Effects of a sympathetic activation by a lower body negative pressure on glucose and lipid metabolism

The effects of a sympathetic activation elicited by a lower body negative pressure (LBNP) (at -15 mmHg for 75 min) were assessed in 7 healthy subjects on two occasions: (i) in post-absorptive conditions, and (ii) during glucose infusion (22.2 mumol kg-1 min-1). LBNP increased plasma norepinephrine concentration and heart rate. It did not alter whole-body glucose metabolism (measured with [6,6-2H]glucose) and glycerol turnover (measured with [1,1,2,3,3-2H]glycerol). Interstitial glycerol concentrations were monitored with microdialysis in subcutaneous adipose tissue and in skeletal muscle. LBNP increased dialysate glycerol concentrations in muscle by 16% (P < 0.03) but not in adipose tissue in post-absorptive conditions, and by 37% in adipose tissue (P < 0.05) but not in muscle during glucose infusion. These results indicate that an LBNP-induced sympathetic activation (i) does not increase endogenous glucose production, and (ii) induces only a slight stimulation of lipolysis in adipose tissue during glucose infusion.     

Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo

Beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) consists of a nonmetabolizable long-chain fatty acid designed to probe the effect exerted by fatty acids on insulin sensitivity. The effect of MEDICA 16 was evaluated in insulin-resistant Zucker (fa/fa) rats in terms of liver, muscle, and adipose tissue response to clamped euglycemic hyperinsulinemia in vivo. Nontreated Zucker rats were insulin resistant, maintaining basal rates of total-body glucose disposal, glucose production in liver, free fatty acid (FFA) flux into plasma, and FFA reesterification in adipose tissue, irrespective of the insulin levels induced. MEDICA 16 treatment resulted in an insulin-induced decrease in hepatic glucose production, together with an insulin-induced increase in total-body glucose disposal. Intracellular reesterification of lipolysed FFA in adipose tissue was specifically activated by MEDICA 16, resulting in a pronounced decrease in FFA release, with a concomitant decrease in plasma FFA. In conclusion, MEDICA 16 treatment results in the sensitization of liver, muscle, and adipose tissue to insulin in an animal model for obesity-induced insulin resistance.     

Lipoprotein lipase transport in plasma: role of muscle and adipose tissues in regulation of plasma lipoprotein lipase concentrations

Lipoprotein lipase (LPL) is synthesized in tissues involved in fatty acid metabolism such as muscle and adipose tissue. LPL is also found in the circulation, but is mostly lipolytically inactive. The proportion of active circulating LPL increases after a fatty meal. We investigated the release of active and inactive LPL from adipose tissue and muscle in the fasting and postprandial states. Arteriovenous concentration gradients of LPL across adipose tissue and forearm muscle were measured in male subjects before and after a fat-rich meal (n = 7) and before and during infusion of a triacylglycerol emulsion (Intralipid) (n = 6). Plasma LPL activity rose after the meal and more so during Intralipid infusion. Plasma LPL mass (>95% inactive LPL) increased after the meal but decreased after Intralipid infusion. In the fasting state (n = 13) muscle efflux of LPL activity was 0.263 +/- 0.098 mU/min per 100 ml of muscle tissue whereas there was an influx of LPL activity to adipose tissue of 0.085 +/- 0.100 mU/min per 100 g of adipose tissue (P < 0. 02 muscle vs. adipose tissue). Similarly in the postprandial state only muscle released LPL activity. Both tissues released LPL mass. In the fasting state efflux was 17.8 +/- 8.8 ng/min per 100 ml muscle and 55.2 +/- 21.3 ng/min per 100 g of adipose tissue (P < 0. 05 muscle vs. adipose tissue). Release of LPL, either active or inactive, was not correlated with levels of non-esterified fatty acids or plasma triacylglycerol. In conclusion, there is a substantial release of LPL from adipose tissue and muscle, most of which is inactive. A small proportion of active LPL seems to be redistributed from muscle to adipose tissue.     

Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo

The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.     

