Uncommon triggers of insulin autoimmune syndrome: a case report.

BACKGROUND: Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial, hypoglycemic episodes. We report a case of a previously healthy 67-year-old man presenting with recurrent fasting hypoglycemia culminating in a diagnosis of insulin autoimmune syndrome linked to omeprazole and probably spices, namely, coriander, and ginger. CASE PRESENTATION: A previously healthy 67-year-old Sinhalese man presented with recurrent syncopal attacks for 3 months, which were found to be hypoglycemic episodes. He experienced mainly fasting hypoglycemic attacks, at a frequency gradually increasing to daily attacks. His cardiovascular, respiratory, abdominal, and neurologic examinations were normal. He was found to have insulin levels > 6000 mU/L and a post-polyethylene glycol insulin recovery of less than 9.5%. Contrast-enhanced computed tomography of the pancreas was normal. The diagnosis of insulin autoantibody syndrome was confirmed by testing for the insulin autoantibody level, yielding a level of > 300 U/mL. With regard to a possible trigger, he had a history of omeprazole intake for 2 weeks, 4 weeks prior to the onset of symptoms. He also consumed an herbal supplement containing coriander and ginger extracts daily for a period of 1 year, approximately 2 years prior to the onset of hypoglycemic attacks. He was commenced on prednisolone 30 mg daily, and hypoglycemic episodes responded dramatically, and thus he was tapered off corticosteroids. CONCLUSION: Omeprazole-induced insulin autoantibody syndrome is likely in this patient; however, the known hypoglycemic effects of coriander and ginger make it worthwhile to consider a possible association with insulin autoantibody syndrome. In addition, this case report highlights the need to consider insulin autoantibody syndrome even in patients presenting with fasting hypoglycemic attacks.

Insulin Autoimmune Syndrome - An After-Meal Roller Coaster Ride.

Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune syndrome induced by carbimazole in a middle-aged Chinese man with underlying Graves' disease, which was managed conservatively with a combination of dietary modification and alpha-glucosidase inhibitor.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

Evaluation among trace elements, clinical parameters and type 1 diabetes according to sex: A new sight of auxiliary prediction in negative insulin auto-antibodies population.

BACKGROUND: Type 1 diabetes (T1D) exhibited sex-specific metabolic status including oxidative stress with dynamic change of trace elements, which emphasized the importance of the evaluation of trace elements according to sex. Besides, the most significant characteristic, insulin auto-antibodies, could not be found in all T1D patients, which needed the auxiliary prediction of clinical parameters. And it would benefit the early detection and treatment if some high-risk groups of T1D could predict and prevent the occurrence of disease through common clinical parameters. Hence, there was an urgent need to construct more effective and scientific statistical prediction models to serve clinic better. This study aimed to evaluate the sex-specific levels of trace elements and the relationship between trace elements and clinical parameters in T1D, and construct sex-specific auxiliary prediction model combined with trace elements and clinical parameters. METHODS: A total of 105 T1D patients with negative insulin auto-antibodies and 105 age/sex-matched healthy individuals were enrolled in First Hospital of Jilin University. Inductively Coupled Plasma Mass Spectrometry was performed for the measurement of calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in the serum, and the data of clinical parameters were received from medical record system. The lambda-mu-sigma method was used to evaluate the relationship between abnormal clinical parameters and trace elements. Training set and validation set were divided for the construction of predictable models in males and females: clinical parameters model, trace element model and the combined model (clinical parameters and trace elements). Goodness fit test, decision curve analysis and other related statistical methods were used to perform data analysis. RESULTS: Lower levels of Mg, Ca, Fe in the serum were found in T1D population in females compared with healthy population, while levels of Fe, Zn and Cu of serum in T1D individuals were higher than those of healthy population in males. Levels of serum Mg, Fe and Cu in T1D group were found with significant sex difference for (P < 0.05), and the levels of Fe and Cu in serum of males were higher than those of females, level of serum Mg in males was lower than those of females. Levels of serum Mg and Zn showed fluctuation trend with increased numbers of abnormal clinical parameters (NACP) in males. Serum Zn in females showed consistent elevated trend with NACP; serum Se increased first and then decreased with NACP in males and females. The auxiliary prediction model (Triglyceride, Total protein, serum Mg) was found with the highest predicted efficiency in males (AUC=0.993), while the model in females (Apolipoprotein A, Creatinine, Fe, Se, Zn/Cu ratio) showed the best predicted efficiency (AUC=0.951). The models had passed the verification in validation set, and Chi-square goodness-of-fit test, DCA results both confirmed their satisfactory clinical applicability. CONCLUSION: Sex-specific difference were found in serum Mg, Fe and Cu in T1D. The combination of triglyceride, total protein and serum Mg for males, and apolipoprotein A, creatinine, Fe, Se, Zn/Cu ratio for females could effectively predict T1D in patients with negative anti-bodies, which would provide alarm for the population with high-risk of T1D and serve the T1D prediction in patients with negative anti-bodies.

