Department of Medicine, Divisions of 1 Geriatrics, 2 Endocrinology, and the Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York 10461
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ABSTRACT |
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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
F1 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 · kg1 · 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
[14C]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.
obesity; caloric restriction
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INTRODUCTION |
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AGING IS CONSIDERED an insulin-resistant state that is associated with obesity, dyslipidemia, hypertension, non-insulin-dependent diabetes mellitus, and coronary heart disease (25). It has previously been demonstrated that fasting plasma insulin levels are increased in both humans and rodents with aging. This is due to impaired suppression of hepatic glucose production (HGP) requiring significant portal hyperinsulinemia (12). The failure of adequate suppression of HGP is a hallmark of fasting hyperglycemia in type 2 diabetes mellitus. In humans, rates of glucose production are normal (8, 13), but the suppression of HGP by insulin (15, 17) is significantly impaired with aging.
Aging is also associated with increased body weight and fat mass (FM), a consequence of relatively high food intake and sedentary lifestyle. More importantly, visceral-abdominal fat (VF) is increased in aging men and women independently of body mass index (9, 14, 29); thus increased VF may be central to impaired suppression of HGP by insulin. Moreover, suppression of HGP by insulin is significantly impaired in younger subjects with increased abdominal obesity (23). Animal models have the advantage of investigating potential mechanisms by which aging and caloric restriction (CR) may affect carbohydrate homeostasis in the absence of other confounding genetic and/or metabolic conditions associated with the syndrome of insulin resistance. Studies in animal models have further supported the notion of the deleterious effect of increased VF on the modulation of hepatic insulin action.
We recently matched VF in young animals by chronic treatment with
3-adrenoreceptor agonist, leptin, or CR. There was a
uniform increase in hepatic insulin action regardless of the method
used (7). Moreover, surgical removal of selected intra-abdominal fat
depots (~10% of total FM) in young rats led to a marked increase in
hepatic insulin action (6). In another study, CR resulted in lower VF
in older rats compared with young rats. The rate of insulin infusion
needed to maintain normal HGP was related to VF and not to total FM
(2).
Although these studies suggest that body fat distribution had a major role in hepatic glucose metabolism, they do not address the question whether aging per se impairs it. Chronic CR was used to maintain FM and VF at youthful levels and to abolish the overwhelming negative effect of fat on hepatic insulin action. In a novel aging model, male F1 hybrid of Brown Norway-Fischer 344 rats (BN/F-344) obtained from the National Institute of Aging (NIA) were studied at 30 (8 mo) and 70% (20 mo) of their average lifespan. This allowed comparison between postdevelopmental and old ages. In this study, we examined whether aging per se impairs the ability of insulin to modulate HGP when CR maintains body composition at youthful levels.
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MATERIALS AND METHODS |
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Animals. Male F1 hybrid of BN/F-344 rats obtained from NIA were used in this study. The F1 hybrid of BN/F-344 produces progeny with the least detrimental pathology and at a later onset compared with other crosses studied (NIA communication). This model combines the advantages of the Sprague-Dawley model, which, like humans, gains a substantial amount of body weight and FM, and the previously popular thin Fischer 344 aging model, which lives longer. Twenty-nine rats were assigned to CR (n = 12) or were fed AL (n = 17). CR was initiated at 2 mo in the CR group, amounting to 55% of the calories consumed by the AL group. The chow contained 64% carbohydrates, 30% proteins, and 6% fats, a physiological fuel value of 3.30 Kcal/g chow. CR rats also received vitamin supplementation. A second group of control rats were fed AL and studied at young adulthood (2 mo; n = 5) and at 30 (8 mo; n = 6) and 70% (20 mo; n = 6) of their average lifespan (obtained by mortality curves provided by NIA). The CR rats were studied at 8 (n = 6) and 20 mo (n = 6). Rats were housed in individual cages and subjected to a standard 12:12-h light-dark (6 AM to 6 PM, 6 PM to 6 AM) cycle. One week before the in vivo study, the rats were anesthetized by inhalation of methoxyflurane, and indwelling catheters were inserted in the right internal jugular vein and in the left carotid artery. This method of anesthesia allowed fast recovery and normal food consumption in ~24 h. The venous catheter was extended to the level of the right atrium; the arterial catheter was advanced to the level of the aortic arch (2, 5, 27). Recovery was continued until body weight was within 3% of their preoperative weight. Studies were performed in awake, unstressed, chronically catheterized rats (2, 5, 27).
