Insulin Independence Research Articles

Shifting the paradigm of type 1 diabetes: a narrative review of disease modifying therapies

A new diagnosis of type 1 diabetes (T1D) may be accompanied by numerous lifelong financial, emotional, and physical challenges, thus advancements in therapies that can delay the onset of clinical disease are crucial. T1D is an autoimmune condition involving destruction of pancreatic beta cells leading to insulin deficiency, hyperglycemia, and long-term insulin dependence. The pathogenesis of T1D is classified into stages, with the first signal being the detection of autoantibodies without any glycemic changes. In the second stage, dysglycemia develops without symptoms, and in stage 3, symptoms of hyperglycemia become apparent, and at this time a clinical diagnosis of T1D is made. As a greater understanding of these stages of T1D have evolved, research efforts have been devoted to delaying the onset of clinical disease. To date, only one medication, teplizumab, has been approved by the Food and Drug Administration (FDA) for the treatment of stage 2 T1D. This narrative review present published trials and ongoing research on disease modifying therapies (DMT) in T1D, the mechanisms of action for each therapy, and the stages of T1D that these interventions are being studied.

Challenges in Beta Cell Replacement for Type 1 Diabetes.

Type 1 diabetes (T1D) presents a significant global health challenge, characterized by immune-mediated destruction of pancreatic beta-cells. Achieving therapeutic goals such as prevention of immune destruction, preservation of beta-cell mass, and automated insulin delivery remains complex due to the disease's heterogeneity. This review explores the advancements and challenges in beta-cell replacement therapies, including pancreas and islet cell transplantation, stem cell-derived β-cell generation, and biotechnological innovations. Pancreas transplantation, especially simultaneous pancreas and kidney transplantation (SPK), has evolved significantly, offering insulin independence and improved quality of life despite surgical and immunological complications. Allogeneic islet transplantation, though less invasive, faces challenges such as donor scarcity, immunosuppressive therapy, and variable long-term success. Innovations in stem cell therapy, particularly using human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), promise an unlimited source of β-cells. However, translating these advances into clinical applications involves overcoming technical, biological, and ethical hurdles. Strategies such as immunomodulation, encapsulation, and genetic engineering are critical to enhancing the viability and integration of transplanted cells. This review provides a comprehensive overview of the scientific intricacies and potential of β-cell replacement therapies, emphasizing the need for continued research to address the remaining challenges and improve diabetes care outcomes.

The impact of diabetes on cardiac remodelling after transcatheter aortic valve implantation

Abstract Background Transcatheter aortic valve implantation (TAVI) induces reverse cardiac remodelling, an important outcome associated with lower mortality. Diabetes mellitus (DM) is common among TAVI patients and is one of the fastest growing chronic conditions worldwide. Despite its propensity to adversely affect myocardium, the influence of DM on post-TAVI remodelling remains poorly understood. Purpose To characterise the influence of DM on cardiac remodelling following TAVI. Methods Retrospective analysis of 202 patients undergoing TAVI at an Australian tertiary centre. 12-month myocardial remodelling was compared between DM and no DM groups. Results Of 202 patients, median age 82 (IQR: 76, 86) years, 50% female and median STS score 3.5 (2.5, 4.9), 62 (31%) had Type II DM. A robust multivariable analysis (C-Statistic 0.83) revealed DM (adjusted odds ratio [aOR] 2.3, p=0.042) and ≥ mild post-procedural paravalvular regurgitation (aOR 2.5, p=0.027) were independent predictors of poor left-ventricular mass index regression (LVMIr). Among diabetic patients, suboptimal disease control was associated with inferior LVMIr (6% vs -9%, p=0.011), while insulin dependency was not (-3% vs 2%, p=0.489). At 12-months, no differences were found in left-atrial remodelling, left and right-ventricular function, and prosthetic valve performance between DM and no DM groups. Poor LVMIr was associated with lower survival in Kaplan Meier analysis (65% vs 85%, log-rank p=0.049). Conclusion Among patients undergoing TAVI, those with DM demonstrate poorer LVMIr at 12-months. Improved glycaemic control may serve as an important strategy to optimise myocardial remodelling in diabetic patients undergoing TAVI.12-Month LVMI Regression

