Thyroid hormones influence the function of essentially every system of the body, including the cardiovascular and metabolic system. Thyroid hormone replacement with levothyroxine (LT4) is the mainstay of pharmacological management for people with (especially clinically overt) hypothyroidism, and it is important to ensure the cardiovascular and metabolic safety of this treatment. This is especially so as in hypothyroidism, cardiometabolic risk factors and cardiovascular disease are highly prevalent conditions and will often coexist in an individual patient. Accordingly, we have reviewed the cardiometabolic consequences of hypothyroidism and intervention with thyroid hormone replacement.

Numerous observational studies and meta-analyses have described multiple potentially adverse cardiometabolic consequences of hypothyroidism, including exacerbation of cardiovascular and metabolic risk factors (especially dyslipidaemia), functional impairment of the heart and vasculature (including accelerated atherosclerosis) and increased risk of advanced cardiovascular outcomes. LT4 usually improves cardiometabolic risk factors in people with hypothyroidism and some (but not all) studies have reported improved vascular and cardiac function in LT4-treated populations. Observational data have suggested the possibility of improved cardiometabolic outcomes with LT4 treatment, particularly in younger people with hypothyroidism, although data from randomised, controlled trials are needed here. Importantly, LT4 (with or without additional triiodothyronine) appears to be safe from a cardiovascular perspective, as long as overtreatment and iatrogenic thyrotoxicosis are avoided.

Overall, the current evidence base supports intervention with LT4 to protect the cardiometabolic health of people with hypothyroidism who require thyroid hormone replacement, although more data on long-term clinical outcomes are needed.

Monoclonal insulin autoimmune syndrome (IAS) is a very rare disease characterized by severe attacks of hypoglycemia caused by circulating anti-insulin antibodies produced by a B-cell clone, usually clonal plasma cells.

We present 2 female Norwegian patients with monoclonal IAS. The anti-insulin antibodies were quantified by immune precipitation and characterized using a 3-step manual in-house assay. Both patients received plasma cell directed therapy.

The first patient received plasma cell directed therapy for a time-limited period and achieved a sustained clinical remission without detectable anti-insulin antibodies. The second patient receives continuous plasma cell directed therapy and is in clinical remission with low values of detectable anti-insulin antibodies.

Plasma cell directed therapy was effective and safe in our 2 cases of monoclonal IAS. We recommend considering plasma cell directed therapy for these patients.

Type 2 diabetes mellitus (T2DM) often leads to vascular complications, such as albuminuria. The role of insulin autoantibodies (IAA) and their interaction with D-dimer in this context remains unclear.

To investigate the characteristics of IAA and its effect on albuminuria in T2DM patients.

We retrospectively analyzed clinical data from 115 T2DM patients with positive IAA induced by exogenous insulin, and 115 age- and sex-matched IAA-negative T2DM patients as controls. Propensity scores were calculated using multivariate logistic regression. Key variables were selected using the least absolute shrinkage and selection operator (LASSO) algorithm. We constructed a prediction model and analyzed the association between IAA and albuminuria based on demographic and laboratory parameters.

The IAA-positive group had significantly higher D-dimer levels [0.30 (0.19-0.55) mg/L vs 0.21 (0.19-0.33) mg/L, P = 0.008] and plasma insulin levels [39.1 (12.0-102.7) μU/mL vs 9.8 (5.5-17.6) μU/mL, P < 0.001] compared to the IAA-negative group. Increases in the insulin dose per weight ratio, diabetes duration, and urinary albumin-to-creatinine ratio (UACR) were observed but did not reach statistical significance. The LASSO model identified plasma insulin and D-dimer as key factors with larger coefficients. D-dimer was significantly associated with UACR in the total and IAA-positive groups but not in the IAA-negative group. The odds ratio for D-dimer elevation (> 0.5 g/L) was 2.88 (95% confidence interval: 1.17-7.07) in the IAA-positive group (P interaction < 0.05).

D-dimer elevation is an independent risk factor for abnormal albuminuria and interacts with IAA in the development of abnormal albuminuria in T2DM patients.

Insulin autoimmune syndrome (IAS), characterized by endogenous hypoglycemia associated with insulin autoantibodies, is a rare cause of hypoglycemia in pediatric patients. Here, we report a case of the youngest patient with IAS in China, and summarize the clinical characteristics of the disease through a narrow review of pediatric cases.

A 3-year-10-month-old Chinese boy presented with unconsciousness. Initially, he was misdiagnosed with hyperinsulinemic hypoglycemia (HH) due to non-ketotic hypoglycemia. Whole exome sequencing (WES) was negative, and no pancreatic space-occupying lesions were identified. He continued to have intermittent episodes of symptomatic hypoglycemia. During an extended oral glucose tolerance test (OGTT), his insulin to C-peptide molar ratio was greater than 1, and anti-insulin antibodies (IAAs) measurements were as high as 54.38 COI (normal range 0-1 COI). High-resolution human leukocyte antigen (HLA) test showed a DRB1*08:03/*12:02 genotype. He was eventually diagnosed with IAS. Hypoglycemic episodes were not observed as long as the patient adhered to the low and frequent carbohydrate diet. Six months later, the patient's anti-insulin antibody had decreased to 10.17 COI, and mildly symptomatic hypoglycemia occasionally occurred in the case of noncompliance with the diet. Based on 11 studies from a literature review and our own case, a total of 12 pediatric patients were analyzed. Most of these patients presented with unconsciousness initially and their episodes of hypoglycemia do not follow a definitive pattern. Adjustments in diet serve as an effective intervention, and spontaneous remission is relatively common.

When differentiating the causes of HH in pediatric patients, IAS should not be overlooked. Elevated levels of IAAs and an inappropriate insulin to C-peptide molar ratio during an extended OGTT are critical indicators.

Not applicable.