Continuous glucose monitoring and Rituximab treatment in insulin autoimmune syndrome.

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare cause of hypoglycemia. It is characterized by hyperinsulinemic hypoglycemia, elevated insulin autoantibody titers, no prior exposure to exogenous insulin and no pathological abnormalities of pancreatic islets. Hypoglycemia usually occurs in the post prandial and post absorptive state. Most cases of IAS are self-limiting, with resolution of symptoms within six months to one year. In intractable cases, treatment modalities include low-carbohydrate meals; acarbose; diazoxide; glucocorticoids; immune-suppressants like Azathioprine, cyclophosphamide, mycophenolate mofetil; plasmapheresis and partial pancreatectomy. Rituximab, an anti CD20 monoclonal antibody, was first used in 2016 in a patient with IAS who did not respond to glucocorticoids. Subsequently, there have been three more case reports of IAS where Rituximab was used along with other modalities of treatment. Here, we report the case of a 64-year old Asian Indian woman who presented with recurrent episodes of severe post prandial hypoglycemia and was diagnosed with insulin autoimmune syndrome. She was managed with continuous glucose monitoring and two doses of Rituximab 10 weeks apart, that resulted in resolution of hypoglycemia. This case report underlies the role of Rituximab as a first line agent for treatment of hypoglycemia in IAS.

Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample.

AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.

Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study.

AIMS/HYPOTHESIS: Prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age were compared with those diagnosed at 6-13 years of age in the TEDDY study. METHODS: Genetically high-risk children (n = 8502) were followed from birth for a median of 9.9 years; 328 (3.9%) were diagnosed with type 1 diabetes. Cox proportional hazard model was used to assess the association of prognostic factors with the risk of type 1 diabetes in the two age groups. RESULTS: Children in the younger group tended to develop autoantibodies earlier than those in the older group did (mean age 1.5 vs 3.5 years), especially insulin autoantibodies (IAA), which developed earlier than GAD autoantibodies (GADA). Children in the younger group also progressed to diabetes more rapidly than the children in the older group did (mean duration 1.9 vs 5.4 years). Children with autoantibodies first appearing against insulinoma antigen-2 (IA-2A) were found only in the older group. The significant diabetes risk associated with the country of origin in the younger group was no longer significant in the older group. Conversely, the diabetes risk associated with HLA genotypes was statistically significant also in the older group. Initial seroconversion after and before 2 years of age was associated with decreased risk for diabetes diagnosis in children positive for multiple autoantibodies, but the diabetes risk did not decrease further with increasing age if initial seroconversion occurred after age 2. Diabetes risk associated with the minor alleles of rs1004446 (INS) was decreased in both the younger and older groups compared with other genotypes (HR 0.67). Diabetes risk was significantly increased with the minor alleles of rs2476601 (PTPN22) (HR 2.04 and 1.72), rs428595 (PPIL2) (HR 2.13 and 2.10), rs113306148 (PLEKHA1) (HR 2.34 and 2.21) and rs73043122 (RNASET2) (HR 2.31 and 2.54) (HR values represent the younger and older groups, respectively). CONCLUSIONS/INTERPRETATIONS: Diabetes at an early age is likely to be preceded by IAA autoantibodies and is a more aggressive form of the disease. Among older children, once multiple autoantibodies have been observed there does not seem to be any association between progression to diabetes and the age of the child or family history. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00279318.

