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.

Kir4.1 deletion prevents salt-sensitive hypertension in early streptozotocin-induced diabetic mice via Na+–Cl− cotransporter in the distal convoluted tubule

“…Previous animal studies revealed an upregulation of SGLT2 expression in Akita and db/db mice [40,41]; however, it is currently controversial about the protein expression of SGLT2 in STZ-induced type 1 diabetic model [41–43]. We found no changes in SGLT2 expression after STZ treatment, which are consistent with a report by Schiazza et al [44]. Thus, HS-induced Na + imbalance and BP changes in STZ mice could not be attributed to changes in proximal tubular sodium reabsorption.…”

How Smell Regulates Metabolism: The Role Of Ectopically Expressed Olfactory Receptors In Lipid and Glucose Homeostasis

“…In particular, Olfr1393, expressed in the kidneys by the proximal tubules, has been confirmed to be involved in glucose reabsorption at renal level by increasing expression and membrane translocation of the sodiumglucose cotransporters SGLT1 and SGLT2 [40], thus increasing blood glucose levels and emerging indeed as an important contributor to T2DM development. Despite the molecular mechanism is not so clear, further studies have confirmed Olfr1393 capability to modulate SGLT1 and SGLT2: infact, SGLT2 expression was reduced in Olfr1393 KO mice, resulting in improvement of hyperglycemia and glucose tolerance [95], [96]. Both in vitro and in vivo studies revealed and increased expression of SGLT2, and thus of glucose reabsorption, in T2DM patients [97]:…”

How smell regulates metabolism: The role of ectopically expressed olfactory receptors in lipid and glucose homeostasis

“…In particular, Olfr1393, expressed in the kidneys by the proximal tubules, has been confirmed to be involved in glucose reabsorption at renal level by increasing expression and membrane translocation of the sodium-glucose cotransporters SGLT1 and SGLT2 [40], thus increasing blood glucose levels and emerging indeed as an important contributor to T2DM development. Despite the molecular mechanism is not so clear, further studies have confirmed Olfr1393 capability to modulate SGLT1 and SGLT2: infact, SGLT2 expression was reduced in Olfr1393 KO mice, resulting in improvement of hyperglycemia and glucose tolerance [95,96]. Both in vitro and in vivo studies revealed and increased expression of SGLT2, and thus of glucose reabsorption, in T2DM patients [97]: although not yet completely understood, it seems that SGLT2 overexpression should be due to a hyperphosphorilaton guided by insulin via PKA and PKC [98,99].…”