Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes

Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca2+/5′-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance

Acute normobaric hypoxia stimulates erythropoietin release

Investigations studying the secretion of EPO (erythropoietin) in response to acute hypoxia have produced mixed results. Further, the errors associated with the various methods used to determine EPO are not well documented. The purpose of the current study was to determine the EPO response of 17 trained male subjects to either an acute bout of normobaric hypoxia (Hy; n = 10) or normoxia (Con; n = 7). A secondary aim was to determine the error associated with the measurement of EPO. After baseline tests, the treatment group (Hy) underwent a single bout of hypoxic exposure (F(I(O(2))) approximately 0.148; 3100 m) consisting of a 90-min rest period followed by a 30-min exercise phase (50% V(O)(2max)). Venous blood samples were drawn pre (0 min) and post (120 min) each test to assess changes in plasma EPO (DeltaEPO). The control (Con) group was subjected to the same general experimental design, but placed in a normoxic environment (F(I(O(2))) approximately 0.2093). The Hy group demonstrated a mean increase in EPO [19.3 (4.4) vs. 24.1 (5.1) mU/mL], p < 0.04, post 120 min of normobaric hypoxia. The calculated technical error of measurement for EPO was 2.1 mU/mL (9.8%). It was concluded that an acute bout of hypoxia, has the capacity to elevate plasma EPO. This study also demonstrates that the increase in EPO accumulation was 2 times greater than the calculated measurement of error

Influence of hypohydration on intermittent sprint performance in the heat

Purpose: To examine the effect of hypohydration on physiological strain and intermittent sprint exercise performance in the heat (35.5 ± 0.6°C, 48.7 ± 3.4% relative humidity). Methods: Eight unacclimatized males (age 23.4 ± 6.2 y, height 1.78 ± 0.04 m, mass 76.8 ± 7.7 kg) undertook three trials, each over two days. On day 1, subjects performed 90 min of exercise/heat-induced dehydration on a cycle ergometer, before following one of three rehydration strategies. On day 2, subjects completed a 36-min cycling intermittent sprint test (IST) with a −0.62 ± 0.74% (euhydrated, EUH), −1.81 (0.99)% (hypohydrated1, HYPO1), or −3.88 ± 0.89% (hypohydrated2, HYPO2) body mass deficit. Results: No difference was observed in average total work (EUH, 3790 ± 556 kJ; HYPO1, 3785 ± 628 kJ; HYPO2, 3647 ± 339 kJ, P = 0.418), or average peak power (EUH, 1315 ± 129 W; HYPO1, 1304 ± 175 W; HYPO2, 1282 ± 128 W, P = 0.356) between conditions on day 2. Total work and peak power output in the sprint immediately following an intense repeated sprint bout during the IST were lower in the HYPO2 condition. Physiological strain index was greater in the HYPO2 vs. the EUH condition, but without changes in metabolic markers. Conclusion: A greater physiological strain was observed with the greatest degree of hypohydration; however, sprint performance only diminished in the most hypohydrated state near the end of the IST, following an intense bout of repeating sprinting

Human monocyte heat shock protein 72 responses to acute hypoxic exercise after 3 days of exercise heat acclimation

The aim of this study was to determine whether short-term heat acclimation (STHA) could confer increased cellular tolerance to acute hypoxic exercise in humans as determined via monocyte HSP72 (mHSP72) expression. Sixteen males were separated into two matched groups. The STHA group completed 3 days of exercise heat acclimation; 60 minutes cycling at 50% V˙O2peak in 40°C 20% relative humidity (RH). The control group (CON) completed 3 days of exercise training in 20°C, 40% RH. Each group completed a hypoxic stress test (HST) one week before and 48 hours following the final day of CON or STHA. Percentage changes in HSP72 concentrations were similar between STHA and CON following HST1 (P=0.97). STHA induced an increase in basal HSP72 (P=0.03) with no change observed in CON (P=0.218). Basal mHSP72 remained elevated before HST2 for the STHA group (P0.05). Percent change in mHSP72 was lower after HST2 in STHA compared to CON (P=0.02). The mHSP72 response to hypoxic exercise was attenuated following 3 days of heat acclimation. This is indicative of improved tolerance and ability to cope with the hypoxic insult, potentially mediated in part by increased basal reserves of HSP72

