Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation

Abstract

The kidney plays an important role in gluconeogenesis during starvation. To clarify the anti-diabetic action of angiotensin receptor blockers, we examined the effects of telmisartan on the sodium-glucose co-transporters (SGLT) and the pathways of renal gluconeogenesis in streptozotocin-induced diabetes mellitus (DM) rats. At 4 weeks, the DM rats treated with/without telmisartan for 2 weeks and normal control rats were used for the study after a 24-hour fast. SGLT2 expressed on the brush border membrane of the proximal convoluted tubules increased in the DM rats, but decreased in the rats treated with telmisartan. The expression of restriction enzymes of gluconeogenesis, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased in the proximal tubules in the DM rats, whereas these enzymes decreased in the kidneys of the rats treated with telmisartan. The elevated cytoplasmic glucose-6-phosphate and glucose levels in the kidney of DM rats significantly decreased in those treated with telmisartan, whereas those levels in the liver did not show significant change. Meanwhile, the high plasma glucose levels in the DM rats during the intravenous insulin tolerance tests were ameliorated by telmisartan. The increased fasting plasma glucose levels after 24 hours of starvation in the DM rats thus returned to the control levels by telmisartan treatment. In conclusion, the increased renal SGLT2 expression, elevated renal gluconeogenesis enzymes and extent of insulin-resistance in the DM rats were ameliorated by telmisartan therapy, thus resulting in decreased plasma glucose levels after 24 hours of fasting.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…Renal gluconeogenesis is enhanced in STZ rats [4,14,46,67,110,173], in murine model knockout for IRecs [174] or IRS1 plus IRS2 [4], in a mix model of high-fat diet plus STZ [175], and in T2D murine models [176,177] demonstrating the essential insulin role.…”

“…SGLT1 is found along all PT segments [59,63], and its density in the BBM and intracellular organelles increases from S1 to S3 being higher in the outer medulla than in the cortex [63,64]. SGLT2 is situated in the renal cortex [65], especially in the S1 and S2 segments [66,67], and its expression is higher in the former [66]. In humans, expression of SGLT2 protein occurs in S1 and S2 whereas SGLT1 is expressed in the S3 segment.…”

“…They predominantly reported higher GLUT1 protein [79][80][81][82] and corresponding mRNA [81][82][83][84][85] contents in the whole kidney and increased GLUT1 protein [86,87] and mRNA [86,88,89] in the cortex. Nonetheless, these studies are yet controversial [22,67,[90][91][92][93]. In STZ rats, S3 GLUT1 mRNA availability raised and returned to its normal values after one month of diabetes induction, while cortical (mainly S1 and S2 segments) GLUT1 remained at low levels until six months.…”

“…Reports of SGLT1 protein [80,84,103] and mRNA [83-85, 92, 93, 98] contents in PTs of T1D murine models are also contradictory while in T2D models only mRNA expression seems to be upregulated [22,90,92,98,100,[103][104][105][106]. SGLT2 has been studied in many models of diabetes, and the results suggest increased protein [32,67,84,85,90,94,99,[107][108][109][110][111] and mRNA [22,32,83,85,100,104,[106][107][108][109]112] contents and activity [108] despite some controversial results [85,93,98,100,105,113].…”

Empagliflozin: a new strategy for nephroprotection in diabetes

“…В модели аутоиммунного СД1 у мышей Akita Ins2 +/C96Y наблюдался больший уровень экспрессии SGLT2, чем у гетерозиготного контроля [11]. В мембранной фракции почечных тканей крыс Sprague Dawley со стрептозотоциновым СД через 2 недели после индукции заболевания наблюдалось повышение содержа-ния белка SGLT2 [16]. В аналогичной модели через 4 не-дели после индукции стрептозотоцинового СД различий в уровне экспрессии гена SGLT2 в тканях почки в сравне-нии с контрольными животными не выявлено [17].…”