Liraglutide for the Treatment of Severe Hypoglycemia Following Total Pancreatectomy and Islet Autotransplantation

Abstract Total pancreatectomy and islet autotransplantation (TPIAT) is an effective treatment for chronic and recurrent acute pancreatitis, and it provides a significant potential additional benefit of insulin independence. Spontaneous hypoglycemia in the absence of insulin therapy following TPIAT is a recognized complication, which has been attributed to lack of protective glucagon responses to hypoglycemia, following intrahepatic islet autotransplantation. We describe the use of liraglutide to treat spontaneous hypoglycemia following TPIAT. Continuous glucose monitoring was used to identify timing of hypoglycemia in relation to meals and monitor treatment effect. Liraglutide has been used for management of hypoglycemia following bariatric surgery, but, to our knowledge, this is the first application of its effective use to treat spontaneous severe hypoglycemia following TPIAT.

The Emerging Role of GLP-1 Agonists in Burn Care: What Do We Know?

Glucagon-like peptide-1 (GLP-1) agonists mimic the action of GLP-1, a hormone that regulates blood glucose levels via stimulation of insulin release and inhibition of glucagon secretion. After burn, the current literature suggests that the use of GLP-1 agonists results in less insulin dependence with similar glucose control and hypoglycemic events to patients receiving a basal-bolus insulin regimen. GLP-1 agonists may also promote wound healing through various mechanisms including angiogenesis and improved keratinocyte migration. Despite the potential benefits, GLP-1 agonists reduce gastrointestinal motility which impacts their widespread adoption in burn care. This dysmotility can result in inadequate nutrition delivery, unintentional weight loss, and is a potential aspiration risk. The net impact of these medications on burn patients is unclear. Given their potential to demonstrate the safety, efficacy, and optimal dosing of various GLP-1 agonists in acute burn management.

6861 Pre- And Peri-Operative Predictors Of Glycemic Outcomes From Total Pancreatectomy And Islet Auto-Transplantation

Abstract Disclosure: E.N. Haddad: None. M. Lansang: None. H. Xiao: None. R. Walsh: None. R. Simon: None. B.A. Hatipoglu: None. K. Zhou: None. Background: There is a lack of information regarding the immediate post-operative period as a predictor of early and long-term insulin independence after total pancreatectomy and islet auto-transplantation (TPIAT). This study examined the baseline and peri-operative variables that are associated with one-year and longer-term insulin independence following TPIAT. Methods: This was a retrospective study of 46 TPIAT patients in a single hospital system between 2010 and 2022. Perioperative variables were compared between short- (one year) and long-term (last follow up outside of year one) insulin-independent versus dependent patients. Multivariable models were used to adjust for clinically important variables. Results: The median age of the cohort at time of TPIAT was 38.5 years (IQR 30, 49). Patients were predominantly white (91%) and 50% were female. Nine (20%) and seven (15%) patients achieved short- and long-term insulin independence, respectively. The patients were followed for a median of 2.8 years (IQR 1.0, 4.7). There were no significant differences in patient demographics (age, sex, ethnicity), duration of pancreatitis, HbA1c, or mixed meal testing results (area under c-peptide curve from 0 to 4 hours) between those achieving insulin independence and those who did not. Short term insulin-independence was associated with higher median transplanted islet equivalents (IEQ)/kg (6,981 vs 4,493, p=0.02), lower units of basal insulin on discharge (7 vs 12, p=0.009), and lower rates of discharge from the hospital with an insulin regimen (67% vs 100%, p=0.006). Short-term insulin independence was also associated with decreased median insulin use in the immediate 24-hour post-operative period (14.3 vs 45.3 units, p=0.03), though this was not statistically significant when adjusting for patient weight (0.23 vs 0.56 units/kg, p=0.13). The odds of having short term insulin independence increased by 80% for every 1,000 increase in IEQ/kg (OR 1.80, CI 1.18 to 3.12, p=0.005) and decreased by 32% for every additional basal unit of insulin on discharge (OR 0.68, CI 0.42 to 0.91, p=0.003). This was no longer statistically significant after adjusting for sex, age, mixed meal testing area under c-peptide curve at 4 hours, and HbA1c. Long-term insulin independence was also associated with transplanted IEQ/kg and basal insulin units at discharge in univariable analysis. None of the patients on insulin or any other antihyperglycemic medication prior to surgery achieved short- or long-term insulin independence. Conclusion: Short- and long-term insulin independence after TPIAT is associated with a higher transplanted IEQ/kg and fewer units of basal insulin at discharge. Immediate post-operative variables can be used to inform the discussions clinicians have with their patients regarding glycemic prognosis following TPIAT. Presentation: 6/2/2024

