Insulin Independence Research Articles

Diffuse calcification of pancreas impairs endocrine function and predicts poor outcome in total pancreatectomy with islet autotransplantation

In patients with chronic pancreatitis, pancreatic calcification is a risk factor for diabetes development, poor islet yield, and metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT). We investigated whether calcification pattern based on computed tomography is associated with outcomes using our database of 200 consecutive TPIAT procedures. Three groups were compared: noncalcification (NC); focal calcification, limited to the pancreas head, body, or tail; and diffuse calcification (DC), with calcification in >2 sections. Maximum changes in outcomes were seen in the DC vs focal calcification group. In the DC group, preoperative hemoglobin A1c levels were higher (P < .01), and stimulated C-peptide levels were lower (P < .01) than in the NC group. Islet isolation from the DC pancreas resulted in the lowest islet equivalent (IEQ) yield and IEQ/kg among the 3 groups (P < .0001), with no insulin independence 12 months posttransplant (P < .05 vs NC group). Notably, at 12 months, the DC group was 91.7% narcotic-free, significantly higher than the NC group (P < .05). Although DC is a sign of diabetes risk after TPIAT, the DC group showed exceptional pain relief. These findings suggest that TPIAT can be beneficial for patients with chronic pancreatitis with severe calcification.

Modern understanding of latent autoimmune diabetes in adults

Latent autoimmune diabetes in adults (LADA) according to various sources is from 4 to 12% of all cases of type 2 diabetes mellitus (T2DM). Its uniqueness lies in the simultaneous combination of autoantibodies to β-cells (characteristic of T1DM) and the possibility of treatment with oral hypoglycemic drugs (characteristic of T2DM) for at least 6 months. This is based on the pathogenesis common for T1DM and T2DM — the presence of an autoimmune reaction with the simultaneous involvement of adaptive and innate immunity, as well as, to a lesser extent, insulin resistance and a number of components of the metabolic syndrome. LADA has more in common with T1DM — the same stages in the development of the disease, from genetic predisposition to the undoubted development of insulin dependence, the difference lies in the duration of each of the periods and the age of manifestation. LADA is characterized by an older age of manifestation of 30–35 years and a slower rate of destruction of β-cells. This article presents data on the diagnosis, progress of LADA, its similarities and differences with other types of DM, and immunological features. The article also analyzes the modern approach to the treatment of patients with LADA and promising methods of treatment. The search for information was processing in published sources attached to the search engines PubMed, Google Scholar, Scopus, Web of Science, eLibrary.ru over the past 10 years. The following medical subject headings were used: latent autoimmune diabetes in adults, diabetes mellitus type 1 and 2, immunology, pancreas, genetic, treatment in various combinations using OR and AND logical operators.

Long-term effects of pancreatic islet transplantation on polyneuropathy in patients with brittle diabetes: A single-center experience.

Pancreatic islet transplantation (ITx) is increasingly used in patients with brittle type 1 diabetes (T1D). If successful, ITx results in insulin-free euglycemia, but its application is limited by a need for lifelong immunosuppression. The aim of this study was to assess the long-term effects of ITx on the occurrence and course of polyneuropathy in a cohort of patients with brittle T1D. In this prospective, single-center study, 13 patients (4 males and 9 females) with brittle T1D had a baseline neurological exam with the calculation of Utah Neuropathy Scale (UNS) and a limited nerve conduction study before ITx, and about yearly after in the patients who achieved insulin independence. Patients were followed for a period of 17 to 133 months. There was no significant difference between UNS and nerve conduction study parameters at baseline and at the end of follow-up, except for significant decreases in peroneal (50.34 ± 6.12 vs. 52.42 ± 6.47 ms, P = 0.005) and ulnar (27.5 ± 2.15 vs. 29.45 ± 2.10 ms, P = 0.009) F-wave latencies and an increase in ulnar sensory nerve conduction velocity (49.98 ± 6.27 vs. 47.19 ± 5.36 m/s, P = 0.04). If successful, ITx has a good long-term safety profile for peripheral nerve toxicity, and a favorable effect on diabetic neuropathy.

