Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance.
BACKGROUND
Complex glycosphingolipids, in majority the ganglioside GM3, surround the insulin receptor in a special membrane compartment (raft) and modulate signaling through this receptor. Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. Gaucher disease is a lysosomal storage disorder in which impaired breakdown of glucosylceramide leads to its accumulation in macrophages. Secondary to this defect, GM3 concentrations, for which glucosylceramide is the precursor, in plasma and several cell types are elevated.


OBJECTIVE
We studied the influence of glycosphingolipid storage on whole body glucose and fat metabolism by measuring insulin-mediated (IMGU) and noninsulin-mediated glucose uptake (NIMGU) and suppression of free fatty acids by insulin.


METHODS
We studied six Gaucher patients, either naive to treatment or with considerable remaining burden of disease, and six matched healthy control subjects in the basal state, during an euglycemic and a hyperglycemic clamp with somatostatin measuring NIMGU and during an euglycemic hyperinsulinemic clamp measuring IMGU, using stable isotopes.


RESULTS
NIMGU (both during euglycemia and hyperglycemia) did not differ between patients and control subjects. IMGU was lower in Gaucher patients, compared with controls. Suppression of lipolysis by insulin tended to be less effective in Gaucher patients.


CONCLUSIONS
Gaucher disease, a lysosomal glycosphingolipid storage disorder, is associated with (peripheral) insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.
Langeveld
Mirjam
M
Academic Medical Center, Department of Endocrinology and Metabolism (F4-247), Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. m.langeveld@amc.uva.nl
Ghauharali
Karen J M
KJ
Sauerwein
Hans P
HP
Ackermans
Mariette T
MT
Groener
Johanna E M
JE
Hollak
Carla E M
CE
Aerts
Johannes M
JM
Serlie
Mireille J
MJ
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D005679:G(M3) Ganglioside / Q000097:blood; D005776:Gaucher Disease / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged
D001786:Blood Glucose; D005679:G(M3) Ganglioside; D005947:Glucose