Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women
Open accessAbstract
African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20–25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.
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African Americans compared to European Americans have higher AIRg.
“Additionally, AA compared to EA as a group, have higher AIRg [23], which has been attributed to both greater beta-cell responsivity and lower hepatic insulin extraction [24].”
From Defining and Characterizing Postprandial Reactive Hypoglycemia (2026) · cites this paper as [24]
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“postchallenge glucose (5, 10), basal hepatic glucose production (11), and insulin clearance compared with Caucasian Americans (10, 12, 13).”
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Smidt, M. F. F.-D., Mendham, A., Hauksson, J., Hakim, O., Stefanovski, D., Clamp, L., Phiri, L., Swart, J., Goff, L., Micklesfield, L., et al. (2020) · European Journal of Endocrinology · doi:10.1530/eje-19-0957 · Cited by 22 · see citing works
Hakim, O., Bello, O., Bonadonna, R., Mohandas, C., Shojaee-Moradie, F., Jackson, N., Boselli, L., Whitcher, B., Shuaib, H., Alberti, K., et al. (2019) · Diabetes, obesity and metabolism · doi:10.1111/dom.13771 · Cited by 22 · see citing works
“Consistently, insulin clearance has been shown to be lower in black populations compared with white populations.(4) However, investigations of ethnic differences in hepatic insulin sensitivity have shown inconsistent findings.”
BackgroundLi, L., & Li, D.-S. (2021) · Frontiers in Sustainability · doi:10.3389/frsus.2021.648138 · Cited by 21
NOVEL ASPECTS OF THE ROLE OF THE LIVER IN CARBOHYDRATE METABOLISM
Bergman, R., Piccinini, F., Kabir, M., & Ader, M. (2019) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2019.05.011 · Cited by 20
“Dr. Gower had performed FSIGT protocols in 47 adult volunteers: 29 of European heritage (European American, EA) and 18 adults of African descent (African American, AA) (29).”
MethodSelf-citationHakim, O., Bonadonna, R. C., Mohandas, C., Billoo, Z., Sunderland, A., Boselli, L., Alberti, K. G. M. M., Peacock, J. L., Umpleby, A. M., Charles‐Edwards, G., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01809 · Cited by 23 · see citing works
“Furthermore, these studies have assessed only the first phase in sulin secretory response, and only indirect assessments of insulin secretion have been performe d, which have limited utility in Black populations as they do not account for hepatic insu li clearance, for which ethnic differences are well established (18…”
BackgroundLower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans
Shah, M. H., Piaggi, P., Looker, H., Paddock, E., Krakoff, J., & Chang, D. (2021) · Diabetologia · doi:10.1007/s00125-020-05348-5 · Cited by 19 · see citing works
Regulation of Insulin Clearance by Non-Esterified Fatty Acids
Najjar, S. M., Abdolahipour, R., Ghadieh, H. E., Jahromi, M. S., Najjar, J. A., Abuamreh, B. A. M., Zaidi, S., Kumarasamy, S., & Muturi, H. T. (2022) · Biomedicines · doi:10.3390/biomedicines10081899 · Cited by 22 · see citing works
“Reduction in insulin clearance has emerged as a major risk factor in metabolic syndrome, including NAFLD, in Hispanics (particularly of Mexican descent [19]), African-Americans [20], African-Caribbeans [21], and Native Americans [22].”
BackgroundRasouli, N., Younes, N., Utzschneider, K. M., Inzucchi, S. E., Balasubramanyam, A., Cherrington, A., Ismail‐Beigi, F., Cohen, R. M., Olson, D. E., DeFronzo, R. A., et al. (2020) · Diabetes Care · doi:10.2337/dc20-1787 · Cited by 20 · see citing works
“first pass and not the extrahepatic componentof insulin clearance (31).”
BackgroundA Systematic Review of Beta Cell Function in Adults of Black African Ethnicity
Ladwa, M., Hakim, O., Amiel, S. A., & Goff, L. M. (2019) · Journal of Diabetes Research · doi:10.1155/2019/7891359 · Cited by 19 · see citing works
“Studies also employed the nonmodified IVGTT (n = 6) [33, 46, 59–62], the tolbutamide-modified IVGTT (n = 4) [43, 44, 51, 63], the hyperglycaemic clamp (n = 4) [30, 47, 64, 65], and the arginine-stimulated response (n = 2) [47, 60].”
BackgroundMethodInfluentialInsulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes
Ladwa, M., Bello, O., Hakim, O., Shojaee‐Moradie, F., Boselli, L., Charles‐Edwards, G., Stadler, M., Peacock, J. L., Umpleby, A. M., Amiel, S. A., et al. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14101 · Cited by 16 · see citing works
Increased β-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults
Armiyaw, L., Sarcone, C., Fosam, A. E., & Muniyappa, R. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa234 · Cited by 19 · see citing works
Sharma, A., Lee-Ødegård, S., Qvigstad, E., Sommer, C., Sattar, N. A., Gill, J. M. R., Gulseth, H. L., Sollid, S. T., Nermoen, I., & Birkeland, K. I. (2022) · Diabetes · doi:10.2337/db22-0622 · Cited by 18 · see citing works
“There are reports, however, suggesting a role of excess insulin in driving insulin resistance, and that suppression of high plasma insulin levels enhances insulin sensitivity (9, 12, 39, 40).”
BackgroundResultAsare-Bediako, I., Paszkiewicz, R. L., Kim, S. P., Woolcott, O., Kolka, C., Burch, M., Kabir, M., Piccinini, F., & Bergman, R. (2018) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00344.2017 · Cited by 11 · see citing works
Self-citationLadwa, M., Bello, O., Hakim, O., Boselli, M., Shojaee-Moradie, F., Umpleby, A., Peacock, J., Amiel, S., Bonadonna, R., & Goff, L. (2021) · Acta Diabetologica · doi:10.1007/s00592-021-01809-4 · Cited by 9 · see citing works
Goff, L. M., Ladwa, M., Hakim, O., & Bello, O. (2019) · Proceedings of The Nutrition Society · doi:10.1017/s0029665119001034 · Cited by 39 · see citing works
Thompson, D., Francis-Emmanuel, P., Barnett, A. T., Osmond, C., Hanson, M. W., Byrne, C., Gluckman, P., Forrester, T., & Boyne, M. (2022) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174422000034 · Cited by 7 · see citing works
Sato, M., Tamura, Y., Kaga, H., Yamasaki, N., Kiya, M., Kadowaki, S., Sugimoto, D., Funayama, T., Someya, Y., Kakehi, S., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9091154 · Cited by 8 · see citing works
“Metabolic clearance of insulin has been shown to differ by ethnicity and sex [58,59].”
BackgroundHyperinsulinaemia as a cause of obesity and cardiometabolic diseases
Guess, N. D., Johnson, J. D., Vaag, A. A., Tahrani, A. A., Corkey, B. E., Bruin, J. E., & Little, J. P. (2026) · Nature Reviews Endocrinology · doi:10.1038/s41574-026-01240-1 · Cited by 7 · see citing works
“In addition, there seem to be differences in insulin clearance rates between people of different ethnicity, which suggests that reduced insulin clearance might be an acquired trait 94 .”
Fowler, L. A., Fernández, J. R., O'Neil, P. M., Parcha, V., Arora, P., Shetty, N., Cardel, M. I., Foster, G. D., & Gower, B. A. (2024) · Archives of Medical Research · doi:10.1016/j.arcmed.2024.103128 · Cited by 4 · see citing works
Self-citationEngel, A. J., Samuel, K., Bass, I., Lin, S., Antoniou, I., Yagnik, R., Port, E., Feldman, S., Friedman, N. B., Boolbol, S., et al. (2026) · Journal of the Endocrine Society · doi:10.1210/jendso/bvag041 · Cited by 3 · see citing works
“This is consistent with previous research showing reduced hepatic but not extrahepatic insulin clearance in African American compared with European American women, contributing to systemic hyperinsulinemia [30].”
Koh, H. E., Patterson, B. W., Reeds, D. N., & Mittendorfer, B. (2022) · Obesity · doi:10.1002/oby.23363 · Cited by 8 · see citing works
Smidt, M. F. F.-D., Mendham, A., Hauksson, J., Alhamud, A., Stefanovski, D., Hakim, O., Swart, J., Goff, L., Kahn, S., Olsson, T., et al. (2021) · Endocrine Connections · doi:10.1530/ec-21-0153 · Cited by 3 · see citing works
Abe, T., Matsubayashi, Y., Muragishi, S., Yoshida, A., Suganami, H., Furusawa, K., Fujihara, K., Tanaka, S., Kaku, K., & Sone, H. (2021) · Journal of Diabetes Investigation · doi:10.1111/jdi.13543 · Cited by 3 · see citing works
Bergman, R. N., Piccinini, F., Bediako, I. A., Kabir, M., Kolka, C. M., Polidori, D., & Ader, M. (2018) · Journal of Diabetes · doi:10.1111/1753-0407.12794 · Cited by 3 · see citing works
“Using this model to analyze data from the laboratory of Barbara Gower and colleagues, we were able to show that insulin degradation by the liver is significantly reduced in African American subjects compared with European American individuals.(28) We have also shown recently that this ethnic difference applies to chil…”
MethodSelf-citationDefining and Characterizing Postprandial Reactive Hypoglycemia
Sweatt, S. K., Thomas, D. M., LaPorte, G. J., Chauff, S., Stefanovski, D., & Gower, B. A. (2026) · Nutrients · doi:10.3390/nu18050822 · Cited by 2 · see citing works
Self-citationCuthbertson, D. J., Whyte, M., Henney, A. E., Alam, U., Goff, L. M., Fielding, B. A., & Umpleby, A. M. (2026) · Obesity Reviews · doi:10.1111/obr.70104 · Cited by 1 · see citing works
“…insulin returning to the liver for degradation and eventually being terminally degraded in the renal proximal tubular cells. first-pass hepatic insulin extraction was demonstrated to be approximately two-thirds lower in African Caribbean volunteers compared with their European counterparts [34].”
