Renal olfactory receptor 1393 (Olfr1393) is an understudied sensory receptor that contributes to glucose handling in the proximal tubule. Our previous studies have indicated that this receptor may serve as a regulator of the sodium glucose co‐transporters (SGLTs) and contributes to the development of glucose intolerance and hyperfiltration in the setting of diet‐induced obesity. We hypothesized that Olfr1393 may have a similar function in Type 1 Diabetes. Using Olfr1393 wildtype (WT) and knockout (KO) mice along with streptozotocin (STZ) to induce pancreatic β‐cell depletion, we tracked the development and progression of diabetes over 12 weeks. Here we report that diabetic male Olfr1393 KO mice have a significant improvement in hyperglycemia and glucose tolerance, despite remaining susceptible to STZ. We also confirm that Olfr1393 localizes to the renal proximal tubule, and have uncovered additional expression within the glomerulus. Collectively, these data indicate that loss of renal Olfr1393 affords protection from STZ‐induced type 1 diabetes and may be a general regulator of glucose handling in both health and disease.
Repeated long-duration hyperoxic dives with intermittent exercise have been shown to significantly reduce aerobic exercise performance at 24-hours post diving. However, the recovery timeframe for performance decrements is unknown. PURPOSE: Examine the effect of repeated long-duration 100% oxygen (O2) dives with moderate exercise on the reduction and recovery of post-dive aerobic exercise performance. METHODS: 14 military trained divers (age 30.6 ± 2.2 yrs; diver experience 6.8 ± 1.4 yrs; V ̇O2max 57.3 ± 2.6 mL/kg/min) completed 5 consecutive 6-hour dives at 1.35 ATA with 18-hour surface intervals while breathing 100% O2. During the dive, moderate cycle ergometer exercise was performed at 58-65% of predicted heart rate (HR) max in alternating 30-minute periods. A time-to-fatigue treadmill run at 85% V ̇O2max was completed 72 hours before dive 1 (PRE), within 2 hours after dive 5 (2-POST), and at 72 hours after dive 5 (72-POST). Cardiac output (Q), stroke volume (SV), HR, and rating of perceived exertion (RPE) were measured during the runs, and all data presented are matched for the last data point of the shortest run. A one-way ANOVA was used to analyze outcomes at PRE, 2-POST, and 72-POST with significance at p<0.05. Data presented as mean ± SEM. RESULTS: Run time significantly decreased from PRE (8.4 ± 0.8 min) to 2-POST (4.6 ± 0.4 min, -45%, p<0.01), and 72-POST (6.3 ± 0.7 min, -25%, p<0.01). Q and SV significantly decreased from PRE (18.6 ± 1.4 L/min; 108.2 ± 8.4 mL) to 2-POST (15.8 ± 0.8 L/min p<0.05; 88.7 ± 4.5 mL, p<0.01), but not at 72-POST (19.4 ± 1.4 L/min, p>0.05; 110.9 ± 7.5 mL, p>0.05). HR and RPE significantly increased from PRE (173.0 ± 2.8 BPM; 14.4 ± 1.0) to 2- POST (176.3 ± 2.5 BPM, p<0.05; 16.4 ± 0.9, p<0.01). HR recovered at 72-POST (174.1 ± 2.6 BPM, p>0.05), but not RPE (15.5 ± 0.7, p<0.05). There were no significant correlations between changes in run times and changes in Q, SV, HR, and RPE. CONCLUSIONS: Repeated long-duration 100% O2 dives with moderate exercise reduce exercise performance within 2 hours and for at least 72 hours post-diving. Q, SV, HR, and RPE were all negatively affected within 2 hours post-diving; however, all but RPE returned to baseline at 72 hours post-diving, suggesting other mechanisms may contribute to the performance decrements.