6745 Complete Remission of Type 1 Diabetes and the Honeymoon Phase: A Case Report

Abstract Disclosure: D. Krinsky: None. E. Brutsaert: None. J.A. Mullally: None. Introduction: Type 1 Diabetes (T1D) is a chronic autoimmune disease resulting in insulin deficiency from pancreatic beta-cell destruction. Recent evidence suggests that it can be a partially relapsing and remitting disease, with some patients with T1D being able to briefly discontinue insulin early in the disease course. This phenomenon has been referred to as the “honeymoon phase.” While this period tends to be short, on the order of weeks to months, we describe a unique case of a patient with T1D with a long remission, lasting about five years. Clinical Case A 21-year-old Mexican-American male (BMI 26) with past medical history of T1D presented with polyuria and a 50-pound unintentional weight loss over a 6-month period. He was first diagnosed with T1D at age 14 years when his Hemoglobin A1c (HbA1C) was 13.3% (normal range 4.0-5.6%) in the setting of hospitalization for diabetic ketoacidosis (DKA). All antibody testing done at that time was negative, but islet cell antibodies were later found to be positive. Insulin therapy was started, weaned, and then completely discontinued at age 16 when the patient’s HbA1c was normal at 5%. The patient had no symptoms of diabetes until 6 months prior to presenting, seven years after his original diagnosis. He was found to be in DKA with a HbA1c >14%. Additionally, insulin (< 3.0; normal range 6-27) and c-peptide (0.43; normal range 0.81-3.85) were low with an elevated glucose of 366. Insulin autoantibody, GAD-65 antibody, and islet cell antibody were negative. His DKA resolved and he was discharged on basal and nutritional insulin. Conclusion: The physiology of the honeymoon phase is not well understood and there is not a clear definition, although stimulated C-peptide levels, insulin requirements, and calculating insulin dose adjusted A1c (IDAA1c) have been commonly used. There is variability in reports of the prevalence of partial remission (PR), estimated to occur in 22-60% of patients, with an average duration of 9 months. Our case is unique in that the patient was diagnosed with T1D at the age of 14 years but was able to discontinue all insulin for five years. His presentation is consistent with a complete remission with insulin independence and normal glycemic control (HbA1C <6%) without the use of hypoglycemic agents. Complete remission has a prevalence of only 6.5%. Prior data has shown factors associated with diabetes remission include male sex, postpubescent age of diabetes onset, and fewer than two positive antibodies; factors seen with our patient. Our case highlights a very long remission of T1D, and a better understanding of the immunologic and metabolic factors at play in the honeymoon phase may pave the way for novel T1D prevention and treatment strategies. Presentation: 6/2/2024

8177 Clinical Characteristics of Ketosis Prone Diabetes: Evaluating Diagnosis and Management Practices in a Real-Life Setting

Abstract Disclosure: Z. Tariq: None. A. Sinha: None. G. Shokry: None. K. Moors: None. S.S. Kodukula: None. Z.I. Saeed: None. Aims: While evidence supports the Aß (Auto-antibody status, Beta-cell function) classification of Ketosis Prone Diabetes (KPD), its implementation by healthcare providers (HCPs) remains unclear. We examined practices in managing KPD in a tertiary-care center and compared features between Aß subgroups. Methods: A retrospective longitudinal cohort study was conducted consisting of individuals aged 18 and above with diabetes who experienced diabetic ketoacidosis (DKA) between 2016 and 2021. Demographics, causes of DKA, auto-antibody status, beta-cell function, clinical characteristics, and follow-up care were assessed. Data were analyzed using descriptive and inferential statistics. Results: Among 1557 individuals with KPD, 11.6% underwent A testing, 20.2% underwent ß testing, and only 9.8% underwent both A and ß testing. HCPs were more likely to assess Aß status among those who were young, Black, and had new-onset diabetes (p<0.001). A-ß+ was the most common (53.9%), and A+ß+ was least common (5.9%) KPD. Clinical characteristics differed among subgroups, with ß- having a leaner BMI and more insulin dependence. Infection was the leading cause of DKA (37.9%), followed by unprovoked DKA (22.6%). Conclusion: Our study further validates and highlights the underutilization of Aß classification in KPD management and emphasizes the need for increased education among HCPs to improve care for people with KPD. Presentation: 6/1/2024