Body composition. Lean body mass (LBM) and FM were calculated from the whole body volume of distribution of water, estimated by tritiated water bolus injection in each experimental rat (2, 5). On the morning of the study, 20 µCi of 3H2O (New England Nuclear, Boston, MA) were injected intra-arterially. Steady state for 3H2O specific activity in rats was generally achieved within 30-45 min, and eight samples were collected between 1 and 1.5 h after injection. The distribution space of water was obtained by dividing the total radioactivity injected by the steady state specific activity of the plasma water, which was assumed to be 93% of the total plasma volume. LBM was determined from the whole body distribution space divided by 0.73 (% water content of LBM). FM was calculated as the difference between total body weight and LBM. Epididymal, mesenteric, and perinephric fat pads were resected and weighed at the end of each experiment. Plasma leptin levels were obtained at the start of the study.
Hyperinsulinemic euglycemic clamp.
At time 0, all rats received a primed continuous (15-40
µCi bolus, 0.4 µCi/min) infusion of HPLC-purified
[3-3H]glucose (New England Nuclear, Boston, MA)
throughout the study. Plasma samples from between minutes 60 and 120 were obtained to determine basal HGP.
At minute 120, a primed continuous infusion of insulin (3 mU · kg1 · min
1)
and a variable infusion of 25% glucose solution was started and was
periodically adjusted to clamp the plasma glucose concentration at the
basal level for the next 120 min of the clamp. Somatostatin (1.5 µg · kg
1 · min
1)
was infused to suppress endogenous insulin secretion. Ten minutes before the end of the in vivo studies,
[U-14C]lactate (20 µCi bolus, 1.0 µCi/min;
New England Nuclear) was administered to determine the contribution of
gluconeogenesis to the hepatic glucose 6-phosphate (G-6-P)
pool. At the end of the insulin infusion, rats were anesthetized
(pentobarbital sodium, 60 mg/kg body wt, iv). The abdomen was quickly
opened, and the liver was freeze-clamped in situ with aluminum tongs
precooled in liquid nitrogen (2, 5, 27). The time from the injection of
the anesthetic until freeze-clamping of the liver was <1 min. All
tissue samples were stored at
80°C for subsequent analysis.
Hepatic glucose fluxes.
The following parameters were obtained to measure hepatic glucose
fluxes during the insulin clamp studies. The direct contribution of
plasma glucose to the hepatic G-6-P pool was calculated from the ratio of specific activities of hepatic
[3H]UDPG (uridine diphosphate glucose) and
plasma glucose after [3-3H]glucose infusion.
This represents the percentage of the hepatic G-6-P pool that
is derived from plasma glucose. The indirect contribution of plasma
glucose to hepatic G-6-P was derived from the ratio of specific
activities of hepatic [14C]UDPG and
[14C]PEP (phosphoenolpyruvate) × 2 after [14C]lactate infusion. This represents
the percentage of the hepatic G-6-P pool that is derived from
PEP-gluconeogenesis. Total glucose output (TGO) is the sum of the HGP + glucose cycling ([3H]UDPG SA / plasma
[3-3H]glucose SA × TGO; SA, specific
activity). Therefore, TGO = HGP / (1 [3H]UDPG SA / plasma
[3-3H]glucose SA). Gluconeogenesis was
estimated from the specific activities of 14C-labeled
hepatic UDPG (assumed to reflect the specific activity of hepatic
G-6-P) and hepatic PEP after the infusion of
[U-14C]lactate and
[3-3H]glucose (2, 4, 7, 26). Therefore,
gluconeogenesis = TGO × [14C]UDPG
SA / [14C]PEP SA × 2. Glycogenolysis
was calculated as the difference between HGP and gluconeogenesis.
Assays and analytical procedures. G-6-P concentrations were measured spectrophotometrically, as previously described (2, 4, 26). Glucose 6-phosphatase (G-6-Pase) activity was performed. This was based on the hydrolysis of free inorganic phosphate (Pi) from G-6-P (26, 28), as previously described. The microsomal fraction was incubated with 10 mM of G-6-P to obtain maximal velocity. A standard curve was constructed with different concentrations of Pi. Each assay was repeated three times from different pieces of individual livers from each study group. Hepatic glycogen level was determined with amyloglucosidase after digestion, as previously described (2, 5). Plasma glucose was measured by the glucose oxidase method (Glucose Analyzer II, Beckman Instruments, Palo Alto, CA). Plasma insulin was measured by RIA using rat insulin standard for basal studies and human insulin standard for insulin clamp studies. Other kits were for plasma glucagon (RIA kit, Linco Research, St. Charles, MO), plasma glycerol (Sigma Diagnostics, St. Louis, MO), plasma leptin (Leptin RIA kit, Linco Research), and plasma concentration of FFA (Waco Pure Chemical Industries, Osaka, Japan). Plasma [3H]glucose radioactivity was measured in duplicates in the supernatants of Ba(OH)2 and ZnSO4 precipitates of plasma samples (20 µl) after evaporation to dryness to eliminate tritiated water. UDPG and PEP concentrations and specific activities in the liver were obtained through two sequential chromatographic separations, as previously reported (2, 4, 26).
