Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age‐related insulin resistance

Mohamad, Mashani; Mitchell, Sarah J.; Wu, Lindsay E.; White, Melanie Y.; Cordwell, Stuart J.; Mach, John; Solon-Biet, Samantha M.; Boyer, Dawn; Nines, Dawn; Das, Abhirup; Li, Shi Yun Catherine; Warren, Alessandra; Hilmer, Sarah N.; Fraser, Robin; Sinclair, David; Simpson, Stephen J.; Cabo, Rafael de; Couteur, David G. Le; Cogger, Victoria C.

doi:10.1111/acel.12481

Cited by 60 publications

(51 citation statements)

References 49 publications

(65 reference statements)

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“…Whereas increased adiposity was the main driver of reduced insulin turnover in aging Mexican Americans, diminished insulin clearance in aged C57BL/6J mice was independent of body composition. This observation is consistent with the recent demonstration of age-related loss of hepatic endothelial fenestrations and diminished insulin uptake associated with reduced insulin clearance in aged mice and rats (42). Our results also raise the question of whether age-related changes in insulin clearance are the consequence of insulin resistance or other aspects of aging.…”

Section: Discussionsupporting

confidence: 93%

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

Ehrhardt

Cui

Dagdeviren

et al. 2019

Obesity

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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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Section: Discussionsupporting

confidence: 93%

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

Ehrhardt

Cui

Dagdeviren

et al. 2019

Obesity

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show abstract

“…This observation is consistent with the recent demonstration of age-related loss of hepatic endothelial fenestrations and diminished insulin uptake associated with reduced insulin clearance in mice and rats [46]. Our results also raise the question of whether age-related changes in insulin clearance are the consequence of aging per se or secondary to insulin resistance.…”

Section: Discussionsupporting

confidence: 93%

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

Ehrhardt

Cui

Dagdeviren

et al. 2018

Preprint

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word count: 263 Main text word count: 3,613 ABSTRACT Aims/hypothesis: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition. Methods: Cohorts of C57BL/6J male mice at 4-8 months of age ('young') and 18-27 mo ('aged') exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps. Results:In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucosestimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets.Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI. Conclusions/interpretation:This study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesityassociated insulin resistance are distinct.

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“…Whereas age-related hyperinsulinaemia, insulin resistance and visceral obesity [41–43] are commonly associated with reduced glucose uptake in skeletal muscle in parallel with a reduction in metabolically active lean mass [33], decreased fenestration in the liver sinusoidal endothelium and other structural changes that reduce insulin uptake by hepatocytes, and hence reduce insulin clearance, have recently emerged as mechanisms underlying age-related hyperinsulinaemia and insulin resistance [44]. The current study provides an alternative mechanism of hyperinsulinaemia in older Cc2 −/− male mutant mice, implicating a progressive reduction in hepatic CEACAM1-mediated insulin clearance that fails to counter persistent GLP-1-mediated release of insulin in older mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene

et al. 2017

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Aims/hypothesis Cc2−/− mice lacking the gene of the carcinoembryonic-antigen-related cell adhesion molecule 2 [Cc2 (also known as Ceacam2)] exhibit hyperphagia that leads to obesity and insulin resistance. This starts at 2 months of age in female mice. Male mutants maintain normal body weight and insulin sensitivity until the last age previously examined (7–8 months), owing to increased sympathetic tone to white adipose tissue and energy expenditure. The current study investigates whether insulin resistance develops in mutant male mice at a later age and whether this is accompanied by changes in insulin homeostasis. Methods Insulin response was assessed by insulin and glucose tolerance tests. Energy balance was analysed by indirect calorimetry. Results Male Cc2−/− mice developed overt metabolic abnormalities at about 9 months of age. These include elevated global fat mass, hyperinsulinaemia and insulin resistance (as determined by glucose and insulin intolerance, fed hyperglycaemia and decreased insulin signalling pathways). Pair-feeding experiments showed that insulin resistance resulted from hyperphagia. Indirect calorimetry demonstrated that older mutant male mice had compromised energy expenditure. Despite increased insulin secretion caused by Cc2 deletion, chronic hyperinsulinaemia did not develop in mutant male mice until about 9 months of age, at which point insulin clearance began to decline substantially. This was probably mediated by a marked decrease in hepatic CEACAM1 expression. Conclusions/interpretation The data demonstrate that at about 9 months of age, Cc2−/− male mice develop a reduction in energy expenditure and energy imbalance which, combined with a progressive decrease in CEACAM1-dependent hepatic insulin clearance, causes chronic hyperinsulinaemia and sustained age-dependent insulin resistance. This represents a novel mechanistic underpinning of age-related impairment of hepatic insulin clearance.

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Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age‐related insulin resistance

Cited by 60 publications

References 49 publications

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

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

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

Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene

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