836-P: Glucose-Dependent Insulin Production and Insulin-Independence in Type 1 Diabetes from Stem Cell–Derived, Fully Differentiated Islet Cells—Updated Data from the VX-880 Clinical Trial

VX-880 is an investigational allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy being evaluated in a phase 1/2 clinical trial in patients with T1D and impaired hypoglycemic awareness and severe hypoglycemia. The phase 1/2 trial has three parts: Part A in which 2 patients are enrolled sequentially and receive half the target dose (presented at ADA 2022), Part B in which 5 patients are enrolled sequentially and receive the target (full) dose, and Part C where 10 patients are enrolled concurrently and receive the target (full) dose. The first two patients infused with VX-880 at half the target dose (in Part A) had restored insulin production and glucose control. One of these patients achieved and has maintained insulin independence, defined as at least one week off exogenous insulin, HbA1C ≤7%, post-prandial serum glucose at 90 minutes ≤180 mg/dL, fasting serum glucose ≤126 mg/dL, and fasting or stimulated C-peptide ≥166 pmol/L (latter 3 measured during mixed-meal tolerance test). The safety profile was consistent with the immunosuppressive regimen used in the study and the perioperative period. Part B is now fully enrolled and multiple patients have been dosed with the full (target) dose. Longer-term data on both patients in Part A and new data on patients who received the full (target) dose in Part B will be provided in the presentation. These results are the first from a clinical trial of allogeneic, fully differentiated, insulin producing, stem cell-derived islets which has demonstrated the potential to restore insulin production and glycemic control and provide insulin independence in patients with T1D. Disclosure T.W.Reichman: Consultant; Sernova, Corp., Research Support; Vertex Pharmaceuticals Incorporated. J.L.Shih: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. D.Melton: None. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Consultant; Vertex Pharmaceuticals Incorporated, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bristol-Myers Squibb Company, Adaptive Biotechnologies, Merck &amp; Co., Inc., Tessera, Novartis. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. J.F.Markmann: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). M.Wijkstrom: None. S.Paraskevas: None. B.Bruinsma: Employee; Vertex Pharmaceuticals Incorporated. G.Marigowda: Employee; Vertex Pharmaceuticals Incorporated.

237-OR: Gastrin Improves Single Islet Transplant Outcomes

Background: Multiple allogenic islet transplants (ITs) are usually required to supply adequate islet mass (~10,000 IEQ/kg) to induce insulin independence. Improving outcomes of a SINGLE islet transplant are needed. Gastrin is a gut hormone that is involved in normal fetal pancreas development. Evidence by our group and others have shown gastrin can support islet cell expansion/function and have anti-inflammatory and pro-angiogenesis effects. We compared outcomes of IT alone across 3 clinical trials using: Edmonton-based (ITA), T-cell depleting (TCD), and TCD immunosuppression with an investigational gastrin analogue (GAS). Methods: Between 2004-2022, a total of 31 evaluable T1D patients without a prior history of transplant received IT-alone under the ITA (n=17), TCD (n=7), and GAS (n=7) clinical trials. Participants in ITA and TCD were eligible to receive up to 3 ITs each. GAS participants received only a single IT and two 30-day courses of gastrin (SQ, BID) at the time of IT and again 6 months later. Immunosuppression included basiliximab or daclizumab + etanercept (ITA) and T-cell depletion (anti-thymoglobulin) + etanercept + anakinra (TCD and GAS). Results: Progressive improvements in engraftment were observed in the ITA, TCD, and GAS trials. Average insulin requirements were reduced by 18, 26, and 33 u/day. GAS subjects showed the most rapid reduction of 30.9 u/day (94%) in the first 2 weeks post-IT, compared to 17.5 u/day (67%) in TCD. Rates of subjects achieving insulin independence with a SINGLE islet transplant were 0, 15, and 57%. Subjects required an average of 3 ITs in ITA, 2 in TCD, and only one IT in GAS to achieve insulin independence. Average numbers of islets required to achieve insulin independence were 13,280, 8,433 and 4,837 IEQ/kg. Conclusion: Gastrin use in the peri-transplant period leads to rapid engraftment, larger magnitude of insulin reduction, and permitted achievement of insulin independence in more than half of subjects after a single islet transplant of less than half the normally targeted islet dose. Disclosure J.Hacker-stratton: None. C.Orr: None. K.Omori: None. M.Qi: None. E.Forouhar: None. M.El-shahawy: None. F.R.Kandeel: None. Funding National Institutes of Health (U24DK098085)