7923 Latent Autoimmune Diabetes of Adulthood (LADA) Complicating Common Variable Immunodeficiency (CVID)

Abstract Disclosure: L. Pathak: None. M.G. Jakoby: None. Introduction: CVID is caused by defective B-lymphocyte maturation that results in immunoglobulin deficiency. Patients with CVID are predisposed to both infections and autoimmune disorders, with approximately 20% experiencing at least one autoimmune complication. We present a patient with LADA complicating CVID. Case A 31-year-old woman was referred for newly diagnosed diabetes mellitus (DM). Medical history was notable for primary hypothyroidism and apparent chronic lymphocytic thyroiditis. A presumptive diagnosis of type 2 DM was made due to obesity, and the patient was treated with metformin. However, she could not tolerate the medication due to diarrhea. Semaglutide was substituted and tolerated without adverse effects. During the first six months of treatment with semaglutide 0.5 mg weekly, HbA1c improved from 6.4 to 5.6%. However, in the next six months, HbA1c increased to 6.6% despite full compliance with medication and stable weight. Anti-glutamic acid decarboxylase (GADA) titer was unequivocally elevated at 69.8 IU/mL (0.0-5.0), though anti-insulin and islet antigen-2 (IA-2) antibodies were undetectable. Insulin glargine was added to the patient’s diabetes regimen, and HbA1c improved to 5.5% three months later. Discussion This patient meets Immunology of Diabetes Society diagnostic criteria for LADA, namely diabetes diagnosed in adulthood (≥ 30 y), elevated diabetes-associated autoantibody titer, and insulin independence for at least six months after diagnosis. Patients with high-titer GADA tend to be younger and have more rapid and significant loss of β-cell function than patients with low GADA titers, and this patient’s rapidly waning glycemic response to semaglutide conforms with this observation. Until recently, autoimmune diabetes in the setting of CVID was thought to be an unusual complication, though the prevalence of type 1 diabetes among CVID patients in the European Society for Immunodeficiency registry is 1.6%, approximately four-fold higher than the general European population. LADA shares genetic features linked to childhood-onset type 1 DM, making it possible or evenly likely that LADA has occurred in cases of CVID, though a careful search of PubMed failed to identify reported cases. This patient illustrates the importance of considering LADA in CVID, particularly with abrupt loss of glycemic response to noninsulin therapeutic agents. Presentation: 6/1/2024