Insulin autoimmune syndrome (IAS) is a rare autoimmune disorder characterized by spontaneous hypoglycemia. The incidence of IAS is higher in East Asian populations compared to other populations. Delayed diagnosis and treatment can lead to recurrent hypoglycemia, significant glucose fluctuations, and adverse clinical outcomes, including life-threatening situations. Currently, no standardized guidelines exist for the diagnosis and treatment of IAS. This consensus aims to provide a systematic summary of the epidemiology, triggers, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of IAS, with the objective of standardizing its clinical management.

Insulin autoimmune syndrome (IAS) is a known cause of hypoglycemia, more commonly observed in Asian populations, but it is rarely seen in Western countries. We present a case of recurrent hypoglycemia in a 53-year-old Caucasian female, attributed to insulin autoantibodies, which responded well to treatment with steroids and dietary modifications. Increasing awareness of IAS among clinicians is crucial to prevent unnecessary, costly, and potentially harmful diagnostic procedures when investigating recurrent and refractory hypoglycemia, and to ensure appropriate management strategies are implemented.

Insulin autoimmune syndrome (IAS) is a serious autoimmune disorder that may cause spontaneous hypoglycemia. IAS is characterized by hyperinsulinemia, normal C-peptide levels and positive anti-insulin antibody. The diagnosis is confirmed by demonstrating the presence of macroinsulin complex by polyethylene glycol (PEG) precipitation or gel filtration chromatography. Although some macrohormones like macroprolactin and some macroenzymes such as macroamylase are seen commonly, macroinsulinemia is a rare condition. In this report, we presented an IAS case from laboratory perspective by using three different immunoassays with different performances in eliminating macroinsulin interference. Besides presenting a case with IAS without hypoglycemia we evaluated the contribution of different immunoassays to the diagnosis of this syndrome. Immunoassays have different features, considering the analysis of macroinsulin or bioavailable insulin. In this case, the superiority or handicap of these immunoassays will be discussed in terms of analysis of total or free insulin.

Insulin autoimmune syndrome or Hirata's disease is a rare condition characterized by hypoglycemia associated with endogenous autoimmune hyperinsulinism. This report concerns the case of a 28-year-old Latin American woman with Graves' disease who developed insulin autoimmune syndrome and then subsequently became pregnant. She displayed symptoms related to severe hypoglycemia due to hyperinsulinemia, elevated C-peptide, and anti-insulin antibodies. Prior to pregnancy she was treated with corticosteroids and had ablative treatment with iodine-131. During follow-up of both conditions, the patient became pregnant, and clinically and biochemically hyperthyroid, for which total thyroidectomy was performed during the second trimester of pregnancy. Anti-insulin antibodies, blood glucose, and C-peptide remained normal throughout pregnancy. At 40 weeks of gestation she gave birth to a healthy female newborn with normal blood glucose values. Molecular genetic analysis determined the following genotypes: HLA-DRB1*03:01 / HLA-DRB1*04:01 in the mother; and HLA-DRB1*04:01 / HLA-DRB1*08:02 in the daughter. Because some HLA-DRB1*04 alleles are associated with susceptibility to insulin autoimmune syndrome induced by environmental factors, the patient was advised regarding the future use of drugs with a sulfhydryl group and possible triggering factors for insulin autoimmune syndrome. At 6-month follow-up the daughter presented normal growth and development, as well as normal plasma glucose values, and this remained the case at five-year follow-up.

Insulin autoimmune syndrome (IAS) is a rare cause of endogenous hyperinsulinemic hypoglycemia triggered by insulin autoantibodies. Through extensive research on IAS in recent years, it has been revealed that the use of exogenous insulin by diabetic patients can result in clinical manifestations similar to those of IAS. This phenomenon is known as exogenous IAS (EIAS). This article describes a case of a patient with EIAS who presented with atypical clinical manifestations. The patient, a middle-aged female with a 17-year history of type 2 diabetes, had been using Insulin Aspart 30 Injection for almost 10 years. She developed severe hyperinsulinemia, low C-peptide levels, positive insulin antibodies, poor postprandial glycemic control, and occasional autonomic nervous system symptoms such as hunger, palpitations, fatigue, and excessive sweating. Despite these symptoms, hypoglycemia was not detected. Switching the type of insulin for two weeks resulted in a significant reduction in insulin dosage, leading to stabilization of fasting and two-hour postprandial blood glucose levels within the target range. This article aims to alert medical professionals about diabetic patients who have hyperinsulinemia, insulin antibodies, and difficulty controlling blood sugar due to EIAS. It is crucial to prevent missed diagnoses, misdiagnoses, and potentially unnecessary surgical interventions through increased awareness.

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hyperinsulinemic hypoglycemia and the presence of insulin autoantibodies in high titers without exogenous insulin use. The C-peptide level during a hypoglycemia episode is useful for differentiating spontaneous hypoglycemia. Generally, low C-peptides are suspicious for exogenous insulin administration. We report a 47-year-old male nurse who presented with an initial episode of hypoglycemia. Despite the pattern of hyperinsulinemic hypoglycemia and low C-peptide, he was diagnosed with IAS based on the presence of insulin autoantibodies. This case underscores the importance of suspecting IAS in non-diabetic adults with hypoglycemia, even in the setting of low C-peptide levels.

Hirata disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia, due to the presence of insulin autoantibodies (IAA) in the circulating blood. These antibodies are immunoglobulin G (IgG), making placental transfer to the fetus possible. To our knowledge, no reports of IAS have been previously described in the neonatal population. We present a case report of hypoglycemia due to a secondary IAS in a neonate and discuss the management and treatment of the disease.

