EFFECTS OF VARIATION IN EXERCISE TRAINING LOAD ON COGNITIVE PERFORMANCES AND NEUROTROPHIC BIOMARKERS IN PATIENTS WITH CORONARY ARTERY DISEASE.

PURPOSE: This study compared the effects of linear (LP) and non-linear (NLP) training periodization on resting cognitive functions, neurotrophic biomarkers (brain-derived neurotrophic factor [BDNF], insulin-like growth factor-1 [IGF-1]), and cathepsin-B in patients with coronary artery disease (CAD). METHODS: Forty-four patients with CAD reported to our laboratory on two occasions to undergo testing procedures before and after training sessions, and were then blindly randomized to NLP or LP for 36 training sessions. Visit 1 included blood samples and a maximal cardiopulmonary exercise testing to get maximal oxygen uptake (V̇O2peak). Visit 2 included cognitive functions assessment. RESULTS: Thirty-nine patients completed the study (LP: n=20, NLP: n=19), with no observed changes in cognitive performances after the training intervention in either group. IGF-1 concentration decreased in both groups (time-effect: p<0.001), while BDNF concentration increased (time-effect: p<0.05) without interaction (p=0.17 and p=0.65, respectively), and cathepsin-B did not change after the intervention (p>0.05). Associations were found between ΔV̇O2peak and ΔBDNF (R2=0.18, p=0.04), and ΔIGF-1 and Δ short-term/working memory (R2=0.17, p=0.01) in the pooled sample, with Δ IGF-1 and ΔBDNF accounting for 10% of the variance in Δ short-term/working memory. In the LP group, associations were found between ΔV̇O2peak and ΔBDNF (R2=0.45, p=0.02), ΔBDNF and Δ short-term/working memory (R2=0.62, p=0.004), ΔIGF-1 and Δ short-term/working memory (R2=0.31, p=0.01), and Δ IGF-1 and Δ executive function (R2=0.22, p=0.04). CONCLUSION: This finding highlights the potential importance of monitoring and targeting BDNF and IGF-1 concentration as potential biomarkers for improving short-term and working memory in the population with CAD.

Combined Deletion of Free Fatty-Acid Receptors 1 and 4 Minimally Impacts Glucose Homeostasis in Mice.

The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these 2 receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice, but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double knock-out animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these 2 receptors only minimally affects glucose homeostasis in vivo in mice.

Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice.

OBJECTIVE: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, ß, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. METHODS: Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, ß, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. RESULTS: Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and ß cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. CONCLUSIONS: Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.