Insulin Withdrawal Research Articles

Human Stem Cell Therapy for the Cure of Type 1 Diabetes Mellitus (T1D): A Hurdle Course between Lights and Shadows

Background: T1D is a severe metabolic disorder due to selective autoimmune pancreatic islet β-cell killing, which results in complete abrogation of endogenous insulin secretion. The affected patients, once the disease is clinically overt, must immediately undertake insulin supplementation according to intensive therapy regimens to prevent the onset of acute and chronic complications, some of them potentially lethal. Replacement of the destroyed β-cells with fresh and vital pancreatic endocrine tissue, either of the whole organ or isolated islets transplantation, started a few decades ago with progressively encouraging results, although exogenous insulin withdrawal was obtained in a minor cohort of the treated patients. The restricted availability of donor organs coupled with general immunosuppression treatment of recipients to avoid graft immune rejection may, at least partially, explain the limited success achieved by these procedures. Results: The introduction of pluripotent stem cells (either of human embryonic origin or adult cells genetically induced to pluripotency) that can be differentiated toward insulin secretory β-like cells could provide an indefinite resource for insulin-producing cells (IPCs). Conclusions: Because the use of human embryos may encounter ethical problems, employment of adult multipotent mesenchymal stem cells (MSCs) extracted from several tissues may represent an alternative option. MSCs are associated with strong immunoregulatory properties that can alter early stages of β-cell-directed autoimmunity in T1D, other than holding the potential to differentiate themselves into β-like cells. Lights and shadows of these new strategies for the potential cure of T1D and their advancement state are reviewed.

911-P: Effect of Dapagliflozin on Blood and Breath Ketones during Supervised Insulin Withdrawal in Adults with Type 1 Diabetes

911-P: Effect of Dapagliflozin on Blood and Breath Ketones during Supervised Insulin Withdrawal in Adults with Type 1 Diabetes

Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial.

To examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. Average glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.

Seasonal Variation of Diabetic Ketoacidosis in Nangarhar University Teaching Hospital

Diabetic ketoacidosis is a life threating acute complication of diabetes mellitus aquiring special care. The aim of the study was to find out seasonal variation in the prevalence of diabetic ketoacidosis in diabetic patients. It was a cross sectional hospital based study conducted over both male and female diabetic patients admitter at the internal medicine ward of Nangarhar University Teaching Hospital during one year. Mean age across DKA was 53.9 ± 14 for DKA negative patients versus 51.3 ± 17.2 for DKA positive patients, P value = 0.26. Winter season was demonstrated with peak DKA positive cases 21 (43.7%) followed by fall 6 (22.2%), summer 11 (12.2%) and spring 10 (10.3%), respectively (P value = 0.01). Common associated factors included infection (72.2%), ischemia (8.2%), insulin withdrawal (7.7%), and others (6.9%) though not statistically different across seasons. There was significant seasonal variation in the prevalence of diabetic ketoacidosis denoting winter season with peak diabetic ketoacidosis. In fact, infection followed by ischemia and insulin withdrawal was the leading associated factor contributing to the prevalence of diabetic ketoacidosis. Season specific special attention should be paid the relevant symptoms of diabetic ketoacidosis for the early detection and treatment of the disease in order to avoid morbidity and mortality.

Belimumab in a Patient with Systemic Lupus Erythematosus with Juvenile Onset and Steroid-induced Diabetes: Clinical Case

Background. The management of children with systemic lupus erythematosus (SLE) is usually associated with lifelong systemic glucocorticoids administration and, thereby, high risk of serious side effects, including steroid-induced diabetes. The belimumab (B-lymphocyte stimulator inhibitor) administration significantly reduces the glucocorticoids dose, the risk and severity of steroid therapy complications. Clinical case description. The patient was diagnosed with SLE at the age of 16 years. Therapy with hydroxychloroquine and oral glucocorticoid at a high dose (methylprednisolone 56 mg per day) was initiated. Steroid-induced diabetes was diagnosed 1 month after the therapy start; avascular necrosis sites were revealed in 2 months. Mycophenolate mofetil made it possible to achieve the disease activity control. However, the belimumab was prescribed 5 months after diagnosis verification due to continuous insulin requirement and avascular necrosis progression. Conclusion. Belimumab is the only genetically engineered biologic drug approved for the treatment of children with SLE. As a result of its use, it was possible to stabilize the patient's condition quickly (within 3 months), to reduce significantly the dose of oral glucocorticoid, methylprednisolone (from 24 to 8 mg/day), to achieve remission of steroidinduced diabetes with further insulin withdrawal, and also to relieve avascular necrosis clinical symptoms.

