Huntington's disease does not appear to increase the risk of diabetes mellitus.
Huntington's disease (HD) is an autosomal, dominantly inherited, neurodegenerative disorder characterised by neurological, cognitive and psychiatric symptoms. HD has been associated with diabetes mellitus, which is, to some extent, supported by studies in transgenic HD mice. In transgenic mice, the severity of the diabetic phenotype appears to correlate with the length of a polyglutamine expansion in the protein huntingtin. In the present study, we investigated the association between diabetes mellitus and HD by performing an oral glucose-tolerance test (OGTT) to evaluate the glucose-tolerance status and OGTT-related insulin release in 14 HD patients. Furthermore, we expressed N-terminal huntingtin fragments with different polyglutamine lengths in an insulinoma-cell line (INS-1E) to investigate how mutant huntingtin influences glucose-stimulated insulin release in vitro. We found no difference between a group of early- and middle-stage HD patients and a large group of control individuals in any of the assessed variables. However, the glucose-stimulated induction of insulin release was significantly reduced in the insulinoma-cell line expressing highly expanded huntingtin compared to cells expressing huntingtin with modestly elongated polyglutamine stretches. These data indicate that insulin release from beta-cells expressing mutant huntingtin appears to be polyglutamine length-dependent, and that polyglutamine lengths within the range normally found in adult onset HD do not influence insulin release. This challenges the assumption of an increased risk of diabetes among HD patients, although our results do not exclude a changed glucose tolerance in end-stage HD patients or in patients with juvenile onset HD. It also raises the question of which extent transgenic mice models reflect the pathology of human HD in this regard.
Boesgaard
T W
TW
Steno Diabetes Center, Gentofte, Denmark.
Nielsen
T T
TT
Josefsen
K
K
Hansen
T
T
Jørgensen
T
T
Pedersen
O
O
Nørremølle
A
A
Nielsen
J E
JE
Hasholt
L
L
D000328:Adult; D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016022:Case-Control Studies; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012307:Risk Factors; D014161:Transduction, Genetic
D001786:Blood Glucose; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007328:Insulin; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins