Endurance training inhibits insulin clearance and IDE expression in Swiss mice.

INTRODUCTION: Endurance training improves peripheral insulin sensitivity in the liver and the skeletal muscle, but the mechanism for this effect is poorly understood. Recently, it was proposed that insulin clearance plays a major role in both glucose homeostasis and insulin sensitivity. Therefore, our goal was to determine the mechanism by which endurance training improves insulin sensitivity and how it regulates insulin clearance in mice. METHODS: Mice were treadmill-trained for 4 weeks at 70-80% of maximal oxygen consumption (VO2 max) for 60 min, 5 days a week. The glucose tolerance and the insulin resistance were determined using an IPGTT and an IPITT, respectively, and the insulin decay rate was calculated from the insulin clearance. Protein expression and phosphorylation in the liver and the skeletal muscle were ascertained by Western blot. RESULTS: Trained mice exhibited an increased VO2 max, time to exhaustion, glucose tolerance and insulin sensitivity. They had smaller fat pads and lower plasma concentrations of insulin and glucose. Endurance training inhibited insulin clearance and reduced expression of IDE in the liver, while also inhibiting insulin secretion by pancreatic islets. There was increased phosphorylation of both the canonical (IR-AKT) and the non-canonical (CaMKII-AMPK-ACC) insulin pathways in the liver of trained mice, whereas only the CaMKII-AMPK pathway was increased in the skeletal muscle. CONCLUSION: Endurance training improved glucose homeostasis not only by increasing peripheral insulin sensitivity but also by decreasing insulin clearance and reducing IDE expression in the liver.

Reduced insulin clearance and lower insulin-degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein-restricted mice.

Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

Taurine-induced insulin signalling improvement of obese malnourished mice is associated with redox balance and protein phosphatases activity modulation.

BACKGROUND & AIMS: Obese protein malnourished mice display liver insulin resistance and taurine (TAU) seems to attenuate this effect. The association between early-life malnutrition and hepatic redox balance in diet-induced insulin resistance is unknown. We investigated TAU supplementation effects upon liver redox state and insulin signalling in obese protein malnourished mice. METHODS: Weaned male C57BL-6 mice were fed a control (14% protein - C) or a protein-restricted diet (6% protein - R) for 6 weeks. Afterwards, mice received a high-fat diet (34% fat - HFD) for 8 weeks (CH - RH). Half of the HFD-mice were supplemented with TAU (5%) throughout the treatment (CHT - RHT). Body and tissues' weight, respiratory quotient (RQ), glucose tolerance and insulin sensitivity, hepatic oxidant and antioxidant markers and insulin cascade proteins were assessed. RESULTS: Protein restriction leads to typical features whereas HFD was able to induce a catch-up growth in RH. HFD-groups showed higher energy intake and adiposity, lower energy expenditure and altered RQ. Glucose tolerance and insulin sensitivity were impaired in HFD-groups and TAU attenuated these effects. H2 O2 content was increased in CHT and RHT despite no differences in antioxidant enzymes and GSH concentration. AKT and PTEN phosphorylation were significantly increased in CHT but not in RHT. CONCLUSION: Our data provide evidence for an association between TAU-induced improved glycaemic control because of PTEN inactivation and higher AKT phosphorylation. These effects seem to be related with altered hepatic redox balance in obese mice, and this effect is impaired by protein malnutrition.

Altered NAD(P)H production in neonatal rat islets resistant to H2O2.

AIMS: We determined the involvement of NAD(P)H generation ability on the resistance of pancreatic islets B-cells to oxidative stress caused by culture exposition to H2O2. MAIN METHODS: We cultured isolated neonatal Wistar rat islets for four days in medium containing 5.6 or 20 mM glucose, with or without H2O2 (200 microM), and analyzed several parameters associated with islet survival in different media. High glucose was used since it protects neonatal islets against the loss of GSIS. KEY FINDINGS: While none of the culture conditions increased the rate of NAD(P)H content at 16.7 mM glucose, the islets resistant to H2O2 and those exposed to 20 mM glucose showed a greater use of the pentose phosphate pathway and increased ATP synthesis from glucose. SIGNIFICANCE: Oxidative stress contributes to the loss of glucose-induced insulin secretion (GSIS) during the onset of diabetes mellitus. Although immature rat islets have reduced GSIS compared to mature islets, they adapt better to oxidative stress and are a good model for understanding the causes involved in the destruction or survival of islet cells. These data support the idea that GSIS and resistance against oxidative stress in immature islets rely on NADH shuttle activities, with little contribution of reduced equivalents from the tricarboxylic acid cycle (TCAC).