Autoimmune hypoglycaemia caused by alpha-lipoic acid: a rare condition in Caucasian patients

Summary Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions. Learning points: IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients. It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery. It should be suspected in the presence of very high serum insulin levels (100–10 000 μU/mL) associated with high C-peptide levels. There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

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Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-18-0122 ◽

2018 ◽

Vol 2018 ◽

Cited By ~ 2

Author(s):

D Cappellani ◽

C Sardella ◽

M C Campopiano ◽

A Falorni ◽

P Marchetti ◽

...

Keyword(s):

Differential Diagnosis ◽

Lipoic Acid ◽

University Hospital ◽

Hypoglycaemic Episode ◽

List Type ◽

Alpha Lipoic Acid ◽

Previous Exposure ◽

Hyperinsulinaemic Hypoglycaemia ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome

Summary Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS. Learning points: Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid. Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available. The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

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Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-21-0043 ◽

2021 ◽

Vol 2021 ◽

Author(s):

Wann Jia Loh ◽

Lily Mae Dacay ◽

Clara Si Hua Tan ◽

Su Fen Ang ◽

Fabian Yap ◽

...

Keyword(s):

Glucose Level ◽

Serum Insulin ◽

Insulin Level ◽

Somatostatin Analogue ◽

List Type ◽

Hyperinsulinaemic Hypoglycaemia ◽

Hypoglycaemia Unawareness ◽

C Peptide ◽

Genetic Causes ◽

Activating Mutation

Summary Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative. Learning points Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative. Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness. Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia. Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK. Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

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A case of low serum insulin levels in a patient with insulinoma

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0041 ◽

2016 ◽

Vol 2016 ◽

Author(s):

Chun-Han Lo ◽

Ding-Ping Sun

Keyword(s):

Ct Scan ◽

Serum Insulin ◽

Laboratory Data ◽

Insulin Level ◽

Laparoscopic Distal Pancreatectomy ◽

List Type ◽

Previous Night ◽

C Peptide ◽

Insulin Levels ◽

Glucose Levels

Summary Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. Traditionally, inappropriately elevated levels of insulin in the face of hypoglycemia are the key to diagnosis. However, contradictory levels of insulin and C-peptide do not necessarily exclude the diagnosis. A 50-year-old female was brought to our emergency department because of conscious disturbance on the previous night. She had no history of diabetes mellitus, and was not using any medications or alcohol. Laboratory data showed low sugar, a significantly low insulin level, and elevated C-peptide. After admission, she had multiple episodes of spontaneous hypoglycemia after overnight fasts without discomfort. It was considered that a neuroendocrine tumor was the source of her hypoglycemia. CT scan of the abdomen revealed a 1.1cm hypervascular nodule in the pancreatic tail. Elective laparoscopic distal pancreatectomy was incorporated into her treatment course. A 1.2×1.0cm homogenous well-encapsulated tumor was resected. We monitored her glucose levels in the outpatient clinic every month for a period of six months. She did not have another episode of spontaneous hypoglycemia. Learning points Insulinoma causes endogenous hypoglycemia – it cannot be ruled out in patients presenting with hypoglycemia and low insulin levels; history and imaging studies should be done for further assessment A 24-h fast test has the same clinical significance as that of 72-h fast test C-peptide is a useful biochemical marker in addition to serum insulin, which can be used to diagnose insulinomas CT scan is used to measure the tumor size and localize the tumor. However, definitive diagnosis is only achieved through histopathologic evaluation of diseased tissue

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Effect of Alpha-lipoic Acid Supplementation on Glycemic Control in the Patients with Metabolic Syndrome: A Randomized Clinical Trial

10.21203/rs.3.rs-37045/v1 ◽

2020 ◽

Author(s):