Insulin antibody syndrome (IAS), also known as Hirata disease, is a rare condition characterized by spontaneous hypoglycemic episodes unrelated to exogenous insulin exposure. It is caused by elevated serum levels of insulin autoantibodies (IAA). IAS typically occurs when a triggering factor, such as medication or viral infection, interacts with a predisposing genetic background. Diagnosing IAS is challenging due to its rarity and the presence of multiple potential causes for hyperinsulinemic hypoglycemia. The presence of Whipple triad-symptoms of hypoglycemia, low plasma glucose concentration, and relief of symptoms after raising plasma glucose-strongly supports the diagnosis of IAS. However, the detection of IAA is considered the most reliable test. Timely diagnosis can facilitate appropriate treatment and prevent unnecessary imaging studies and invasive procedures, thereby reducing costs. Currently, no definitive guidelines exist for managing IAS. Most management strategies involve supportive measures due to the high rate of spontaneous remission, with hypoglycemia often managed through dietary interventions. However, a few medications have shown benefit. Although predominantly observed in the Japanese population, IAS cases have been reported in other ethnicities, including Caucasians. This report presents a unique case of IAS in an African American male.

Dr. Hirata of Japan first described insulin autoimmune syndrome (IAS) in 1970. Seven hundred ninety-five cases of this rare syndrome have been reported from Japan and China and 29 from India. IAS has the following characteristic features 1) severe spontaneous attacks of hyperinsulinemic hypoglycaemia, 2) high total immunoreactive insulin levels, 3) elevated insulin autoantibody (IAA) titres, 4) no prior exposure to exogenous insulin, and 5) no pathological abnormalities of the pancreatic islet cells.

We treated six cases of IAS with high doses of prednisolone for 4-6 weeks and then gradually reduced the doses. Diagnosis of IAS was established by documenting Whipple's triad of symptoms and signs of hypoglycaemia, blood sugar <55 mg/dl, improvement of symptoms with dextrose infusion, inappropriately increased insulin levels >3 uU/ml, C-peptide levels >0.6 ng/ml, and increased titres of anti-insulin autoantibodies. Insulinoma and non-pancreatic tumours were ruled out by CECT (contrast-enhanced computerised tomography) or MRI (magnetic resonance imaging) of the abdomen and if necessary endoscopic ultrasonography and gallium 68 Dotanoc PET (positron enhanced tomography). Autoimmune screening and serum electrophoresis were done to rule out multiple myeloma. Monitoring of the patient's blood sugars was done by the laboratory, glucometer readings, and a freestyle libre glucose monitoring system.

Remission of hypoglycaemic episodes, hyperglycaemic episodes, and marked reduction of serum insulin and insulin autoantibodies in four out of six patients with diet therapy and steroids. Two patients resistant to steroids were treated with rituximab successfully. Patient 6 developed serious complications of cytomegalovirus and Pneumocystis carnii after rituximab, which were treated successfully.

A careful history including recent infections, medications, and vaccinations provides vital clues in the evaluation. An increased awareness of IAS will prevent unnecessary and costly investigations and surgery. Although it is often self-remitting, steroids are contributory in severe cases. Immunosuppressives are used successfully in cases refractory to steroids. Continuous glucose monitoring system (CGMS), by freestyle libre glucose monitoring system, provided real-time blood sugar values, total time in hypoglycaemia, and total time in the range (TIR), which proved very valuable in managing IAS patients. Low CGMS values should be corroborated clinically and with laboratory or glucometer values.

Hypoglycaemic syndromes are rare in apparently healthy individuals and their diagnosis can be a difficult challenge for clinicians as there are no shared guidelines that suggest how to approach patients with a suspect hypoglycaemic disorder. Since hypoglycaemia symptoms are common and nonspecific, it's necessary to document the Whipple Triad (signs and/or symptoms compatible with hypoglycaemia; relief of symptoms following glucose administration; low plasma glucose levels) before starting any procedure. Once the triad is documented, a meticulous anamnesis and laboratory tests (blood glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate and anti-insulin antibodies) should be performed. Results can guide the physician towards further specific tests, concerning the suspected disease. In this review, we consider all current causes of hypoglycaemia, including rare diseases such as nesidioblastosis and Hirata's syndrome, describe appropriate tests for diagnosis and suggest strategies to differentiate hypoglycaemia aetiology.

As our understanding of the pathophysiology of diabetes evolves, we increasingly recognize that many patients may have a form of diabetes that does not neatly fit with a diagnosis of either type 1 or type 2 diabetes. The discovery and description of these forms of "atypical diabetes" have led to major contributions to our collective understanding of the basic biology that drives insulin secretion, insulin resistance, and islet autoimmunity. These discoveries now pave the way to a better classification of diabetes based on distinct endotypes. In this review, we highlight the key biological and clinical insights that can be gained from studying known forms of atypical diabetes. Additionally, we provide a framework for identification of patients with atypical diabetes based on their clinical, metabolic, and molecular features. Helpful clinical and genetic resources for evaluating patients suspected of having atypical diabetes are provided. Therefore, appreciating the various endotypes associated with atypical diabetes will enhance diagnostic accuracy and facilitate targeted treatment decisions.

Insulin autoimmune syndrome (IAS) is a severe manifestation of spontaneous hypoglycemia. It is characterized by elevated levels of immune-reactive insulin and highly potent insulin autoantibodies (IAAs), which are induced by endogenous insulin circulating in the bloodstream. It is distinguished by recurring instances of spontaneous hypoglycemia, the presence of IAA within the body, a substantial elevation in serum insulin levels, and an absence of prior exogenous insulin administration. Nevertheless, recent studies show that both conventional insulin and its analogs can induce IAS episodes, giving rise to the notion of non-classical IAS. Therefore, more attention should be paid to these diseases.

