Autoimmune hypoglycemia due to alpha-lipoic acid: Report of two cases

ABSTRACT

Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycemia characterized by the presence of insulin autoantibodies. Alpha-lipoic acid (ALA), a widely used nutraceutical, has been increasingly recognized as a potential trigger for IAS. We report two cases of ALA-induced IAS in Indian patients and review existing literature to highlight its clinical presentation, diagnostic challenges, and management strategies. In the first case, rapid-onset severe hypoglycemia mandated the use of oral steroids with gradual tapering and stoppage over a duration of few months, while in the second case, mild hypoglycemia was essentially managed with dietary modifications alone and the condition remitted on its own. ALA-induced IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia. Early recognition and appropriate management can prevent severe complications and avoid unnecessary investigations to evaluate other causes of hyperinsulinemia.

Introduction

Hypoglycemia in a non-diabetic and apparently well individual is uncommon. Of the autoimmune causes of hypoglycemia, insulin autoimmune syndrome (IAS) is more prevalent. Most common causes of IAS are systemic autoimmune disorders, hematological malignancies, viral infections, and drugs. Drugs causing IAS usually have sulfhydryl groups, such as methimazole, captopril, penicillamine, procainamide, alpha-lipoic acid (ALA), and others.[1]

ALA (thioctic acid or 1,2 dithiolane-3-pentanoic acid) is an important cofactor in number of enzyme systems, a potent antioxidant, and has been used as a nutraceutical for decades.[2] Due to its sulfhydryl group, it is hypothesized that ALA cleaves the disulfide bond of insulin, hence exposing the cryptic regions of insulin molecule to T cells. There are differences in human leucocyte antigen (HLA) predisposition of IAS as in HLA, DRB1 * 0406 has been linked with development of IAS in East Asians while DRB1 * 0403 is associated in Caucasians. In the insulin molecule, glutamate at position 74 and serine at position 37 have been proposed as the site of cryptic antigens that are exposed to T cells, subsequently resulting in production of insulin antibodies by B cells.[3]

We report two cases of IAS secondary to exposure of ALA and review the literature for similar presentation between Indians and affected individuals elsewhere. We searched through PubMed, SCOPUS, Web of Science, and Excerpta Medica dataBASE (EMBASE) and found seven reported cases from 2011 to 2024 in India.

Case 1

A 57-year-old lady, whose body mass index was 24.4 kg/m² (weight 78 kg and height 160 cm) with no comorbidities and who was previously well, had mild right-sided facial pain for few weeks. Her physician prescribed nutritional supplement containing ALA for 2 weeks (300 mg twice a day) and suggested to consult a neurologist if the pain persisted. By 1 week, since the symptoms got reduced, she discontinued the medication.

About 2 weeks later, she started to develop nocturnal episodes of palpitations and sweating approximately 6–8 h after dinner. She developed disorientation, for which she was taken to the emergency department of a nearby hospital. Her capillary blood glucose was 44 mg/dL during presentation, which was treated with intravenous (IV) 25% dextrose, after which she got better instantaneously. Subsequently, she started to eat frequently to prevent recurrent episodes of hypoglycemia. She presented to our hospital with the symptoms of hypoglycemia persisting even after frequent intake of food.

During one of the episodes of hypoglycemia, the sample was analyzed for insulin (>200 μU/mL) [>437 pmol/L] and C-peptide (6.2 ng/mL) [2.1 nmol/L]. Since the insulin levels were disproportionately higher than the C-peptide level (molar ratio >0.2), insulin autoantibodies (IAAs) level was determined and was found to be high (345 mU/L, reference range 2.7–24.8). Computed tomography of the abdomen with pancreatic protocol was done to look for pancreatic lesions, but was normal. Workup for other autoimmune systemic disorders, myeloma, and connective tissue disorders was negative. Considering the frequency of hypoglycemic episodes, she was started on prednisolone 30 mg (0.5 mg/kg) for 1 week followed by gradual tapering. The frequency of hypoglycemic episodes reduced and by 1 month, she had no episodes of hypoglycemia. By the third month, her titer of IAA dropped to 144 mU/L and she was on 5 mg prednisolone. Five months after the exposure, her antibody titer was 32 mU/L and she was weaned off steroids. The last follow-up was 2 months after stopping steroids (7 months from exposure), when she was asymptomatic.

Case 2

A 55-year-old gentleman, who was obese and with no other comorbidities, presented to a neurologist with progressive subacute-onset left lower leg pain and weakness while walking. He was started on pregabalin (75 mg/day), ALA (300 mg/day), and vitamin B12 (1000 μg/day). After 5 days, he discontinued using all the medications due to excessive sleepiness.

After 1 week, he started developing episodes of anxiety, hunger, and palpitations, especially in early hours of the day, which resolved with eating food rich in carbs. He got serum insulin (>200 µΥ/mL) and C-peptide (10.8 ng/mL) tested in a random sample. With these reports, he consulted this hospital for further management. He was monitored with continuous glucose monitoring system for hypoglycemia episodes, but did not record any episodes. He was advised 72-h prolonged fast for clarification.

While undergoing fast, he had an episode of symptomatic hypoglycemia by the eighth hour, wherein the venous blood glucose was 47 mg/dL, insulin was inappropriately high (2104 μU/mL) [14,612 pmol/L], and C-peptide was not suppressed (5.1 ng/mL) [1.7 nmol/L]. The molar ratio of insulin to C-peptide was 8.5. Considering the temporal association with ALA exposure, IAS was suspected and IAA was high (234 mU/L). He was counseled regarding the condition and the benign and self-resolving nature of the problem. He was advised to have small frequent meals with complete avoidance of simple carbs. He was encouraged to take corn-based diet and complex carbs along with protein rich food. By 1 month, since the antibody levels were decreasing with no worsening of symptoms, he was managed conservatively.

Discussion

Herein, we report two cases of IAS due to ALA – a 57-year-old woman who experienced severe symptomatic hypoglycemia requiring corticosteroid therapy, which led to a gradual resolution of symptoms and a reduction in IAA levels over 3 months and a 55-year-old man, who demonstrated milder symptoms that resolved with dietary modifications alone. This variability in clinical presentation underscores the heterogeneity of IAS and the importance of individualized management approaches.

The proposed hypothesis behind IAS is that IAAs bind to insulin that is released from the beta cells of islets in response to stimulus. Hence, small quantity of free active insulin is available for biological action and leads to hyperglycemia, which stimulates further insulin release. Disproportionate levels of insulin due to excessive stimulation of beta cells and slow release from antigen–antibody complexes results in hypoglycemia by 2–6 h after meals. The degree of hypoglycemia depends on antibody characteristics, the titer achieved, and the affinity to insulin, and hence is variable in people with IAS.

On reviewing the literature, about 60 cases of IAS due to ALA have been reported.[4] The diagnosis relies on clinical suspicion, biochemical findings, and exclusion of other causes of hyperinsulinemic hypoglycemia, such as insulinoma or sulfonylurea use. The absence of a widely recognized diagnostic algorithm necessitates a comprehensive approach, including a detailed drug history and autoimmune panel of investigations.

Few features were distinct between patients from India (both the current cases included) in comparison to patients from elsewhere [Table 1]. About 46% of patients from elsewhere were people with diabetes, in comparison to 14% in Indian patients. Because of its immunomodulatory and antioxidant effects, ALA could be prescribed more in people with diabetes who complain of neuropathy-related symptoms. Other attributes like dose of ALA, time duration between stoppage of ALA and onset of symptoms, and duration of ALA intake show numerical differences between groups. When tested (statistically by Mann–Whitney U test), null hypothesis could not be rejected, meaning that there were no significant differences in groups. But due to disproportionate numbers in both groups, the results needs to be interpreted with caution.

Table 1.

Differences in the clinical and laboratory characteristics of people with insulin autoimmune syndrome due to ALA

Parameter	Indians (n)	Non-Indians (n)
Age in years	55 (9)	61 (37)
Female sex in %	77 (9)	75 (37)
Diabetes in %	14 (9)	46 (37)
Dose of ALA in mg/day	300 (3)	600 (20)
Duration of ALA intake in weeks	1.1 (4)	2.5 (8)
Time between discontinuation of ALA and onset of hypoglycemia in weeks	4 (4)	1.5 (10)
Blood glucose in mg/dL	44 (4)	40 (35)
C-peptide in ng/mL	10.8 (3)	9.2 (36)
Insulin antibody titer (mean ± SD), U/L	234±32 (3)	323±68 (6)
Time for remission of hypoglycemia in weeks
(a) With steroids	4 (1)	8 (13)
(b) Without steroids	6 (4)	10 (6)
Time for remission of IAA in weeks	NA	28 (7)

Median values are presented, except insulin antibody titer. ALA=alpha-lipoic acid, IAA=insulin autoantibody, NA=not available, SD=standard deviation

Sixty percent required steroids for symptom control. Steroids not only helped in reducing the titer of antibodies, but also directly increased gluconeogenesis and glycogenolysis, thereby increasing plasma glucose and preventing hypoglycemia. While symptoms remitted in 2 months in the group receiving steroids, it was 2.5 months in those who were managed conservatively. But the median time for disappearance of antibodies was 6 months.

Treatment options for management of IAS due to ALA depend on the severity and timing of symptoms. Simple dietary interventions like reducing simple carbs and high-calorie carbs and including complex carbs would be helpful in mild postprandial hypoglycemia. Glucosidase inhibitors, steroids, immunosuppressive agents like mycophenolate mofetil, and rituximab have also been used according to severity. In severe cases, plasmapheresis use has also been reported.[4]

Conclusion

These cases emphasize the need for clinicians to recognize ALA as a potential trigger for IAS, especially in regions where it is used as a dietary supplement. Increased reporting of such cases will aid in understanding the epidemiology and optimal management strategies for IAS. Future studies should explore genetic predisposition, pathophysiological mechanisms, and standardized treatment protocols to enhance patient outcomes.

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.