Glucose Tolerance

At a young age, time-dependent alterations in blood glucose in the glucose tolerance test (GTT) were similar among (—/—), (tg/—), and (tg/tg) rats when fed ad libitum (Figure 31.3A).

In (—/—) rats, aging impaired glucose tolerance, particularly in the AL group (Figure 31.3B); in the CR group, it was mostly inhibited. In (tg/—) rats, glucose intolerance was also observed in the AL group at old age (Figure 31.3C); CR inhibited aging-related impairment. In (tg/tg) rats, time-dependent changes in blood glucose did not differ between young and old or AL and CR groups (Figure 31.3D).

Serum insulin concentrations during the GTT were measured in (—/—) and (tg/—) rats using samples drawn

Figure 31.3. Glucose tolerance of transgenic rats; the effect of calorie restriction and aging. Values represent the mean ± SE of 4 to 7 rats. Y represents an age of 6 to 7 months, and O represents an age of 24 months. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction (A) or age and time and their interaction (B—D) on blood glucose tolerance.

Figure 31.3. Glucose tolerance of transgenic rats; the effect of calorie restriction and aging. Values represent the mean ± SE of 4 to 7 rats. Y represents an age of 6 to 7 months, and O represents an age of 24 months. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction (A) or age and time and their interaction (B—D) on blood glucose tolerance.

from the tail vein (Yamaza et al., 2004). Serum insulin concentrations were transiently elevated at 15 min in (—/—) rats at young age (Figure 31.4A); there was no insulin surge during the GTT in (tg/—)-AL, (tg/—)-CR or (—/—)-CR rats.

If serum samples were prepared from trunk blood after decapitation, insulin levels at 15 min after glucose load were increased in (—/—)-CR and (tg/—)-AL rats as in (—/ —)-AL rats, but the level was significantly lower by 7580% in (—/—)-CR and (tg/—)-AL rats (Figure 31.4B), although values fluctuated. Serum insulin concentrations during the GTT fluctuated largely in old rats (data not shown, but refer to Shimokawa (2005)) and no transient increases were detected. On a whole, however, serum insulin levels were greater in (—/—)-AL rats compared with (tg/—)-AL and (—/—)-CR rats.

The data described here indicate that in transgenic rats, glucose is effectively transported into tissues with lower concentrations of insulin as in CR rats, and the islet cell insulin response to a rise in blood glucose is blunted in transgenic and CR rats. Similarly, this suggests that CR modulates glucose metabolism and insulin responses through a reduction in the GH-IGF-1 axis.

Glucose disposal occurs as a result of both insulinmediated and non-insulin-mediated glucose uptake (IMGU and NIMGU, respectively (Baron et al., 1988)).

By definition, IMGU can occur only in insulin-sensitive tissues, such as skeletal muscles and fat tissues, while, in the absence of insulin, NIMGU can occur in both insulin-sensitive and non-insulin-sensitive tissues including the central nervous system, peripheral nerves, visceral organs, and blood cells (Ferrannini et al., 1985). A study conducted by Wetter et al. (1999) demonstrated that glucose uptake during the period before feeding, at which point serum insulin levels are lowered, is not reduced in most tissues of CR rats; in contrast, white and brown fat tissues showed increased glucose uptake rates. In the period after feeding—that is, postprandially, at which point the serum insulin concentration is increased— insulin-sensitive tissues such as skeletal muscles and fat tissues displayed an increase in glucose uptake in the AL and CR groups, while in some skeletal tissues and mesenteric fat, the glucose uptake tended to be greater in CR rats. GLUT4, the predominant glucose transporter expressed by skeletal muscle, seems to account for most of the insulin-stimulated glucose transport in muscles (Rodnick et al., 1992). In the epitrochlearis muscle, CR increases the amount of cell surface GLUT-4 in response to insulin (Dean et al., 1998). In human placental GH-overexpressing mice that exhibit severe insulin resistance, insulin-stimulated GLUT-4 translocation to the plasma membrane was shown to be reduced (Barbour