In this case report, we present a rare case of non-classical IAS in an 83-year-old male patient who present with symptoms of a psychiatric disorder. Upon symptom onset, the patient exhibited Whipple's triad (including hypoglycemia, blood glucose level less than 2.8 mmol/L during onset, and rapid relief of hypoglycemic symptoms after glucose administration). Concurrently, his serum insulin level was significantly elevated, which contradicted his C-peptide levels. After a comprehensive examination, the patient was diagnosed with exogenous insulin autoimmune syndrome. Considering that the patient had type 2 diabetes mellitus and a history of exogenous insulin use before disease onset, it was presumed that non classical IAS was induced by this condition. The PubMed database was used to search for previous cases of IAS and non-classical IAS to analyze their characteristics and treatment approaches.

The occurrence of non-classical IAS is associated with exogenous insulin or its analogs, as well as with sulfhydryl drugs. Symptoms can be effectively alleviated through the discontinuation of relevant medications, administration of hormones or immunosuppressants, plasma exchange, and lifestyle adjustments.

Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis, characterized by serum autoantibodies to the insulin receptor (AIRAbs). Patients typically present with severe insulin resistance. A mixed hyper- and hypoglycemia phenotype may also occur, as may isolated hypoglycemia. The classic biochemical pattern comprises elevated insulin levels despite hypoglycemia; however, a small proportion of cases demonstrate "isolated hypoglycemia with low insulin." The primary objectives of this systematic review were to identify the clinical characteristics and outcome of this subgroup.

Systematic review of cases with hypoglycemia with suppressed insulin. Exclusions: hyperglycemia, elevated insulin, AIRAbs not confirmed.

PubMed, Medline, and Embase databases were searched up until February 2023 and complemented by manual citation search. The Joanna Briggs Institute critical appraisal checklist for case reports was used to assess bias.

A total of 5342 articles were identified after duplicate removal. Eleven, all case reports, met all inclusion criteria and were included. Cases belonging to this subgroup were more diverse in sex, age, and ethnicity when compared with type B insulin resistance as a whole. Of the 11 cases, 3 developed lymphoma. High-dose corticosteroid therapy appeared to be effective therapy for the hypoglycemia, with often rapid response.

Isolated hypoglycemia with low insulin forms a rare subgroup of type B insulin resistance. These patients lack the common characteristics of hyperinsulinemic hypoglycemia and hyperglycemia/insulin resistance. Furthermore, while coexisting autoimmune disease is commonly observed, there is potentially an association with aggressive lymphoma, the onset of which may be delayed.

Hypoglycemia is common in diabetic populations using insulin or insulin secretagogues, but rare in non-diabetics. A 60-year-old non-diabetic male presented with repeated episodes of abnormal behavior persisting for 10-15 minutes for seven days, associated with sweating, intense hunger, and relief on food intake, with no history of insulin or secretagogue intake, with stable vitals and normal systemic examination. Laboratory tests during attacks revealed low blood sugar, high serum insulin, and normal C-peptide levels, with no evidence of pancreatic or extrapancreatic hyperinsulinism, and serum anti-insulin antibody levels >100 U/ml. Based on these results, he was diagnosed with autoimmune insulin syndrome (AIS). Treatment with low-carb meals, oral prednisolone, and acarbose led to the resolution of symptoms. Hirata syndrome, though rare in India, requires consideration as a differential diagnosis to avoid unnecessary invasive procedures.

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.

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.

The aetiology of type 1 diabetes (T1D) is considered multifactorial with the contribution of the MHC on chromosome 6 being most important. Multiple factors also contribute to the aetiology of colorectal neoplasia, but the final event causing the change from normal mucosa to polyp and from polyp to cancer is due to a single somatic mutation event. Repeated formation of colorectal neoplasia within an at-risk population results in a predictable, tapering, exponential neoplasia distribution. Critical mutations driving colorectal neoplasia formation occur in mutation-prone DNA. These observations led to three hypotheses related to T1D. First, a single somatic mutation within the MHC of antigen presenting cells results in a change in phenotype from normal to T1D. Second, the distribution of additional autoimmune diseases (AAIDs) among persons with T1D adheres to a predictable, tapering, exponential distribution. And third, critical mutations driving development of T1D occur in mutation-prone DNA. To address the hypotheses in an orderly fashion, a new analytical method called genome-wide aetiology analysis (GWEA) consisting of nine steps is presented. All data required for GWEA of T1D are obtained from peer-reviewed publications or publicly available genome and proteome databases. Critical GWEA steps include AAID distribution among persons with T1D, analysis of at-risk HLA loci for mutation-prone DNA, determination of the role of non-MHC genes on GWAS, and verification of human data by cell culture or animal experiments. GWEA results show that distribution of AAID among persons with T1D adheres to a predictable, tapering, exponential distribution. A single, critical, somatic mutation within the epitope-binding groove of at-risk HLA loci alters HLA-insulin-peptide-T-cell-receptor (TCR) complex binding affinity and creates a new pathway that leads to loss of self-tolerance. The at-risk HLA loci, in particular binding pockets P1, P4 and P9, are encoded by mutation-prone DNA: GC-rich DNA sequence and somatic hypermutation hotspots. All other genes on GWAS can but do not have to amplify the new autoimmune pathway by facilitating DNA mutations, changing peptide binding affinity, reducing signal inhibition or augmenting signal intensity. Animal experiments agree with human studies. In conclusion, T1D is caused by a somatic mutation within the epitope-binding groove of an at-risk HLA gene that affects HLA-insulin-peptide-TCR complex binding affinity and initiates an autoimmune pathway. The nature of the peptide that binds to a mutated epitope-binding groove of an at-risk HLA gene determines the type of autoimmune disease that develops, that is, one at-risk HLA locus, multiple autoimmune diseases. Thus, T1D and AAIDs, and therefore common autoimmune diseases, share a similar somatic mutation-based aetiology.

The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.

Hypoglycemia is common in patients with glucose regulation disorders and related diabetic treatments but is rare in nondiabetic patients. Severe hypoglycemia can cause harm to patients' cognition, consciousness, central nervous system, cardiovascular and cerebrovascular system, and even death. However, the most fundamental way to control hypoglycemia is to identify the cause and deal with the primary disease. This article introduces 3 cases of nondiabetic hypoglycemia with different causes, aiming to improve our understanding of nondiabetic hypoglycemia and improve the ability of early diagnosis and differential diagnosis.

