Potential Effect of Cinnamaldehyde on Insulin Resistance Is Mediated by Glucose and Lipid Homeostasis

Abstract

Diabetes mellitus is a metabolic syndrome that has grown globally to become a significant public health challenge. Hypothesizing that the plasma membrane protein, transient receptor potential ankyrin-1, is a pivotal target in insulin resistance, we investigated the mechanism of action of cinnamaldehyde (CIN), an electrophilic TRPA1 agonist, in skeletal muscle, a primary insulin target. Specifically, we evaluated the effect of CIN on insulin resistance, hepatic glycogen accumulation and muscle and adipose tissue glucose uptake. Furthermore, the in vitro role of CIN in glucose uptake and intracellular signaling was determined in insulin-resistant rats whose calcium influx was analyzed. Moreover, the serum lipid profile was assessed following short-term CIN treatment in rats, and lipid tolerance was analyzed. The effects of CIN on insulin resistance were mediated by TRPA1, with downstream signaling involving the activation of PI3-K, MAPK, PKC, as well as extracellular calcium and calcium release from intracellular stores. Additionally, cytoskeleton integrity was required for the complete action of CIN on glucose uptake in muscle. CIN also ameliorated the serum lipid profile and improved triglyceride tolerance following acute vivo exposure.

Keywords: adipose tissue; cinnamaldehyde; glucose uptake; glycogen; insulin resistant; lipids; skeletal muscle.

Figure 1

Effect of CIN (5 days, 20 mg/kg) on the insulin-tolerance test in insulin-resistant rats. N = 5, *** p ≤ 0.001 compared to control (vehicle); ^# p ≤ 0.05 compared to dexamethasone group.

Figure 2

Action of CIN on hepatic glycogen accumulation in insulin-resistant rats, after 5 days of in vivo treatment. N = 5, ^# p ≤ 0.05 compared with control (vehicle); * p ≤ 0.05 compared with the dexamethasone group.

Figure 3

Effect of CIN on [¹⁴C]-glucose uptake in (A) soleus skeletal muscle and (B) adipose tissue from insulin-resistant rats, treated for 5 days. N = 5, * p ≤ 0.05 and ** p ≤ 0.01 compared with control (vehicle); ^# p ≤ 0.05 compared with dexamethasone group.

Figure 4

Mechanism of action by which CIN induces [¹⁴C]-glucose uptake in skeletal muscle from insulin-resistant rats. Involvement of TRPV1 (capsaicin) and TRPA1 (AITC) (A); PI3-K (wortmannin) and p38 MAPK (SB 239063) (B); L-type VDCC (nifedipine) and calcium from stores (BAPTA-AM) (C); cytoskeleton (colchicine) and actin (cytochalasin) (D); and PKC (RO-3104320) (E). Pre-incubation time = 30 min; incubation time = 60 min. N = 6 for each group. *** p ≤ 0.001 and ** p ≤ 0.01 compared to control group. ^### p ≤ 0.001 and ^# p ≤ 0.05 compared to CIN group.

Figure 5

Mechanism of action of CIN on ⁴⁵Ca²⁺ influx in skeletal muscle. Involvement of calcium from intracellular stores (BAPTA-AM) and extracellular calcium by L-type VDCC (nifedipine). Pre-incubation time = 30 min; incubation time = 60 min. N = 6 for each group. *** p ≤ 0.001, compared to control group and ^### p ≤ 0.001, compared to CIN group.

Figure 6

Effect of CIN on (A) triglycerides, (B) total cholesterol, (C) HDL cholesterol and (D) LDL cholesterol in insulin-resistant rats after 5 days of treatment with dexamethasone. N = 6 for each group. *** p ≤ 0.001; ** p ≤ 0.01 and * p ≤ 0.05, compared to the control group. ^### p ≤ 0.001; ^## p ≤ 0.01 and ^# p ≤ 0.05, compared to the dexamethasone group.

Figure 7

Acute effect of CIN on the oral triglyceride tolerance test in normal rats overloaded with an enriched lipid emulsion, at 0 to 6 h. N = 6. *** p ≤ 0.001 and ** p ≤ 0.01, compared to the respective value for the lipid emulsion group.