Resistance training for 3 months improves both leg strength and walking endurance in healthy, community-dwelling elderly persons. This finding is relevant to older persons at risk for disability, because walking endurance and leg strength are important components of physical functioning.

Studies were conducted to determine whether regional free fatty acid (FFA) release is differentially regulated by insulin. Systemic, leg, and splanchnic palmitate rate of appearance ([9,10-(3)H]palmitate) was measured in 26 healthy adults using the euglycemic-hyperinsulinemic clamp technique to achieve a physiological range of plasma insulin concentrations. We found that insulin inhibited systemic, leg, and splanchnic palmitate release in a dose-dependent fashion over the range of insulin infused (0-1.0 mU x kg(-1) x min(-1)). Progressive hyperinsulinemia changed the leg from a net producer to a net FFA consumer, whereas the splanchnic bed converted from a net FFA consumer to a net producer. At the 0.5 mU x kg(-1) x min(-1) insulin infusion rate, leg FFA release was almost completely suppressed, whereas even with the 1.0 mU x kg(-1) x min(-1) insulin infusion rate, splanchnic FFA release decreased by only approximately 65% (P < 0.05 leg vs. splanchnic). These results demonstrate the regional heterogeneity of insulin-regulated FFA release in vivo, and indicate that visceral adipose tissue lipolysis is more resistant to insulin suppression than is leg lipolysis in humans.

To define the mechanism of insulin's anticatabolic action, the effects of three different dosages of insulin (0.25, 0.5, and 1.0 mU x kg(-1) x min(-1)) versus saline on protein dynamics across splanchnic and skeletal muscle (leg) beds were determined using stable isotopes of phenylalanine, tyrosine, and leucine in 24 healthy subjects. After an overnight fast, protein breakdown in muscle exceeded protein synthesis, causing a net release of amino acids from muscle bed, while in the splanchnic bed protein synthesis exceeded protein breakdown, resulting in a net uptake of these amino acids. Insulin decreased (P < 0.003) muscle protein breakdown in a dose-dependent manner with no effect on muscle protein synthesis, thus decreasing the net amino acid release from the muscle bed. In contrast, insulin decreased protein synthesis (P < 0.03) in the splanchnic region with no effect on protein breakdown, thereby decreasing the net uptake of the amino acids. In addition, insulin also decreased (P < 0.001) leucine nitrogen flux substantially more than leucine carbon flux, indicating increased leucine transamination (an important biochemical process for nitrogen transfer between amino acids and across the organs), in a dose-dependent manner, with the magnitude of effect being greater on skeletal muscle than on the splanchnic bed. In conclusion, muscle is in a catabolic state in human subjects after an overnight fast and provides amino acids for synthesis of essential proteins in the splanchnic bed. Insulin achieves amino acid balance across splanchnic and skeletal muscle beds through its differential effects on protein dynamics in these tissue beds.

The catabolic state of poorly controlled type 1 diabetes has largely been attributed to insulin deficiency. However, the role of hyperglucagonemia, which occurs concomitantly with insulin deficiency, has not been fully investigated. We studied the effects of hyperglucagonemia during insulin deprivation on energy expenditure (using indirect calorimetry) and protein metabolism (using L-[1-(13)C,15N]leucine and L-[1-(13)C]leucine as tracers) in 12 type 1 diabetic subjects. Five protocols were used: insulin treatment, insulin deprivation, insulin deprivation with suppression of endogenous glucagon with somatostatin (SRIH) and growth hormone replacement, insulin deprivation with endogenous glucagon suppression with SRIH (no growth hormone replacement), and insulin deprivation with SRIH and a high level of glucagon replacement (no growth hormone replacement). It was observed that leucine oxidation and the resting metabolic rate (RMR) were significantly lower during insulin treatment and insulin deprivation with concomitant SRIH infusion (lowering glucagon) than during insulin deprivation alone. Replacement of glucagon at a high level during SRIH infusion in the insulin-deprived state increased leucine oxidation and the RMR. Hyperglucagonemia was also associated with a trend for decreased protein synthesis. Hyperglucagonemia did not affect leucine transamination. Insulin replacement decreased leucine flux and oxidation. Leucine oxidation (R2 = 0.79) and the RMR (R2 = 0.81) were seen, by multiple regression analysis, to correlate with glucagon levels and not with other hormones. We conclude that while insulin deficiency increases protein breakdown, hyperglucagonemia is primarily responsible for the increased leucine oxidation and RMR seen during insulin deprivation.

We evaluated the influence of insulin on fractional mixed skeletal muscle protein synthesis (FMPS) in eight type I (insulin-dependent) diabetic patients in the postabsorptive state. FMPS was calculated from the increment in [13C]leucine in mixed skeletal muscle protein obtained by serial percutaneous needle biopsy during a continuous 8-h intravenous infusion of L-[13C]leucine. We used the plasma [13C]-alpha-ketoisocaproate (representing intracellular leucine labeling) as the precursor pool of protein synthesis for our calculations. FMPS during the insulin treatment (0.0472 +/- 0.0046%/h; plasma glucose 4.6 +/- 1.0 mM) was not different from FMPS during insulin deprivation (0.0499 +/- 0.0046%/h; plasma glucose 16.4 +/- 0.5 mM). Using plasma [13C]-alpha-ketoisocaproate at isotopic plateau for calculation of leucine flux and as the precursor for leucine oxidation, we further confirmed the findings of our group and others that insulin treatment decreases leucine flux, leucine oxidation, and the nonoxidative portion of leucine flux. Our data on direct measurement of FMPS provide further evidence that the anabolic effect of insulin in the postabsorptive type I diabetic patient is mediated via reduction of proteolysis rather than by increasing protein synthesis.