1498-P: Preemptive Insulin Supplementation for Islet Graft Protection, Optimal Blood Glucose Control, and Fetal Development during the Pregnancy in Insulin-Independent Patient after Islet Transplantation

Pregnancy increases metabolic demand for insulin, which may lead to the exhaustion of intraportally transplanted islets and postgestational hyperglycemia. Here we report a successful long-term preservation of islet graft function after two subsequent pregnancies while applying preemptive insulin supplementation. 29-year-old female with T1DM achieved long-term insulin independence with HbA1c &amp;lt;5.8% after a single intraportal islet transplant. Before conception, mycophenolate was replaced with azathioprine and tacrolimus target trough level was decreased to 4-6ng/ml. The patient became pregnant twice, 5 years and 7.5 years after her islet transplantation. During the first and second pregnancy patient preemptively supplemented with insulin up to 35-70u/day and up to 35 units daily, respectively to target fasting blood glucose below 90mg/ml. Postpartum the patient was successfully weaned off insulin maintaining optimal blood glucose control with HbA1c below 5.7%. Islet graft function before and after the pregnancy remained optimal as reflected by BETA-2 above 17 and comparable c-peptide secretion and peak blood glucose levels below 130mg/ml during the 8.5-year follow-up in Mixed Meal Tolerance Test. Both newborns were premature and delivered at 34 weeks with emergent c-sections due to preeclampsia. Unfortunately, the first newborn died due to necrotizing enterocolitis. The second child has been developing appropriately up-to-date three months after her birth. Our report confirms that insulin supplementation during pregnancy in insulin-independent patients after islet transplantation was safe and effective in maintaining optimal blood glucose control and islet graft function in the long term. It also underscores the high-risk nature of pregnancy in islet transplant recipients and the need for close clinical monitoring. Disclosure S.Gondek: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

1425-P: C-Peptide and Islet Autoantibodies at Diagnosis Predict Long-Term ß-Cell Function and Insulin Dependence in Pediatric Diabetes

We asked if assessment of islet autoimmunity and β cell function in children at diabetes diagnosis is useful for prognosis, using the “Aβ” system, [“A” representing autoimmunity (A+ = ≥1 autoantibody; A- = no antibodies), “β” representing β cell function (β+ = random serum C-peptide ≥0.6 ng/mL; β- = C-peptide &amp;lt;0.6 ng/mL)]. We followed β cell function longitudinally with 2h post-prandial urinary C-peptide-creatinine ratio (UCPCR) at 3-12 wk (V1) and 6-12 m (V2). We compared clinical characteristics, glycemia and β cell function at baseline and clinical outcomes at V2 between the groups. The cohort (n=74) was 50% female, 76% White, 22% non-Hispanic Black, 2% Other, 47% Hispanic. Median age (25p-75p) was 12.6 (8.5-14.6) years, median BMI 70.7 (16.7-96.1) %ile. Phenotypic frequencies were A+β- (36.5%), A-β+ (29.7%), A+β+ (31.1%) and A-β- (2.7%). Baseline serum C-peptide correlated with UCPCR at V1 (r=0.37, p=0.03). Adjusting for age, sex, race/ethnicity, and BMI, UCPCR at V2 was higher in A-β+ than A+β- (β=1.18, 95% CI:0.31-2.07, p=0.009). Fully 36% of A-β+ but none of A+β+ and A+β- were insulin-independent at V2 (p&amp;lt;0.001). The remaining results are shown in Table 1. The A-β+ phenotype at diagnosis predicts sustained β cell function and potential insulin-independence after 6-12 months. Random serum C-peptide at diagnosis correlates with 2h post-prandial UCPCR at 3-12 weeks. Disclosure M.Tosur: Advisory Panel; Provention Bio, Inc. A.Balasubramanyam: None. X.C.Huang: None. S.Deen: None. S.Uysal: None. M.Astudillo: None. W.Hagopian: Research Support; Janssen Research &amp; Development, LLC, Provention Bio, Inc., Randox R &amp; D. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. F.Jahoor: None. M.J.Redondo: None. Funding Texas Children's Hospital (to M.T.); Rutherford Fund (to A.B.); National Institutes of Health (K23DK129821 to M.T.)

