Insulin Signaling and Insulin Sensitizing in Muscle and Liver of Obese Monkeys: Peroxisome Proliferator-Activated Receptor Gamma Agonist Improves Defective Activation of Atypical Protein Kinase C

Abstract

Obesity, the metabolic syndrome, and aging share several pathogenic features in both humans and non-human primates, including insulin resistance and inflammation. Since muscle and liver are considered key integrators of metabolism, we sought to determine in biopsies from lean and obese aging rhesus monkeys the nature of defects in insulin activation and, further, the potential for mitigation of such defects by an in vivo insulin sensitizer, rosiglitazone, and a thiazolidinedione activator of the peroxisome proliferator-activated receptor gamma. The peroxisome proliferator-activated receptor gamma agonist reduced hyperinsulinemia, improved insulin sensitivity, lowered plasma triglycerides and free fatty acids, and increased plasma adiponectin. In muscle of obese monkeys, previously shown to exhibit defective insulin signaling, the insulin sensitizer improved insulin activation of atypical protein kinase C (aPKC), the defective direct activation of aPKC by phosphatidylinositol (PI)-3,4,5-(PO 4 ) 3 , and 5 0 -AMPactivated protein kinase and increased carnitine palmitoyltransferase-1 mRNA expression, but it did not improve insulin activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase (IRS-1=PI3K), protein kinase B, or glycogen synthase. We found that, although insulin signaling was impaired in muscle, insulin activation of IRS-1=PI3K, IRS-2=PI3K, protein kinase B, and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3,4,5-(PO 4 ) 3 . Antioxid. Redox Signal. 14, 207-219.

Pioglitazone Increases Whole Body Insulin Sensitivity in Obese, Insulin-Resistant Rhesus Monkeys

“…These dysmetabolic monkeys did not have overt type 2 diabetes. Thus, we have documented that hepatic insulin resistance as a whole (in comparison to hepatic insulin signaling) appears to not be as late of an event in the progression to overt diabetes as previously suggested using pharmacological insulin doses [ 3 , 6 , 8 ], although the more severe peripheral insulin resistance in these monkeys agrees with the notion that it does develop first [ 41 ].…”

“…Unfortunately without biopsies or magnetic resonance spectroscopy data, this remains only a hypothesis. It must also be noted that it has previously been shown that while there is no defect in insulin’s regulation of hepatic glycogen metabolism in dysmetabolic monkeys [ 6 ], there is a defect in insulin-stimulated protein kinase B (PKB/Akt) activity [ 8 ], perhaps suggesting that hepatic insulin resistance in them may manifest in the regulation of gluconeogenesis via PKB and forkhead box protein O1[ 40 ]. These dysmetabolic monkeys did not have overt type 2 diabetes.…”

Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome

“…Phase II clinical trial data in patients with T2DM demonstrated that body weight increased to a lesser extent with aleglitazar, when compared with pioglitazone in a head-to-head comparison study [32]. Although the direct comparison between aleglitazar and pioglitazone was not performed in our study, previous thiazolidinediones studies in rhesus monkeys [15,33] support the notion that gains in body weight would be less evident with aleglitazar.…”

High‐fat diet‐induced changes in liver thioredoxin and thioredoxin reductase as a novel feature of insulin resistance

“…In the liver, insulin actions include activation of insulin receptor substrate (IRS)-1-dependent phosphoinositide 3-kinase (PI 3-kinase), protein kinase B/Akt [26] and forkhead box O1 (Foxo1), in which a major role of hepatic Akt is to restrain the activity of Foxo1 [27] . Decrease in Trx/TrxR is associated with insulin resistance, suggesting potential role of insulin signaling in mediating this process.…”