Relationship between insulin-mediated glucose disposal by muscle and adipose tissue lipolysis in healthy volunteers

The present study was performed in 17 nondiabetic subjects and was initiated to determine whether enhanced adipose tissue lipolysis, either basal or catecholamine induced (isoproterenol), and/or resistance to insulin inhibition of isoproterenol-stimulated lipolysis were correlated with resistance to insulin-mediated glucose disposal by muscle. Insulin-mediated glucose disposal was assessed by determining the steady state plasma glucose (SSPG) concentration during the insulin suppression test [180 min infusion of somatostatin (350 micrograms/h), insulin (25 mU/m2min), and glucose (240 mg/m2.min)]. On another occasion, plasma FFA and glycerol concentrations were determined at the end of 3 sequential infusion periods (IP): IP1, somatostatin (350 micrograms/h) plus basal insulin replacement (5 mU/m2.min); IP2, somatostatin (350 micrograms/h), insulin (5 mU/m2.min), and isoproterenol (270 ng/m2.min); and IP3, somatostatin (350 micrograms/h), isoproterenol (270 ng/m2.min), and insulin (10 mU/m2.min). SSPG concentrations correlated with FFA concentrations during all 3 infusion periods after adjustment for age, gender, body mass index, insulin concentration, and ratio of waist to hip girth (IP1:r = 0.61; P < 0.03; IP2: r = 0.70; P < 0.01; IP3: r = 0.65; P < 0.02). Correlations between SSPG and glycerol concentrations were also highly statistically significant (IP1: r = 0.62; P < 0.03; IP2: r = 0.65; P < 0.02; IP3: r = 0.70; P < 0.01). These results demonstrate for the first time that plasma FFA and glycerol concentrations are increased commensurate with the degree of resistance to insulin-mediated glucose disposal at a basal insulin level, in response to isoproterenol stimulation, and after insulin inhibition of isoproterenol-stimulated lipolysis.     

Inhibition of paracrine angiotensin-converting enzyme in vivo: effects on interstitial glucose and lactate concentrations in human skeletal muscle

Microdialysis was used to selectively assess the effect of the paracrine renin-angiotensin system (RAS) on interstitial glucose and lactate concentration profiles in skeletal muscle of healthy volunteers (n = 8) during basal and insulin-stimulated conditions. Paracrine RAS was selectively inhibited by local retrodialysis with enalaprilate. Under basal conditions, local administration of enalaprilate (2 micrograms mL-1) increased interstitial dialysate glucose concentration from 0.71 +/- 0.14 mmol L-1 to 0.84 +/- 0.14 mmol L-1 and decreased the serum interstitial gradient (SIGglu) compared with baseline (P < 0.02). Under clamp conditions, enalaprilate, even at the lowest concentration (0.02 microgram mL-1), increased interstitial dialysate glucose concentration from 0.77 +/- 0.11 mmol L-1 to 1.02 +/- 0.09 mmol L-1 and decreased SIGglu compared with baseline (P < 0.01). Interstitial lactate concentrations slightly increased during basal as well as during clamp conditions (P < 0.05 vs. baseline). Selective inhibition of paracrine muscle angiotensin-converting enzyme (ACE) increases interstitial glucose and lactate concentrations and decreases SIGglu in muscle by facilitating transcapillary glucose transport. This effect is more pronounced during hyperinsulinaemia and may be of clinical relevance in diabetic patients treated with therapeutic doses of enalapril.     

Origin of endocrine-metabolic changes in the weanling rat ventromedial syndrome

Destruction of the ventromedial hypothalamic nuclei (VMN) in the weanling rat without injury to the median eminence results in a series of somatic, endocrine, and metabolic changes that are characterized by normal food and water intake but decreased linear growth, normal body weight but increased carcass fat and reduced carcass protein, lean body mass, and water. The endocrine alterations comprise hyperinsulinemia in the face of normoglycemia, hypertriglyceridemia and hypercholesterolemia and reduced growth hormone levels. The metabolic changes include greater oxidation of glucose and incorporation into lipid and reduced palmitate oxidation but increased incorporation into lipid. Weanling rats with VMN lesions are normophagic in absolute terms, relative to body weight and per metabolic unit, but their nocturnal feeding and weight gain cycles are disrupted and their locomotor activity is reduced. The VMN are involved in the long-term control of feeding - as in the mature rat - as shown by intragastric preloading studies and dietary density manipulation, glucose preference tests and intraperitoneal injections with glucose. Hyperinsulinemia and hypertriglyceridemia are present four days after the VMN operation in the presence of subnormal food intake and plasma glucose levels. Manipulations of the fat content of the diet revealed that the hyperlipidemia is of both endogenous and exogenous origin and that lipoprotein lipase is increased; a 48-hour fast reduced the hyperlipidemia to control levels, however. This suggests that weanling VMN rat tissue may have an impaired ability to take up circulating lipid. An increased incorporation of glycerol into lipid may be due to induction of glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed neither depressed lipolysis nor diminished lipolytic activity per milligram of tissue protein. Glucose oxidation and incorporation into adipose tissue is increased in several tissues in vitro and there is enhanced glucose disappearance from plasma and incorporation into tissue lipids in vivo. These changes develop within a short time after lesion production and persist at least partially up to six months: glucose utilization in liver increases already four hours after the operation whereas it takes 72 hours to commence in adipose tissue. Insulin resistance is not apparent either in vivo or in vitro. The decreased growth hormone levels are not critical to the metabolic changes, nor is the hyperinsulinemia totally necessary. The metabolic changes also appear on several different types of diet and persist with fasting. The latter does not reduce insulin sensitivity of VMN rat tissues, wheras it does so in normal rats. Mature rats developed the same metabolic changes even in the absence of hyperphagia. The metabolic alterations can be blocked by pharmacologic doses of glucocorticoids, but are enhanced by the administration of estrogen...     