267-OR: ADA Presidents' Select Abstract: Combining an SGLT Inhibitor with a Glucagon Receptor Agonist (GRA) in Subjects with Type 1 Diabetes—A Randomized Clinical Trial

SGLTi treatment improves glycemic control and reduces insulin dosing but increases the risk of diabetic ketoacidosis (DKA). Combination therapy (SGLTi + GRA) could augment glycemic and insulin dosing benefits while mitigating DKA risk. Subjects with T1D (n=12) received 4-week insulin-adjunctive treatments with (a) SGLTi (dapagliflozin 10 mg) + placebo and (b) SGLTi + GRA (volagidemab 70 mg) in a cross-over, double-blind design. At baseline and end of each treatment, CGM and insulin dosing were recorded, and subjects completed an 8-hr insulin withdrawal test (IWT). Average glucose improved with both SGLTi (138 mg/dL; P &amp;lt; 0.01) and SGLTi + GRA (131 mg/dL; P &amp;lt; 0.01) compared to Baseline (150 mg/dL). Total daily insulin dose was reduced with SGLTi (0.52 U/kg/day) compared to Baseline (0.56 U/kg/day; P = 0.06) and was reduced further with SGLTi + GRA treatment (0.41 U/kg/day; P &amp;lt; 0.01 vs SGLTi). Peak beta-hydroxybutyrate (BHB) concentrations during IWT were lower with SGLTi + GRA treatment (2.03 mmol/L) than with SGLTi alone (2.44 mmol/L; P = 0.04); there was no significant difference in peak BHB with either treatment vs Baseline (2.14 mmol/L). Treatment with SGLTi + GRA improved glycemic control, reduced insulin use, and mitigated ketosis during hypoinsulinemia. These data suggest that combination adjunctive therapy may be effective to address multiple metabolic abnormalities in T1D. Disclosure S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., REMD Biotherapeutics, Eli Lilly and Company. M.J.Le roux: None. E.R.Giovannetti: None. A.Armstrong: None. L.Carter: None. R.L.Thomas: None. J.M.Gregory: Advisory Panel; Eli Lilly and Company, vTv Therapeutics, Other Relationship; Medtronic. J.Pettus: Advisory Panel; Sanofi, Novo Nordisk, Lilly, MannKind Corporation, Consultant; Carmot Therapeutics, Inc., Diasome. Funding National Institutes of Health (P30DK063491, UL1TR001442); Diabetes Research Connection

Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells.

Autophagy is a cellular catabolic process that degrades and recycles cellular materials. Autophagy is considered to be beneficial to the cell and organism by preventing the accumulation of toxic protein aggregates, removing damaged organelles, and providing bioenergetic substrates that are necessary for survival. However, autophagy can also cause cell death depending on cellular contexts. Yet, little is known about the signaling pathways that differentially regulate the opposite outcomes of autophagy. We have previously reported that insulin withdrawal (IW) or corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem (HCN) cells. On the other hand, metabolic stresses caused by 2-deoxy-D-glucose (2DG) and glucose-low (GL) induce autophagy without death in HCN cells. Rather, we found that 2DG-induced autophagy was cytoprotective. By comparing IW and CORT conditions with 2DG treatment, we revealed that ERK and JNK are involved with 2DG-induced protective autophagy, whereas GSK-3β regulates death-inducing autophagy. These data suggest that cell death and survival-promoting autophagy undergo differential regulation with distinct signaling pathways in HCN cells.

Impact of the hepatoselective glucokinase activator TTP399 on ketoacidosis during insulin withdrawal in people with type 1 diabetes.

To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D). Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n=12) or placebo (n=11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater. During the 7- to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( -27.6 vs. -4.4mg/dL [-1.5 vs. -0.2 mmol/L]; P=0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants. When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA.

