Differences in
glucose uptake in peripheral and neural tissues account for the reduced efficacy of
insulin in nervous tissues. Herein, we report the design of short
peptides, referred as
amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved
glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of
insulin-insensitive
glucose transporter 1 (GLUT1). AAC2 interacted specifically with the
leptin receptor (LepR) and activated
atypical protein kinase C zeta (PKCς) to increase
glucose uptake. The effects induced by AAC2 were absent in
leptin receptor-deficient predipocytes and in Leprdb mice. In contrast, AAC2 established
glycemic control altering food intake in
leptin-deficient Lepob mice. Therefore, AAC2 activated the LepR and acted in a
cytokine-like manner distinct from
leptin. In a monogenic Ins2Akita mouse model for the phenotypes associated with
type 1 diabetes, AAC2 rescued systemic
glucose uptake in these mice without an increase in
insulin levels and adiposity, as seen in
insulin-treated Ins2Akita mice. In contrast to
insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in Ins2Akita mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKCς/GLUT1 axis, offers an effective strategy to broaden
glycemic control for the prevention of
diabetic complications of the nervous system and, possibly, other
insulin insensitive or resistant tissues.