Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Mice and Humans

Overview

Journal Obesity (Silver Spring)

Specialties Endocrinology
Nutritional Sciences
Physiology

Date 2019 Feb 26

PMID 30801985

Citations 22

Authors

Nicole Ehrhardt

Jinrui Cui

Sezin Dagdeviren

Suchaorn Saengnipanthkul

Helen S Goodridge

Jason K Kim

Louise Lantier

Xiuqing Guo

Yii-Der I Chen

Leslie J Raffel

Thomas A Buchanan

Willa A Hsueh

Jerome I Rotter

Mark O Goodarzi

Miklos Peterfy

Affiliations

Soon will be listed here.

Abstract

Objective: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.

Methods: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps.

Results: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.

Conclusions: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.

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References

Short K, Vittone J, Bigelow M, Proctor D, Rizza R, Coenen-Schimke J . Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes. 2003; 52(8):1888-96. DOI: 10.2337/diabetes.52.8.1888. View

Bergman R, Stefanovski D, Buchanan T, Sumner A, Reynolds J, Sebring N . A better index of body adiposity. Obesity (Silver Spring). 2011; 19(5):1083-9. PMC: 3275633. DOI: 10.1038/oby.2011.38. View

Bailey C, Flatt P . Hormonal control of glucose homeostasis during development and ageing in mice. Metabolism. 1982; 31(3):238-46. DOI: 10.1016/0026-0495(82)90059-2. View

Liljenquist J, Horwitz D, Jennings A, Chiasson J, Keller U, Rubenstein A . Inhibition of insulin secretion by exogenous insulin in normal man as demonstrated by C-peptide assay. Diabetes. 1978; 27(5):563-70. DOI: 10.2337/diab.27.5.563. View

Ropelle E, Pauli J, Cintra D, da Silva A, De Souza C, Guadagnini D . Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Diabetes. 2012; 62(2):466-70. PMC: 3554348. DOI: 10.2337/db12-0339. View

Edgerton D, Kraft G, Smith M, Farmer B, Williams P, Coate K . Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion. JCI Insight. 2017; 2(6):e91863. PMC: 5358484. DOI: 10.1172/jci.insight.91863. View

Halter J, Musi N, Horne F, Crandall J, Goldberg A, Harkless L . Diabetes and cardiovascular disease in older adults: current status and future directions. Diabetes. 2014; 63(8):2578-89. PMC: 4113072. DOI: 10.2337/db14-0020. View

Xiang A, Azen S, Raffel L, Tan S, Cheng L, Diaz J . Evidence for joint genetic control of insulin sensitivity and systolic blood pressure in hispanic families with a hypertensive proband. Circulation. 2001; 103(1):78-83. DOI: 10.1161/01.cir.103.1.78. View

Oya J, Nakagami T, Yamamoto Y, Fukushima S, Takeda M, Endo Y . Effects of age on insulin resistance and secretion in subjects without diabetes. Intern Med. 2014; 53(9):941-7. DOI: 10.2169/internalmedicine.53.1580. View

10.

Zeger S, Liang K . Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986; 42(1):121-30. View

11.

Goodarzi M, Taylor K, Guo X, Quinones M, Cui J, Li X . Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait. Diabetes. 2005; 54(4):1222-7. DOI: 10.2337/diabetes.54.4.1222. View

12.

Basu R, Breda E, Oberg A, Powell C, Dalla Man C, Basu A . Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance. Diabetes. 2003; 52(7):1738-48. DOI: 10.2337/diabetes.52.7.1738. View

13.

Leiter E, Premdas F, Harrison D, Lipson L . Aging and glucose homeostasis in C57BL/6J male mice. FASEB J. 1988; 2(12):2807-11. DOI: 10.1096/fasebj.2.12.3044905. View

14.

Karakelides H, Irving B, Short K, OBrien P, Nair K . Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes. 2009; 59(1):89-97. PMC: 2797949. DOI: 10.2337/db09-0591. View

15.

Fischer K, Hoffman J, Sloane L, Gelfond J, Soto V, Richardson A . A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY). 2016; 8(10):2370-2391. PMC: 5115894. DOI: 10.18632/aging.101059. View

16.

Basu R, Dalla Man C, Campioni M, Basu A, Klee G, Toffolo G . Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes. 2006; 55(7):2001-14. DOI: 10.2337/db05-1692. View

17.

Ainsworth B, Haskell W, Leon A, Jacobs Jr D, Montoye H, Sallis J . Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc. 1993; 25(1):71-80. DOI: 10.1249/00005768-199301000-00011. View

18.

Farmer T, Jenkins E, OBrien T, McCoy G, Havlik A, Nass E . Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp. Am J Physiol Endocrinol Metab. 2014; 308(3):E206-22. PMC: 4312835. DOI: 10.1152/ajpendo.00406.2014. View

19.

Chandler-Laney P, Phadke R, Granger W, Fernandez J, Munoz J, Dalla Man C . Age-related changes in insulin sensitivity and β-cell function among European-American and African-American women. Obesity (Silver Spring). 2010; 19(3):528-35. PMC: 3074467. DOI: 10.1038/oby.2010.212. View

20.

Lessard-Beaudoin M, Laroche M, Demers M, Grenier G, Graham R . Characterization of age-associated changes in peripheral organ and brain region weights in C57BL/6 mice. Exp Gerontol. 2015; 63:27-34. DOI: 10.1016/j.exger.2015.01.003. View