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Spontaneous high-frequency insulin oscillations are easily entrainable to exogenous glucose in vitro and in vivo, but this property is lost in type 2 diabetes (2-DM). We hypothesized that this lack of entrainment in 2-DM would be specific to glucose. This was tested in nine control and ten 2-DM subjects. Serial blood s sampling at 1-min intervals was carried out for 60 min in the basal state and for 120 min while small (1-60 mg/kg) boluses of arginine were injected intravenously at exactly 29-min intervals. Samples were analyzed for insulin concentrations, and time series analysis was carried out using spectral analysis. In control subjects, the mean period of basal plasma insulin oscillations was 10.3 [+ or -] 1.3 min and was entrained by arginine to a mean period of 14.9 [+ or -] 0.6 min (P < 0.00001 vs. basal). Similarly, in 2-DM subjects, spontaneous insulin oscillations were entrained by arginine; mean basal insulin period was 10.0 [+ or -] 1.0 min and 14.5 [+ or -] 1.8 min with arginine boluses (P < 0.00001). All of the primary peaks observed in spectral analysis were statistically significant (P < 0.05). Percent total power of primary peaks ranged from 17 to 68%. Thus arginine boluses entrain spontaneous high-frequency insulin oscillations in 2-DM subjects. This represents a distinct and striking difference from the resistance of the [beta]-cell to glucose entrainment in 2-DM. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in 2-DM is likely a glucose-specific manifestation of [beta]-cell secretory dysfunction. [beta]-cell dysfunction

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat. chain elongation; stearoyl-coenzyme A desaturase; tissue fatty acid composition

Underestimation of gluconeogenesis by the [[U-.sup.13][C.sub.6]]glucose method: effect of lack of isotope equilibrium. Am J Physiol Endocrinol Metab 282: E376-E385, 2002. First published October 16, 2001; 10.1152/ajpendo.00210.2001.--Among the many tracer methods to indirectly estimate gluconeogenesis in humans, the [[U-.sup.13][C.sub.6]]glucose method as proposed by Tayek and Katz (Am J Physiol Endocrinol Metab 270: E709-E717, 1996; Am J Physiol Endocrinol Metab 272: E476-E484, 1997) has the advantage of being able to simultaneously estimate hepatic glucose output and fractional gluconeogenesis. However, Landau et al. (Landau BR, J Wahren, K Ekberg, SF Previs, D Yang, and H Brunengraber. Am J Physiol Endocrinol Metab 274: E954-E961, 1998) have shown that this method underestimates the rate of gluconeogenesis. The underestimation has been attributed to tracer dilution by other three-carbon substrates and the lack of isotopic steady state. Using a computer simulation of [[U-.sup.13][C.sub.6]]glucose infusion, we demonstrate that the lack of isotope equilibrium in both the lactate and glucose compartments contributes substantially to the underestimation of gluconeogenesis. [[U-sup.13][C.sub.6]]glucose experiments were performed with the addition of a primed constant infusion of [[U-.sup.13][C.sub.3]]lactate and the delay in M3 glucose equilibrium estimated from the isotopic steady-state value determined by modeling M3 glucose to a single-exponential fit. We found that, even with the addition of [[U-.sup.13][C.sub.3]]lactate infusion, the M3 glucose enrichment of the last timed sample was ~20% less than the isotopic steady-state value. Thus the lack of isotopic equilibrium of the glucose compartment potentially accounts for 20% of the underestimation of gluconeogenesis. The underestimation of gluconeogenesis using [[U-.sup.13][C.sub.6]] glucose without the additional infusion of [[U-.sup.13][C.sub.3]] lactate in previous publications is expected to be even greater because of the lack of isotope equilibrium in both the lactate and glucose compartments. These findings are consistent with the results from our computer simulation. mathematical modeling; mass isotopomer distribution analysis, stable isotopes

Spontaneous high-frequency insulin oscillations are easily entrainable to exogenous glucose in vitro and in vivo, but this property is lost in type 2 diabetes (2-DM). We hypothesized that this lack of entrainment in 2-DM would be specific to glucose. This was tested in nine control and ten 2-DM subjects. Serial blood sampling at 1-min intervals was carried out for 60 min in the basal state and for 120 min while small (1–60 mg/kg) boluses of arginine were injected intravenously at exactly 29-min intervals. Samples were analyzed for insulin concentrations, and time series analysis was carried out using spectral analysis. In control subjects, the mean period of basal plasma insulin oscillations was 10.3 ± 1.3 min and was entrained by arginine to a mean period of 14.9 ± 0.6 min (P < 0.00001 vs. basal). Similarly, in 2-DM subjects, spontaneous insulin oscillations were entrained by arginine; mean basal insulin period was 10.0 ± 1.0 min and 14.5 ± 1.8 min with arginine boluses (P ± 0.00001). All of the primary peaks observed in spectral analysis were statistically significant (P ± 0.05). Percent total power of primary peaks ranged from 17 to 68%. Thus arginine boluses entrain spontaneous high-frequency insulin oscillations in 2-DM subjects. This represents a distinct and striking difference from the resistance of the β-cell to glucose entrainment in 2-DM. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in 2-DM is likely a glucose-specific manifestation of β-cell secretory dysfunction. [ABSTRACT FROM AUTHOR]

Stearoyl-CoA desaturase (SCD) is a key enzyme in the conversion of stearate to oleate (C18:0 to C18:1), and palmitate to palmitoleate (C16:0 to C16:1). There are two mouse SCD genes (SCD1 and SCD2). While SCD 1 is the isoform of SCD highly expressed in the liver and adipose tissue, and its expression is induced during adipocyte differentiation with dexamethasone and insulin, SCD2 is constitutively expressed in preadipocytes. The objective of the study is to evaluate the effect of SCD inhibition on fatty acid composition and turnover in NIH3T3 preadipocytes. NIH3T3 preadipocytes were grown in culture for 72 hours with [U-[sup 13]C] stearate and [1, 2 [sup 13]C]-acetate with 1) DMSO or 2) 0.8 µM of SCD inhibitor 06811M1005 (generously provided by CompleGen, Inc.). Analysis of fatty acid mass isotopomers was performed by gas chromatography/mass spectroscopy (GCMS). Fatty acid composition and the desaturation indices were calculated from the gas chromatogram. In cells cultured with SCD inhibitor 06811M1005 in [U-[sup 13]C]-stearate and [1,2 [sup 13]C]-acetate, the desaturation index for C18:1 n-9 was significantly reduced by ∼30% (p<0.03). There was a reduction in the conversion of U-stearate to U-oleate from 64% to 38% (p<0.04) when SCD was inhibited. While 13C isotopomer enrichment of palmitate and stearate reached the same plateau levels in treated and untreated cells, 13C isotopomer enrichment of oleate in the treated cells was significantly lower than control suggesting reduced oleate turnover during the study period. We conclude: NIH3T3 preadipocytes differentiate either in the presence of dexamethasone and insulin or PPAR υ agonist into adipocytes with phenotypes having different expression of SCD1. SCD inhibitor 06811M 1005 probably acts equally on SCD1 and SCD2 in the preadipocytes resulting in a change in desaturation index. Contrary to the expectation of reduced de novo lipogenesis, SCD inhibition primarily reduced on the conversion of stearate to oleate and the turnover of oleate without affecting the uptake and de novo synthesis of palmitate or stearate. [ABSTRACT FROM AUTHOR]