134-OR: Associations of Growth Hormone (GH) Mediators with Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

T2D in youth has a more severe phenotype than in adults, with puberty as a potential contributor to this difference. Pubertal changes in GH mediators (e.g., insulin-like growth factor 1 (IGF-1), growth hormone receptor (GHR), insulin-like growth factor binding protein 1 (IGFBP-1)) may impact insulin sensitivity and beta cell function. We examined associations of GH mediators with loss of glycemic control in youth with T2D using the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort (N= 310). We performed paired comparison of plasma concentrations of IGF-1, GHR, and IGFBP-1 (ELISA), between 0mo and 36mo based on TODAY primary outcome of loss of glycemic control vs. maintained glycemic control (LGC vs MGC), with LGC defined as HbA1c ≥ 8% for 6 months and/or insulin dependence. We studied associations of GH mediators with HbA1c, insulinogenic index, oral disposition index, and 1/fasting insulin. Models were adjusted for age, sex, race, treatment arm, and baseline HbA1c (linear regression). Mean plasma IGF-1 (ng/mL) was lower in LGC group at 0mo (LGC: 451 ± 141, MGC: 485 ± 155, p = 0.04), and at 36mo (LGC: 340 ± 117, MGC: 400 ± 136, p&amp;lt; 0.0001). Increase in IGF-1 between 0-36mo predicted lower HbA1c at 36mo (B = -3.2E-3, SE = 9.0E-4, p &amp;lt; 0.001). Higher GHR was associated with higher HbA1c (B = 1.2E-2, SE = 3.0E-3, p &amp;lt; 0.001) and lower 1/fasting insulin (B = -6.6E-4, SE = 2.1E-4, P &amp;lt; 0.01) at 0mo. Increase in GHR between 0-36mo predicted higher 36mo HbA1c (B = 3.0E-2, SE = 9.4E-3, p &amp;lt; 0.01). IGFBP-1 was positively associated with 1/fasting insulin at 0m (B = 1.1E-3, SE = 4.9E-4, p = 0.03). In exploratory analyses stratified by Tanner stage (TS) at study entry, GH mediators changed differentially between TS 1-3 (n = 31) vs TS 4-5 (n = 274). In conclusion, GH mediators differed based on primary outcome in TODAY, and were associated with HbA1c and insulin sensitivity. Whether changes in GH mediators contribute to, or are the result of, changes in glucose metabolism is a key area for future studies. Disclosure C.Lu: None. D.Wolfs: None. L.El ghormli: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. E.M.Isganaitis: None. Funding National Institutes of Health (2T32DK007260-46); National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK061230-16)

1729-P: Role of ß-Cell Senescence in Islet Transplantation

Islet transplantation (Tx) is an effective intervention to prevent severe hypoglycemia and provide insulin independence in type 1 diabetes (T1D). Previous studies have shown that islets from older donors are less effective in reversing blood glucose (BG) than those of younger ones. Cellular senescence leads to age-related β-cell dysfunction and drives alloimmune responses to organs from older donors, but can be targeted with senolysis. However, the mechanism of pancreatic β-cell senescence in transplant grafts and its pathological significance are unknown. Therefore, we performed two types of islet Tx to test the hypothesis that cellular senescence may play a role in loss of graft functionality/viability and that the use of senolysis may ameliorate it: 1) overnight cultured 600 IEQ islets from normoglycemic rats were transplanted into kidney capsule of streptozotocin-induced diabetic immunodeficient mice (Stz-Ms). After 2 weeks, the grafts were removed and compared with the cultured islets (control). In Stz-Ms, the nuclear exclusion rate of Hmgb1 and p21-positive cells tended to increase, and the mRNA levels of p16, Il-6, and β-cells related genes were significantly higher than in control islets indicating β-cell senescence after transplantation. To test if the elimination of p16 positive senescent β-cells from transplanted islets improved BG levels, 2) 440 IEQ islets from INK-ATTAC mice (p16Ink4a mediated apoptosis through targeted activation of caspase) were transplanted into Stz-Ms and treated intraperitoneally with BB Homodimerizer (BB) or vehicle for 2 terms of 3 consecutive days, of which 2 weeks of rest. With senolysis, there was a decrease in fed glucose levels and p16 mRNA expression while expression of hallmark β-cell genes increased by 74%, which correlates with improved response to high glucose. In conclusion, islet transplantation increases β-cell senescence in grafts and senolysis improves β-cell function. This has important implications in increasing graft function and survival in the treatment of T1D. Disclosure K.Iwasaki: None. P.Carapeto: None. C.Aguayo-mazzucato: None. Funding Manpei Suzuki Diabetes Foundation

