common causes of hypoglycemia in nondiabetic patients are surreptitious use of drugs , insulinoma , extrapancreatic tumors and autoimmune hypoglycemia . autoimmunity causes hypoglycemia in two ways : ( a ) insulin - receptor antibodies having insulinomimetic action and ( b ) insulin autoimmune syndrome ( ias ) , in which antibodies first bind insulin , forming a complex , and subsequently , regardless of the glucose levels , release it , causing hypoglycemia . ias has shown strong association with the use of medications containing sulfhydryl group , autoimmune disorders , plasma cell dyscrasias and hla dr4 . a 72-year - old man of indian origin had first episode of hypoglycemia 2 months earlier when , 4 - 5 h after taking lunch , he was found to be disoriented . he was taken to the nearby hospital where level of his plasma blood glucose was found to be 20 mg / dl and intravenous 10% dextrose infusion reversed his symptoms . during hospital he was not a known diabetic and was not taking any drug known to cause hypoglycemia . result of routine investigations , including hemogram and renal , liver and thyroid function tests , were not significant . during one such episode , plasma blood glucose level was 15 mg / dl and the corresponding serum insulin was 123 mu / l . with provisional diagnosis of insulinoma , imaging studies , including ultrasonography , dual phase computed tomography ( ct ) and magnetic resonance ( mr ) imaging of abdomen , mr and ct angiography of the abdomen and contrast - enhanced ct of chest , were done sequentially . review of past history revealed that the patient had ischemic cerebral infarct 8 years back when he was detected to have hypertension . pantoprazol , aspirin , clopidogrel , torsemide , isosorbide dinitrate , atenolol , atorvastatin and amlodipine . general and systemic physical examination did not reveal any abnormality . during his stay in the endocrine ward during one such episode , the plasma blood glucose level was 29 mg / dl , serum insulin was 3162 mu / l and serum c - peptide was 19.05 ng / ml ( latter two measured by electrochemiluminescence immunoassay , using a roche elecsys 2010 immunoassay analyzer , gmbh , mannheim , germany ] , while serum cortisol and growth hormone responses were adequate . pmol / l ( normal fasting value < 20 pmol / l , measured by radioimmunoassay ; millipore corporation , merck millipore headquarters , 290 concord road , billerica , ma 01821 usa ) . trans - esophageal ultrasonography also failed to locate any lesion . extended oral glucose tolerance test ( ogtt ) with 75 g of glucose showed paradoxical hyperglycemia followed by hypoglycemia with very high insulin levels [ figure 1 ] . other immunological findings of the patient showed elevated rheumatoid factor titers ( > 256 , normal 0 - 20 ) and antinuclear antibody titers on hep-2 substrate ( 1:80 , normal < 1:20 ) . the serum immunoglobulin g ( igg ) level was 2416 mg / dl ( normal 960 - 1968 mg / dl ) , igm was 473 mg / dl ( normal 125 - 380 mg / dl ) and iga was 146 mg / dl ( normal 90 - 242 mg / dl ) , as measured by enzyme - linked immunosorbent assay . samples for human leukocyte antigen ( hla ) studies were collected , which showed hla - a*02 , a * 11 , b * 35 , b * 51 , drb1 * 0403 and drb1 * 0404 . extended oral glucose tolerance test at the time of initial evaluation review of patient 's drug intake revealed that he was taking three drugs , viz . pentoprazol , clopidogril and torsemide , which contained sulfur and hydrogen atoms . under the plan to stop usage of these drugs one by one , to begin with , pentoprazole was discontinued and the patient was advised to take meals in small quantities frequently . as a follow - up thereof , the patient was observed keenly during the next week for any hypoglycemic symptoms , which were noticed to have subsided gradually . review after 3 months , with extended ogtt , showed quantum decrease in serum insulin levels along with disappearance of the hyperglycemic phase , which feature was subsisting earlier . in the changed scenario , maximum blood glucose level reached was 183 mg / dl at 1 h [ figure 2 ] . subsequent follow - up during the next 6 months revealed that the patient did not have any symptoms of hypoglycemia and was healthy . clinically , ias presents by way of symptoms of hypoglycemia , which can surface either in the postprandial or in the postabsorptive phases . in such patients , total serum insulin levels are very high in comparison with those seen in the patients of insulinoma , in as much as insulin levels are just inappropriate and rarely more than 100 mu / l in the latter category . besides , serum - free insulin level may be normal or high with incompletely suppressed plasma c - peptide level . in such cases , serum proinsulin levels have also been demonstrated to be very high . ias has been observed to be associated with the