Case 1 is a 19-year-old female with a history of recurrent coma, and magnetic resonance imaging and endoscopic ultrasound of the pancreas suggest insulinoma. Case 2 is a 74-year-old male with a history of viral hepatitis, and computerized tomography shows multiple nodules in the liver, which is diagnosed as liver cancer. Case 3 is a 39-year-old female with a history of taking methimazole, who tested positive for insulin antibodies, and was diagnosed with insulin autoimmune syndrome.

All 3 patients were diagnosed with nondiabetic hypoglycemia, but the causes varied, and included insulinoma, non-islet cell tumor-induced hypoglycemia, and insulin autoimmune syndrome.

Case 1 underwent pancreatic tail resection; case 2 refused anti-tumor treatment and received glucose injections for palliative treatment only; and case 3 stopped taking methimazole.

After surgery, the blood sugar in case 1 returned to normal, and the blood sugar in case 2 was maintained at about 6.0 mmol/L. The symptoms of hypoglycemia gradually improved in case 3 after stopping the medication.

Non-diabetic hypoglycemia requires further examination to clarify the cause, and the correct differential diagnosis can provide timely and effective treatment, improving the patient's prognosis.

Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially.

An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association.

Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed.

The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

We present a young woman with treatment resistant insulin autoimmune syndrome (IAS) with a protracted course. Her serum insulin level was 6945 pmol/l (<160), C-peptide 4042 pmol/L (<1480), anti-insulin antibodies 5305 U/mL (<0.4) were monoclonal IgG kappa. After 12 h of fasting, her blood glucose fell to 1.2 mmol/L. Post-meal blood glucose peaked at 12.2 mmol/L with reactive hypoglycaemia below 2 mmol/L. Frequent meals and continuous blood glucose monitoring were helpful, but further treatments advocated in the literature with prednisolone, rituximab, plasmapheresis, cyclophosphamide and ciclosporin were without beneficial effect. Based on this case and a review of the literature, we propose that IAS is not one but two different diseases with different therapeutic strategies. The first disease, polyclonal IAS, predominates in Asia and is characterized by polyclonal anti-insulin antibodies, association with certain HLA genotypes and other autoimmune conditions, medications and viral infections possibly triggering the disease, a possible female predominance among young patients and a tendency towards spontaneous remission. The other disease, monoclonal IAS, predominates in Caucasians. Typical features are monoclonal anti-insulin antibodies, only weak HLA association, no drug predisposition, no sex difference, rare remission and conventional therapy often being without any clinical effect. We suggest that monoclonal IAS with IgG or IgA anti-insulin antibodies should receive therapy targeting plasma cells rather than lymphocytes.

IAS may be considered as two separate diseases, polyclonal and monoclonal. The presence of either polyclonal or monoclonal antibodies should determine the choice of treatment for IAS. In polyclonal IAS, discontinuation of a triggering medication and treatment of triggering conditions should be the backbone of therapy. Monoclonal IAS should receive treatment targeting plasma cells.

Exogenous insulin antibody syndrome (EIAS) rarely occurs in type 1 diabetes and should be considered in those with blood glucose levels outside the target range requiring greater than 2 units/kg/day of insulin without obesity. We describe the novel treatment of this condition using mycophenolate mofetil monotherapy in a pediatric patient in the outpatient setting.

A 17-year-old Caucasian male with type 1 diabetes experienced an abrupt increase in insulin requirements from 1.7 to 3.3 units/kg/day. Total insulin level was 7 µIU/mL with free insulin of 4.8 µIU/mL (68% of the total insulin), suggesting the presence of insulin antibodies. Switching from insulin aspart to glulisine was unsuccessful as insulin requirements increased to 4.4 units/kg/day. Treatment with oral mycophenolate mofetil decreased insulin requirements to 1.4 units/kg/day after 7 months. Total and free insulin levels improved to 5.2 and 4.6 µIU/mL, respectively (free insulin was 88% of total insulin). No adverse effects were encountered.

Mycophenolate mofetil monotherapy is successful in safely treating EIAS in a pediatric patient.

To describe a case report of a patient with symptoms associated with metabolic alterations 1 month after having COVID-19.

Laboratory tests, clinical evaluations, and body composition assessments were performed by specialists.

The patient presented excessive sweating, hot flashes, dizziness, blurred vision, and seizure. Laboratory tests indicated low glucose levels after convulsions (50, 42.7, and 55 mg/dL), high insulin levels (basal, 638 µIU/mL; 2-hour, >1000 µU/mL), and positivity for anti-insulin antibodies. The patient was diagnosed with insulin autoimmune syndrome. Treatment with azathioprine and nutritional recommendations improved remission.

SARS-CoV-2 infection or vaccination might induce insulin tolerance failure.

