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

Mohamad M, Mitchell SJ, Wu LE, White MY, Cordwell SJ, Mach J, Solon-Biet SM, Boyer D, Nines D, Das A, Catherine Li SY, Warren A, Hilmer SN, Fraser R, Sinclair DA, Simpson SJ, de Cabo R, Le Couteur DG, Cogger VC - Aging Cell (2016)

Bottom Line: While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown.To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling.Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.

No MeSH data available.


Related in: MedlinePlus

(a) Acute defenestration of the LSEC was induced by P407 within 24 h of injection as measured from scanning electron micrographs (n = 10 control and 11 P407‐treated rats, P < 0.05). (b) Sample scanning electron micrographs of the LSEC to illustrate more pronounced examples of defenestration in control and P407‐treated rats (original micrographs 15 000× magnification, fenestrations are indicated by an *). (c) There was a 20% reduction in the fractional volume of distribution of insulin with P407‐induced defenestration (n = 12 control and 8 P407‐treated rats, P = 0.01). (d) MID outflow curves for insulin and the extracellular marker, sucrose. As seen with the age‐related defenestration, insulin exits the liver prior to sucrose in the P407‐treated rats, indicating a restricted access to the entire extracellular space. (e) 14C‐insulin uptake by the liver was found to be significantly reduced with defenestration, but was found to be unchanged in the muscle and the fat (n = 6 control and 6 P407‐treated rats P = 0.04). (f) Fasting and fed insulin levels were found to be significantly elevated following the P407‐induced defenestration (n = 6 control and 6 P407‐treated rats, fasting P < 0.05, fed P = 0.005). (g) C‐peptide levels were found to be significantly decreased with P407‐induced defenestration in the fed state (n = 5 control and 5 P407‐ rats, P = 0.03). (h) Glucagon levels were found to be suppressed in the fasting and fed states in P407‐treated rats (n = 4 control and 4 P407‐treated rats, fasting P = 0.02; fed P = 0.016).
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acel12481-fig-0004: (a) Acute defenestration of the LSEC was induced by P407 within 24 h of injection as measured from scanning electron micrographs (n = 10 control and 11 P407‐treated rats, P < 0.05). (b) Sample scanning electron micrographs of the LSEC to illustrate more pronounced examples of defenestration in control and P407‐treated rats (original micrographs 15 000× magnification, fenestrations are indicated by an *). (c) There was a 20% reduction in the fractional volume of distribution of insulin with P407‐induced defenestration (n = 12 control and 8 P407‐treated rats, P = 0.01). (d) MID outflow curves for insulin and the extracellular marker, sucrose. As seen with the age‐related defenestration, insulin exits the liver prior to sucrose in the P407‐treated rats, indicating a restricted access to the entire extracellular space. (e) 14C‐insulin uptake by the liver was found to be significantly reduced with defenestration, but was found to be unchanged in the muscle and the fat (n = 6 control and 6 P407‐treated rats P = 0.04). (f) Fasting and fed insulin levels were found to be significantly elevated following the P407‐induced defenestration (n = 6 control and 6 P407‐treated rats, fasting P < 0.05, fed P = 0.005). (g) C‐peptide levels were found to be significantly decreased with P407‐induced defenestration in the fed state (n = 5 control and 5 P407‐ rats, P = 0.03). (h) Glucagon levels were found to be suppressed in the fasting and fed states in P407‐treated rats (n = 4 control and 4 P407‐treated rats, fasting P = 0.02; fed P = 0.016).

Mentions: Because aging is a multifactorial process where many fundamental cellular processes are affected, we further investigated the role of the LSEC in hepatic insulin handling using an acute model of defenestration generated by P407. Hematoxylin and eosin staining of the liver sections from the control and P407 rats confirmed that they were free of diseases (Supplementary information). P407‐induced defenestration was confirmed with scanning electron microscopy, and the significant reduction in LSEC porosity of about 30% was similar to that seen with aging (Fig. 4a–b). We also confirmed that P407 was associated with the increased blood levels of cholesterol and triglycerides (Supplementary information), which is a well‐recognized effect of this agent (Johnston, 2004; Cogger et al., 2006).