241-OR: Preservation of Islet Graft Function and Blood Glucose Control after Total Pancreatectomy with Islet Autotransplantation in Patients with Chronic Pancreatitis and Intractable Pain—Nine-Year Follow-up

Background: Total pancreatectomy is a last resort treatment for patients with chronic pancreatitis and intractable abdominal pain, however its utility has been hampered by the uncertain endocrine outcomes of islet transplantation and risk of postsurgical diabetes. Here, we present our 9-year clinical results after total pancreatectomy and islet transplantation. Materials and Method: Forty-one patients with chronic or recurrent acute pancreatitis were treated with TPIAT over the last 9 years at the University of Chicago Medical Center. There were 15 male and 26 female with a median age of 33 (6-65) and with median BMI of 25 (17-39). Five (12%) patients were already diabetic prior to surgery. Islet isolation was performed at a local laboratory compliant with current Good Manufacture Practice regulations. Islet purification was implemented in 4 (10%) cases to reduce islet pellet volume below 20mL for intraportal infusion. Results: All patients required opioids for pain control prior to surgery. Most of the patients (93%) reported resolution of pancreatic-type pain by postoperative year one. The number of patients requiring opioids for different type or location of pain declined over time from 13 (31%) at 1 year to 5 (12%) at 5 years after TPIAT. During TPIAT patients received on average 211,000±111,000 islet equivalents (IEQ), 2,500±1,600,). The majority of patients (95%) maintained endocrine beta cell function during follow up (serum c-peptide &amp;gt;0.5ng/ml). Over 40% of patients maintained long-term insulin independence: 44% (15/34) at 1-year and 45% (5/11) at 5-year follow-up. Conclusions: TPIAT successfully provided pancreatic pain resolution of pancreatic pain and preservation of the endocrine beta cell function in majority of the patients with no mortality. Islet autotransplantation prevented diabetes in over 40% of patients. Disclosure W.Lin: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. S.Gondek: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020595)

239-OR: Glycemic Control after Total Pancreatectomy with Islet Autotransplantation—Results from a Single Center with Large Cohort of Patients

Total pancreatectomy and islet autotransplantation (TPIAT) for refractory chronic pancreatitis has been performed at our center from 2006. We employed anti-inflammatory treatment using IL-1β and TNF-α blockers to improve graft outcomes. We present results on islet characteristics and glycemic control post-TPIAT from this large cohort of patients. Our database of 200 consecutive TPIAT procedures performed were retrospectively reviewed. We collected demographics, pancreas and islet characteristics. Patient follow-ups were performed at 3, 6, 12 m and then annually. Outcomes measures included glycemic control, pain relief and narcotic use. Baseline patient characteristics (age, sex, BMI, etiology, C-peptide and HbA1c, duration of symptoms) and isolation results were shown in Table 1A and post-TPIAT fasting glucose, HbA1c, C-peptide and daily insulin use in Table 1B. The insulin independence rate at 3, 6 and 12 months increased with time from 15%, 24 % and 27%, respectively). At 1 year, pain score was significantly improved (p&amp;lt;0.0001). Narcotic free rate also increased to 47% at 6 months and 56% at 1 year. Most post-TPIAT patients preserved hypoglycemic awareness and good pain relief. A cohort of patients remained normoglycemic without insulin and this group can be further studied to identify the factors that prevent the incidence of T3cDM after TPIAT. Disclosure A.Hakim mohammed: None. C.Darden: None. J.Kirkland: None. J.Kuncha: None. J.D.Mattke: None. M.C.Lawrence: None. B.Naziruddin: None.

1481-P: Islet Cell Autoantibody Formation and Its Effect on Insulin Requirement after Total Pancreatectomy with Islet Autotransplantation (TPIAT)

