Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease.
OBJECTIVE
The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntington's disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels.


METHODS
Huntington's disease mice were treated with an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist, exendin-4 (Ex-4), to test whether euglycemia could be achieved, whether pancreatic dysfunction could be alleviated, and whether the mice showed any neurological benefit. Blood glucose and insulin levels and various appetite hormone concentrations were measured during the study. Additionally, motor performance and life span were quantified and mutant huntingtin (mhtt) aggregates were measured in both the pancreas and brain.


RESULTS
Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntington's disease. The treatment also improved motor function and extended the survival time of the Huntington's disease mice. These clinical improvements were correlated with reduced accumulation of mhtt protein aggregates in both islet and brain cells.


CONCLUSIONS
Targeting both peripheral and neuronal deficits, Ex-4 is an attractive agent for therapeutic intervention in Huntington's disease patients suffering from diabetes.
Martin
Bronwen
B
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA.
Golden
Erin
E
Carlson
Olga D
OD
Pistell
Paul
P
Zhou
Jie
J
Kim
Wook
W
Frank
Brittany P
BP
Thomas
Sam
S
Chadwick
Wayne A
WA
Greig
Nigel H
NH
Bates
Gillian P
GP
Sathasivam
Kirupa
K
Bernier
Michel
M
Maudsley
Stuart
S
Mattson
Mark P
MP
Egan
Josephine M
JM
D054392:Adipokines / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D054439:Ghrelin / Q000097:blood; D006816:Huntington Disease / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D010455:Peptides / Q000627:therapeutic use*; D011863:Radioimmunoassay; D015996:Survival Rate; D014688:Venoms / Q000627:therapeutic use*
D054392:Adipokines; D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide