Reduced access to insulin-sensitive tissues in dogs with obesity secondary to increased fat intake.

Physiological hyperinsulinemia provokes hemodynamic actions and augments access of macromolecules to insulin-sensitive tissues. We investigated whether induction of insulin resistance by a hypercaloric high-fat diet has an effect on the extracellular distribution of macromolecules to insulin-sensitive tissues. Male mongrel dogs were randomly selected into two groups: seven dogs were fed an isocaloric control diet ( approximately 3,900 kcal, 35% from fat), and six dogs were fed a hypercaloric high-fat diet ( approximately 5,300 kcal, 54% from fat) for a period of 12 weeks.

Physiological hyperinsulinemia in dogs augments access of macromolecules to insulin-sensitive tissues.

Pharmacological doses of insulin increase limb blood flow and enhance tissue recruitment for small solutes such as glucose. We investigated whether elevating insulin within the physiological range (68 +/- 6 vs. 425 +/- 27 pmol/l) can influence tissue recruitment of [(14)C]inulin, an inert diffusionary marker of molecular weight similar to that of insulin itself.

Endurance training delays age of decline in leg strength and muscle morphology.

Purpose: It has been reported that maximal strength peaks at approximately 30 yr of age, plateaus, and remains relatively stable for the next 20 yr, with an age-related decline in strength becoming significant after age 50. Much of the research attributes this decrease in peak force to age-associated reductions in muscle mass, with a selective atrophy and reduction in Type II fiber area and number being the primary factors. The influence that chronic endurance training has upon age-associated changes in muscular strength and muscle morphology has been largely undetermined.

Mechanism of action in dogs of slow-acting insulin analog O346.

We compared metabolic effects as well as plasma and interstitial fluid kinetics of fatty acid-acylated insulin, Lys(B29)(N(epsilon)-omega-carboxynonadecanoyl)-des(B30) human insulin (O346), with previously determined kinetics of native insulin and insulin detemir. Euglycemic clamps with iv injection of O346 (90 pmol/kg) or saline control were performed in 10 male mongrel dogs under inhalant anesthesia. The t(1/2) for the clearance of O346 from plasma was 375.

Burst-like control of lipolysis by the sympathetic nervous system in vivo.

Rapid oscillations of visceral lipolysis have been reported. To examine the putative role of the CNS in oscillatory lipolysis, we tested the effects of beta(3)-blockade on pulsatile release of FFAs. Arterial blood samples were drawn at 1-minute intervals for 120 minutes from fasted, conscious dogs (n = 7) during the infusion of saline or bupranolol (1.

Albumin binding of acylated insulin (NN304) does not deter action to stimulate glucose uptake.

NN304 [Lys(B29)-tetradecanoyl des(B30) human insulin] is a potentially therapeutic insulin analog designed to exhibit protracted glucose-lowering action. In dogs with infusion rates similar to insulin itself, NN304 exhibits similar glucose uptake (R(d)) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the approximately 2% unbound NN304 concentration.

Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion.

A defect in transcapillary transport of insulin in skeletal muscle and adipose tissue has been proposed to play a role in the insulin resistance that leads to type 2 diabetes, yet the mechanism of insulin transfer across the capillary endothelium from plasma to interstitium continues to be debated. This study examined in vivo the interstitial appearance of insulin in hindlimb using the fatty acid acylated insulin analog Lys(B29)-tetradecanoyl des-(B30) human insulin, or NN304, as a marker for insulin transport. If the insulin transport were a saturable process, then "swamping" the capillary endothelial insulin receptors with native insulin would suppress the subsequent appearance in interstitial fluid of the insulin analog NN304.