Introduction: Long term insulin requirements following TPIAT range from insulin independence to full (high) dose daily insulin (&amp;gt;0.5 units/kg/day). Markers of islet cell autoimmunity are used in children to predict type 1 diabetes risk. However, no studies have explored whether an association exists between islet cell autoimmunity and insulin requirement following TPIAT in children. We hypothesized that children with islet cell autoantibody formation were more likely to have a persistent insulin requirement following TPIAT. Methods: All children who underwent TPIAT between 2015 and 2021 at our institution were eligible for inclusion. Islet cell autoimmunity was defined as positive islet cell autoantibody screen for one or more of the following types of autoantibodies: Glutamic Acid Decarboxylase (GAD), Islet Antigen-2 (IA-2), Insulin (IAA), or Zinc Transporter 8 (ZnT8). Patients were screened prior to TPIAT and every six months following TPIAT for up to three years. In all, 73 patients were included in the analysis. Total daily insulin dose was determined for each patient at each time interval. Chi-square or Fisher’s exact tests were used to compare proportions. Results: Of patients with 12-month data (n=38), 47% of islet cell autoantibody negative patients were off insulin vs 26% of antibody positive patients (p=0.19). This trend was significant at 18, 24, and 36 months after TPIAT. At 18 months, 90% (9/10) of antibody negative patients were off insulin vs 29% (4/14) of antibody positive patients (p=0.005). At 24 months, 73% (8/11) of antibody negative patients were off insulin vs 23% (3/13) of antibody positive patients (p=0.04). At 36 months, 100% (8/8) of antibody negative patients were off insulin compared to 0% (0/9) of antibody positive patients (p&amp;lt;0.0001). Conclusions: The presence of pancreatic islet cell antibodies was associated with persistent insulin requirement after TPIAT. Disclosure A.R.Lavik: None. C.M.O.Lowe: None. S.E.Tellez: None. L.Hornung: None. C.Heinzman: None. J.D.Nathan: None. M.Abu-el-haija: None. D.A.Elder: None.

Clinical and HLA genotype analysis of immune checkpoint inhibitor-associated diabetes mellitus: a single-center case series from China.

To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China. We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing. The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m2, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 vs 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (P<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB1*0901-DQA1*03-DQB1*0303 (DR9) and DRB1*0405-DQA1*03-DQB1*0401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA1*0501-DQB1*0201 (DR3) and DR9 haplotypes were less frequent (17.7% vs 2.3%; P=0.011 and 34.4% vs 15.9%; P=0.025), whereas the protective haplotypes (DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301) were more frequent in ICI-DM patients (2.1% vs 13.6%; P=0.006 and 4.2% vs 15.9%; P=0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (P<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB1*0405-DQB1*0401 or DRB1*0901-DQB1*0303). ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1years, including one patient 9years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1mL/min to 50.2 ± 27.1mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies.

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence.

Enrichment of stem cell-derived pancreatic beta-like cells and controlled graft size through pharmacological removal of proliferating cells.

Transplantation of limited human cadaveric islets into type 1 diabetic patients results in ∼35months of insulin independence. Direct differentiation of stem cell-derived insulin-producing beta-like cells (sBCs) that can reverse diabetes in animal models effectively removes this shortage constraint, but uncontrolled graft growth remains a concern. Current protocols do not generate pure sBCs, but consist of only 20%-50% insulin-expressing cells with additional cell types present, some of which are proliferative. Here, we show the selective ablation of proliferative cells marked by SOX9 by simple pharmacological treatment invitro. This treatment concomitantly enriches for sBCs by ∼1.7-fold. Treated sBC clusters show improved function invitro and invivo transplantation controls graft size. Overall, our study provides a convenient and effective approach to enrich for sBCs while minimizing the presence of unwanted proliferative cells and thus has important implications for current cell therapy approaches.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.

Metabolic Outcomes in Pediatric Patients One-Year Post-Total Pancreatectomy with Islet Autotransplantation after Early Pump Initiation.

We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following a total pancreatectomy with islet autotransplantation (TPIAT). We investigated metabolic outcomes of this population at one-year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. We retrospectively reviewed 40 patients post-TPIAT previously studied at 10-days post-surgery (15 used MDI and 25 used pump therapy immediately post-ICU, and all were discharged on pump therapy). Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. one-year (via mixed meal testing) HbA1c, fasting glucose, insulinogenic index, and the area under the curve (AUC) for insulin and c-peptide. More patients were off insulin at one year in the early pump group compared to the MDI group (45% vs. 13%, p = 0.07). Of all patients off insulin, 100% of the early pump users weaned off by six months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg, were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97 vs. 122 mg/dL, p = 0.003), while AUC c-peptide was greater in early pump users at one-year post-TPIAT but did not reach significance (median 57.0 vs. 50.3 ng/mL × minutes, p = 0.14). Other metabolic outcomes did not differ between groups. Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Younger TPIAT age (p = 0.02) and early pump users (p = 0.04) were significantly associated with insulin independence at one year. This study was limited by sample size. Early pump use may have long-term benefits in post-TPIAT endogenous insulin secretion.