The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. For patients with cardiovascular disease taking clopidogrel for vascular protection, this adverse event hypoglycemia increases the risk of cardiovascular events. However, discontinuing clopidogrel leaves patients without appropriate antiplatelet therapy. Treating IAS with glucocorticoids is also risky for these patients' primary cardiovascular diseases. Early recognition and appropriate treatment of clopidogrel-induced IAS (CIAS) would be beneficial for patients. This research aimed to discover the clinical features and investigate optimal therapeutic management of CIAS. We systematically searched for cases of CIAS in PubMed and Embase and performed data mining in Food and Drug Administration Adverse Event Reporting System (FAERS). In the CIAS series, clinical features were summarized and compared to 287 IAS cases, including demographic information, HLA alleles, onset, and symptoms. The therapeutic effect of glucocorticoids was compared between the receiving group and the not-receiving group. The possibilities of common antiplatelet drugs to induce hypoglycemia/IAS were investigated with chemical structure and FAERS reports. A CIAS series of 51 patients was established. CIAS had an onset age of 74.8±8.6 years old, 92.2% male, and a balanced proportion of East Asians and non-East Asians. Confusion occurred more frequently in CIAS than in IAS from various causes, while the other symptoms and hypoglycemia types were similar. The recovery time was approximately the same whether using glucocorticoids/immunotherapy in CIAS or not. Among common antiplatelet drugs, ticagrelor and rivaroxaban were unlikely to induce hypoglycemia/IAS. Clopidogrel is a distinctive cause of IAS featuring an elderly male presenting confusion as the symptom of hypoglycemia. Glucocorticoids/immunotherapy might not be necessary for the long-term recovery of CIAS. To balance the risks of hypoglycemia and cardiovascular events, substituting clopidogrel with ticagrelor and rivaroxaban might be considered.

Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially.

An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association.

Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed.

The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Insulin autoimmune syndrome is a rare cause of recurrent hypoglycemic episodes that can mimic various other pathological problems leading to unnecessary diagnostic assessments and interventions. Here, we report a case of a healthy non-diabetic male in his 50s presenting with recurrent episodes of hypoglycemia with no prior exposure to exogenous insulin. During a 72-hour fasting test, his glucose levels reached 22 mg/dl within less than three hours. The lab tests showed insulin of 1000 μIU/mL and C-peptide of 4.99 ng/ml. On further evaluation, high titers of insulin autoantibodies (IAA) >100 U/ml (normal = <10 U/ml) were consistent with insulin autoimmune syndrome diagnosis. This case thus highlights the importance of including IAA titers in first-line investigations for hypoglycemia in a non-diabetic patient with strikingly high blood insulin levels.

This study aimed to investigate the clinical implications of fasting serum insulin (FINS) levels in subjects with type 2 diabetes who were receiving insulin therapy.

A total of 1,553 subjects with type 2 diabetes [774 subjects who had never received insulin treatment (N-INS) and 779 subjects who were receiving insulin therapy (constant insulin treatment, C-INS)] admitted to the Department of Endocrinology and Metabolism of Peking University People's Hospital were enrolled in this study. Their FINS levels were measured and those with hyperinsulinemia were identified. The underlying mechanisms of hyperinsulinemia were revealed by measuring insulin antibodies (IAs) and analyzing changes in FINS levels before and after polyethylene glycol (PEG) precipitation. In addition, the clinical characteristics of patients with different types of hyperinsulinemia were compared.

Higher FINS levels and a higher incidence (43.8%, 341/779) of hyperinsulinemia (FINS > 15μIU/mL) were observed in subjects with C-INS than in subjects with N-INS. Among subjects with C-INS and hyperinsulinemia, 66.9% (228/341) were IAs positive, and the incidence of IAs was found to be positively associated with FINS level. By performing PEG precipitation, we found that all subjects without IAs (i.e., those with real hyperinsulinemia) and 31.1% of subjects (71/228) with IAs (i.e., those with both real and IAs-related hyperinsulinemia) still had hyperinsulinemia after PEG precipitation, whereas FINS levels in the other 68.9% of subjects (157/228) with IAs were normal (IAs-related hyperinsulinemia) after PEG precipitation. Comparisons between the groups showed that subjects with real hyperinsulinemia showed more obvious insulin resistance characteristics, including higher lipid levels, BMIs, and homoeostasis model assessment2-estimated insulin resistance (HOMA2-IR) index, and were more likely to have hypertension, obesity, and metabolic syndromes (p < 0.05). However, the risk of hypoglycemia and glucose variability increased significantly in subjects with IAs compared with those without IAs. A cutoff of FINS to serum C-peptide ratio (≥ 9.3μIU/ng) could be used to screen IAs in clinical practice with 83.3% sensitivity and 70% specificity.

It is necessary to measure FINS in subjects with C-INS to distinguish between types of hyperinsulinemia, which should help to tailor treatment regimens.

Observational studies have suggested a relationship between type-1 diabetes mellitus (T1DM) and systemic lupus erythematosus (SLE). In both autoimmunities, 25-hydroxyvitamin D (25-OHD) deficiency is common. However, the causality between T1DM, 25-OHD level and SLE remains largely unknown.

Independent genetic variants associated with T1DM, 25-OHD level, and SLE from the largest genome-wide association studies were used to conduct two-sample bidirectional Mendelian randomization (BIMR) and two-step Mendelian randomization (MR) analysis to estimate causal relationship between T1DM, 25-OHD level and SLE, and further multivariable Mendelian randomization (MVMR) was used to verify direct causality of T1DM and 25-OHD level on SLE. A series of sensitivity analysis as validation of primary MR results were performed.

Consistent with the results of BIMR, there was strong evidence for a direct causal effect of T1DM on the risk of SLE (ORMVMR-IVW = 1.249, 95% CI = 1.148-1.360, PMVMR-IVW = 1.25×10-5), and 25-OHD level was negatively associated with the risk of SLE (ORMVMR-IVW = 0.305, 95% CI = 0.109-0.857, PMVMR-IVW = 0.031). We also observed a negative causal effect of T1DM on 25-OHD level (ORBIMR-IVW = 0.995, 95% CI = 0.991-0.999, PBIMR-IVW = 0.030) while the causal effect of 25-OHD level on the risk of T1DM did not exist (PBIMR-IVW = 0.106). In BIMR analysis, there was no evidence for causal effects of SLE on the risk of T1DM and 25-OHD level (PBIMR-IVW > 0.05, respectively).

Our MR analysis suggested that there was a network causal relationship between T1DM, 25-OHD level and SLE. T1DM and 25-OHD level both have causal associations with the risk of SLE, and 25-OHD level could be a mediator in the causality of T1DM and SLE.

