Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes
•We found that fasting glucose even in the upper range of target is associated with excess ketone production. This excess production is compensated by higher urinary ketone excretion.Sodium Glucose Linked Transporter inhibition (SGLTi) dampens this compensatory mechanism, especially in women. Findin...
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| creator | Scarr, Daniel Lovblom, Erik Ye, Hongping Liu, Hongyan Bakhsh, Abdulmohsen Verhoeff, Natasha J. Wolever, Thomas M.S. Lawler, Patrick R. Sharma, Kumar Cherney, David Z.I. Perkins, Bruce A. |
| description | •We found that fasting glucose even in the upper range of target is associated with excess ketone production. This excess production is compensated by higher urinary ketone excretion.Sodium Glucose Linked Transporter inhibition (SGLTi) dampens this compensatory mechanism, especially in women. Findings provide evidence to explain ketone elevations with SGLTi use and sex-specific differences in DKA risk.
We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex.
In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4–6 mmol/L) and mild hyperglycemia (9–11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis.
Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5–13.6] vs. 3.5[2.2–7.0] µmol/mmol creatinine during euglycemia, p |
| doi_str_mv | 10.1016/j.diabres.2023.111031 |
| format | Article |
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We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex.
In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4–6 mmol/L) and mild hyperglycemia (9–11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis.
Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5–13.6] vs. 3.5[2.2–7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3–1.6] vs. 0.4 % [0.2–0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05–0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001).
Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.</description><identifier>ISSN: 0168-8227</identifier><identifier>EISSN: 1872-8227</identifier><identifier>DOI: 10.1016/j.diabres.2023.111031</identifier><identifier>PMID: 38036220</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>3-Hydroxybutyric Acid ; Blood Glucose - analysis ; Diabetes Mellitus, Type 1 - drug therapy ; Female ; Glucose ; Humans ; Hyperglycemia - drug therapy ; Ketones - therapeutic use ; Male ; Sodium ; Symporters</subject><ispartof>Diabetes research and clinical practice, 2024-01, Vol.207, p.111031-111031, Article 111031</ispartof><rights>2023</rights><rights>Copyright © 2023. Published by Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c228t-e514cd1681bb0926b320a1f6327a060917fdfed2299eb4684c8646ebe8161c1d3</cites><orcidid>0000-0002-6774-8924 ; 0000-0002-5885-0046</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.diabres.2023.111031$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38036220$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Scarr, Daniel</creatorcontrib><creatorcontrib>Lovblom, Erik</creatorcontrib><creatorcontrib>Ye, Hongping</creatorcontrib><creatorcontrib>Liu, Hongyan</creatorcontrib><creatorcontrib>Bakhsh, Abdulmohsen</creatorcontrib><creatorcontrib>Verhoeff, Natasha J.</creatorcontrib><creatorcontrib>Wolever, Thomas M.S.</creatorcontrib><creatorcontrib>Lawler, Patrick R.</creatorcontrib><creatorcontrib>Sharma, Kumar</creatorcontrib><creatorcontrib>Cherney, David Z.I.</creatorcontrib><creatorcontrib>Perkins, Bruce A.</creatorcontrib><title>Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes</title><title>Diabetes research and clinical practice</title><addtitle>Diabetes Res Clin Pract</addtitle><description>•We found that fasting glucose even in the upper range of target is associated with excess ketone production. This excess production is compensated by higher urinary ketone excretion.Sodium Glucose Linked Transporter inhibition (SGLTi) dampens this compensatory mechanism, especially in women. Findings provide evidence to explain ketone elevations with SGLTi use and sex-specific differences in DKA risk.
We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex.
In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4–6 mmol/L) and mild hyperglycemia (9–11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis.
Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5–13.6] vs. 3.5[2.2–7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3–1.6] vs. 0.4 % [0.2–0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05–0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001).
Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.</description><subject>3-Hydroxybutyric Acid</subject><subject>Blood Glucose - analysis</subject><subject>Diabetes Mellitus, Type 1 - drug therapy</subject><subject>Female</subject><subject>Glucose</subject><subject>Humans</subject><subject>Hyperglycemia - drug therapy</subject><subject>Ketones - therapeutic use</subject><subject>Male</subject><subject>Sodium</subject><subject>Symporters</subject><issn>0168-8227</issn><issn>1872-8227</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctu2zAQRYkiReOm_YQWXGYjl6RkmloFQZA-0ADdtGuCIkf2GBKpkFRQ_0M_uvQj2WY1M8CZO7hzCfnE2ZIzLr_slg5NFyEtBRP1knPOav6GLLhai0oJsb4gi8KpY39J3qe0Y4zJulm9I5e1YrUUgi3Iv5-Qgwc6xeBmmzF4aryj8NdGOE7wBJ66OaLf0BEHR7f7CeJm2FsY0RzhvAWK42RspqGnKTicx2ozzDYkoDZUORqfphAzRIp-ix0eldHTXLQopwcnkCF9IG97MyT4eK5X5M_X-99336uHX99-3N0-VFYIlStY8ca64o13HWuF7GrBDO9lLdaGSdbyde96cEK0LXSNVI1VspHQgeKSW-7qK3J90i2uH2dIWY-YLAyD8RDmpIVqizgTDSvo6oTaGFKK0Osp4mjiXnOmD0HonT4HoQ9B6FMQZe_z-cTcjeBetp4_X4CbEwDF6BNC1MkieAsOI9isXcBXTvwHO4ieWg</recordid><startdate>202401</startdate><enddate>202401</enddate><creator>Scarr, Daniel</creator><creator>Lovblom, Erik</creator><creator>Ye, Hongping</creator><creator>Liu, Hongyan</creator><creator>Bakhsh, Abdulmohsen</creator><creator>Verhoeff, Natasha J.</creator><creator>Wolever, Thomas M.S.</creator><creator>Lawler, Patrick R.</creator><creator>Sharma, Kumar</creator><creator>Cherney, David Z.I.</creator><creator>Perkins, Bruce A.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6774-8924</orcidid><orcidid>https://orcid.org/0000-0002-5885-0046</orcidid></search><sort><creationdate>202401</creationdate><title>Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes</title><author>Scarr, Daniel ; Lovblom, Erik ; Ye, Hongping ; Liu, Hongyan ; Bakhsh, Abdulmohsen ; Verhoeff, Natasha J. ; Wolever, Thomas M.S. ; Lawler, Patrick R. ; Sharma, Kumar ; Cherney, David Z.I. ; Perkins, Bruce A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c228t-e514cd1681bb0926b320a1f6327a060917fdfed2299eb4684c8646ebe8161c1d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>3-Hydroxybutyric Acid</topic><topic>Blood Glucose - analysis</topic><topic>Diabetes Mellitus, Type 1 - drug therapy</topic><topic>Female</topic><topic>Glucose</topic><topic>Humans</topic><topic>Hyperglycemia - drug therapy</topic><topic>Ketones - therapeutic use</topic><topic>Male</topic><topic>Sodium</topic><topic>Symporters</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Scarr, Daniel</creatorcontrib><creatorcontrib>Lovblom, Erik</creatorcontrib><creatorcontrib>Ye, Hongping</creatorcontrib><creatorcontrib>Liu, Hongyan</creatorcontrib><creatorcontrib>Bakhsh, Abdulmohsen</creatorcontrib><creatorcontrib>Verhoeff, Natasha J.</creatorcontrib><creatorcontrib>Wolever, Thomas M.S.</creatorcontrib><creatorcontrib>Lawler, Patrick R.</creatorcontrib><creatorcontrib>Sharma, Kumar</creatorcontrib><creatorcontrib>Cherney, David Z.I.</creatorcontrib><creatorcontrib>Perkins, Bruce A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes research and clinical practice</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Scarr, Daniel</au><au>Lovblom, Erik</au><au>Ye, Hongping</au><au>Liu, Hongyan</au><au>Bakhsh, Abdulmohsen</au><au>Verhoeff, Natasha J.</au><au>Wolever, Thomas M.S.</au><au>Lawler, Patrick R.</au><au>Sharma, Kumar</au><au>Cherney, David Z.I.</au><au>Perkins, Bruce A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes</atitle><jtitle>Diabetes research and clinical practice</jtitle><addtitle>Diabetes Res Clin Pract</addtitle><date>2024-01</date><risdate>2024</risdate><volume>207</volume><spage>111031</spage><epage>111031</epage><pages>111031-111031</pages><artnum>111031</artnum><issn>0168-8227</issn><eissn>1872-8227</eissn><abstract>•We found that fasting glucose even in the upper range of target is associated with excess ketone production. This excess production is compensated by higher urinary ketone excretion.Sodium Glucose Linked Transporter inhibition (SGLTi) dampens this compensatory mechanism, especially in women. Findings provide evidence to explain ketone elevations with SGLTi use and sex-specific differences in DKA risk.
We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex.
In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4–6 mmol/L) and mild hyperglycemia (9–11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis.
Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5–13.6] vs. 3.5[2.2–7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3–1.6] vs. 0.4 % [0.2–0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05–0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001).
Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>38036220</pmid><doi>10.1016/j.diabres.2023.111031</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-6774-8924</orcidid><orcidid>https://orcid.org/0000-0002-5885-0046</orcidid></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 3-Hydroxybutyric Acid Blood Glucose - analysis Diabetes Mellitus, Type 1 - drug therapy Female Glucose Humans Hyperglycemia - drug therapy Ketones - therapeutic use Male Sodium Symporters |
| title | Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes |
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