835-P: The Hepatoselective Glucokinase Activator (GKA) TTP399 Does Not Increase Risk of Ketoacidosis in Type 1 Diabetes (T1D)

Identification of adjunctive, oral pharmacotherapies to treat T1D has been limited by risk of DKA. TTP399, an oral hepatoselective GKA, significantly improves glycemia in individuals with T1D compared to placebo. This double-blind, randomized, placebo-controlled, Phase 1 mechanistic study examined whether TTP399 decreases ketogenesis during insulin withdrawal. Individuals with T1D (n=23) using insulin pump therapy were randomized to TTP399 or placebo for 7-days after which an insulin withdrawal test (IWT) was performed. Insulin pumps were disconnected for up to hours to induce ketogenesis. TTP399 significantly reduced fasting glucose (-27.6 vs. -4.4 mg/dL, p = 0.03) . During the treatment period, adverse events were fewer in TTP399-treated subjects. No hypoglycemic events &amp;lt;54mg/dL were observed in the TTP399 group compared with 2 subjects in the placebo group. Following insulin withdrawal, no significant differences in mean duration of IWT or beta-hydroxybutyrate (BOHB) at termination were observed between treatment groups (Figure 1A) . Serum bicarbonate was numerically higher and urine acetoacetate was qualitatively lower in TTP399-treated subjects (Figure 1A) . No patients on TTP399 met prespecified criteria for DKA while 43% of subjects on placebo did (Figure 1B, p = 0.03) . These data suggest that TTP399 treatment improves glucose control with no increased risk of DKA. Disclosure K.Klein: None. S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., Lilly. J.L.Freeman: Employee; vTv Therapeutics, Stock/Shareholder; vTv Therapeutics. S.Madduri: None. E.R.Giovannetti: None. C.Valcarce: Employee; vTv Therapeutics. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. J.Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi, Consultant; Carmot Therapeutics, Inc., Diasome. Funding JDRF international

985-P: Prediction Models Combining Clinical Measures Identify Participants with Youth-Onset Diabetes Who Maintain Insulin Secretion

With the high prevalence of pediatric obesity, it is challenging to accurately classify diabetes (DM) type, especially in a diverse population of youth. Maintained fasting C-peptide ≥ 0.75ng/ml (250pmol/L) , a level associated with type 2 diabetes and successful insulin withdrawal in adult cohorts, may have implications for treatment and risks of acute complications. We developed clinical prediction models to identify individuals with youth onset DM who will retain endogenous insulin secretion. We studied 2991 youth in the SEARCH study (DM diagnosed ≤ age years) to develop logistic regression based prediction models using clinical measures (race/ethnicity, BMI Z-score, age at diagnosis, triglycerides and HDL-C) with or without islet autoantibodies (Aab) (GADA, IA-2A, ZnT8A) , to identify those with fasting C-peptide ≥ 0.75ng/ml at 3-yr (median 75 months) DM duration. Model covariates (measured median 9 months duration) were chosen based on previous literature and availability. A prediction model using clinical measures was highly accurate in identifying participants with C-peptide ≥75 ng/ml (17% of participants, 3% and 59% of those with and without positive Aab) : area under receiver operator curve (AUC ROC) 0.950 (95%CI 0.938-0.962) , model pseudo-R2 0.69. Adding Aab improved discrimination to AUC ROC 0.976 (0.968,0.983) , pseudo-R2 0.81. In internal validation, optimism was very low, with excellent calibration (slope 0.995-0.999) . Performance remained high in difficult to classify groups: AUC ROC was 0.947 (0.927, 0.966) in those with negative Aab and 0.923 (0.960, 0.984) (model with Aab) in youth with high BMI (Z-score &amp;gt;2) . Discrimination was lower in non-Hispanic white participants (AUC ROC 0.94) compared to participants of other race and ethnic groups (AUC ROC 0.97-0.99) (model with Aab) . In conclusion, prediction models combining routine clinical measures can accurately identify youth with DM who maintain endogenous insulin secretion. Disclosure A.Jones: None. A.H.Williams: None. S.M.Marcovina: None. C.Pihoker: None. J.Divers: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. B.Shields: None. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. D.Dabelea: None. W.Hagopian: Research Support; Janssen Research &amp; Development, LLC. E.Lustigova: None. A.S.Shah: None. A.K.Mottl: Advisory Panel; Bayer AG, Board Member; Bayer AG, Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. R.Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck &amp; Co., Inc. Funding Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and the National Institute of Diabetes and Digestive and Kidney Diseases. This work is also supported by NIH RO1 awards DK124395 and DK121843-01.

