Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance

Katherine Chen, Alice Jih, Sarah T. Kavaler, William S. Lagakos, Dayoung Oh, Steven M. Watkins, Jane J. Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9 –39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.

Original languageEnglish (US)
Pages (from-to)E293-E301
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume309
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Insulin Resistance
Salicylates
Diet
Glucose
Inflammation
Glucagon-Like Peptide 1
Docosahexaenoic Acids
High Fat Diet
Hyperglycemia
Type 2 Diabetes Mellitus
Oral Administration
Blood Glucose
Cytoplasm
Anti-Inflammatory Agents
Obesity
Macrophages
Liver
Pharmaceutical Preparations
Therapeutics
Glucagon-Like Peptide-1 Receptor

Keywords

  • Docosahexaenoic acid
  • Insulin-resistance
  • Obesity
  • Salicylate

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance. / Chen, Katherine; Jih, Alice; Kavaler, Sarah T.; Lagakos, William S.; Oh, Dayoung; Watkins, Steven M.; Kim, Jane J.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 309, No. 3, 01.01.2015, p. E293-E301.

Research output: Contribution to journalArticle

Chen, Katherine ; Jih, Alice ; Kavaler, Sarah T. ; Lagakos, William S. ; Oh, Dayoung ; Watkins, Steven M. ; Kim, Jane J. / Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 309, No. 3. pp. E293-E301.
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