HYPERINSULINEMIC HYPOGLYCEMIA, EXERCISE-INDUCED
HHF7
EIHI
Exercise-induced hyperinsulinemic hypoglycemia
Hyperinsulinism due to SLC16A1 deficiency
Hyperinsulinism due to monocarboxylate transporter 1 deficiency
Burman et al. (1992) described a brother and sister who had recurrent syncope due to severe hyperinsulinemic hypoglycemia. The brother presented at age 42 with a 15-year history of syncopal episodes after vigorous exercise; his 34-year-old sister reported ... Burman et al. (1992) described a brother and sister who had recurrent syncope due to severe hyperinsulinemic hypoglycemia. The brother presented at age 42 with a 15-year history of syncopal episodes after vigorous exercise; his 34-year-old sister reported a 20-year history of syncope and near-syncope, particularly when dieting. Using treadmill exercise as a provocative test, both patients were found to have severe postexercise hypoglycemia with marked hyperinsulinism. The male patient underwent an 80% distal pancreatectomy; histology revealed diffuse islet cell hyperplasia, and he was subsequently successfully treated with diazoxide. When evaluated 6 years after presentation, the patient had adopted a sedentary lifestyle, stopped taking diazoxide, and was asymptomatic. His sister, who initially refused treatment, continued to have hypoglycemic episodes over the next 5 years and eventually began taking diazoxide with no further symptoms. Neither sib had any evidence of multiple endocrine neoplasia type I (131100), and there was no history of endocrine disorders in other family members (3 other sibs and 4 children of the patients). Meissner et al. (2001) reported 2 unrelated teenagers with exercise-induced hyperinsulinemic hypoglycemia. A 16-year-old boy had a 2-year history of syncope, primarily after vigorous exercise, and was noted to have severe hypoglycemia during a syncopal episode. Physical examination, including psychomotor development, was normal. He developed symptomatic hypoglycemia after a 12-hour fast; serum ammonia levels were repeatedly normal. Diagnostic laparotomy revealed no pancreatic abnormalities and several pancreatic biopsies showed normal pancreatic histology. He was treated with diazoxide and his blood glucose remained stable as long as he avoided exercise. The second patient was a 15-year-old girl with hypoglycemia-like symptoms with prolonged exercise, particularly swimming. She had a history of hypoglycemic seizures and syncope in infancy and had a normal liver biopsy and MRI of the pancreas at age 5. Exercise tests in both patients revealed hyperinsulinemic hypoglycemia 20 to 50 minutes after exercise, caused by a massive burst of insulin secretion within a few minutes of the start of exercise. Otonkoski et al. (2003) examined family members of the 15-year-old girl studied by Meissner et al. (2001) and of another patient who presented with exercise-induced hyperinsulinemic hypoglycemia and identified 10 additional affected individuals over multiple generations in the 2 Finnish families, with an autosomal dominant mode of inheritance. Affected members were diagnosed with exercise-induced hyperinsulinism based on hypoglycemia and a greater than 3-fold increase in plasma insulin induced by a 10-minute bicycle exercise test. An intravenous bolus of pyruvate caused a 5.6-fold increase in plasma insulin in patients compared to a 0.9-fold increase in controls (p less than 0.001). Pyruvate transport into cultured fibroblasts from the proband of the second Finnish family originally reported by Meissner et al. (2001) was normal. The severity of the condition was variable, with some affected individuals suffering recurrent severe hypoglycemia whereas others had minimal symptoms.
In the unrelated boy and girl with exercise-induced hyperinsulinism and pyruvate-stimulated insulin secretion originally reported by Meissner et al. (2001), Otonkoski et al. (2003) sequenced the genes encoding CD147 and the 8 known monocarboxylate transporter proteins; no mutations ... In the unrelated boy and girl with exercise-induced hyperinsulinism and pyruvate-stimulated insulin secretion originally reported by Meissner et al. (2001), Otonkoski et al. (2003) sequenced the genes encoding CD147 and the 8 known monocarboxylate transporter proteins; no mutations were identified. In affected members of 2 Finnish families, previously examined by Otonkoski et al. (2003) and segregating autosomal dominant exercise-induced hyperglycemic hypoglycemia mapping to chromosome 1p, Otonkoski et al. (2007) identified a 163G-A transition (600682.0003) and a 25-bp duplication (600682.0004), respectively, in the 5-prime UTR of the SLC16A1 gene. In a German proband previously reported by Meissner et al. (2001), they identified several sequence variants, including a 2-bp insertion. All 3 mutations were located within the binding sites of several transcription factors; functional studies demonstrated induction of SLC16A1 expression in beta cells, where SLC16A1 is not usually transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin release despite ensuing hypoglycemia. Otonkoski et al. (2007) stated that this represents a novel disease mechanism based on the failure of cell-specific transcriptional silencing of a gene that is highly expressed in other tissues. Quintens et al. (2008) noted that repression of certain ubiquitously expressed housekeeping proteins is necessary in pancreatic beta cells, in order to prevent the insulin toxicity that might result from exocytosis under conditions when circulating insulin is unwanted, citing low-K(m) hexokinases (see HK1, 142600) and monocarboxylic acid transporters (MCTs) as examples. The absence of MCTs in beta cells explains the so-called 'pyruvate paradox' whereby pyruvate, despite being an excellent substrate for mitochondrial ATP production, does not stimulate insulin release when added to beta cells. The importance of this disallowance is exemplified by patients who have gain-of-function MCT1 promoter mutations and loss of the pyruvate paradox, with resultant exercise-induced inappropriate insulin release.