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Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport
  1. Ele Ferrannini1,
  2. Ricardo Pereira-Moreira2,
  3. Marta Seghieri3,
  4. Eleni Rebelos3,
  5. Aglécio L Souza2,
  6. Valeria B Chueire2,
  7. Caterina Arvia4,
  8. Elza Muscelli2
  1. 1Institute of Clinical Physiology, CNR, Pisa, Italy
  2. 2Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
  3. 3Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  4. 4Fondazione Toscana Gabriele Monasterio, Pisa, Italy
  1. Correspondence to Professor Ele Ferrannini; ferranni{at}ifc.cnr.it

Abstract

Introduction Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.

Methods We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination.

Results During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion.

Conclusions Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.

  • insulin
  • kidney
  • glucose transport
  • sodium glucose cotransporter
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Footnotes

  • EF and RP-M contributed equally.

  • Contributors EF designed the experiments. EF, R-PM and EM analyzed the data and wrote the paper. R-PM, MS, ER, ALS, VBC, CA and EM conducted the experiments. All authors read and approved the final version of the manuscript. EF is the guarantor of this manuscript.

  • Funding This work was supported in part through an investigator-initiated grant by Boehringer-Ingelheim Italia (IIS 1245.115). R-PM received financial support from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) Finance Code 001.

  • Competing interests EF has participated in scientific advisory boards for Boehringer Ingelheim, Eli Lilly, and Sanofi; has been involved in ad hoc consulting for Janssen, AstraZeneca, and Mitsubishi Tanabe; has participated in occasional speaking engagements for AstraZeneca, Novo Nordisk, Sanofi, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, and Merck Sharp & Dohme; and has received research grant support from Boehringer Ingelheim and AstraZeneca.

  • Patient consent for publication Not required.

  • Ethics approval Studies were conducted according to Declaration of Helsinki principles; participants gave their written informed consent, and the study was approved by both ethics committees (EudraCT 2015-005727-80, CAAE 44961615.6.0000.540).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request, the reasonable request being an additional analysis plan to test a new hypothesis formulated by a named investigator.

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