Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels ( -50, -550, -750 MuM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from -50 to -750 gM) decreased glucose uptake in a dose-dependent fashion (from -9 to -4 mg/kg per min). The decrease was caused mainly (-2/3) by a reduction in glycogen synthesis and to a lesser extent ( 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration ( -750MM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium ( -550MM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by -50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level. (J. Clin. Invest. 1994. 93:2438-2446

Insulin secretion was studied in healthy volunteers at three different levels of glycemia. Plasma glucose was clamped at approximately 5, approximately 8.8 and approximately 12.6 mM for 68 h. Measured were serum insulin concentration and insulin secretion rates (ISR), the latter by deconvolution of plasma C-peptide concentration. Rhythmic patterns of ISR were identified (with a refined first-order Fourier transform) at all three glucose concentrations tested but were most clearly seen at 12.6 mM. ISR and serum insulin concentration changed in a circadian (approximately 24 h) rhythm, increasing from a nadir between midnight and 6 A.M. and reaching a peak between noon and 6 P.M. At 12.6 mM hyperglycemia, the amplitude of the insulin concentration cycles was greater than that of the ISR cycles (+/- 13.0 vs. +/- 8.7%) due to a decrease in insulin clearance (from 1.55 to 0.5 l/min, P < 0.01). Plasma melatonin levels (a marker of light-dark rhythmicity) changed in the opposite direction, i.e., they peaked when ISR bottomed and bottomed when ISR peaked. We concluded that normal human subjects have a circadian rhythm of insulin secretion, which becomes more apparent with rising ISR, and that circadian changes in ISR, rising during the day and falling during the night, may be one explanation for the well-established observation that glucose tolerance and insulin responses to glucose and meals are higher in the morning than at night.

No abstract

Pisa syndrome is a rare type of truncal dystonia. Its development is associated commonly with neuroleptic treatment, but there are rare idiopathic cases or those related to neurodegenerative disorders. Recently, an association between cholinesterase inhibitors and Pisa syndrome has been described. The authors report two patients, one with Alzheimer's disease treated with risperidone and another with Parkinson's disease who presented this kind of dystonia after donepezil initiation. In the first patient the condition resolved after discontinuation of risperidone, and in the second one the condition resolved when donepezil was withdrawn. In patients with pharmacologic or degenerative dopaminergic neurotransmission disorders, cholinergic excess may induce this peculiar type of dystonia.

We measured the net rates of skeletal muscle glycogen synthesis and glycolysis (conversion of [3-3H]glucose to 3H2O) in healthy overnight-fasted volunteers. Two studies were performed. In study 1, seven subjects participated in two paired infusions under basal conditions of either [2-3H]glucose (H2) or [3-3H]glucose (H3). Total glucose uptake (Rd) and rates of whole body 3H2O formation (3H2O Ra) were measured. With H2, Rd and 3H2O Ra were similar. With H3, 3H2O Ra, equal to glycolysis, was 65% of Rd. In study 2, six different subjects underwent a 3-h, 40 mU.m-2 x min-1 euglycemic insulin clamp. [6,6-2H2]glucose was infused throughout and H3 was infused during the last hour of the study. Open muscle biopsies were obtained at 150 and 180 min. Glycogen synthesis was assessed by three independent means: 1) direct measurement, as 3H disintegrations per minute in isolated muscle glycogen per plasma H3 specific activity; 2) extrapolation from the activity of glycogen synthase assayed in the presence of the concentrations of glucose 6-phosphate and UDP-glucose measured in the biopsy; and 3) the difference between Rd and glycolysis. Despite a wide range in Rd [24.5-58.8 mumol.kg fat-free mass (FFM)-1 x min-1] and glycolysis (14.2-26.1), the three methods yielded similar results of 20.0 +/- 3.9, 22.5 +/- 3.7, and 20.6 +/- 3.7 mumol.kg FFM-1 x min-1 and correlated highly with each other (r2 = 0.92-0.96). Our results (study 1) indicate that the rate of plasma tritiated water formation reflects the intracellular detritiation of tritiated glucose. Under hyperinsulinemic conditions (study 2) the net rate of muscle glycogen synthesis can be accurately estimated from the glycogen synthase activity and from the difference between total glucose uptake and glycolysis. Thus, at high physiological plasma insulin concentrations resulting in submaximal stimulation of muscle glycogen synthesis, the latter can be accurately measured in humans.