset equaled 8,9% [7.4; 10.45]. Ketosis/diabetic ketoacidosis was registered in 47.8%. The duration of the diabetes was 1.7 years at the moment of examination [0.7; 2.9]. The fasting level of C-peptide - 1.37 mμg/ml [1.0.9; 2.19], insulin level (n = 26) - 13.93 uU/ml [9.57; 19.77]. The maximum level of stimulated secretion of C-peptide (n = 21) - 5.13 mμg/ml [3.05; 6.07], of insulin secretion (n = 21) - 58.59 uU/ml [31.02; 79.74]. Higher HOMA of insulin resistance (n = 25) was detected in 72% of the examined patients. In the study of pancreatic autoantibodies, an increase in ICA was detected in 57% (median of titer 1.68 [0.28;11.7]), IA-2 - 67% (192.8 ME/ml [65; 310.1]), GAD - 59% (90.25 ME/ml [32.27; 214.6]), ZnT8 - 82% (350.5 [90.4; 506.05]). The presence of 2 or more autoantibodies is found in 94% of cases. Dyslipidemia was observed in 34.8%, arterial hypertension was identified in 23% of patients. Received therapy: insulin 82%; metformin 0.02%; metformin + insulin 5.7%. Median daily dose per patient was 0.3 U/kg [0.2; 0.5]. Conclusion: T1DM in adolescents with obesity and overweight has a similar clinical picture both with T1DM (insulin dependence, high titer of autoantibodies, ketosis) and T2DM (slow progression of the disease, low insulin requirement, preserved secretion of c-peptide, and insulin for more than 1.5 years). We hypothesize that obesity and insulin resistance may contribute to DM onset at an earlier date, even if a satisfactory function of pancreatic beta-cells is still preserved. Given that the onset of the disease in our group falls on adolescence it seems that pubertal insulin resistance also contributes to the features of the course of the disease. Understanding the role of obesity in the progression of disorders of carbohydrate metabolism will allow postponing the acute manifestation of the disease and initiation of insulin therapy through lifestyle modifications in patients at risk. A long period of preserved insulin secretion opens up the possibility of new personalized therapies.

Paraneoplastic Hypoglycemia Leading to Insulin Independence in a Patient With Type 1 Diabetes

Introduction: Hypoglycemia is a rare paraneoplastic manifestation of several non-islet cell tumors (NICT) that is rarely reported in individuals with diabetes. We report the first case of a patient with type 1 diabetes (T1D) and a recurrent gastrointestinal stromal tumor (GIST) who required discontinuation of all insulin therapy with continuous parenteral glucose infusions to avoid hypoglycemia. Case: The patient is an underweight (BMI 14.9 kg/m2) 59-year-old female with a 24-year history of T1D treated with insulin pump therapy who was diagnosed with GIST in 2003. Following surgical resection with postoperative adjuvant therapy, she remained tumor free until 2012 when she had disease recurrence unresponsive to several tyrosine kinase inhibitors. In 2014, she reported frequent episodes of documented hypoglycemia despite continued reductions in basal insulin infusion rates. Laboratory testing following several hours of insulin discontinuation revealed undetectable insulin and C-peptide levels, low IGF-1, normal IGF-2, and an IGF-2: IGF-1 ratio of 7.86. Thyroid, kidney and adrenal tests were normal. Initiation of prednisone alone then in combination with octreotide did not abate the hypoglycemia. During a hospitalization for hypoglycemia, exogenous insulin therapy was discontinued and 10% dextrose infusions started. Attempts at weaning the dextrose infusions resulted in hypoglycemia, prompting insertion of a PICC line prior to discharge home with continuous 25% dextrose infusions at 40-60 mg per hour. Discussion: NICT hypoglycemia (NICTH) is characterized by excessive tumor production of IGF-2 or pro-IGF-2. The structure of IGF-2 is similar to insulin, allowing cross reactivity at the insulin receptor. IGF binding proteins (IGFBPs) are responsible for transporting IGF-2 in plasma. Abnormal processing of the gene for IGF-2 results in increased production of the more biologically active pro-IGF-2 that does not form a complex with IGFBP3 and is available to interact with insulin receptors. In patients with normal IGF-2 (chronic kidney disease, poor nutritional status), an IGF-2: IGF-1 ratio >3 can be used to confirm NICTH. IGFBP-3 was not measured in this patient but it is likely this was low due to her poor nutritional status. The most definitive treatment for NICTH is resection of the tumor. Pharmacological management can be considered in patients who are not surgical candidates, but is not always successful as was observed in this patient. Conclusion:This is an unusual case of malignancy associated hypoglycemia in a woman with type 1 diabetes who required discontinuation of all insulin therapy as well as continuous dextrose infusions to achieve euglycemia and briefly maintain an acceptable quality of life over a period of several months.

An Atypical Case of Latent Autoimmune Diabetes of Adults

Introduction: Latent autoimmune diabetes of adults (LADA) is an adult-onset, slowly progressing subtype of autoimmune type 1 diabetes mellitus (T1DM), that is often misdiagnosed as T2DM. We present an atypical case of LADA that was presented in an uncommonly late age with high titres of anti-glutamic acid decarboxylase antibodies(GADA). Clinical Case: A 78 year old male presented with alcohol intoxication and hyperglycemia. His serum glucose was 441mg/dL with negative urine ketones. Arterial blood gas showed pH 7.36, HCO3- 20mmol/L, pCO2 37.1mmHg. Anion gap was 11. HbA1c level was 16%. His body weight was 43.2kg with a BMI of 16.6. He was having polyuria and polydipsia, and was recently diagnosed with T2DM. His low BMI and symptoms raised suspicion for LADA. GADA titres revealed to be greater than 250IU/mL. A diagnosis of LADA was made. He was discharged on insulin. Conclusion: LADA shares the same genetic and autoimmune profiles with T1DM, but its insidious presentation overlaps with that of T2DM, often delaying diagnosis and adequate treatment. Our case of confirmed LADA at a late age of 78 is atypical, but warrants that adults newly diagnosed with diabetes should be screened for LADA if there are atypical findings. Among the anti-islet antibodies, GADAs are the most sensitive self antigen-antibody markers of autoimmune diabetes. The GADA titre is often used to stratify the risk of progression to insulin dependence in LADA, as a higher titre suggests severe β-cell loss in the pancreas. High GADA titres at the time of diagnosis at an elderly age is also an uncommon finding for LADA. Autoimmune diseases with aggressive autoimmune responses present early, while indolent progressions lead to late onset of symptoms and diagnosis. Thus it is unusual for our patient to have significantly high GADA levels. As pathophysiology of LADA is yet to be understood, further research may reveal the autoimmune process of GADA and the role of titres in disease activity and progression. There are no current therapeutic guidelines for LADA. Our patient was eventually discharged on insulin given his high HbA1c with high titres of GADA, but there were questions regarding the use of oral glycemic control agents due to his history of noncompliance. The use of oral agents for LADA remains an area of ongoing research. The general understanding is that due to its autoimmune etiology, insulin is eventually required. Early insulin therapy preserves residual β-cell function, improves glycemic control, and reduces the risk of long-term complications. As treatment goals of LADA would be to improve glycemic control with preserving residual β-cell function, further research may establish treatment guidelines for LADA. Monitoring anti-islet antibodies and c-peptide titres may play a role in establishing the timing to introduce oral agents and/or insulin for optimal treatment of LADA.