Associations of insulin-induced lipodystrophy in children, adolescents, and young adults with type 1 diabetes mellitus using recombinant human insulin: a cross-sectional study.

OBJECTIVE: Insulin-induced lipodystrophy is of two types, lipohypertrophy and lipoatrophy. Lipodystrophy often leads to worsening of glycemic control in type 1 diabetes mellitus. Our objective was to identify the clinical, immunological, and other factor(s) associated with the development of lipodystrophy. METHODS: In this observational cross-sectional hospital-based study, 95 children, adolescents, and young adults with type 1 diabetes mellitus were observed for the development of lipodystrophy. Injection technique, insulin dose, and glycemic parameters were noted. Serum TNF-α, IL-1ß, and anti-insulin antibody levels were measured. Histopathological examination of the lipodystrophic area was done in a small number of people. RESULTS: Among the participants, 45.2% of participants had lipohypertrophy and 4.2% had lipoatrophy exclusively; 3.1% of participants had coexisting lipohypertrophy and lipoatrophy. Improper injection site rotation technique was more common in participants with lipohypertrophy in comparison to those without lipodystrophy. The age of onset of diabetes, duration of insulin use, and the number of times of needle reuse were not significantly different between the lipohypertrophy and nonlipodystrophy groups. Serum TNF-α, IL-1ß, and anti-insulin antibody levels; HbA1c; rate of hypoglycemia; and body weight-adjusted dose requirement were higher among the participants with lipohypertrophy. On histopathology, scant, or no inflammatory infiltrate was found in lipoatrophic and lipohypertrophic areas, respectively. CONCLUSION: Improper insulin injection technique and higher levels of proinflammatory cytokines and anti-insulin antibody are associated with lipodystrophy in type 1 diabetes mellitus. HbA1c and rate of hypoglycemia are higher in people with lipodystrophy.

A Novel Type of Extreme Insulin Resistance: Nonhypoglycemic Insulin Autoimmune Syndrome.

CONTEXT: Extreme insulin resistance is caused by genetic defects intersecting with the insulin action pathway or by the insulin receptor antibodies. Insulin autoimmune syndrome (IAS) is not considered one of the causes of extreme insulin resistance. OBJECTIVE: This work aimed to expand the current knowledge of extreme insulin resistance and to propose the diagnostic criteria and management strategy of a novel type of extreme insulin resistance. METHODS: A patient with IAS never experienced hypoglycemia but had persistent hyperglycemia and extreme insulin resistance with treatment with 200 U of intravenous insulin per day. Immunoreactive insulin (IRI), free insulin, and total insulin were measured. The ratio of free insulin to total insulin (insulin-free ratio, IFR) was calculated. RESULTS: Extreme insulin resistance has not been reported to be caused by IAS. At admission, IRI and free insulin were undetectable in our patient; total insulin was more than 20 160 pmol/L; and the IFR was lower than 0.03% (control, 90.9%). After adding 500 U porcine insulin to the precipitate containing insulin antibodies, the IRI was still undetectable. Since the patient started glucocorticoid therapy, the free insulin has gradually increased to 11.16 pmol/L, his total insulin has decreased to 5040 pmol/L, and the IFR has increased to 18.26%. Intravenous insulin was stopped, with good glycemic control. CONCLUSION: High-affinity insulin autoantibodies with a large capacity can induce a novel type of extreme insulin resistance characterized by extremely high total insulin and very low free insulin levels. The IFR can be used to evaluate therapeutic effects.

Insulin autoimmune syndrome: a rare cause of spontaneous hypoglycaemia in non-diabetic individuals.