usage of drugs like insulin , sulfonylureas ; sh - containing medicines ( methimazole , captopril , penicillamine etc . ) , hydralazine , procainamide , isoniazid and -interferone etc . , in association with autoimmune disorders , plasma cell dyscrasias , alcoholic liver disease and organ transplant patients . most of the patients respond to small frequent meals  six or more times  in a day . alfa - glucosidase inhibitors may sometimes be helpful in decreasing the postprandial levels of immunoreactive insulin in the sera and resultantly , reducing postprandial hypoglycemic episodes . such patients who did not respond to the said treatment were treated with prednisolone , diazoxide , octreotide and plasmapheresis , with variable results . in the backdrop of the foregoing analytic review of the facts described herein above , it may be possible that subsidence of hypoglycemia could have been part of the natural course of the disease , which is corroborated by the fact that there was spontaneous remission in 189 of 226 ( 83.6% ) japanese patients of ias . there is a strong genetic predisposition as revealed by hla association studies ; 96% ( 48 out of 50 ) of japanese patients were dr4 ( odds ratio 39.9 ; p < 10 ) , while 12 ( 24% ) were dr9 positive . all 48 dr4-positive japanese ias patients possessed dqa1 * 0301/dqb1 * 0302 regardless of differences in dr4 alleles . two korean and the one chinese ias responder patient were positive for drb1 * 0406/dqa1 * 0301/dqb1 * 0302 . these alleles are 10 - 30 times more prevalent in the japanese and in the koreans in comparison with the caucasians . this distribution tends to explain the higher prevalence of the aforesaid disorder in the japanese population . the present case was also found to be hla - dr4 homozygous , and the resolution analysis revealed it to be drb1 * 0403/*0404 . the exact mechanism of hypoglycemia in ias has not been found , but it is postulated that sulphydryl group interacts with disulfide bond in the insulin molecule , making the latter more immunogenic . most of the cases reported from japan are following the use of sulphhydryl group - containing drugs , while cases reported from other parts of the world are more frequently associated with autoimmune diseases or plasma cell dyscrasias . our patient was taking drugs , and both rheumatoid factor and antinuclear antibodies were positive . no test could be performed to demonstrate the presence of specific antibody in our case ; nonetheless , based on cumulative clinical and biochemical parameters and spontaneous remission of hypoglycemia , it fits well in this syndrome . the subject was taking three drugs that contained sulfur and hydrogen atoms , namely pantoprazole [ figure 3 ] , clopidogril and torsemide . pantoprazole ( ( 5-(difluoromethoxy 2-(((3,4-dimethoxy-2-pyridinyl ) methyl ) sulfinyl)-1h - benzimidazole sodium ) is a prodrug that requires activation in an acid environment . after absorption into systemic circulation , it diffuses into the parietal cells of the stomach and accumulates in the acidic secretory canaliculi . here , it is activated by proton - catalyzed formation of a thiophillic sulfenamide or sulfenic acid . this activated form reacts by covalent binding with sulfhydryl group of cysteines , the extracelluar domain of the h + k - atpase . we postulate that the activated form of sulfenamide or sulfenic acid may bind with disulfide bond in the insulin molecule , making the latter more immunogenic . the patient , being free of symptoms , did not agree to pantoprazole - rechallenge . all the same , learning points from the case are the clues to suspect ias , specifically , a very high serum insulin level but no detectable tumor in a patient of endogenous hyperinsulinemic hypoglycemia . paradoxical hyperglycemia in the glucose tolerance test is also remarkable . suspecting this rare entity is crucial as it will spare the patient from avoidable aggressive investigations and unwarranted surgical procedures .
we are hereby reporting a case of a 72-year - old indian man , who , in the absence of a detectable tumor , presented with symptomatic hypoglycemia in the postabsorptive state ( 3 - 5 h after meal ) . 
 his serum levels of insulin and c - peptide were very high . 
 he was not taking any hypoglycemic drug . 
 hypoglycemic episodes completely subsided after withdrawal of pentoprazole and incorporation of small frequent meals in the dietary plan . 
 six months after the initial presentation , the subject became free of hypoglycemic episodes . 
 although insulin autoimmune syndrome ( ias ) is the third leading cause of spontaneous hypoglycemia in japan , it is extremely uncommon in the western countries . till 2009 , 
 more than 200 cases from japan and as many as 58 cases outside asia have been reported . to the best of our knowledge , 
 this is the first case of ias reported from india .