Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent
Authors Attie AD, Schueler KM, Keller MP, Mitok KA, Simonett SP, Hudkins KL, Mehrotra K,
Graham MJ, Lee RG, Alpers CE
Submitted By Alan Attie on 5/5/2021
Status Published
Journal Laboratory investigation; a journal of technical methods and pathology
Year 2021
Date Published
Volume : Pages Not Specified : Not Specified
PubMed Reference 33911188
Abstract The etiology of diabetic nephropathy in type 2 diabetes is multifactorial.
Sustained hyperglycemia is a major contributor, but additional contributions
come from the hypertension, obesity, and hyperlipidemia that are also commonly
present in patients with type 2 diabetes and nephropathy. The leptin deficient
BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which
hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present.
We have shown that reversal of the constellation of these metabolic
abnormalities with leptin replacement can reverse the morphologic and functional
manifestations of diabetic nephropathy. Here we tested the hypothesis that
reversal specifically of the hypertriglyceridemia, using an antisense
oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the
interactions of VLDL (very low density lipoproteins) with the LDL receptor, is
sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment
resulted in reduction of circulating ApoC-III protein levels and resulted in
substantial lowering of triglycerides to near-normal levels in diabetic mice
versus controls. Antisense treatment did not ameliorate proteinuria or
pathologic manifestations of diabetic nephropathy, including podocyte loss.
These studies indicate that pathologic manifestations of diabetic nephropathy
are unlikely to be reduced by lipid-lowering therapeutics alone, but does not
preclude a role for such interventions to be used in conjunction with other
therapeutics commonly employed in the treatment of diabetes and its

Investigators with authorship
Charles AlpersUniversity of Washington
Alan AttieUniversity of Wisconsin-Madison