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycaemia, characterised by recurrent hypoglycaemic episodes secondary to insulin autoantibodies in individuals who are not exposed to exogenous insulin. We are reporting a case of IAS in a 64-year-old gentleman, who presented with predominant postprandial hypoglycaemic episodes. On biochemical evaluation, he was found to have hyperinsulinemic hypoglycaemia. Localisation studies with MRI abdomen and endoscopic ultrasound (EUS) were negative for pancreatic tumour. Tests sent for insulin antibody levels were elevated. The patient was treated with frequent meals, acarbose and glucocorticoids. Patient condition improved and did not experience hypoglycaemia on follow-up.

Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years.

CONTEXT: We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context. DESIGN: HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. RESULTS: By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01). CONCLUSIONS: In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.

Prevalence of autoantibodies in type 1 diabetes mellitus pediatrics in Mazandaran, North of Iran.

Objectives Type 1 diabetes is an autoimmune disease. Its most important immunologic markers are pancreatic beta-cell autoantibodies. This study aimed to determine diabetes mellitus antibodies frequency among children and adolescents with type 1 diabetes. Methods This descriptive study evaluated the frequency of four diabetes autoantibodies (glutamic acid decarboxylase 65 autoantibodies [GADA], islet cell autoantibodies [ICA], insulin autoantibodies [IAA], tyrosine phosphatase-like insulinoma antigen-2 antibodies [IA-2A]) and their serum level in children and adolescents diagnosed with type 1 diabetes mellitus at the diabetes department of Bou-Ali-Sina Hospital and Baghban Clinic, Sari, Iran, from March 2012 to March 2018. The relationship between the level of different antibodies and age, gender, and diabetes duration were determined. A two-sided p value less than 0.05 indicated statistical significance. Results One hundred forty-two eligible patient records were screened. The average age at diabetes diagnosis was 4.2 ± 4.4 years. The median duration of diabetes was 34.0 (12.7-69.7) months. 53.5% of patients were female, and 81.7% of them had at least one positive autoantibody, and ICA in 66.2%, GADA in 56.3%, IA-2A in 40.1%, and IAA in 21.8% were positive. The type of the autoantibodies and their serum level was similar between females and males but there was a higher rate of positive autoantibodies in females. The level of IA-2A and ICA were in positive and weak correlation with age at diagnosis. Conclusions More than 80% of pediatric and adolescent patients with type 1 diabetes were autoantibody-positive. ICA and GADA were the most frequently detected autoantibodies. The presence of antibodies was significantly higher in females.

Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study.

OBJECTIVE: The first-appearing ß-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody. RESULTS: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D. CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.

The association between anti-insulin aspart antibodies and the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in children and adolescents with type 1 diabetes.

BACKGROUND: Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) ensuring ultrafast absorption and effect. AIM: To compare the pharmacokinetics between faster aspart and IAsp, based on free or total IAsp measurement, and investigate the association between anti-IAsp antibodies and faster aspart and IAsp pharmacological properties in children and adolescents with type 1 diabetes (T1D). METHODS: In a randomized, two-period crossover trial, 12 children, 16 adolescents, and 15 adults (6-11, 12-17, and 18-64 years) received 0.2 U/kg double-blindsingle-dose subcutaneous faster aspart or IAsp followed by a standardized liquid meal test. RESULTS: Across age groups, the pharmacokinetic profile was left-shifted including greater early exposure for faster aspart vs IAsp irrespective of free or total IAsp assay. Onset of appearance occurred 2.4 to 5.0 minutes (free) or 1.8 to 3.0 minutes (total) earlier for faster aspart vs IAsp (P < .05). Treatment ratios (faster aspart/IAsp) for 0 to 30 minutes IAsp exposure were 1.60 to 2.11 and 1.62 to 1.96, respectively (children, free: P = .062; otherwise P < .05). The ratio of free/total IAsp for overall exposure (AUCIAsp,0-t ) was negatively associated with anti-IAsp antibody level across age. Pooling with a previous similar trial showed no clear association between anti-IAsp antibodies and meal test 1- or 2-hour postprandial glucose increment independent of age and insulin treatment (R2 ≤ .070; P ≥ .17). CONCLUSIONS: In children and adolescents with T1D, faster aspart provides ultrafast pharmacokinetics irrespective of free or total IAsp assay. Elevated anti-IAsp antibodies are associated with higher total IAsp concentration, but do not impact faster aspart and IAsp glucose-lowering effect.

