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Loss of renal olfactory receptor 1393 leads to improved glucose homeostasis in a type 1 diabetic mouse model.

ABSTRACT: 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.

SUBMITTER: Schiazza AR

PROVIDER: S-EPMC8652410 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Loss of renal olfactory receptor 1393 leads to improved glucose homeostasis in a type 1 diabetic mouse model.

Schiazza Alexis R AR Considine Elizabeth G EG Betcher Madison M Shepard Blythe D BD

Physiological reports 20211201 23

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 knockou ...[more]

PMID: 34877823

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Project description:IntroductionRoux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis.MethodsSprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry.ResultsAt 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ± 3.8 mg/dl vs. 99.1 ± 2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption.ConclusionWe demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.

Dataset Information

Loss of renal olfactory receptor 1393 leads to improved glucose homeostasis in a type 1 diabetic mouse model.

Publications

Loss of renal olfactory receptor 1393 leads to improved glucose homeostasis in a type 1 diabetic mouse model.

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