Renal Glycosuria Triggers a Coordinated Mannose and Glutamine Metabolic Program to Maintain Glucose Homeostasis

Nadia Rashid; Moses Otunla; Nazmul Hasan; Michael J. Hodges; Heba H. Qaissi; Tumininu S. Faniyan; Pontiana Ritika Clement; Penghui Lin; Mohamed M.Y. Kaddah; Teresa A. Cassel; Donald A. Morgan; Kamal Rahmouni; Kavaljit H. Chhabra

doi:10.1016/j.celrep.2026.117804

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Renal Glycosuria Triggers a Coordinated Mannose and Glutamine Metabolic Program to Maintain Glucose Homeostasis

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Renal Glycosuria Triggers a Coordinated Mannose and Glutamine Metabolic Program to Maintain Glucose Homeostasis

Nadia Rashid, Moses Otunla, Nazmul Hasan, Michael J. Hodges, Heba H. Qaissi, Tumininu S. Faniyan, Pontiana Ritika Clement, Penghui Lin, Mohamed M.Y. Kaddah, Teresa A. Cassel, …

Cell reports (Cambridge), Vol.45(8), 117804

08/12/2026

DOI: 10.1016/j.celrep.2026.117804

PMID: 42593967

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Abstract

Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and showed increased incorporation of mannose-derived carbon into oxidative metabolism while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, consistent with reliance on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-coordinated metabolic program associated with maintenance of systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors. [Display omitted] •Renal glycosuria increases mannose metabolism in the kidney.•Renal glycosuria induces systemic glucose-sparing adaptations.•Glutamine metabolism supports renal and systemic glucose compensation.•Targeting mannose and glutamine may improve SGLT2-inhibitor efficacy. Rashid et al. show that during renal glycosuria, the kidney coordinates a mannose and glutamine metabolic program that sustains systemic glucose homeostasis. Skeletal muscle spares glucose while mannose- and glutamine-derived carbon supports glucose production, revealing adaptations that may inform strategies to improve the glucose-lowering efficacy of SGLT2 inhibitors.

glucose metabolism

glycosuria

metabolic reprogramming

mouse model

Details

Title: Subtitle: Renal Glycosuria Triggers a Coordinated Mannose and Glutamine Metabolic Program to Maintain Glucose Homeostasis
Creators: Nadia Rashid - University of Kentucky
Moses Otunla - University of Kentucky
Nazmul Hasan - University of Kentucky
Michael J. Hodges - University of Kentucky
Heba H. Qaissi - University of Kentucky
Tumininu S. Faniyan - University of Rochester
Pontiana Ritika Clement - University of Rochester
Penghui Lin - Markey Cancer Center
Mohamed M.Y. Kaddah - Markey Cancer Center
Teresa A. Cassel - University of Kentucky
Donald A. Morgan - Iowa City VA Health Care System
Kamal Rahmouni - Iowa City VA Health Care System
Kavaljit H. Chhabra - University of Kentucky
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.45(8), 117804
DOI: 10.1016/j.celrep.2026.117804
PMID: 42593967
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: Elsevier Inc
Grant note: Bill Gatton Foundation University of Kentucky Barnstable Brown Diabetes and Obesity Research Center: R01 HL162773, R01 HL172944 National Institutes of Health: R01 HL162773, R01 HL172944, DK124619, DK140148 US Department of Veterans Affairs: I01 BX004249, IK6 BX006040 University of Iowa Fraternal Order of Eagles Diabetes Research Center: I01 BX004249 NIH: P30CA177558
We thank Jason Kim, UMass Chan Medical School, for help with the clamp study, and Dalbir Kaur Chhabra for assistance with the bioinformatics analyses. Bill Gatton Foundation postdoctoral fellowship to N.H., administered by the Barnstable Brown Diabetes and Obesity Research Center. Start-up funds from the University of Kentucky including the Barnstable Brown Diabetes and Obesity Research Center, and the Diabetes and Obesity Research Priority Area, and National Institutes of Health grants DK124619 and DK140148 to K.H.C. with a subaward to K.R. K.R. is also supported by National Institutes of Health grants R01 HL162773 and R01 HL172944, US Department of Veterans Affairs grants I01 BX004249 and IK6 BX006040 and the University of Iowa Fraternal Order of Eagles Diabetes Research Center. The SIRM work was carried out through the shared resources of the University of Kentucky Markey Cancer Centerfunded in part by NIH grant P30CA177558.
Language: English
Date published: 08/12/2026
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9985218397402771

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