Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome

Church, D B; Cardoso, Luís; Kay, Richard G.; Williams, Claire L; Freudenthal, Bernard; Clarke, Catriona; Harris, Julie; Moorthy, Myuri; Karra, Efthmia; Gribble, Fiona M.; Reimann, Frank; Burling, Keith; Williams, Alistair J K; Munir, Alia; Jones, T. Hugh; Führer, Dagmar; Moeller, Lars C.; Cohen, Mark L.; Khoo, Bernard; Halsall, David; Semple, Robert K.

doi:10.1210/jc.2018-00972

Cited by 26 publications

(27 citation statements)

References 45 publications

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“…113,114 In case of severe hypoglycemic episodes, intravenous glucose administration may be necessary, especially in order to prevent nightly glycemic fluctuations. 88 Among the strategies aimed at reducing insulin release, somatostatin analogues, 40,115 diazoxide 41,115,116 and even pancreatectomy 18,79 have been proposed, with variable results.…”

Section: Therapymentioning

confidence: 99%

<p>Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description</p>

Cappellani¹,

Macchia²,

Falorni³

et al. 2020

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Insulin autoimmune syndrome (IAS), also named Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.

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Section: Therapymentioning

confidence: 99%

<p>Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description</p>

Cappellani¹,

Macchia²,

Falorni³

et al. 2020

DMSO

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“…In addition, we found that application of sunitinib also resulted in an impairment of insulin sensitivity as determined by ITT and GTT assays and an increase in the levels of serum IAA. Therefore, we considered that sunitinib-induced hypoglycemia is associated with a decrease in glucose intake due to gastrointestinal toxicity, hyperinsulinemia and generation of IAA ( Church et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension

et al. 2021

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Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.

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“…Heparinized plasma samples from 7 patients with IAS were evaluated for potential interference with a C-peptide immunoassay by the UK Severe Insulin Resistance Supra-Regional Assay Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge. A summary of the clinical characteristics of patients studied, the investigations undertaken on initial presentation, and the case histories have been published ( 6 , 7 ). Nonfasting blood samples were collected on ice, and plasma separated and frozen at −80 °C until analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Hyperinsulinemic hypoglycemia with high C-peptide usually indicates endogenous insulin hypersecretion ( 8 ). High C-peptide immunoreactivity has been reported in IAS, even in the face of frequent profound hypoglycemia ( 6 , 7 , 9–17 ). This has the potential to confuse managing clinicians since normal endogenous C-peptide production by the pancreas is inhibited in response to exogenous insulin-induced hypoglycemia ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Increased C-Peptide Immunoreactivity in Insulin Autoimmune Syndrome (Hirata Disease) Due to High Molecular Weight Proinsulin

et al. 2021

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Background Determination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS. Methods Precipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC–MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC–MS/MS analysis. Gel filtration chromatography coupled to LC–MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay. Results Polyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC–MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC–MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes. Conclusions Antibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results.

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Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome

Cited by 26 publications

References 45 publications

<p>Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description</p>

<p>Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description</p>

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension

Increased C-Peptide Immunoreactivity in Insulin Autoimmune Syndrome (Hirata Disease) Due to High Molecular Weight Proinsulin

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