title: Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues.
abstract: BACKGROUND
  Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms.
  
  
  METHODS
  Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹⁸F-FDG uptake was quantified as the maximum standardized uptake value.
  
  
  RESULTS
  All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹⁸F-FDG uptake. Everolimus reduced tumor and muscle ¹⁸F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%.
  
  
  CONCLUSIONS
  Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, RB Groningen, The Netherlands. e.g.e.de.vries@int.umcg.nl
authors.forename: Helle-Brit
authors.initials: HB
authors.lastname: Fiebrich
authors.forename: Ester J M
authors.initials: EJ
authors.lastname: Siemerink
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Brouwers
authors.forename: Thera P
authors.initials: TP
authors.lastname: Links
authors.forename: Wouter S
authors.initials: WS
authors.lastname: Remkes
authors.forename: Geke A P
authors.initials: GA
authors.lastname: Hospers
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001786:Blood Glucose; D000068338:Everolimus; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D007328:Insulin; D019788:Fluorodeoxyglucose F18; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus