TITLE:
Host Factors Alter Effects of Angiopoietin-Like Protein 8 on Glucose Homeostasis in Diabetic Mice
AUTHORS:
Sichen Liu, Emily M. Smith, Timothy H. King, Lindsey Glenn, Michelle Trevino, So Hyun Park, Yui Machida, Ciriaco Villaflor, Wojciech Grzesik, Margaret A. Morris, Yumi Imai, Jerry L. Nadler
KEYWORDS:
Angiopoietin-Like Protein 8, Type 1 Diabetes, NOD, 12-Lipoxygenase, Beta Cells, Glucose Homeostasis
JOURNAL NAME:
Journal of Diabetes Mellitus,
Vol.6 No.4,
November
17,
2016
ABSTRACT: Recovery of functional beta cell mass offers a
biological cure for type 1 diabetes. However, beta cell mass is difficult to
regain once lost since the proliferation rate of beta cells after youth is very
low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the
regulation of lipoprotein lipase activity, was reported to increase beta cell
proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short
term (3 to 8 days) in non-diabetic mice showed little or no increase in beta
cell proliferation. Here, we examined the effect of ANGPTL8 on glucose
homeostasis in models that have not been examined previously. We expressed
mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin
and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD
mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes
to insulitis and loss of beta cell function in NOD, in an effort to determine
whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated
expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated
mice without an increase in beta cell proliferation or serum insulin
concentration. While ANGPTL8 did not reverse hyperglycemia in overtly
hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice,
ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower
glucose levels in 12LOKO NOD were not associated with higher serum insulin
levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not
increase beta cell proliferation in NOD mice or streptozotocin treated mice in
agreement with studies in non-diabetic mice, it lowers blood glucose levels in
multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating
that host factors influence the impact of ANGPTL8 on glucose homeostasis.