Adrenergic regulation of human adipose tissue metabolism in situ during mental stress

The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P < 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.     

GH but not IGF-I or insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomised rats

Changes in GH secretion are associated with changes in serum lipoproteins, utilisation of fuels and body composition. Since lipoprotein lipase (LPL) is a key enzyme in the regulation of lipid and lipoprotein metabolism, changes in LPL activity may contribute to these effects of GH. The present study was undertaken to investigate the role of GH and the GH-dependent growth factor, IGF-I, in the regulation of LPL in heart, skeletal muscle and adipose tissue. Female rats were hypophysectomised at 50 days of age. One week later, hormonal therapy was commenced. All hypophysectomised rats received l-thyroxine and cortisol. Adipose tissue, the heart, soleus and gastrocnemius muscles were excised after 1 week of hormonal therapy. The effect of insulin injections on adipose tissue and heart LPL activity was also studied. In separate experiments, LPL activity in post-heparin plasma was measured. Hypophysectomy had no effect on adipose tissue LPL activity, whereas activity was reduced in heart, soleus and gastrocnemius muscle tissues. GH treatment had no significant effect on LPL activity in adipose tissue or soleus muscle, but increased the LPL activity in heart and gastrocnemius muscle. GH treatment increased post-heparin plasma LPL activity. Recombinant human IGF-I treatment (1.25 mg/kg per day) markedly reduced LPL activity in adipose tissue, but had no effect in muscle tissues. The effect of IGF-I treatment on adipose tissue LPL was not reflected by a decrease in post-heparin plasma LPL activity. Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity. In adipose tissue, LPL mRNA levels tended to decrease as a result of IGF-I treatment. In the muscle tissues, no significant effects of hypophysectomy, GH or IGF-I treatment on LPL mRNA levels were observed.%It is concluded that GH increases heart and skeletal muscle tissue LPL activity, which probably contributes to an increased post-heparin plasma LPL activity. The effect of GH on muscle LPL activity is probably not mediated by IGF-I or insulin. Insulin and IGF-I have opposite effects on LPL activity in adipose tissue.     

Acute effects of the beta 3-adrenoceptor agonist, BRL 35135, on tissue glucose utilisation

1. The acute effects of BRL 35135 (BRL) on tissue glucose utilisation index (GUI) in vivo were investigated in anaesthetized rats by use of 2-deoxy-[3H]-glucose. 2. Intravenous injection of BRL caused a dose-dependent increase in GUI in skeletal muscle, and white and brown adipose tissue; plasma insulin and fatty acid concentrations were also increased. Chronic treatment with BRL added to the diet caused a 34 fold increase in basal GUI of brown adipose tissue (BAT), but had no effect on GUI in other tissues. After chronic treatment, the acute tissue response to an intravenous maximal dose of BRL had disappeared completely in all tissues apart from the soleus muscle. 3. A high dose (20 mg kg-1) of the non-selective beta-antagonist, propranolol, inhibited the acute effect of BRL on GUI in BAT, but failed to affect GUI in muscle. A lower dose (1 mg kg-1) of the antagonist also inhibited the BAT response, but had little or no effect on the response in Type I (working) muscles such as soleus and adductor longus (ADL), and potentiated the response in Type II (non-working) muscles such as tibialis and extensor digitorium longus (EDL). 4. A low dose (1 mg kg-1) of the selective beta 1-antagonist, atenolol, had no effect on the BRL response but the same dose of the selective beta 2-antagonist, ICI 118551, potentiated significantly the effect of BRL on GUI in most muscles without altering plasma insulin levels. 5. It is concluded that: (i) the heterogeneous tissue responses of different muscle fibre types in the presence of P-antagonists indicates that BRL affects muscle GUI directly, in addition to effects mediated by increases in plasma insulin concentration; (ii) the resistance of the BRL response to conventional P-adrenoceptor antagonists implicates an atypical adrenoceptor mediating the GUI response in skeletal muscle, but this may not be identical to the adipose tissue P3-adrenoceptor; (iii) the potentiation of BRL responses by ICI 118551 indicates an inhibitory P2-adrenoceptor-mediated component in the muscle GUI response to BRL.     

