Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function

the GRADE Research Group

doi:10.1111/dom.15072

Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function

the GRADE Research Group

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Aim: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

Original language	English (US)
Pages (from-to)	1995-2004
Number of pages	10
Journal	Diabetes, Obesity and Metabolism
Volume	25
Issue number	7
DOIs	https://doi.org/10.1111/dom.15072
State	Published - Jul 2023

Bibliographical note

Funding Information:
The GRADE study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under Award Number U01 DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34 DK088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The United States Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541 and UL1 TR002548. Educational materials were provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies was provided by Becton, Dickinson and Company, Bristol‐Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States Department of Veterans Affairs. The study sponsors/funders were not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of this report.

Publisher Copyright:
© 2023 John Wiley & Sons Ltd.

Keywords

HOMA
immunoassay
insulin analogues
insulin sensitivity
oral glucose tolerance test
type 2 diabetes
β-cell function

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/dom.15072

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Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function. / the GRADE Research Group.
In: Diabetes, Obesity and Metabolism, Vol. 25, No. 7, 07.2023, p. 1995-2004.

Research output: Contribution to journal › Article › peer-review

@article{9e3c8bf09b1f4e729fa2300d4900ba6a,

title = "Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function",

abstract = "Aim: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.",

keywords = "HOMA, immunoassay, insulin analogues, insulin sensitivity, oral glucose tolerance test, type 2 diabetes, β-cell function",

author = "{the GRADE Research Group} and Seegmiller, {Jesse C.} and Schmit, {David J.} and Arends, {Valerie L.} and Steffes, {Michael W.} and Kahn, {Steven E.} and Naji Younes",

note = "Funding Information: The GRADE study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under Award Number U01 DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34 DK088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The United States Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541 and UL1 TR002548. Educational materials were provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies was provided by Becton, Dickinson and Company, Bristol‐Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States Department of Veterans Affairs. The study sponsors/funders were not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of this report. Publisher Copyright: {\textcopyright} 2023 John Wiley & Sons Ltd.",

year = "2023",

month = jul,

doi = "10.1111/dom.15072",

language = "English (US)",

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pages = "1995--2004",

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T1 - Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes

T2 - Implications for estimating insulin sensitivity and β-cell function

AU - the GRADE Research Group

AU - Seegmiller, Jesse C.

AU - Schmit, David J.

AU - Arends, Valerie L.

AU - Steffes, Michael W.

AU - Kahn, Steven E.

AU - Younes, Naji

N1 - Funding Information: The GRADE study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under Award Number U01 DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34 DK088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The United States Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541 and UL1 TR002548. Educational materials were provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies was provided by Becton, Dickinson and Company, Bristol‐Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States Department of Veterans Affairs. The study sponsors/funders were not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of this report. Publisher Copyright: © 2023 John Wiley & Sons Ltd.

PY - 2023/7

Y1 - 2023/7

N2 - Aim: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

AB - Aim: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

KW - HOMA

KW - immunoassay

KW - insulin analogues

KW - insulin sensitivity

KW - oral glucose tolerance test

KW - type 2 diabetes

KW - β-cell function

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SN - 1462-8902

VL - 25

SP - 1995

EP - 2004

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

IS - 7

ER -

Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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