Objective To explore the clinical characteristics of patients with exogenous insulin-induced antibody syndrome (EIAS) and the clinical outcome after 24 weeks follow-up. Methods A total of 16 cases with EIAS after insulin therapy from January 2015 to June 2018 were enrolled.Laboratory data such as general clinical data,fasting blood glucose (FBG),glycosylated hemoglobin (HbA1c),fasting insulin (FINS),2-hour insulin (2hINS),and insulin antibody (IA) were observed at 12 and 24 weeks after the adjustment of drug treatment. Results Serum FINS and 2hINS levels of 16 EIAS patients were significantly increased,and the separation of insulin and C-peptide was observed,and insulin antibodies of these cases were positive.Twelve weeks after the withdrawal of insulin or change of insulin dosage form,FINS and 2hINS levels decreased significantly (in all cases) or returned to normal (in 2 cases).At the 24th week,insulin levels of 12 patients became to the normal range,and 9 patients had negative IA,and no hypoglycemia occurred in all patients. Conclusion When diabetic patients treated with exogenous insulin,the insulin level and insulin antibody should be detected to avoid missed diagnosis or misdiagnosis of EIAs when hypoglycemia,large fluctuation of blood glucose and,difficulty in glucose control occur.In most patients with EIAS,insulin level can significantly decrease within 24 weeks after insulin withdrawal or dosage change,while the time for IA to turn negative is relatively lag.
BERSON SA,YALOW RS,BAUMANA,et al.Insulin-I131 metabolism in human subjects:demonstration of insulin binding globulin in the circulation of insulin treated subjects[J].J Clin Invest,1956,35(2):170-190.
RADERMECKER RP,RENARDE,SCHEEN AJ.Circula-ting insulin antibodies:influence of continuous subcutaneous or intraperitoneal insulin infusion,and impact on glucose control[J].Diabetes Metab Res Rev,2009,25(6):491-50l.
The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti-insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti-IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti-IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low-glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non-purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients.
SU CT,LIN YC.Hyperinsulinemic hypoglycemia associa-ted with insulin antibodies caused by exogenous insulin analog[J].Endocrinol Diabetes Metab Case Rep,2016.DOI:10.1530/EDM-16-0079.
Summary: Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure. Learning points: Insulinomas are usually benign and managed surgically. Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare. Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis. Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones. The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.
WONG SL,PRIESTANA,HOLMES DT.Recurrent hypo-glycemia from insulin autoimmune syndrome[J].J Gen Intern Med,2014,29(1):250-254.
Insulin autoimmune syndrome (IAS) is an uncommon cause of hyperinsulinemic hypoglycemia characterized by autoantibodies to endogenous insulin in individuals without previous exposure to exogenous insulin. IAS is the third leading cause of spontaneous hypoglycemia in Japan, and is increasingly being recognized worldwide in non-Asian populations. We report a case of IAS in a Caucasian woman with recurrent complaints of hypoglycemia, with laboratory findings of serum glucose 2.5 mmol/L (45 mg/dL), insulin 54,930 pmol/L (7,909 mu IU/mL), connecting peptide (C-peptide) 4,104 pmol/L (12.4 ng/mL), and a corresponding insulin to C-peptide molar ratio of 13.4 during a spontaneous hypoglycemic event. Autoantibodies to insulin were markedly elevated at > 50 kU/L (> 50 U/mL). IAS should be considered in the differential diagnosis of hypoglycemia in non-diabetic individuals. Distinction from insulinoma is especially crucial to prevent unwarranted invasive procedures and surgical interventions in hypoglycemic patients.
ZHAO TY,LIF,XIONG ZY.Frequent reoccurrence of hypoglycemia in a type 2 diabetic patient with insulin antibodies[J].Mol Diagn Ther,2010,14(4):237-241.
BACKGROUND: Insulin antibody (IAb) may be produced in patients receiving long-term, animal-derived insulin, leading to insulin resistance or hypoglycemia. There have been very few reports of hypoglycemia caused by IAb in patients taking recombinant human insulin. CASE REPORT: We report the case of an 82-year-old male patient with type 2 diabetes mellitus who suffered repeated episodes of severe hypoglycemia-related symptoms (including coma) prior to admission. The patient had been taking Novolin 30R, a premixed human insulin. The patient's IAb level was markedly elevated, and hypoglycemia caused by recombinant human insulin treatment-induced IAb production was diagnosed. Acarbose and metformin were prescribed, and the patient recovered uneventfully. The patient ceased taking these medications, and he was subsequently treated with recombinant human insulin to combat hyperglycemia. This was followed by reoccurrence of hypoglycemic coma. The patient was advised to avoid taking recombinant human insulin for the rest of his life and to control hyperglycemia with acarbose and metformin. CONCLUSIONS: Although rare, hypoglycemia caused by recombinant human insulin-induced IAb production should be considered in patients with type 2 diabetes who experience repeated episodes of hypoglycemia.
SARERBORNM,BRINKSV,JISKOOTW,et al.Immu-noiogical mechanism underlying the immune response to recombinant human protein therapeutics[J].Trends Pharmacol Sci,20l0,3l(2):53-59.