Clearance of lipoprotein remnant particles in adipose tissue and muscle in humans

A major proportion of triglycerides in plasma triglyceride-rich lipoproteins (TRL) are removed in peripheral tissues by lipoprotein lipase, and hypothetically a minor proportion can also be removed by whole-lipoprotein particle uptake. This second removal pathway has not previously been directly demonstrated in humans. Simultaneous blood samples were drawn from arterialized blood, a vein draining the subcutaneous abdominal adipose tissue, and a deep antecubital vein of the forearm to provide arterio-venous gradients from blood-draining adipose tissue and muscle in seven male subjects. The men were given a fat-rich mixed meal containing vitamin A and the triglyceride and retinyl palmitate (RP) concentrations were quantified in the plasma. Density gradient ultracentrifugation was used to isolate TRL fractions, in which triglycerides, RP, apoB-48, and apoB-100 were quantified. There was clearance of triglycerides in muscle and adipose tissue and, in addition, removal of RP. By analysis of the TRL subfractions, the RP removal was likely to be confined to the largest chylomicron remnant particles. For the Sf > 400 fraction, the area under curve (AUC) relative to arterial for triglycerides were 79% (66-91%) and 81% (72-89%) in adipose tissue and muscle venous outflow, respectively (each P < 0.02 versus arterial). The corresponding values for RP were 87% (73-101%) and 85% (69-100%), respectively, (each P < 0.05 versus arterial). In the Sf 60-400 fraction there was further uptake of triglycerides, but not of RP. We hypothesize that the periphery could be of importance for removal of the largest chylomicron remnants, as their size might partially exclude them penetrating the fenestrated hepatic sinusoidal endothelium to reach the hepatic chylomicron remnant receptors.     

The insulin sensitizer, BRL 49653, reduces systemic fatty acid supply and utilization and tissue lipid availability in the rat

Thiazolidinediones are oral insulin-sensitizing agents that may be useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). BRL 49653 ameliorates insulin resistance and improves glucoregulation in high-fat-fed (HF) rats. It is known that thiazolidinediones bind to the peroxisome proliferator-activated receptor (PPAR gamma) in fat cells, but the extent to which the improved glucoregulation and hypolipidemic effects relate to adipose tissue requires clarification. We therefore examined BRL 49653 effects on lipid metabolism in HF and control (high-starch-fed [HS]) rats. The diet period was 3 weeks, with BRL 49653 (10 mumol/kg/d) or vehicle gavage administered over the last 4 days. Studies were performed on animals in the conscious fasted state. In HF rats, rate constants governing 3H-palmitate clearance were unaffected by BRL 49653. This finding, taken with a concurrent decrease of fasting plasma nonesterified fatty acids (NEFA) (P < .01, ANOVA), demonstrated that systemic NEFA supply and hence absolute utilization are reduced by BRL 49653. Hepatic triglyceride (TG) production (HTGP) assessed using Triton WR1339 was unaffected by diet or BRL 49653. In liver, BRL 49653 increased insulin-stimulated conversion of glucose into fatty acid in both HF (by 270%) and HS (by 30%) groups (P < .05). Relative to HS rats, HF animals had substantially elevated levels of muscle diglyceride (diacylglycerol[DG] by 240%, P < .001). BRL 49653 significantly reduced muscle DG in HF (by 30%, P < .05) but not in HS rats. The agent did not reduce the intake of dietary lipid. In conclusion, these results are consistent with a primary action of BRL 49653 in adipose tissue to conserve lipid by reducing systemic lipid supply and subsequent utilization. The parallel effects of diet and BRL 49653 treatment on insulin resistance and muscle acylglyceride levels support the involvement of local lipid oversupply in the generation of muscle insulin resistance.     