Nafiseh Kaviyani ◽

Seyed Ali Keshavarz ◽

Behnood Abbasi

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Clinical Trial ◽

Glycemic Control ◽

Lipoic Acid ◽

Serum Insulin ◽

Alpha Lipoic Acid ◽

Acid Supplementation ◽

Positive Effects ◽

Significant Difference

Abstract BackgroundMetabolic syndrome is a collection of metabolic disorders. It is an important risk factor for progression towards type 2 diabetes and coronary artery diseases. Alpha-lipoic acid also plays a role as a co-factor for multi-enzyme complexes catalyzing oxidative. Antioxidant properties of alpha-lipoic acid (ALA) are associated with insulin-like effects. The present study examined the effect of alpha-lipoic acid supplementation on glycemic control in the patients with metabolic syndrome.MethodsA total of 46 patients with metabolic syndrome have participated in this double-blind randomized parallel-group clinical trial, 23 patients in one group received 600 mg of alpha-lipoic acid supplement and 23 patients in another group received the placebo for 12 weeks. RCT protocol was registered at ClinicalTrials.gov and it is available using NCT03589690 code. Fasting blood sugar (FBS), Serum insulin, Hemoglobin A1c (HbA1c), insulin resistance, were measured at the beginning and the end of the study. Dietary intake of participants was examined at the beginning of the study and this information was evaluated using Nutritionist 4 (N4) software. Studied information was analyzed by SPSS-24 software.ResultsThere were significant decreases in FBS levels (P = 0.009), serum insulin (P = 0.02), and insulin resistance (P = 0.001) between the two groups. Also, the HbA1c levels (P = 0.16) had no significant difference between the two groups.ConclusionALA is a potent antioxidant that it might be able to improve the blood glucose levels, serum insulin and insulin resistance; thus it will have positive effects on promoting the health levels in the patients with metabolic syndrome.Trial registrationNCT03589690

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Insulin autoimmune syndrome in an Argentine woman taking α-lipoic acid: A case report and review of the literature

SAGE Open Medical Case Reports ◽

10.1177/2050313x18819601 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1881960 ◽

Cited By ~ 3

Author(s):

Valentina Izzo ◽

Carla Greco ◽

Diana Corradini ◽

Marco Infante ◽

Maria Teresa Staltari ◽

...

Keyword(s):

Lipoic Acid ◽

Serum Insulin ◽

Strong Association ◽

Antioxidant Properties ◽

Dna Typing ◽

Sulfhydryl Group ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

First Case ◽

High Level

Insulin autoimmune syndrome is an unusual cause of spontaneous hypoglycaemia in non-Asian populations. In the majority of cases, this syndrome appears a few weeks after the administration of drugs containing a sulfhydryl group. A strong association between this syndrome and HLA-DR4 has been shown. Only seven cases have been described in non-Asian patients. We report the first case of insulin autoimmune syndrome in an Argentine woman taking alfa-lipoic acid. She developed hypoglycaemic symptoms approximately 1 month after starting therapy. Blood sampling collected during an episode of symptomatic hypoglycaemia showed low blood glucose level (2.39 mmol/L), high level of serum insulin (1971.55 pmol/L), inappropriately high level of C-peptide (2.36 nmol/L) and high levels of insulin antibodies (274.78 IU/mL). HLA-DNA typing identified DRB1*04:03. Due to the widespread use of alfa-lipoic acid for its antioxidant properties, clinicians should be aware that it may trigger an autoimmune hypoglycaemia in people with a genetic predisposition.

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Abstract 3444: The Effect of Alpha Lipoic Acid on Porcine Coronary Stent Restenosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_778-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Myung Ho Jeong ◽

Eun Hui Bae ◽

Sang Yup Lim ◽

Jae Youn Moon ◽

Ju Han Kim ◽

...

Keyword(s):

Coronary Arteries ◽

Lipoic Acid ◽

Bare Metal Stents ◽

Metal Stents ◽

Control Group ◽

List Type ◽

Bare Metal ◽

Alpha Lipoic Acid ◽

Stent Group ◽

Injury Score

Objective: We evaluated the ability of alpha lipoic acid (ALA) to affect on coronary instent restenosis (ISR) in a porcine model. Methods: In vitro experiment: We stimulated porcine VSMC using G-CSF in the presence or absence of ALA. Activation of Akt, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT)-3 were determined using western blot. And also, cell proliferation and migration assay were determined. In vivo experiment:Balloon overdilation injuries were performed in 2 coronary arteries in 12 pigs. Four weeks after the balloon overdilation injury, 24 bare metal stents were placed for 24 injured coronary arteries. We randomized into two groups (12 stents per group; control group: aspirin and clopidogrel only, ALA group: aspirin and clopidogrel plus 100 mg/kg ALA during 4 weeks). 16 bare metal stents were implanted randomized two coronary arteries in 8 pigs. Group I was control stent group (n=8), Group II was ALA coated stent group (n=8). Follow-up coronary angiogram (CAG) and histopathologic assessment were performed at 4 weeks after stenting. Results: G-CSF increased the phosphorylation of ERK and STAT-3, but after pretreatment of ALA, the phosphorylation of ERK and STAT-3 were significantly reduced. On histopathologic analysis, injury score, internal elastic lamina(IEL) area did not differ significantly between the two groups. The neointimal area was 7.3±0.9 mm2 in control group and 2.2±1.1 mm2 in ALA group (p<0.001), and the histopathologic area of stenosis(AS) was 75.9±8.5 % in control group, 23.5±10.5 % in ALA group (p<0.001). The injury score and IEL area were not significantly different between the two groups. The neointimal area was 7.4±1.1 mm2 in control group and 1.4±0.8 mm2 in ALA group (p<0.001), and the AS was 77.6±10.9 % in control group, 15.6±7.6 % in ALA group (p<0.001). The number of inflammatory cells within neointima was lower in ALA group (63.2±23.7 % vs. 17.6±11.6 %, p<0.001). Conclusion: ALA inhibits the activation of ERK, STAT-3 and proliferation of VSMC. Both high dose of oral ALA and ALA coated stents inhibit neointimal hyperplasia in a porcine ISR model