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RESULTS |
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Body composition and biochemical characteristics.
FM increased with age more than fourfold between 2 and 8 mo and more
than sixfold between 2 and 20 mo in the AL group (P < 0.01 between all ages; Table 1). The total FM
was attenuated to about threefold less in the CR group compared with
the 8- and 20-mo AL groups. Even more significantly, the approximately
four- to sixfold increase in VF with age in the AL group was completely prevented in the CR group. VF in the CR group is similar to that in the
young control (2-mo AL) group. Moreover, the weight of the various fat
depots, such as epididymal, perinephric, and mesenteric, were identical
in the young control and CR groups.
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Glucose production.
The basal HGP was similar in all the groups (11.8 ± 0.5, 11.2 ± 0.9, and 12.3 ± 1.5 in 2-, 8-, and 20-mo AL rats and 11.2 ± 1.6 and
11.9 ± 0.8 mg · kg1 · min
1
in 8- and 20-mo CR rats, respectively; Fig.
1A). During the insulin clamp
studies, the steady-state plasma insulin levels were similarly increased to physiological postprandial levels in all groups (Table 3). Steady-state plasma glucose levels were
also similar in all groups. Hyperinsulinemia did not result in changes
in the plasma FFA levels between the 8- and 20-mo AL groups, whereas
plasma glycerol levels decreased by ~20%. However, FFA and glycerol
levels were similarly decreased by ~30% in the CR group. The plasma
glucagon levels during physiological hyperinsulinemia were increased in all groups compared with the young control, but there was no
significant difference between the AL and CR groups at 8 and 20 mo,
respectively (70 ± 5.0, 80.4 ± 5.6, and 76.9 ± 4.4 pg/ml in 2-, 8-, and 20-mo AL rats vs.85 ± 5.4 and 76.2 ± 7.6 pg/ml
in 8- and 20-mo CR rats, respectively).
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Hepatic glucose fluxes.
The direct contribution of plasma glucose to the hepatic G-6-P
pool was significantly increased by ~70% in the CR group. The indirect contribution of plasma glucose to hepatic G-6-P was
increased by >50% in the CR group. The TGO was similar between the
AL and the CR groups at 8 mo (10.5 ± 0.6 and 9.7 ± 1.4 mg · kg1 · min
1,
respectively). However, it was significantly increased at 20 mo in the
AL group compared with the CR group (13.2 ± 1.3 and 10.4 ± 0.6 mg · kg
1 · min
1,
respectively; Table 4).
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DISCUSSION |
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This study demonstrates that insulin action on modulating HGP is not impaired by aging per se but by age-related increase in FM and VF. Rats were chronically caloric restricted from young adulthood to maintain body composition at youthful levels. This allows unveiling a defect specific to aging per se, rather than one related to body fat and its distribution. This experimental manipulation provided evidence supporting the hypothesis that the capacity of insulin to regulate hepatic glucose flux is not impaired with aging.
Decrease in liver function is clinically relevant for age-related drug clearance (18). A reduction in the expression of many transcription factors' binding activity to DNA (31) and binding capacity and affinity of some nuclear receptors (24) was demonstrated in aging livers. Surprisingly, many enzymatic pathways were shown to be intact in various aging models. Thus it may be possible that impaired insulin action on modulating HGP in aging may be partly due to changes in the expression of enzymes and a variety of transcription factors relevant to insulin action.
The progressive increases in fasting plasma insulin levels in humans (12) and in animal models (5) with aging and in the presence of normal glucose levels suggest hepatic insulin resistance, but this impairment was never shown to be independent of increased FM or abdominal obesity observed with aging. We demonstrated this resistance in the AL group, where fasting plasma insulin levels and percentage of body fat increased two- to threefold, and VF increased by about fivefold between 2 and and 20 mo. Total VF increased >50% with only a 5% increase in body weight between 8- and 20-mo AL groups. These further support the conclusion that impaired fat distribution is an aging phenomenon in rats. As expected, hyperinsulinemia compensates for hepatic resistance, and thus basal HGP was similar in all AL groups. However, the percentage of suppression of HGP by physiological hyperinsulinemia was maximal in young adulthood (56%) and impaired at 8 mo (29%) and at 20 mo (15%) in the AL group. In fact, there was a good correlation between VF and percentage of suppression of HGP (r2 = 0.842; P < 0.001).