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ISHIZUKAT,OGAWAS,MORIT,et al.Characteristics of the antibodies of two patients who developed daytime hyperglycemia and morning hypoglycemia because of insulin antibodies[J].Diabetes Res Clin Pract,2009,84(2):e21-23.
We encountered two patients who developed daytime hyperglycemia and early morning hypoglycemia because of insulin antibody (IA) that the affinity was extremely lower and the capacity extremely higher than those of IA in the insulin autoimmune syndrome, after their insulin treatment were changed from human insulin to analog insulin.
FINEBERG SE,HUANGJ,BRUNELLER,et al.Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes[J].Diabetes Care,2003,26(1):89-96.
OBJECTIVE: To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies. RESEARCH DESIGN AND METHODS: A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years' duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12-81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays. RESULTS: Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro. CONCLUSIONS: The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin.
JASSAMN,AMINN,HOLLANDP,et al.Analytical and clinical challenges in a patient with concurrent type 1 diabetes,subcutaneous insulin resistance and insulin autoimmune syndrome[J].Endocrinol Diabetes Metab Case Rep,2014,2014:130086.
UNLABELLED: A 48-year-old hypertensive and diabetic patient presented with a 10-year history of progressive right facial pain, tinnitus, hearing loss, sweating, and palpitations. Investigations revealed a 5.6 cm vascular tumor at the carotid bifurcation. Her blood pressure (BP) was 170/110, on lisinopril 20 mg od and amlodipine 10 mg od and 100 U of insulin daily. A catecholamine-secreting carotid body paraganglioma (CSCBP) was suspected; the diagnosis was confirmed biochemically by determining plasma norepinephrine (NE) level, 89 000 pmol/l, and chromogranin A (CgA) level, 279 mug/l. Meta-iodobenzylguanidine and octreotide scanning confirmed a single tumor in the neck. A week after giving the patient a trial of octreotide 100 mug 8 h, the NE level dropped progressively from 50 000 to 25 000 pmol/l and CgA from 279 to 25 mug/l. Treatment was therefore continued with labetalol 200 mg twice daily (bid) and long-acting octreotide-LA initially using 40 mg/month and later increasing to 80 mg/month. On this dose and with a reduced labetalol intake of 100 mg bid, BP was maintained at 130/70 and her symptoms resolved completely. CgA levels returned to normal in the first week and these were maintained throughout the 3 month treatment period. During tumor resection, there were minimal BP fluctuations during the 10 h procedure. We conclude that short-term high-dose octreotide-LA might prove valuable in the preoperative management of catecholamine-secreting tumors. To the best of our knowledge, this is the first report on the successful use of octreotide in a CSCBP. LEARNING POINTS: The value of octreotide scanning in the localization of extra-adrenal pheochromocytoma.Control of catecholamine secretion using high-dose octreotide.This is a report of a rare cause of secondary diabetes and hypertension.
TRABUCCHIA,IACONO RF,GUERRA LL,et al.Characterization of insulin antibodies by surface plasmon resonance in two clinical cases:brittle diabetes and insulin autoimmune syndrome[J].PLoS One,2013,8(12):e84099.
Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.
QUANH,TANH,LIQ,et al.Immunological hypoglycemia associated with insulin antibodies induced by exogenous insulin in 11 Chinese patients with diabetes[J].J Diabetes Res,2015,2015:746271.
IONESCU-TIRGOVISTEC,MINCUI,SIMIONESCUL,et al.Disappearance rate of insulin antibodies after discountinuing insulin treatment in 42 type 2 (non-insulin-dependent) diabetic patients[J].Diabetologia,1984,27(6):592-595.
The disappearance rate of insulin antibodies was studied after cessation of insulin treatment which had been given for 3 months to 6 years in 42 Type 2 (non-insulin-dependent) diabetic patients. Insulin antibodies were measured before and 15 days after interruption of insulin treatment, and every 30 days until the disappearance of insulin antibodies. The mean +/- SD value of insulin binding in the entire group before the interruption of insulin treatment was 32 +/- 14%. There was no relationship between the antibody level at that time and the duration of insulin treatment. However, the insulin antibody level was significantly higher in 17 diabetic patients on an insulin dose of greater than 20 U/day (p less than 0.02) than in 25 on an insulin dose of less than 20 U/day (39 +/- 13% versus 28 +/- 12%). A positive correlation was found between initial insulin binding and the time required for it to fall below 10% (r = 0.74). Antibodies were absent 60 days after discontinuing insulin treatment in eight of ten subjects presenting with initial binding of less than 20%. In contrast, in only two of 12 patients with an initial binding of greater than 40% were insulin antibodies detectable 150 days after discontinuation of insulin therapy. Disappearance of insulin antibodies sometimes took up to 1 year and occasionally even more than 2 years.
Enhancement of postprandial endogenous insulin secretion rather than exogenous insulin injection ameliorated insulin antibody-induced unstable diabetes:a case report
, 王晓丽