Glucagon Test Is a Useful Predictor of Withdrawal From Insulin Therapy in Subjects With Type 2 Diabetes Mellitus.

There are many tests for evaluating endogenous insulin secretory capacity. However, there are only a limited number of studies that have examined in detail in clinical practice which method most accurately reflects the ability to secrete endogenous insulin especially in hyperglycemic state. The purpose of this study was to find the endogenous insulin secretory capacity and a possible predictor of insulin withdrawal in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia. In the endogenous insulin secretory test during hospitalization, CPR, CPR index, and ΔCPR after glucagon loading were all significantly higher in the insulin withdrawal group. On the other hand, there were no difference in fasting CPR index, HOMA-β, SUIT, and 24-hour urinary CPR excretion between the two groups. In the glucagon test of the insulin withdrawal group, the cutoff value of ΔCPR was 1.0 ng/mL, the withdrawal rate of ΔCPR of 1.0 ng/mL or more was 69.2%, and the withdrawal rate of less than 1.0 ng/mL was 25.0%. In conclusion, it is likely that glucagon test is the most powerful tool for predicting the possibility of insulin withdrawal as well as for evaluating endogenous insulin secretory capacity in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia.

Ethanolic extract of Anogeissus leiocarpus ameliorates hyperglycaemia, hepato-renal damage, deranged electrolytes and acid-base balance in alloxan-induced diabetes in dogs

Anti-diabetic effects of ethanolic extract of stem bark of Anogeissus leiocarpus were investigated in alloxan monohydrate-induced acute type 1 diabetes mellitus (TIDM) extending into chronicity and organic damages in 12 adult Nigerian indigenous dogs assigned 4 groups of 3 each, namely: non-diabetic controls (ND), diabetic untreated (DU), diabetic insulin-treated (DI) and diabetic extract-treated (DE). All parameters were analysed using standard procedures. Hyperglycaemia occurred in the diabetic dogs; blood glucose significantly (P < 0.001) increased in the DU group compared with other groups. The ethanolic extract significantly (P < 0.001) decreased blood glucose levels like insulin (P < 0.002). Haematology revealed macrocytic normochromic anaemia; significantly decreased PCV (P < 0.001), Hb (P < 0.001), RBC (P < 0.001), WBC (P < 0.05). Neutrophils (P < 0.05) and lymphocytes (P < 0.05) in DU. Organic damage biomarkers, ALT, ALP activities (P < 0.05), albumin and urea concentrations significantly increased in DU. Hyponatremia, loss of bicarbonates (P < 0.05), hyperkalemia and hyperchloridaemia occurred in DU. The ethanolic extract corrected these haemato-biochemical abberations and produced positive anion-gap like the non-diabetic controls while those of DU and DI were negative with more bicarbonates retention in DI group. While hyperglycaemia relapsed after insulin withdrawal, normoglycaemia remained without reoccurrence of hyperglycaemia after withdrawal of A. leiocarpus extract. This alloxan-induced TIDM in Nigerian indigenous dogs showed that ethanolic extract of A. leiocarpus reduces blood glucose and may prevent development into T2DM.

Clinical course of different long-acting insulin therapies-glargine U100, U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes: a multicenter retrospective observational study (JDDM65 study).

This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies-glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.

Mini-review: Glucagon responses in type 1 diabetes - a matter of complexity.