6674 Non-Progressive Diabetes Leading to Neurologic Diagnosis

Abstract Disclosure: F.L. Thelmo: None. M. Murugesh: None. B. Simon: None. Introduction: The autoantibody GAD (anti-glutamic acid decarboxylase) is highly associated with Type 1 diabetes (T1DM) and Latent Autoimmune Diabetes in Adulthood (LADA). If GAD is detected before the onset of overt diabetes, typically 80% of patients with abnormal glucose tolerance progress to insulin deficiency and the need for insulin treatment after 5 years.[1] Stiff Person Syndrome (SPS) is also associated with GAD antibodies, but in SPS, the GAD antibodies are believed to be different epitopes that target GABA production in neuromuscular pathways. We present a case of presumed LADA that did not progress for 30 years, with progressive neurologic symptoms leading to a diagnosis of SPS in later adulthood.Case: A 52-year-old female presented for evaluation of T1DM and worsening neuropathies. She had a long history of prediabetes, with mildly elevated glucose values noted on labs since her early twenties. There was no family history of T1DM or autoimmune conditions. Six years ago, she sought endocrine evaluation. HgbA1c values were 6.1 to 6.6%. Intermittent use of continuous glucose monitoring (CGM) revealed post-prandial hyperglycemia up to 180mg/dL, occasionally (but rarely) exceeding 200mg/dL. She recalls being told that she had positive antibodies (unclear which ones tested) and given a diagnosis of T1DM. She declined insulin and maintained glycemic control with carbohydrate restriction and exercise; there were no episodes of diabetic ketoacidosis. She then developed neurologic symptoms: fullness, tightness and bloating in the abdomen (diagnosed with gastroparesis on scanning) and after a COVID 19 booster in 2021, muscle spasms in the legs and back with worsening abdominal tightness. At the time of her current presentation, A1C was 6.4%, glycated albumin was 14.4% (prediabetes range 13.6 - 15.5%) and CGM time in range was 99%. A non-fasting C-peptide was 3.6 ng/mL (1.1- 4.4ng/mL) with glucose of 119 mg/dL. Repeat antibody testing revealed undetectable IA-2 and ZnT8 antibodies, but GAD was grossly elevated at 1,015.3 U/mL. Given the unusually high GAD titer, SPS was suspected, and this diagnosis was confirmed on referral to neurology. The patient was advised to liberalize diet and will be monitored with HgbA1c and serial C-peptide levels to assess progression in the future. Discussion: While high GAD antibody levels are associated with progression to insulin dependence in adults with LADA, in SPS the GAD titers tend to be even higher2. The presence of only one auto-antibody for T1DM (and not multiple), long-standing non-progressive hyperglycemia, and normal C-peptide pointed away from autoimmune diabetes being the etiology for mild glucose intolerance in this patient. If neurologic symptoms are present, high GAD should prompt the evaluation for other syndromes associated with GAD antibody epitopes such as SPS. Presentation: 6/2/2024

6698 Rapidly Progressive Type 1 Diabetes Mellitus Complicated By Hyperglycemic Crisis And Bowel Ischemia

Abstract Disclosure: D. Bondarenko: None. D. Deyar: None. R. Nadeem: None. M. Herrera: None. L.E. Arzeno: None. Introduction: Type 1 diabetes mellitus (T1DM) stems from insulin deficiency due to islet-related autoantibodies. Misclassification of T1DM as type 2 diabetes mellitus (T2DM) occurs in 40% of those developing T1DM after age 30. Fulminant T1DM (FT1DM), described in East Asia, exhibits rapid progression and is diagnosed by ketosis, blood glucose ≥288 mg/dL, HgbA1c <8.7%, and fasting C-peptide <0.3 ng/mL. We present a case of rapidly progressing T1DM in a white male presenting as a hyperglycemic crisis (HC) complicated by multiorgan failure and bowel ischemia. CASE:A 52-year-old male, T2DM diagnosed by HgbA1c of 8% (normal <5.7%) 1 month prior, presented to the emergency room obtunded with two days of nausea and vomiting. Vital signs were normal other than tachycardia and tachypnea. Blood work showed pH 7.0 (normal 7.31-7.41), creatinine 4.58 mg/dL (0.7-1.3 mg/dL), glucose >1500 mg/dL (normal 65-139 mg/dL), beta-hydroxybutyrate 114.7 mg/dL (normal 0.2-2.8 mg/dL), lactate 5.7 mmol/L (normal 0.5-2 mmol/L), serum osmolarity 438 mOsmol/kg (normal 275-295 mOsmol/kg), WBC 26.2 B/L (4-11 B/L) and 4% bands (normal 0%), Hgb A1c 17.1% , C-peptide 0.11 ng/mL (0.8 - 3.85 ng/mL), GAD65 1:600 - 1:1200 (normal < 1:600). He was intubated Day 1-5. HC was treated with intravenous (IV) fluids and IV insulin infusion. He transitioned to subcutaneous insulin by Day 2. 10 days hemodialysis achieved renal recovery. He was diagnosed with latent autoimmune diabetes of adult (LADA). No triggers were identified for his HC. From Day 1, his abdominal exam was notable for guarding. Initial abdominal computed tomography (CT) was normal. Abdominal pain and distension persisted despite normalized blood work. Repeat CT showed ileus vs obstruction. Surgery on Day 12 showed multifocal bowel ischemia requiring surgical resection. Conclusion: FT1DM is a subtype of T1DM seen in Asia characterized by rapid β-cell destruction with hyperglycemia and ketoacidosis. LADA subset of T1DM manifests in adults and may take up to three years to progress to insulin dependence. Triggers for both include autoimmunity, infections, and pregnancy. HC has been associated with increased risk of occlusive and nonocclusive bowel ischemia. While this case does not meet all criteria of FT1DM, the rapid progression of the HgbA1c and disease severity is an unusual presentation of LADA. Raising awareness of the complications of this severe metabolic disorder can improve timely interventions and medical outcomes. Presentation: 6/1/2024