Our study demonstrated that impaired suppression of HGP by insulin was due to increased glycogenolysis in the aging AL rats. Gluconeogenesis remained unchanged in this group. The molecular mechanism for resistance to hepatic insulin action was investigated in vitro using cytosol of livers obtained from 2- and 20-mo old AL rats (10). The receptor autophosphorylation and the levels of insulin receptor substrate-1 and -2 associated with phosphatidylinositol 3-kinase were reduced with aging, whereas the number of insulin receptors remained unchanged. Impairment in the regulatory role of insulin-dependent protein kinase C and calcium in hepatocytes from the older age groups (30) is suggested as a downstream mechanism for our observation. Thus the resistance to insulin action in the liver causes a decrease in the ability of insulin to modulate glycogen stores in AL rats.
Our study, however, was designed to distinguish between the indirect effects of aging in modulating body fat distribution and the possible direct effects of insulin action that are consequences of the aging liver. CR matched similar amounts of the total fat and VF in the young control and old CR groups. The ability of insulin to suppress HGP was increased twofold in the CR group when compared with the age-matched AL group. The CR group at all ages exhibited rates of glycogenolysis (as well as gluconeogenesis) similar to those of the young control group, i.e., normalizing the defect in modulating glycogen storage. Of note, while CR had been shown to modulate many of the aging processes (3), some hepatic activities (such as proteasomal activity) were shown to be modulated (28), whereas others (such as cytosolic and mitochondrial enzyme activities) were unchanged by CR (1). The defects in the insulin signaling pathway in the aging liver (and in obesity) are yet to be determined after CR. Taking the age-related increase in fat depots into account, these data suggest that aging per se does not directly impair the ability of the liver to respond to physiological hyperinsulinemia. However, our study could not adequately assess the relative importance of the decrease in a specific fat depot, because both FM and VF were decreased significantly by CR. Mounting evidence in this animal model implicates VF specifically in modulating hepatic insulin action (2, 6, 7).
Our findings also contribute to the understanding of some controversies related to hepatic glucose metabolism. First, it was suggested that insulin's suppression of HGP is mediated indirectly by a decrease in FFA (21). Interestingly, FFA levels in the 20-mo AL group did not change during hyperinsulinemia. This suggests that the 15% decrease in HGP is directly due to insulin. Second, the rates of gluconeogenesis remained constant in all animals, despite varying hepatic insulin sensitivity. This is consistent with the data in fasting rats (22) and humans (16) and as reviewed by Cherrington (11). This further suggests that insulin regulates hepatic glycogen storage more than gluconeogenesis. Third, although the kinetics of enzymes involved in HGP such as G-6-Pase, glucokinase, or phosphoenolpyruvate carboxykinase often change in diabetes (19, 20), they are often normal in insulin-resistant states. The significant increase in G-6-P (20-80% between 8- and 20-mo AL vs. CR group) with unchanged expression of G-6-Pase indicates that increased HGP and TGO are due to increased levels of the substrate utilizing this enzyme (Table 4). On the other hand, G-6-Pase activity is increased in young adult rats compared with aging rats whose HGP, TGO, and glycogen stores are lowest. The discordance between G-6-Pase activity and hepatic glucose fluxes underlines the limitations of in vitro determination of G-6-Pase activity. Finally, increased G-6-P levels are contributed by glycogen, because hepatic glycogen stores remained high in the presence of increased glycogenolysis in the AL group compared with the CR group (Table 4).
The young control group had similar VF to that of the CR group but had significantly better suppression of HGP, increased formation of G-6-P from the direct and indirect pathways, increased hepatic G-6-Pase levels, and decreased hepatic glycogen levels. These suggest that changes related to development occur at this young age (5). Alternatively, the differences between the CR and the young control groups may reflect some early changes related to aging. Overall, CR restored hepatic glucose homeostasis in aging comparable to that of young adulthood.
We conclude that body fat and its distribution impair hepatic insulin action, and aging per se has no significant physiological impact on insulin action.
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ACKNOWLEDGEMENTS |
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The authors wish to thank Robin Squeglia and Rong Liu for expert technical assistance.
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FOOTNOTES |
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This work was supported by grants from the National Institutes of Health (KO8 AG-00639 and R29 AG-15003 to N.Barzilai, R01 DK-45024 and ROI DK-48321 to L.Rossetti), the American Diabetes Association, and the Core Laboratories of the Albert Einstein Diabetes Research and Training Center (DK-20541). Dr. Barzilai is a recipient of the Paul Beeson Physician Faculty Scholar in Aging Award; Dr. Rossetti is the recipient of a Career Scientist Award from the Irma T. Hirschl Trust.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: N. Barzilai, Divisions of Geriatrics and Endocrinology, Dept. of Medicine, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave., New York, NY 10461 (E-mail: barzilai{at}aecom.yu.edu).
Received 3 August 1999; accepted in final form 6 December 1999.
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