Figure 31.4. (A) Serum insulin concentrations during the glucose tolerance test. Serum samples were prepared from blood drawn from the tail vein. Values represent the mean ± SD of 3 to 6 rats. Reproduced from (Yamaza et al., 2004) by copyright permission of Elsevier. (B) Blood glucose concentrations after glucose load using the same amount of glucose as in the glucose tolerance test. Blood glucose was measured in serum samples prepared from trunk blood at decapitation. Values represent the mean ± SD of 4 to 5 rats. 2-f ANOVAwas used to analyze the main effects of rat group and time and their interaction. (C) Serum insulin concentrations after glucose load. Serum samples were the same as those in (B). Values represent the mean ± SD of 4 to 5 rats. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction.

Figure 31.4. (A) Serum insulin concentrations during the glucose tolerance test. Serum samples were prepared from blood drawn from the tail vein. Values represent the mean ± SD of 3 to 6 rats. Reproduced from (Yamaza et al., 2004) by copyright permission of Elsevier. (B) Blood glucose concentrations after glucose load using the same amount of glucose as in the glucose tolerance test. Blood glucose was measured in serum samples prepared from trunk blood at decapitation. Values represent the mean ± SD of 4 to 5 rats. 2-f ANOVAwas used to analyze the main effects of rat group and time and their interaction. (C) Serum insulin concentrations after glucose load. Serum samples were the same as those in (B). Values represent the mean ± SD of 4 to 5 rats. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction.

et al., 2004), suggesting that the somatotropic axis has an inhibitory effect on cell surface translocation of GLUT4. Therefore, we speculate that CR enhances the GLUT4 translocation machinery in insulin-sensitive tissues by reducing the inhibitory effect of the GH-IGF-1 axis. The effect of the reduced GH-IGF-1 axis and CR on noninsulin-mediated mechanisms of glucose uptake remains to be assessed.

Glucose is the prime modulator of insulin secretion, although the precise mechanisms and factors involved in the insulin secretion process are not fully understood. The findings described above suggest that CR and the reduced GH-IGF-1 axis suppress the islet insulin response to a blood glucose rise. The mechanisms of glucose rises and the islet response in long-lived rodents remain to be elucidated.

Body Fat, the Blood Lipid Profile, Leptin and Adiponectin

GH deficiency affects lipid as well as carbohydrate metabolism, resulting in fat accumulation in the body (Gola et al., 2005) and inducing insulin resistance and related disorders. As described above, the transgenic rats exhibited a number of characteristics indicating increased insulin sensitivity. The following section describes selected parameters related to fat metabolism in transgenic rats.

Aging tended to increase the fat content of the AL groups; however, when subjected to CR, the fat content was expectedly reduced. The aging-related increase was therefore prohibited in CR groups, but not in transgenic rat groups fed ad libitum.

The serum triacylglycerol (TG) concentration was reduced in (tg/tg) rats, but statistically insignificant between (—/—) and (tg/—) rats. CR reduced the serum TG concentration, but there was no difference between the CR1 and CR2 groups. Total serum cholesterol levels did not differ among rat groups, although CR resulted in a slight reduction (Table 31.6). HDL-cholesterol was greatest in (tg/tg) rats followed by (tg/—) and (—/—) rats, respectively. Correspondingly, serum concentrations of LDL-cholesterol were slightly greater in (—/—) rats compared with (tg/—) and (tg/tg) rats. HDL-cholesterol levels were slightly but significantly greater in CR1 compared to CR2 phase rats. As a result, LDL-cholesterol levels were particularly reduced in CR1 phase rats. The serum free fatty acid concentration did not differ among rat groups, but was reduced in CR1 phase rats and elevated in CR2 phase rats. Thus, transgenic rat strains, either (tg/—) or (tg/tg), exhibited no deleterious lipid metabolism profile; rather, the slightly lower concentration of total cholesterol and higher concentration of HDL-cholesterol in (tg/tg) rats suggested that a suppressed GH-IGF-1 axis yields some beneficial effects in animals.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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