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Rare association of insulin autoimmune syndrome with ankylosing spondylitis

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-15-0090 ◽

2015 ◽

Vol 2015 ◽

Cited By ~ 2

Author(s):

Nishant Raizada ◽

S H Rahaman ◽

D Kandasamy ◽

V P Jyotsna

Keyword(s):

Ankylosing Spondylitis ◽

Serum Insulin ◽

High Serum ◽

List Type ◽

Rare Association ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Learning Points ◽

Very High ◽

Hyperinsulinemic Hypoglycaemia

Summary Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycaemia, which is known to occur in association with the use of sulfhydryl-containing drugs and autoimmune disorders. We describe a patient with hitherto an unreported association of IAS with ankylosing spondylitis. We have also performed and described a simplified method of polyethylene glycol (PEG) precipitation of an insulin bound antibody in the serum. Learning points IAS should be considered in differential diagnosis of endogenous hyperinsulinemic hypoglycaemia. Ankylosing spondylitis can be associated with IAS apart from several other autoimmune diseases. Very high serum insulin levels (100–10 000 μU/ml) are frequently seen in IAS. When faced with very high serum insulin before suspecting insulinoma, it is advisable that PEG precipitation of serum be done to identify antibody bound insulin. A clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.

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Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0079 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 6

Author(s):

Chih-Ting Su ◽

Yi-Chun Lin

Keyword(s):

High Serum ◽

Insulin Antibodies ◽

Insulin Analog ◽

Hyperinsulinemic Hypoglycemia ◽

Oral Glucose ◽

List Type ◽

Exogenous Insulin ◽

C Peptide ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome

Summary Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. Learning points: Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia. Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia. Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin.

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Diazoxide use for neonatal hyperinsulinaemic hypoglycaemia in a low-resource setting: A Case Report

Annals of Health Research ◽

10.30442/ahr.0603-11-97 ◽

2020 ◽

Vol 6 (3) ◽

pp. 338-343

Author(s):

AO Adekoya ◽

TE Adekanye ◽

OO Abolurin ◽

OO Adebawojo ◽

FG Ajayi ◽

...

Keyword(s):

Perinatal Asphyxia ◽

Serum Insulin ◽

Male Infant ◽

Serum Cortisol ◽

High Serum ◽

Intravenous Glucose ◽

Hyperinsulinaemic Hypoglycaemia ◽

Resource Setting ◽

Low Resource Setting ◽

Hydrocortisone Administration

The management of neonatal hyperinsulinaemic hypoglycaemia remains a major challenge in hospitalized newborns globally. Diazoxide is one of the recommended therapeutic options. We report a late preterm, male infant of a diabetic mother who suffered severe perinatal asphyxia and had persistent hypoglycaemia requiring progressively increasing intravenous glucose concentrations to as high as 12.5 mg/kg/minute along with intravenous hydrocortisone administration. A critical sample revealed inappropriately high serum insulin, inappropriately low serum cortisol and growth hormone responses. Urinalysis was negative for ketones. With the persistence of hypoglycaemia, oral diazoxide at 5 mg/kg/day with oral hydrochlorothiazide was administered. The infant was diazoxide-responsive with complete resolution of hypoglycaemia. Diazoxide therapy was discontinued after 14 days and he was discharged after one month of admission. This report emphasizes the importance of diazoxide in the management of neonatal transient hyperinsulinaemic hypoglycaemia. The availability and cost of diazoxide, as well as the endocrine and metabolic tests, are major concerns in resource-poor settings.

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