Random C-Peptide and Islet Antibodies at Onset Predict β Cell Function Trajectory and Insulin Dependence in Pediatric Diabetes

ContextIdentification of prognostic biomarkers in pediatric diabetes is important for precision medicine. ObjectiveWe assessed whether C-peptide and islet autoantibodies are useful to predict the natural history of children with new-onset diabetes. MethodsWe prospectively studied 72 children with new-onset diabetes (median follow-up: 8 months) by applying the Aβ classification system (“A+”: islet autoantibody positive, “β+”: random serum C-peptide≥1.3 ng/mL at diagnosis). Beta-cell function was assessed longitudinally with 2h post-prandial/stimulated urinary C-peptide-to-creatinine ratio (UCPCR) 3-12 weeks (V1) and 6-12 months after diagnosis (V2). We obtained a type 1 diabetes genetic risk score (T1D GRS2) for each participant, and compared characteristics at baseline, and clinical outcomes at V2. ResultsThe cohort was 50% male. Racial distribution was 76.4% White, 20.8% Black and 2.8% Asian or other races. A total of 46.5% participants were Hispanic. Median age (Q1-Q3) was 12.4 (8.3-14.5) years. The Aβ subgroup frequencies were 46 A+β-(63.9%), 1 A-β-(1.4%), 4 A+β+(5.6%), and 21 A-β+(29.2%). Baseline serum C-peptide correlated with UCPCR at both V1 (r=0.36, p=0.002) and V2 (r=0.47, p<0.001). There were significant subgroup differences in age, race, frequency of diabetic ketoacidosis and T1D GRS2 (p<0.01). At V2, the two β- subgroups had lower UCPCR and higher HbA1c compared with the two β+ subgroups (p<0.001 and p=0.02, respectively). Thirty-eight percent of A-β+ but none of the other subgroups were insulin-independent at V2 (p<0.001). ConclusionsC-peptide and islet autoimmunity at diagnosis define distinct phenotypes and predict beta-cell function and insulin dependence 6-12 months later in racially/ethnically diverse children with new-onset diabetes.

Semaglutide exposure and its association with adverse outcomes in diabetic patients undergoing transforaminal lumbar interbody fusion for lumbar degenerative disc disease.

Semaglutide, a novel glucagon-like peptide-1 receptor agonist, has transformed the therapeutic landscape for type 2 diabetes mellitus. However, its effect on osteoclast activity and its potential to induce weight-related muscle loss raises concerns about its impact on spine surgery outcomes. As such, evaluating semaglutide's influence on transforaminal lumbar interbody fusion (TLIF) is imperative, given the procedure's reliance on successful bony fusion to prevent postoperative instability and further interventions. Using an all-payer database (MARINER), the authors analyzed data from patients with type 2 diabetes mellitus who were 18-74 years of age and who underwent short-segment fusion (≤ 3-level) TLIFs between January 2018 and October 2022. Patients were either exposed to semaglutide or not. A comprehensive 1:3 (exposure vs no exposure) matching was performed based on age, sex, obesity, hypertension, coronary artery disease, chronic kidney disease, smoking status, osteoporosis, levels of surgery, and basal-bolus insulin dependence. Kaplan-Meier survival curves and log-rank testing were performed to study the probability of additional lumbar fusion surgery within 1 year. After the 1:3 matching, 1781 patients were identified, with 447 in the semaglutide-exposed cohort and 1334 in the nonexposed cohort. Most patients in both groups were 55-69 years old, and 59.3% were female. Analysis showed that the likelihood of undergoing additional lumbar fusion surgery within 1 year post-TLIF was significantly higher in the semaglutide-exposed group than in the nonexposed group (OR 11.79, 95% CI 8.17-17.33). Kaplan-Meier plots and log-rank testing further confirmed a statistically significant divergent probability in the need for additional surgery within 1 year between the cohorts (log-rank, p < 0.001). Semaglutide exposure appears to be associated with a higher likelihood of additional lumbar fusion surgeries within 1 year post-TLIF, especially in patients receiving the medication for longer durations. Although the mechanisms remain speculative, potential impacts on bone turnover and the onset of muscle loss may be contributory factors. Further research is needed to elucidate the exact mechanisms and to develop strategies for optimizing surgical outcomes in these patients.

Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient

We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data metall study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.

Autoantibodies against beta cells to predict early insulin requirements in pediatric patients with clinically diagnosed type 2 diabetes.

Autoimmunity has emerged as a probable disease modifier in patients with clinically diagnosed type 2 diabetes mellitus (T2DM), that is, patients who have insulin resistance, obesity, and other cardiovascular risk factors, suggesting that the presence of glutamic acid decarboxylase (anti-GAD65), islet antigen 2 (anti-IA2), and zinc transporter 8 (anti-Zn8T) antibodies could have deleterious effects on beta cell function, causing failure and earlier requirement for insulin treatment. To evaluate anti-GAD65, anti-IA2 and anti-Zn8T as predictors of early insulin requirement in adolescents with a clinical diagnosis of T2DM. This was a case-control study in patients with clinically diagnosed with T2DM (68 cases and 64 controls with and without early insulin dependence respectively), male and female, aged 12-18 years. Somatometry, blood pressure, glucose, insulin, C-peptide, glycated hemoglobin A1c, and lipid profiles were assessed. ELISA was used to measure anti-GAD65, anti-IA2, and anti-Zn8T antibodies. Descriptive statistics, Pearson's χ 2 test, Student's t test, and logistic regression was performed. P < 0.05 was considered statistically significant. There were 132 patients (53.8% female), with a mean age was 15.9 ± 1.3 years, and there was a disease evolution time of 4.49 ± 0.88 years. The presence of anti-GAD65, anti-IA2, and anti-Zn8T positivity was found in 29.5%, 18.2%, and 15.9%, respectively. Dividing the groups by early or no insulin dependence showed that the group with insulin had a higher frequency of antibody positivity: anti-GAD65 odds ratio (OR): 2.42 (1.112-5.303, P = 0.026); anti-IA2: OR: 1.55 (0.859-2.818, P = 0.105); and anti-Zn8T: OR: 7.32 (2.039-26.279, P = 0.002). Anti-GAD65 positivity was high in our study. Anti-GAD65 and anti-Zn8T positivity showed a significantly depleted beta cell reserve phenotype, leading to an increased risk of early insulin dependence.

Islet transplantation in Korea.

Type 1 diabetes mellitus is characterized by absolute insulin deficiency, which requires life-long insulin replacement. Exogenous multiple-daily insulin injections are most commonly prescribed for patients with type 1 diabetes mellitus. However, exogenous insulin supply often fails to cope with real-time changing life-log variables, such as activity, diet and stress, which results in recurrent hypo- and hyperglycemia in patients with type 1 diabetes mellitus. Islet transplantation is an ideal method to treat patients with type 1 diabetes mellitus, as it can restore the endogenous capacity of glucose-stimulated insulin secretion. However, due to donor scarcity and technical barriers, only a limited number of islet transplantations have been carried out in Asia, including South Korea. Since 2013, our center has carried out two allogenic islet transplantations, with one case leading to near total insulin independence after one-to-one islet transplantation. Although the other patient failed to restore endogenous insulin production, there was a remarkable improvement in hypoglycemia. We speculate that islet transplantation remains an important and ideal treatment option for patients with type 1 diabetes mellitus who suffer from recurrent severe hypoglycemia.

Shedding more than weight: Metabolic and bariatric surgery and the journey to insulin independence in insulin-treated type 2 diabetes