Olfactory receptor 1393 (Olfr1393) is a G‐protein coupled receptor ectopically expressed in the murine kidney and liver that has functionality in glucose reabsorption via the sodium‐glucose linked‐transporters (Sglts). Due to the recent therapeutic advances regarding inhibition of the Sglts for both type 1 (T1D) and type 2 (T2D) diabetes, we sought to elucidate the contribution of Olfr1393 to the development and progression of the disease. Previously, we determined that Olfr1393 knockout (KO) mice exhibit improved glucose tolerance and attenuated glomerular hyperfiltration when challenged with a high fat diet (60% kcal from fat) to induce early stages of T2D as compared to their wildtype (WT) counterparts. This was linked to the reduced expression of SGLT2 within the proximal tubule of the KO mice. To determine if Olfr1393 is also involved in T1D, both KO and WT mice were challenged with low‐dose injections of Streptozotocin (STZ; 55 mg/kg BW) or vehicle control (PBS; 55 mg/kg BW) for 5 days to induce depletion of pancreatic β cells. In as little as 2 weeks, both KO and WT male STZ‐treated mice presented with hyperglycemia (2hr fasting blood glucose; WT STZ ‐ 433 ± 32.6 mg/dL, KO STZ ‐ 309 ± 22.6 mg/dL, WT V ‐ 169.7 ± 7.96 mg/dL, KO V ‐ 169.6 ± 10.9 mg/dL), although this hyperglycemia was significantly attenuated in KO mice (p < 0.005). At five weeks, this change was even more pronounced with a significant improvement in hyperglycemia noted even after an overnight fast (WT STZ ‐ 473 ± 28.35 mg/dL, KO STZ ‐ 300 ± 36.24 mg/dL). This improved phenotype is not a result of decreased sensitivity to STZ as islet cell area is similar between STZ‐treated KOs and WTs (WT STZ ‐ 4218 ± 826.5 um2, KO STZ ‐ 4913 ± 2335 um2). The improvement in blood glucose levels also correlated with a significant improvement in glucose tolerance noted in the diabetic KO mice (AUC: WT STZ ‐ 35471 ± 3279, KO STZ ‐ 2868 ± 2118; p<0.01). Notably, all improvement was seen in the male mice as STZ induced a sex dependent phenotype of T1D with female mice found to be resistant to the development of hyperglycemia (2hr fasting blood glucose; WT STZ ‐ 167.7 ± 29.16 mg/dL, KO STZ ‐ 178.0 ± 31.92 mg/dL, WT V ‐ 131.0 ± 38.59 mg/dL, KO V ‐ 144.4 ± 15.92 mg/dL). Contrary to data obtained in our T2D model, neither diabetic WT nor KO mice presented with the commonly noted diabetes‐induced hyperfiltration as measured by transdermal clearance of FITC‐sinistrin; this tracked with a lack of an alteration in glomerular area or morphology as assessed by PAS histological analysis. Additionally, we did not detect any changes in plasma electrolytes (iSTAT Chem8+) or blood pressure (via tail cuff BP‐2000 Blood Pressure Analysis System). Given the improved diabetic phenotype, efforts are currently underway to determine if loss of Olfr1393 leads to changes in the expression or localization of renal SGLT1 and/or SGLT2 in the setting of T1D. Collectively, our data has uncovered a novel regulator of glucose handling, and sheds light on how the modulation of this pathway inf...
Divers often perform repeated dives with taxing activity using various underwater breathing apparatuses (UBA), which may increase total energy expenditure (TEE) and alter energy balance (EB) and physical ability. However, data is lacking regarding metabolic and muscular responses to repeated diving. We tested the hypotheses that repeated diving induces negative EB and decreases muscular force, but these decrements would not be affected by UBA. 16 military divers participated in 3 4‐hr dives (31 ± 2 °C) at 1.3 ata, with 20‐hr surface intervals, while wearing a MK25 (n=8, age: 33.8 ± 4.4 yr) UBA with 100% oxygen or MK20 (n=8, age: 36.0 ± 4.7 yr) with air. During dives, subjects alternated 30 min rest and cycling exercise at 60% HRmax. EB was calculated as TEE – energy intake (EI). TEE was measured via doubly labeled water (DLW; 4‐8 atom % 2H2O and 8‐12 atom % 18O). Urine samples were taken before each dive, and for 4 days after diving to assess differences in EB diving and non‐diving (control) days. EI was assessed via food logs. EB, TEE, and EI were normalized to body weight. Before and after each dive, peak force (PF) and rate of power development (RPD) were measured on a force plate during 3 countermovement jumps (3J) and while hopping in place for 10 sec (Hop). EB and muscular power were analyzed with mixed model ANOVAs (UBA: MK25 vs MK20, Diving: Dive Day (DD) vs Control Day (CD), Dive: Pre vs Post Dive, Repeated Diving: Dive 1, 2, 3). There was no effect of UBA on EB during dive days (MK25: ‐12.8 ± 8.9 kcal/kg; MK20: ‐8.4 ± 6.2 kcal/kg); but, EB did increase during diving (p < 0.01, DD: ‐13.0 ± 7.6 kcal/kg; CD: ‐6.7 ± 10.4 kcal/kg). There was no effect of UBA on TEE (p = 0.16, MK25: 37.6 ± 5.6 kcal/kg, MK20: 42.3 ± 2.5 kcal/kg) during dive days; but, TEE (p < 0.01) increased on dive days compared to control (DD: 39.6 ± 5.2 kcal/kg; CD: 31.2 ± 7.0 kcal/kg). There was no effect of UBA or diving on EI. 3J‐RPD (p < 0.01) and Hop‐RPD increased (p < 0.01) with repeated diving (3J‐RPD – D1: 11.7 ± 3.9 kW/s vs. D2: 13.0 ± 4.0 kW/s, p > 0.05; D1 vs. D3: 13.7 ± 3.9 kW/s, p < 0.01; D2 vs. D3, p > 0.05; Hop‐RPD – D1: 37.4 ± 21.6 kW/s vs. D2: 46.1 ± 29.0 kW/s, p = 0.02; D1 vs. D3: 49.9 ± 27.1 kW/s, p < 0.01; D2 vs. D3, p > 0.05). There was a group effect for 3J‐PF (p = 0.02) and 3J‐RPD (p < 0.01) with higher PF (MK25: 1948 ± 205 N; MK20: 1655 ± 223 N) and RPD (MK25: 15.2 ± 3.5 kW/s; MK20: 10.4 ± 2.9 kW/s) in MK25, but no other effects. Repeated 4‐hr exercise dives induce negative EB due to higher TEE, independent of UBA. RPD increased after repeated diving; however, further research is needed to determine mechanisms.
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