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

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          Abstract

          Background

          The 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.

          Methods

          The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis.

          Results

          A 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).

          Conclusions

          EIAS 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.

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          Most cited references29

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          Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.

          The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.
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            Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.

            The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle). We recommend evaluation and management of hypoglycemia only in patients in whom Whipple's triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.
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              Immunological mechanism underlying the immune response to recombinant human protein therapeutics.

              Recombinant human (rhu) protein therapeutics are powerful tools to treat several severe diseases such as multiple sclerosis and diabetes mellitus, among others. A major drawback of these proteins is the production of anti-drug antibodies (ADAs). In some cases, these ADAs have neutralizing capacity and can interfere with the efficacy and safety of the drug. Little is known about the immunological mechanisms underlying the unwanted immune response against human homolog protein therapeutics. This article aims to provide current insights into recent immunological developments and to link this with regard to production of ADAs. A particular focus is given to aggregates being present in a rhu protein formulation and their impact on the immune system, subsequently leading to breakage of tolerance and formation of ADAs. Aggregation is one of the key factors in immunogenicity and by reducing aggregation one can reduce immunogenicity and make drugs safer and more efficient. Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                wongcj@csu.edu.cn
                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central (London )
                1758-5996
                7 April 2021
                7 April 2021
                2021
                : 13
                : 38
                Affiliations
                [1 ]GRID grid.431010.7, Department of Pharmacy, , The Third Xiangya Hospital, Central South University, ; No. 138 Tongzipo Road, YueLu District, Changsha, 410013 Hunan China
                [2 ]GRID grid.501248.a, Drug Clinical Trial Center, , Zhuzhou Central Hospital, ; Zhuzhou, China
                [3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Xiangya School of Pharmaceutical Science, , Central South University, ; Changsha, China
                Author information
                http://orcid.org/0000-0001-6067-8305
                Article
                658
                10.1186/s13098-021-00658-z
                8028117
                34801066
                163f3ac0-e834-4e05-8d58-f908e5f7b3a8
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 19 February 2021
                : 25 March 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81900344
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004735, Natural Science Foundation of Hunan Province;
                Award ID: 2018JJ3795
                Award Recipient :
                Funded by: State Administration of Traditional Chinese Medicine of Hunan
                Award ID: 201335
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Nutrition & Dietetics
                insulin autoimmune syndrome,exogenous insulin,insulin autoantibodies,hypoglycemia

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