BackgroundType 2 diabetes (T2D) imposes a significant health burden, necessitating lifelong pharmacological interventions, with insulin being one of the cornerstone therapies. However, these regimens are associated with health risks and psychological stressors. This study aimed to examine the rates of insulin-treated T2D remission and cessation or reduction in the dosage of insulin therapy after metabolic and bariatric surgery (MBS). MethodsThis was a retrospective analysis of patients with a preoperative diagnosis of insulin-treated T2D who underwent primary laparoscopic sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD/DS) with a minimum of 3 and up to 5 years of follow-up. The average daily dose for each type of insulin, measured in units, was calculated at annual intervals. ResultsAmong 287 patients included, 201 (70%) underwent RYGB, 66 (23%) underwent SG, and 20 (7%) underwent BPD/DS. The average follow-up period was 4.6 ± 0.7 years. At 5 years follow-up, the mean total weight loss was the highest in the BPD/DS subgroup at 37.5% ± 11.6%. Insulin usage decreased significantly from complete dependency at baseline to 36.2% just 1 year postoperatively, and the use of noninsulin antidiabetic drugs decreased from 79.4% initially to 26.1%. These results were sustained throughout the study period. The subgroup analysis indicated that, 5 years after surgery, T2D remission was the highest after BPD/DS (73.7%) compared with RYGB (43.2%) and SG (23.3%) (P < .001). ConclusionMBS is a transformative approach for achieving significant remission in insulin-treated T2D and reducing insulin requirements. Our findings reinforce the efficacy of these surgical interventions, particularly highlighting the promising potential of procedures that bypass the proximal small intestine, such as BPD/DS and RYGB.

High glutamic acid decarboxylase antibody titers may be associated with a decline in β-cell function over time and future insulin deficiency in latent autoimmune diabetes in adults

AimsLatent autoimmune diabetes in adults (LADA) is characterized by positive islet-associated autoantibodies including glutamic acid decarboxylase antibody (GADA), and gradual decline in insulin secretion, progressing to insulin dependency. This cross-sectional study aimed to determine whether GADA by enzyme-linked immunosorbent assay (GADA-ELISA) titer of ≥180 U/mL could be associated with decline in β-cell function in participants with LADA. MethodsSixty-three participants with LADA were recruited and an association between insulin secretion capacity and disease duration was investigated. Insulin peptide-specific inflammatory immunoreactivity was investigated to determine the disease’s activity. ResultsThere was a significant inverse correlation between disease duration and C-peptide index in participants with GADA-ELISA titer of ≥180 U/mL (Spearman’s r (rs) = –0.516, p < 0.01). The positivity rate of insulin peptide-specific inflammatory immunoreactivity was significantly higher in those with ≥180 U/mL than in those with <180 U/mL (p < 0.05). In participants with human leukocyte antigen (HLA)-DRB1*04:05, a significant inverse correlation was observed between disease duration and C-peptide index in those with ≥180 U/mL (rs = −0.751, p < 0.01). ConclusionsGADA-ELISA titer of ≥180 U/mL, especially with HLA-DRB1*04:05, might reflect higher disease activity and may be associated with decline in β-cell function over time and future insulin dependency in LADA.

Prediction of retinopathy through machine learning in diabetes mellitus

Aims: Development of a machine learning model on an electronic health record (EHR) dataset for predicting retinopathy in people with diabetes mellitus (DM), analysis of its explainability. Methods: A public dataset based on EHR records of patients diagnosed with DM located in İstanbul, Turkiye (n=77724) was used. The categorical variable indicating a retinopathy-positive diagnosis was chosen as the target variable. Variables were preprocessed and split into training and test sets with the same ratio of class distribution for model training and evaluation respectively. Four machine learning models were developed for comparison: logistic regression, decision tree, random forest and eXtreme Gradient Boosting (XGBoost). Each algorithm’s optimal hyperparameters were obtained using randomized search cross validation with 10-folds followed by the training of the models based on the results. The receiver operating characteristic (ROC) area under curve (AUC) score was used as the primary evaluation metric. SHapley Additive exPlanations (SHAP) analysis was done to provide explainability of the trained models. Results: The XGBoost model showed the best results on retinopathy classification on the test set with a low amount of overfitting (AUC: 0.813, 95% CI: 0.808-0.819). 15 variables that had the highest impact on the prediction were obtained for explainability, which include eye-ear drugs, other eye diseases, Disorders of refraction, Insulin aspart and hemoglobin A1c (HbA1c). Conclusion: Early detection of retinopathy based on EHR data can be successfully detected in people with diabetes using machine learning. Our study reports that the XGBoost algorithm performed best in this research, with the presence of other eye diseases, insulin dependence and high HbA1c being observed as important predictors of retinopathy.

Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes.

β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.