Short-term isothermic heat acclimation elicits beneficial adaptations but medium-term elicits a more complete adaptation

Purpose To investigate the effects of 60 min daily, short-term (STHA) and medium-term (MTHA) isothermic heat acclimation (HA) on the physiological and perceptual responses to exercise heat stress. Methods Sixteen, ultra-endurance runners (female = 3) visited the laboratory on 13 occasions. A 45 min sub-maximal (40% Wmax) cycling heat stress test (HST) was completed in the heat (40 °C, 50% relative humidity) on the first (HSTPRE), seventh (HSTSTHA) and thirteenth (HSTMTHA) visit. Participants completed 5 consecutive days of a 60 min isothermic HA protocol (target Tre 38.5 °C) between HSTPRE and HSTSTHA and 5 more between HSTSTHA and HSTMTHA. Heart rate (HR), rectal (Tre), skin (Tsk) and mean body temperature (Tbody), perceived exertion (RPE), thermal comfort (TC) and sensation (TS) were recorded every 5 min. During HSTs, cortisol was measured pre and post and expired air was collected at 15, 30 and 45 min. Results At rest, Tre and Tbody were lower in HSTSTHA and HSTMTHA compared to HSTPRE, but resting HR was not different between trials. Mean exercising Tre, Tsk, Tbody, and HR were lower in both HSTSTHA and HSTMTHA compared to HSTPRE. There were no differences between HSTSTHA and HSTMTHA. Perceptual measurements were lowered by HA and further reduced during HSTMTHA. Conclusion A 60 min a day isothermic STHA was successful at reducing physiological and perceptual strain experienced when exercising in the heat; however, MTHA offered a more complete adaptation

High intensity exercise decreases IP6K1 muscle content & improves insulin sensitivity in glucose intolerant individuals

Context Insulin resistance in skeletal muscle contributes to whole body hyperglycaemia and the secondary complications associated with type 2 diabetes. Inositol hexakisphosphate kinase-1 (IP6K1) may inhibit insulin-stimulated glucose transport in this tissue type. Objective Muscle and plasma IP6K1 were correlated with two-compartment models of glucose control in insulin-resistant hyperinsulimic individuals. Muscle IP6K1 was also compared following two different exercise trials. Methods Nine pre-diabetic [HbA1c; 6.1 (0.2) %)] were recruited to take part in a resting control, a continuous exercise (90% of lactate threshold) and a high-intensity exercise trial (6 x 30 sec sprints). Muscle biopsies were drawn pre- and post each 60-minute trial. A labeled ([6,62H2]glucose) intravenous glucose tolerance test (IVGTT) was performed immediately after the second muscle sample. Results Fasting muscle IP6K1 content did not correlate with SI2* (P = 0.961). High-intensity exercise reduced IP6K1 muscle protein and mRNA expression (P = 0.001). There was no effect on protein IP6K1 content following continuous exercise. Akt308 phosphorylation of was significantly greater following high-intensity exercise. Intermittent exercise reduced hepatic glucose production (HGP) following the same trial. The same intervention also improved SI2* and this was significantly greater compared to the continuous exercise improvements. Our in vitro experiment demonstrated that the chemical inhibition of IP6K1 increased insulin signaling in C2C12 myotubes. Conclusions The in vivo and in vitro approaches used in the current study suggest that a decrease in muscle IP6K1 may be linked to whole body improvements in SI2*. In addition, high-intensity exercise reduces HPG in insulin-resistant individuals

Influence of hypohydration on intermittent sprint performance in the heat

To examine the effect of hypohydration on physiological strain and intermittent sprint exercise performance in the heat (35.5 ± 0.6°C, 48.7 ± 3.4% relative humidity)