In recent years the role of altered alpha cell function and glucagon secretion in type 1 diabetes has attracted scientific attention. It is well established that glucagon responses to hypoglycemia are absent in type 1 diabetes, but more uncertain whether it is intact following other physiological and metabolic stimuli compared with nondiabetic individuals. The aim of this review is to (i) summarize current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses after other stimuli in individuals with type 1 diabetes and nondiabetic individuals. Available data suggest that in type 1 diabetes the absence of glucagon secretion after hypoglycemia is irreversible. This is a scenario specific to hypoglycemia, since other stimuli, including administration of amino acids, insulin withdrawal, lipopolysaccharide exposure and exercise lead to substantial glucagon responses though attenuated compared to nondiabetic individuals in head‐to‐head studies. The derailed glucagon secretion is not confined to hypoglycemia as individuals with type 1 diabetes, as opposed to nondiabetic individuals display glucagon hypersecretion after meals, thereby potentially contributing to insulin resistance. The complexity of these phenomena may relate to activation of distinct regulatory pathways controlling glucagon secretion i.e., intra‐islet paracrine signaling, direct and autonomic nervous signaling.

Clinical Characteristics of Withdrawal of Basal Insulin Therapy Among Japanese Patients with Type 2 Diabetes: A Multicenter Retrospective Observational Study.

IntroductionThis study aimed to examine retrospectively the clinical backgrounds of Japanese patients with type 2 diabetes (T2D) who successfully withdrew from insulin use after being started on basal insulin in an outpatient setting.MethodsThe study population comprised 376 insulin-naïve patients who were started on basal insulin (glargine U100, glargine U300, or degludec) for the management of T2D and followed the treatment regimen for at least 6 months in 13 institutions in Japan. The clinical courses of the study participants were compared based on outpatient clinic medical records for the three different types of basal insulin prescribed by categorizing the participants into two groups retrospectively: those who successfully withdrew from insulin therapy and those who did not, during a 6-month observation period. The clinical determinants for insulin withdrawal were assessed using a Cox proportional hazard model.ResultsGlycated hemoglobin was improved in all participants regardless of basal insulin type. Of the 376 study participants, 61 successfully withdrew from basal insulin therapy. After adjustment was made for several confounders, the positive determinant factors for successful withdrawal of insulin were short duration of diabetes and high body mass index at the start of study, and the negative determinant factor was use of insulin secretagogues at the start. The types of basal insulin used by the study participants were not significant determinants of successful insulin withdrawal in this study.ConclusionsUse of basal insulin is a powerful option for the treatment of T2D. In patients with high BMI and/or short duration of diabetes, short-term insulin therapy is a promising strategy for the treatment of T2D before the initiation of insulin secretagogues, since such patients have the potential to successfully withdraw from basal insulin use even in an outpatient setting.

Insulin Withdrawal in Diabetic Kidney Disease: What Are We Waiting for?

The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20–40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m2 and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m2. Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.

Prolonged Honeymoon Period in a Thai Patient With Adult-Onset Type 1 Diabetes Mellitus - Metabolic Flexibility in Autoimmune Diabetes?

Abstract Background: ‘Honeymoon’ period among people with type 1 diabetes mellitus (T1DM) refers to the period of time (mostly less than 1 year) which beta-cell is still able to produce insulin to maintain good glycemic control shortly following the development of diabetes. This phenomenon remained incompletely understood but previous studies showed that absence of diabetic ketoacidosis (DKA) at initial presentation, short duration of symptoms, older age at presentation, and strenuous exercise could be potential factors. Herein, we report a 24-year old Thai patient with T1DM who has been in sustained complete remission for more than 5 years while he is maintaining low carbohydrate intake and regular exercise. Clinical Case: A 24-year-old male presented with a 6-month history of polyuria, polydipsia and weight loss of 15 kilograms (baseline BMI at 27.8 kg/m2). His initial laboratory data showed plasma glucose 398 mg/dL and A1C 9.3%. No ketonemia was found. He was diagnosed with stage 3 of Type 1 DM based on clinical presentation and positive pancreatic auto-antibodies (anti-GAD and anti-IA2). Euthyroid Hashimoto’s thyroiditis was also diagnosed based on his enlarged thyroid gland and positive thyroid auto-antibodies. He was started on basal-bolus insulin regimen for only 2 month and then A1C reversed to 5.9% within 2 months. Insulin was gradually withdrawn and completely stopped. Mixed meal stimulation test (MMST) was firstly evaluated at the second year of his diagnosis. The result revealed stimulated C-peptide at 5.5 ng/dL. Next-generation sequencing panel for monogenic diabetes revealed negative results. The patient maintains healthy lifestyle habit with low carbohydrate intake and regular exercise 5–6 times per week. His body weight was maintained at 60–63 kilograms during the past 4 years. His A1C was maintained between 5.0 to 6.0% without any anti-diabetic medication for more than 5 years. Repeated MMST in every 6–12 months still revealed preserved beta-cell functions and normal stimulated plasma glucose. Interestingly, repeated pancreatic auto-antibodies at 3 years after diagnosis showed negative anti-GAD and anti-IA2, but positive anti-ZnT8. The patient was advised to maintain his bodyweight and healthy behavior together with closely regular OPD follow-up. Conclusion: Restored beta-cell function with completely insulin withdrawal in new-onset T1DM has been reported in very few cases which have some common factors as in our patient (low carbohydrate intake with regular exercise). Delaying autoimmune activity by reducing metabolic load in newly diagnosed T1DM might play a role in maintaining a honeymoon period and could lead to an innovative therapeutic option in new-onset T1DM.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by exogenous insulin in diabetic patients

