Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation

Abstract

Increased total fat mass (FM) and visceral fat (VF) may account in part for age-associated decrease in hepatic insulin action. This study determined whether preventing the changes in body fat distribution abolished this defect throughout aging. We studied the F(1) hybrid of Brown Norway-Fischer 344 rats (n = 29), which we assigned to caloric restriction (CR) or fed ad libitum (AL). CR (55% of the calories consumed by AL) was initiated and used at 2 mo to prevent age-dependent increases in FM and VF. AL rats were studied at 2, 8, and 20 mo; CR rats were studied at 8 and 20 mo. VF and FM remained unchanged throughout aging in CR rats. AL-fed rats at 8 and 20 mo had over fourfold higher FM and VF compared with both CR groups. Insulin clamp studies (3 mU. kg(-1). min(-1) with somatostatin) were performed to assess hepatic insulin sensitivity. Prevention of fat accretion resulted in a marked improvement in insulin action in the suppression of hepatic glucose production (HGP) (6.3 +/- 0.3 and 7.2 +/- 1.2 mg. kg(-1). min(-1) in 8- and 20-mo CR rats vs. 8.3 +/- 0.5 and 10.8 +/- 0.9 mg. kg(-1). min(-1) in 8- and 20-mo AL rats, respectively). The rate of gluconeogenesis (by enrichment of hepatic uridine diphosphate glucose and phosphoenolpyruvate pools by [(14)C]lactate) was unchanged in all groups. The improvement in hepatic insulin action in the CR group was mostly due to effective suppression of glycogenolysis (4.4 +/- 0.3 and 4.9 +/- 0.3 mg. kg(-1). min(-1) in 8- and 20-mo CR rats vs. 5.8 +/- 0.6 and 8.2 +/- 1.0 mg. kg(-1). min(-1) in 8- and 20-mo AL rats, respectively). The results demonstrated the preservation of hepatic insulin action in aging CR rats. Therefore, body fat and its distribution are major determinants of age-associated hepatic insulin resistance.

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

“…Aged F344/BN rats are associated with insulin resistance and glucose intolerance, as shown in several previous reports [15,18,44]. In the present study, we also observed impaired glucose tolerance, as indicated by the elevated blood glucose levels after glucose loading in the aged obese F344/BN rats.…”

Acute effects of 17β-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats

“…We have found significant increases in this parameter in both young and aged animals, although it was more evident in aged animals; therefore, aging impairs insulin clearance (Table 1). Taking these results together, in agreement with other authors (Barzilai and Rossetti 1996), hepatic insulin resistance is suggested because it causes a decrease in the ability of insulin to modulate glycogen stores during aging (Gupta et al 2000). In this case, estradiol (AE) and high dose of genistein (AG2) also appeared to improve the insulin clearance Groups C and G2 of young rats spent significantly more time searching in the target quadrant (black bars).…”

“…At the present time, we do not have a plausible explanation for these results. Likewise, it has been previously demonstrated that the increase in fasting serum insulin is due to impaired suppression of hepatic glucose production, which requires significant portal hyperinsulinemia (Gupta et al 2000).…”

Age is an Important Risk Factor for Type 2 Diabetes Mellitus and Cardiovascular Diseases

“…Aging process is also associated with reduced compensatory beta cell mass function of the pancreas and to insulin resistance (Maneilly and Elliott, 1999) as well as with decreased mitochondrial function that contributes to insulin resistance (Petersen et al, 2003). A study by Gupta et al (2000) showed that hepatic insulin resistant was related to body fat and its distribution, and hepatic insulin action could be preserved by caloric restriction in aging caloric restriction rat.…”