The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring autoantibodies in type 1 diabetes and the concordance of results across laboratories. IASP organises international workshops distributing anonymised serum samples to participating laboratories and centralises the collection and analysis of results. In this report, we describe the results of assays measuring IAA submitted to the IASP 2018 and 2020 workshops.

The IASP distributed uniquely coded sera from individuals with new-onset type 1 diabetes, multiple islet autoantibody-positive individuals, and diabetes-free blood donors in both 2018 and 2020. Serial dilutions of the anti-insulin mouse monoclonal antibody HUI-018 were also included. Sensitivity, specificity, area under the receiver operating characteristic curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95) and concordance of qualitative/quantitative results were compared across assays.

Results from 45 IAA assays of seven different formats and from 37 IAA assays of six different formats were submitted to the IASP in 2018 and 2020, respectively. The median ROC-AUC was 0.736 (IQR 0.617-0.803) and 0.790 (IQR 0.730-0.836), while the median pAUC95 was 0.016 (IQR 0.004-0.021) and 0.023 (IQR 0.014-0.026) in the 2018 and 2020 workshops, respectively. Assays largely differed in AUC (IASP 2018 range 0.232-0.874; IASP 2020 range 0.379-0.924) and pAUC95 (IASP 2018 and IASP 2020 range 0-0.032).

Assay formats submitted to this study showed heterogeneous performance. Despite the high variability across laboratories, the in-house radiobinding assay (RBA) remains the gold standard for IAA measurement. However, novel non-radioactive IAA immunoassays showed a good performance and, if further improved, might be considered valid alternatives to RBAs.

To review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus.

A literature review was performed using the PubMed and Google Scholar databases.

Hypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non-diabetes-related medications, and non-islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient's symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms.

We provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.

The number of recognised distinct autoimmune diseases (AIDs) has progressively increased over the years with more than 100 being reported today. The natural history of AIDs is characterized by progression from latent and subclinical to clinical stages and is associated with the presence of the specific circulating autoantibodies. Once presented, AIDs are generally chronic conditions. AIDs have the tendency to cluster and co-occur in a single patient. Autoimmune thyroid diseases (AITD) are the most prevalent of AIDs in the world population, and about one-third of the AITD patients also present with a non-thyroid AID during their life-span. Furthermore, patient with non-thyroid AIDs often presents with a form of AITD as a concurrent condition. Many of the clusters of AIDs are well characterized as distinctive syndromes, while some are infrequent and only described in case reports.

In this review, we describe the wide spectrum of the combinations and the intricate relationships between AITD and the other AIDs, excluding Addison's disease. These combinations are collectively termed type 3 Autoimmune Polyglandular Syndrome (APS-3), also called type 3 Multiple Autoimmune Syndrome (MAS-3), and represent the most frequent APS in the world populations.

Numerous associations of AITD with various AIDs could be viewed as if the other AIDs were gravitating like satellites around AITD located in the center of a progressively expanding galaxy of autoimmunity.

Exogenous insulin can induce insulin antibodies that have a low affinity/high binding capacity. Similar to what is observed in insulin autoimmune syndrome, these insulin antibodies can cause fasting hypoglycemia and postprandial hyperglycemia, a phenomenon known as "exogenous insulin antibody syndrome" (EIAS). Cases of EIAS in patients with type 1 and type 2 diabetes have been sporadically reported, mainly in Asia. However, there has been no report on EIAS in patients with diabetes secondary to total pancreatectomy treated with insulin analogs. A 74-year-old man with diabetes after total pancreatectomy had been treated with continuous subcutaneous insulin infusion using an insulin analog, lispro, and developed recurrent early morning hypoglycemia even after discontinuation of nocturnal basal insulin. His fasting serum lispro level was high even approximately 9 h after the last lispro dose. He had a high titer (72.7%) of insulin antibodies, and a Scatchard analysis revealed low affinity/high binding capacity. These findings suggested that the patient's recurrent early morning hypoglycemia was associated with insulin antibodies against lispro, and we, therefore, switched from lispro to another insulin analog, glulisine. His hypoglycemia improved, accompanied by a dramatic decrease in his insulin antibodies and serum glulisine levels. Early morning hypoglycemia in patients with diabetes secondary to total pancreatectomy may often be explained by high glycemic variability, malnutrition, and/or glucagon deficiency. However, in cases of recurrent early morning hypoglycemia, EIAS should be considered as a potential differential diagnosis.

Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia.

We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition.

We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients.

We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%.

Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.

Pancreatic neuroendocrine tumors, or pNETs, represent a rare and clinically heterogenous subset of pancreatic neoplasms. One such pNET, the insulinoma, is found to be malignant in just 4% of all insulinomas. Due to the exceedingly uncommon occurrence of these tumors, there is controversy regarding the optimal evidence-based management for these patients. We therefore report on a 70-year-old male patient admitted with 3 months of episodic confusion with concurrent hypoglycemia. The patient was found to have inappropriately elevated endogenous insulin levels during these episodes, and somatostatin-receptor subtype 2 selective imaging revealed a pancreatic mass metastatic to local lymph nodes, spleen, and the liver. Fine needle aspiration of pancreatic and liver lesions confirmed the diagnosis of a low grade pancreatic neuroendocrine tumor. Molecular analysis of tumor tissue revealed a novel mutational profile consistent with pNET. The patient was initiated on octreotide therapy. However, treatment with octreotide alone demonstrated limited efficacy in controlling the patient's symptoms, prompting consideration of other therapies.