Abstract #1402477: Sixth-Nerve Palsy in Uncontrolled Type 1 Diabetes with Insulin Dependence

Diabetic retinopathy is the most common and well-known ophthalmologic complications in diabetic patients. However, oculomotor palsy is one of the most frequent neuro-ophthalmologic complications of diabetic patients. Specifically, sixth nerve palsy is the most common, however infrequently studied. Our patient is a 51-year-old female with a past medical history of insulin-dependent diabetes mellitus, hypertension, chronic sinusitis, and chronic pain syndrome that presented with complaints of worsening headache and diplopia. Patient was hemodynamically stable on admission. Upon examination of the eye, the patient's right eye did not cross the midline in lateral gaze and was found to have diplopia in primary and lateral gaze of left eye. She was found to have recurrent sixth nerve palsy upon further evaluation of her visual deficit. Labs showed creatinine of 0.61 mg/dl (0.66-1.25 mg/dL), sodium of 129 mmol/L (135-145 mmol/L), potassium of 4.4 mmol/L (3.5-5.1 mmol/L), an anion gap of 2 mmol/L (3-13 mmol/L), blood glucose in the 300-400 mg/dL range (70-100 mg/dL) with most recent blood glucose of 168 mg/dL. Her hemoglobin A1C is 13.0 (< 6%). Her complete blood count shows a white blood cell count of 6,000/uL (3,600-10,700/uL) and a hemoglobin of 14 g/dL (13.0-18.0 g/dL). Magnetic resonance venography of the head was negative for cerebral venous sinus thrombosis and magnetic resonance imaging of the brain was negative for acute abnormalities. She was treated with basal insulin of 30 units nightly and bolus insulin of 3 units three times a day before meals for type 1 diabetes with hyperglycemia with long-term insulin use. Visual deficit was treated by observation by ophthalmology with symptomatic help through eyeglass prisms. She was discharged after one night of hospital stay with recommendations to control her home basal insulin with a carbohydrate-controlled bolus dose during meals. She was recommended to follow-up with endocrinology outpatient to discuss use of insulin pump to better control her diabetes. Sixth-nerve palsy is a frequent but lesser-known neuro-ophthalmologic complication of poorly controlled diabetic patients. Studies have shown a higher incidence of diabetes in patients with sixth-nerve palsy, warranting a more focused medical evaluation along with close observation and tighter control of blood glucose levels and hemoglobin A1C.

Electrophysiological evidence of diabetes' impacts on central conduction recoveries in degenerative cervical myelopathy after surgery.

To assess the impact of diabetes mellitus (DM) on the postoperative motor and somatosensory functional recoveries of degenerative cervical myelopathy (DCM) patients. Motor and somatosensory evoked potentials (MEP and SSEPs) and modified Japanese Orthopedic Association (mJOA) scores were recorded in 27 diabetic (DCM-DM group) and 38 non-diabetic DCM patients (DCM group) before and 1 year after surgery. The central motor (CMCT) and somatosensory (CSCT) conduction time were recorded to evaluate the conductive functions of the spinal cord. The mJOA scores, CMCT and CSCT improved (t test, p < 0.05) in both of the DCM-DM and DCM groups 1year after surgery. The mJOA recovery rate (RR) and CSCT recovery ratio were significantly worse (t test, p < 0.05) in the DCM-DM group compared to the DCM group. DM proved to be a significant independent risk factor for poor CSCT recovery (OR = 4.52, 95% CI 2.32-7.12) after adjusting for possible confounding factors. In DCM-DM group, CSCT recovery ratio was also correlated with preoperative HbA1 level (R = - 0.55, p = 0.003). Furthermore, DM duration longer than 10years and insulin dependence were risk factors for lower mJOA, CMCT and CSCT recoveries among all DCM-DM patients (t test, p < 0.05). DM may directly hinders spinal cord conduction recovery in DCM patients after surgery. Corticospinal tract impairments are similar between DCM and DCM-DM patients, but significantly worsened in chronic or insulin-dependent DM patients. The dorsal column is more sensitively affected in all DCM-DM patients. Deeper investigation into the mechanisms and neural regeneration strategies is needed.