Rebello, C. J., Morales, T. S., Chuon, K., Dong, S., Lam, V., Purner, D., Lewis, S. T., Lakey, J. R. T., Beyl, R. A., & Greenway, F. L. (2023) · Obesity Reviews · doi:10.1111/obr.13625 · Cited by 3 · see citing works
“81 The low metabolic clearance rate may explain why Blacks have lower fasting c-peptide but higher fasting insulin concentrations than Whites, which is consistent with reduced insulin clearance.”
BackgroundViskochil, R., Lyden, K., Staudenmayer, J., Keadle, S., Freedson, P., & Braun, B. (2019) · Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme · doi:10.1139/apnm-2018-0802 · Cited by 2 · see citing works
“These increases in insulin have been attributed to greater insulin secretion, however recent evidence suggests that insulin clearance and hepatic insulin extraction (HIE) also contribute to the regulation of peripheral insulin concentrations (Lee et al. 2013; Piccinini et al. 2017).”
BackgroundFasting C-peptide Values Among Adolescents in the National Health and Nutrition Examination Surveys
Soni, P. Y., Wang, Y., Eckert, G., & Ismail, H. (2021) · Diabetes, obesity and metabolism · doi:10.1111/dom.14611 · Cited by 1 · see citing works
Bergman, R., & Piccinini, F. (2020) · Diabetes Care · doi:10.2337/dci20-0080 · Cited by 1
“In the IVGTT studies performed in African American adults by Gower and colleagues (5) and in children by Fernandez and colleagues (6), we concluded that hepatic (but not extrahepatic) insulin clearance is lower in African American adults and children than in European American adults and children.”
BackgroundSelf-citationBleich, D. (2020) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgaa136 · Cited by 1
Lu, B., Li, P., Crouse, A. B., Grimes, T., Smith, A. N., Might, M., Ovalle, F., & Shalev, A. (2026) · Metabolites · doi:10.3390/metabo16030204
“Self-reported sex and race were included as fixed effects, as both have previously been reported to contribute to differences in insulin clearance rates [14,15].”
β-cell function in black South African women: Associations with insulin clearance and ectopic fatPreprint
Smidt, M. F., Mendham, A., Hauksson, J., Alhamud, A., Stefanovski, D., Hakim, O., Swart, J., Goff, L., Kahn, S., Olsson, T., et al. (2020) · doi:10.21203/rs.3.rs-35455/v1
“This model was used in two studies that included African American adults [6,8], but the association of CLp with β-cell function measures was not assessed and needs further clari cation.”
BackgroundMethodResultInfluential
- Authors
- Piccinini, F., Polidori, D. C., Gower, B. A., & Bergman, R. N.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Janssen Research & Development, San Diego, CA
- University of Alabama at Birmingham (US)
- Corresponding author
- Bergman, Richard N.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-07-14
- Volume
- 66
- Issue
- 10
- Pages
- 2564-2570
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5606316
- OpenAlex
- W2734827144
- Cited by
- 73
- References
- 36
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 12 · 2020: 17 · 2019: 10 · 2018: 12
- FWCI
- 10.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-58278, P30-DK-079626, P30-DK-56336, UL1-RR-02577)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hepatic insulin clearance, insulin degradation, African American women, European American women, ethnic differences, insulin resistance, type 2 diabetes risk, first-pass extraction, C-peptide, frequently sampled intravenous glucose tolerance test, mathematical modeling
- MeSH terms
- Adult, Black or African American, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Humans, Insulin, Liver, Models, Theoretical, White People, Young Adult
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