Although insulin is an essential medicine and a life-saving drug, it has also been incriminated in many poisoning deaths; accidental, suicidal and some with malicious intent. Overdosing with insulin precipitates a life-threatening state of hypoglycemia and if untreated leads to coma, irreversible brain damage and death. Normally, the pancreatic β-cells secrete equimolar amounts of insulin and C-peptide into the portal venous blood, although under physiological conditions the plasma concentration ratio (insulin/C-peptide) is less than unity, because insulin is more susceptible to hepatic first-pass metabolism. A high ratio of insulin/C-peptide in plasma from a poisoned patient is compelling evidence that pharmaceutical insulin was administered, which does not contain C-peptide. The analysis of insulin and C-peptide was traditionally done by immunoassay methods (RIA and/or ELISA), although high resolution LC-MS/MS is more suitable for forensic purposes and permits the identification of insulin analogues. Use of insulin as a murder weapon is exemplified by the case of Colin Norris, a male nurse found guilty of murdering four elderly patients and the attempted murder of a fifth by injecting them with insulin. However, the prosecution evidence against Norris was mainly circumstantial and hearsay. Toxicological evidence against Norris consisted of a high insulin/C-peptide concentration ratio in plasma from one of the victims. This analysis was done by an immunoassay method at a clinical laboratory and not a forensic laboratory. Analytical procedures, including chain-of-custody routines, are more stringent at forensic laboratories. Since his conviction, some of the medical evidence against Norris has been called into question, especially the prevalence of spontaneous attacks of hypoglycemia in elderly and frail patients with co-morbidities.

Clopidogrel is a cornerstone antiplatelet drug used in cardiovascular, cerebrovascular, and peripheral artery diseases. The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. Discontinuing clopidogrel and substituting it with ticagrelor has been revealed as an effective treatment in previous studies. Since hypoglycemia serves as a risk factor for cardiovascular and cerebrovascular events, we aimed to determine the association between hypoglycemia/IAS and clopidogrel and to investigate whether clopidogrel is a modifiable and causal risk factor of hypoglycemia/IAS.

MEDLINE, Embase, Cochrane databases, and clinical trial registries were searched for randomized controlled trials (RCTs) of clopidogrel from inception to 28 February 2022. RCTs comparing clopidogrel with placebo or other antiplatelet drugs were eligible if meeting the inclusion criteria: 1) clopidogrel was administrated 75 mg qd orally as a long-term antiplatelet prescription at least for months, and 2) hypoglycemia-inducible drugs were not used in the control arm. One investigator abstracted articles and performed a quality assessment. Uncertainties were resolved by discussions with two investigators independently. Odds ratio (OR) and risk difference (RD) were calculated and performed with subgroup analyses. The pre-specified protocol was registered in PROSPERO (CRD42022299622).

Six trials with 61,399 participants in total fulfilled the criteria and were included in the meta-analysis. Clopidogrel might not be associated with higher hypoglycemia odds (OR 0.95, 95% CI 0.65 to 1.40). However, Asian participants (p = 0.0437) seemed more likely to develop clopidogrel-associated hypoglycemia. Clopidogrel-associated hypoglycemia occurred at the highest rate of 0.03% (RD -0.00023, 95% CI -0.00077 to 0.00031), and this increased to 0.91% (RD 0.00210, 95% CI -0.00494 to 0.00914) in an aging population and to 0.18% (RD 0.00040, 95% CI -0.00096 to 0.00177) when Asian ratio of the population was elevated.

We raise the concern that clopidogrel might be a modifiable and causal risk factor of hypoglycemia. The Asian population might be more vulnerable and need additional care.

https://www.crd.york.ac.uk/prospero, identifier CRD42022299622.

This study aimed to further quantify the relationship between insulin antibodies (IAs) and the 2-hour insulin to C-peptide molar ratio (2h-ICPR) using a multiple linear regression model in T2DM patients.

A total of 274 T2DM patients from April 2019 to December 2022 in Xiang'an Hospital of Xiamen University were included in this study. Multiple Linear Model Fitting was conducted on the candidate independent variables (age, BMI, HbA1c, and 2h-ICPR) for the multiple linear regression. The linear relationship between insulin antibodies (IAs) and the significant independent variables was presented by making multiple linear regression equations.

The total demographic characteristics of the included patients were as follows: age (51.92±13.10 years), BMI (24.94±3.99 kg/m²), HbA1c (9.70±2.39%), 2h-ICPR (0.12±0.11), and IAs (0.37±1.12COI). Linear relationships of independent variables: age (r=0.163, p=0.007), 2h-ICPR (r=0.259, p=0.001), BMI (r=0.007, p=0.907) and 2h-ICPR (r=0.092, p=0.129). Multiple linear regression: age (unstandardized β=0.014, 95% CI: 0.004-0.024, p=0.004), 2h-ICPR (unstandardized β=2.758, 95% CI: 1.555-3.962, p≤0.001). The regression equation: .

The quantitative relationship between 2h-ICPR and insulin antibodies was . 2h-ICPR can be a preliminary screening indicator for insulin antibody testing in patients with type 2 diabetes.

Islet autoimmune syndrome (IAS) is an autoimmune disease caused by high concentrations of insulin autoantibodies (IAA) in the blood. It is characterized by hyperinsulinemia and spontaneous hypoglycemia. The incidence of IAS is low, and the hypoglycemia symptom is usually mild. Hence, the severe manifestations (up to seizures and coma) are rarely reported. Here, we reported two cases of Graves' disease who developed insulin autoimmune syndrome after methimazole treatment. The patients exhibited sudden hypoglycemic coma after receiving methimazole treatment for approximately 2 or 6 months. The patients' serum glucose levels were below 2.8 mmol/L, and laboratory tests showed high levels of serum insulin and high titers of insulin autoantibodies. Patient 1 discontinued methimazole treatment and the hypoglycemic symptoms disappeared after 7 days. However, patient 2 experienced severe hypoglycemia after discontinuation of methimazole, and the patient condition improved after glucocorticoid therapy. He developed thyroid storm during the treatment, and his condition improved after receiving standard treatment procedures for thyroid storm. To the best of our knowledge, this is the first case report of IAS in Graves' disease with thyroid storm.