BackgroundThe exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention.MethodsThe literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis.ResultsA total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60).ConclusionsEIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.

POS-692 Euglycemic Diabetic Ketoacidosis Related to SGLT2 Inhibitor Use in Kidney Transplant Patient with Squamous Cell Carcinoma

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have renal protective effect in diabetic and non-diabetic patients with significant reduction of cardiovascular events. The data is emerging for the short-term efficacy and safety of SGLT2 inhibitor in diabetic kidney transplant patients. Diabetic ketoacidosis is a well recognized side effect of SGLT2i with variable predisposing factors. There is limited data regarding the use of SGLT2i in oncology patients. We described a case of diabetic kidney transplant patient on dapagliflozin who developed DKA during active therapy for squamous cell carcinoma. A 65 years old female, known to have hypertension and diabetes mellitus type 2 leading to end stage renal disease. She underwent living unrelated kidney transplantation in 2018. Her home medications included insulin glargine, dapagliflozin 10 mg, pantoprazole 40mg, prednisolone 7.5 mg daily, cyclosporine 125 mg q12 hours and atorvastatin 20mg. She was diagnosed with right inner cheek moderately differentiated keratinizing squamous cell carcinoma with submandibular lymphadenopathy (Stage: cT4aN2M0). She was initiated on concurrent chemotherapy (Cetuximab) and radiotherapy. Cycle 4 of therapy was complicated with poor oral intake and severe mucositis for 3 days prior to admission. She had evidence of acute kidney injury stage 1 in transplanted kidney (serum creatinine increased from baseline of 58 to 110 micromole/l). Other laboratory investigations revealed hyperkalemia 5.7mmol/l, metabolic acidosis 6mmol/l, high anion gap metabolic acidosis, normal lactate level, arterial PH of 7.1, ketones were positive in urine and blood glucose level of 12mmol/l. She was diagnosed with severe euglycemic diabetic ketoacidosis DKA, due to SGLT2i (dapagliflozin 10 mg) and starvation. She required critical care admission with rigorous IV hydration, insulin infusion per DKA protocol, IV sodium bicarbonate, IV hydrocortisone and IV cyclosporine. Her clinical condition improved by fifth day of critical care. Urinary tract infection and re-feeding syndrome post nasogastric enteral feeding complicated her hospital course. Dapagliflozin was held and next cycle of chemo-radiotherapy was delayed. Some of the potential risk factors for euglycemic DKA induced by SGLT2 inhibitors are infections, withdrawal of insulin, starvation, dehydration and acute kidney injury. The underlying pathophysiologic process of ketoacidosis induced by SGLT2 inhibitors is not well established. There are few case reports describing this complication in diabetic oncology patients, leading to discontinuation of the drug. The use of SGLT2 inhibitor is limited in diabetic kidney transplant patients and about 100 cases reported in literature without evidence of DKA in short-term follow up. To the best of our knowledge, this is the first case describing a successful management of dapagliflozin-induced euglycemic DKA in kidney transplant patient with squamous cell carcinoma. SGLT2 inhibitor associated eDKA is very rare in oncology patients and this is the first case reported in kidney transplant patient who was on active chemotherapy and radiotherapy for squamous cell carcinoma. We suggest to hold SGLT2i therapy during active oncology treatment especially in the setting on severe mucositis.