Effect of glycerol on lipogenic enzyme activities and on fatty acid synthesis in the rat and chicken

The influence of glycerol on the rates of fatty acid snythesis in liver slices from rats and chickens in pieces of adipose tissue from rats was first studied. Then the effect of dietary glycerol on lipid metabolism in rats and cheickens was examined. Media containing 3 or 10 mM glycerol depressed the rate of glucose conversion to fatty acids in rat liver slices. However, media containing up to 25 mM glycerol did not influence the rate of fatty acid synthesis in chick liver slices. The inhibitory action of glycerol in rat liver slices might occur at the level of glucose (or glycogen) conversion to pyruvate because glycerol did not inhibit pyruvate or acetate conversion to fatty acids. Rats and chickens were fed glycerol containing diets for either 3 days or 3 weeks. Feeding diets containing 20.5 parts glycerol (22% of dietary energy) to rats or chickens did not influence the growth rate of the animals. However, substitution of 42.2 parts glycerol (43% of dietary energy) for glucose in the diet significantly depressed food intake and growth rate in both rats and chickens. The activities of citrate cleavage enzyme, fatty acid synthetase and malic enzyme in livers of rats fed the glycerol-containing diets were dramatically increased. However, this stimulation of enzyme activity occurred without a concomitant increase in the in vivo rate of fatty acid synthesis in the rat liver. In the chicken, unlike the rat, dietary glycerol did not stimulate but instead decreased hepatic malic enzyme and fatty acid synthetase activities. No significant differences in adipose tissue lipogenic enzyme activities or in the rates of fatty acid synthesis were observed in rats fed glycerol-containing diets. The lipogenic response to glycerol feeding depends on the species as well as the organ.     

Effects of physiological hypercortisolemia on the regulation of lipolysis in subcutaneous adipose tissue

Cortisol is known to increase whole body lipolysis, yet chronic hypercortisolemia results in increased fat mass. The main aim of the study was to explain these two apparently opposed observations by examining the acute effects of hypercortisolemia on lipolysis in subcutaneous adipose tissue and in the whole body. Six healthy subjects were studied on two occasions. On one occasion hydrocortisone sodium succinate was infused i.v. to induce hypercortisolemia (mean plasma cortisol concentrations, 1500 +/- 100 vs. 335 +/- 25 nmol/L; P < 0.001); on the other occasion (control study) no intervention was made. Lipolysis in the s.c. adipose tissue of the anterior abdominal wall was studied by measurement of arterio-venous differences, and lipolysis in the whole body was studied by constant infusion of [1,2,3-2H5]glycerol for measurement of the systemic glycerol appearance rate. Hypercortisolemia led to significantly increased arterialized plasma nonesterified fatty acid (NEFA; P < 0.01) and blood glycerol concentrations (P < 0.05), with an increase in systemic glycerol appearance (P < 0.05). However, in s.c. abdominal adipose tissue, hypercortisolemia decreased veno-arterialized differences for NEFA (P < 0.05) and reduced NEFA efflux (P < 0.05). This reduction was attributable to decreased intracellular lipolysis (P < 0.05), reflecting decreased hormone-sensitive lipase action in this adipose depot. Hypercortisolemia caused a reduction in arterialized plasma TAG concentrations (P < 0.05), but without a significant change in the local extraction of TAG (presumed to reflect the action of adipose tissue lipoprotein lipase). There was no significant difference in plasma insulin concentrations between the control and hypercortisolemia study. Site-specific regulation of the enzymes of intracellular lipolysis (hormone-sensitive lipase) and intravascular lipolysis (lipoprotein lipase) may explain the ability of acute cortisol treatment to increase systemic glycerol and NEFA appearance rates while chronically promoting net central fat deposition.     

Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.     