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

Mohamad M, Mitchell SJ, Wu LE, White MY, Cordwell SJ, Mach J, Solon-Biet SM, Boyer D, Nines D, Das A, Catherine Li SY, Warren A, Hilmer SN, Fraser R, Sinclair DA, Simpson SJ, de Cabo R, Le Couteur DG, Cogger VC - Aging Cell (2016)

(a) Acute defenestration of the LSEC was induced by P407 within 24 h of injection as measured from scanning electron micrographs (n = 10 control and 11 P407‐treated rats, P < 0.05). (b) Sample scanning electron micrographs of the LSEC to illustrate more pronounced examples of defenestration in control and P407‐treated rats (original micrographs 15 000× magnification, fenestrations are indicated by an *). (c) There was a 20% reduction in the fractional volume of distribution of insulin with P407‐induced defenestration (n = 12 control and 8 P407‐treated rats, P = 0.01). (d) MID outflow curves for insulin and the extracellular marker, sucrose. As seen with the age‐related defenestration, insulin exits the liver prior to sucrose in the P407‐treated rats, indicating a restricted access to the entire extracellular space. (e) 14C‐insulin uptake by the liver was found to be significantly reduced with defenestration, but was found to be unchanged in the muscle and the fat (n = 6 control and 6 P407‐treated rats P = 0.04). (f) Fasting and fed insulin levels were found to be significantly elevated following the P407‐induced defenestration (n = 6 control and 6 P407‐treated rats, fasting P < 0.05, fed P = 0.005). (g) C‐peptide levels were found to be significantly decreased with P407‐induced defenestration in the fed state (n = 5 control and 5 P407‐ rats, P = 0.03). (h) Glucagon levels were found to be suppressed in the fasting and fed states in P407‐treated rats (n = 4 control and 4 P407‐treated rats, fasting P = 0.02; fed P = 0.016).
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acel12481-fig-0004: (a) Acute defenestration of the LSEC was induced by P407 within 24 h of injection as measured from scanning electron micrographs (n = 10 control and 11 P407‐treated rats, P < 0.05). (b) Sample scanning electron micrographs of the LSEC to illustrate more pronounced examples of defenestration in control and P407‐treated rats (original micrographs 15 000× magnification, fenestrations are indicated by an *). (c) There was a 20% reduction in the fractional volume of distribution of insulin with P407‐induced defenestration (n = 12 control and 8 P407‐treated rats, P = 0.01). (d) MID outflow curves for insulin and the extracellular marker, sucrose. As seen with the age‐related defenestration, insulin exits the liver prior to sucrose in the P407‐treated rats, indicating a restricted access to the entire extracellular space. (e) 14C‐insulin uptake by the liver was found to be significantly reduced with defenestration, but was found to be unchanged in the muscle and the fat (n = 6 control and 6 P407‐treated rats P = 0.04). (f) Fasting and fed insulin levels were found to be significantly elevated following the P407‐induced defenestration (n = 6 control and 6 P407‐treated rats, fasting P < 0.05, fed P = 0.005). (g) C‐peptide levels were found to be significantly decreased with P407‐induced defenestration in the fed state (n = 5 control and 5 P407‐ rats, P = 0.03). (h) Glucagon levels were found to be suppressed in the fasting and fed states in P407‐treated rats (n = 4 control and 4 P407‐treated rats, fasting P = 0.02; fed P = 0.016).
Mentions: Because aging is a multifactorial process where many fundamental cellular processes are affected, we further investigated the role of the LSEC in hepatic insulin handling using an acute model of defenestration generated by P407. Hematoxylin and eosin staining of the liver sections from the control and P407 rats confirmed that they were free of diseases (Supplementary information). P407‐induced defenestration was confirmed with scanning electron microscopy, and the significant reduction in LSEC porosity of about 30% was similar to that seen with aging (Fig. 4a–b). We also confirmed that P407 was associated with the increased blood levels of cholesterol and triglycerides (Supplementary information), which is a well‐recognized effect of this agent (Johnston, 2004; Cogger et al., 2006).

Bottom Line: While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown.To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling.Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.

No MeSH data available.


Related in: MedlinePlus