Insulin autoimmune syndrome - time to remember.

Not required for Clinical Vignette.

Efficacy and Safety of Inhaled Human Insulin (Exu hera®) Compared to Subcutaneous Insulin in Children Ages 6 to 11 Years with Type 1 Diabetes Mellitus: Results of a 3-Month, Randomized, Parallel Trial.

AIM: To compare the efficacy and safety of Exubera® (EXU) with subcutaneous (SC) insulin in children, ages 6-11 years, with type 1 diabetes mellitus. DESIGN AND METHODS: 121 children were randomized to receive EXU or SC insulin, plus intermediate/ long-acting insulin for 12 weeks. Change in HbA1c was the primary efficacy endpoint. RESULTS: Decreases from baseline HbA1c were comparable between treatment groups ( difference between adjusted mean decrease from baseline [EXU - SC insulin], -0.23 [95% CI, -0.49, 0.03]). Differences between groups on pulmonary function tests were small and not significant. Mild to moderate cough occurred in 24.6% of EXU versus 6.8% of SC insulin patients. The risk for hypoglycemia was comparable between EXU and SC insulin (relative risk 0.88 [95% CI, 0.71, 1.11]). Increased insulin antibodies with EXU were not associated with clinical findings. CONCLUSION: The efficacy and safety profiles shown in this study are the foundation for further investigation of EXU in this population.

Efficacy and Safety of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Treated for 26 Weeks with Multiple Daily Injections in Combination with Insulin Glargine: A Randomized Open-Label Trial (GEMELLI 1).

Background: This study compared the efficacy, safety, and immunogenicity of insulin aspart biosimilar/follow-on biologic product SAR341402 (SAR-Asp) with originator insulin aspart-NovoLog®/NovoRapid® (NN-Asp) in people with type 1 diabetes (T1D) or type 2 diabetes (T2D) treated with multiple daily injections in combination with insulin glargine (Lantus®; Gla-100). Materials and Methods: This 6-month, randomized, open-label, phase 3 study (NCT03211858) enrolled 597 people with T1D (n = 497) or T2D (n = 100). Participants were randomized 1:1 to mealtime SAR-Asp (n = 301) or NN-Asp (n = 296) in combination with Gla-100. The primary objective was to demonstrate noninferiority (by 0.3% margin in the intent-to-treat population) of SAR-Asp versus NN-Asp in HbA1c change from baseline to week 26. Immunogenicity was also assessed in terms of anti-insulin aspart antibody (AIA) status (positive/negative) and titers during the study. Results: HbA1c was similarly improved in both treatment groups (SAR-Asp -0.38%; NN-Asp -0.30%); the least squares mean difference at week 26 for SAR-Asp minus NN-Asp was -0.08% (95% confidence interval: -0.192 to 0.039), thus meeting the criteria for noninferiority between SAR-Asp and NN-Asp and inverse noninferiority of NN-Asp versus SAR-Asp. Changes in fasting plasma glucose and seven-point self-monitored plasma glucose profile, including postprandial glucose excursions, and insulin dosages were similar in both groups at week 26. Safety and tolerability, including AIA responses (incidence, prevalence), hypoglycemia, and adverse events (including hypersensitivity events and injection site reactions), were similar between groups. Conclusions: SAR-Asp demonstrated effective glycemic control with a similar safety and immunogenicity profile to NN-Asp in people with diabetes treated for 26 weeks.

Insulin Autoimmune Syndrome After Exposure to Clopidogrel: A Case Report.

BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. CASE REPORT: IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. A review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. CONCLUSION: SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.

Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series.

BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS. CASE PRESENTATION: We report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed. CONCLUSION: High levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.