Effect of caloric restriction on basal insulin levels and the in vivo lipogenesis and glycogen synthesis from glucose in the Koletsky obese rat

Fasting plasma immunoreactive insulin levels increased with age in hyperinsulinemic Koletsky obese rats, being almost four times as high as in lean siblings at 3 mo (40 +/- 5 muU/ml) and rising steadily to 82 +/- 4 muU/ml at 6 mo (about seven times higher than lean siblings). Restricting the food intake of the obese rats markedly reduced but did not normalize the hyperinsulinemia, which in these rats was accompanied by normal plasma glucose concentrations. The incorporation in vivo of D-U-14C-glucose into tissue lipids and glycogen was measured 1 hr after the intravenous injection of 1 g glucose (containing 100 muDi D-U-14C-glucose) per kg body weight in obese rats eating ad libitum, obese rats after 3 mo on a restricted food intake, and lean siblings. All tissues (heart, diaphragm, skeletal muscle, and adipose tissues and liver) of obese rats exhibited a significantly greater lipogenesis from glucose than those of lean siblings. Dietary restriction of the obese rats reduced the 14C incorporation into lipid to levels not significantly different from lean controls in all tissues except skeletal muscle and liver, where, although greatly reduced, lipogenesis was still significantly higher than in lean rats. Glycogen synthesis tended to be greater in all tissues of obese rats than in lean animals. Dietary restriction of obese rats did not greatly affect glycogen synthesis.     

Benfluorex normalizes hyperglycemia and reverses hepatic insulin resistance in STZ-induced diabetic rats

We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of NIDDM, induced by injection of STZ 5 days after birth and characterized by frank hyperglycemia, hypoinsulinemia, and hepatic and peripheral insulin resistance. We assessed the following: 1) basal blood glucose and insulin levels, 2) glucose tolerance and glucose-induced insulin release in vivo and in vitro, and 3) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. The in vivo insulin response of several individual tissues also was evaluated under the steady-state conditions of the clamp, using the uptake of the glucose analogue 2-deoxy-D-glucose as a relative index of glucose metabolism. In the benfluorex-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (8.1 +/- 0.2 mM compared with 10.5 +/- 0.5 mM in the pair-fed untreated diabetic rats and 6.1 +/- 0.2 mM in the benfluorex-treated nondiabetic rats), whereas the basal and glucose-stimulated intravenous glucose tolerance test plasma insulin levels were not improved. Such a lack of improvement in the glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the pair-fed untreated diabetic rats, the basal glucose production and overall glucose utilization were significantly increased, and during hyperinsulinemia both liver and peripheral tissues revealed insulin resistance. In the benfluorex-treated diabetic rats, the basal glucose production and basal overall glucose utilization were normalized. After hyperinsulinemia, glucose production was normally suppressed, whereas overall glucose utilization was not significantly improved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytochrome P450 1A-like proteins expressed in the islets of Langerhans and altered pancreatic beta-cell secretory responsiveness

1. The cytochrome P450 (CYP) mixed-function oxidase system is widely distributed in body tissues and plays a key role in the metabolism of endogenous and exogenous compounds. Little attention has been paid to the expression of the system in the islets of Langerhans. The current study has examined the expression and potential role of the CYP1A family within the islets of Langerhans of control and 3-methylcholanthrene (3-MC)-induced Wistar rats. 2. CYP1A expression within pancreatic slices and islets from 3-MC-induced and control rats demonstrated that CYP1A-like protein levels were induced by 3-MC pretreatment (25 mg kg-1 day-1; i.p. for 3 days). 3. Effects of 3-MC-induction on beta-cell secretory responsiveness were investigated by use of rat collagenase-isolated islets. Insulin release from control islets incubated with 3 mM glucose (basal) was 1.4 +/- 0.2 ng/islet h-1 (mean +/- s.e.mean, n = 7). Incubation with 16.7 mM glucose, 25 mM KCl, 100 microM arachidonic acid, or 100 microM carbachol caused a 4.4, 7.0, 4.0 and 4.2 fold, respectively, increase in insulin release (P < 0.001). Forskolin (2 microM), or phorbol 12-myristic 13-acetate (10 nM) potentiated glucose-stimulated insulin release 1.2 and 1.6 fold (P < 0.01) whereas adenalin (1 microM) caused a 76% inhibition (P < 0.01). 4. Islets from 3-MC pretreated animals displayed similar responsiveness to all agents tested except arachidonic acid, carbachol and forskolin. Insulin release in response to arachidonic acid and carbachol was enhanced 5.2 and 5.0 fold, respectively, by 3-MC pretreatment (P < 0.001 compared to control islets incubated with 3 mM glucose); the effect of forskolin on insulin output was significantly decreased (20%; P < 0.01) compared to control islets. 5. 3-MC pretreatment did not cause any significant differences in food intake, plasma glucose or total islet insulin content. Incubation of islets with 3-MC in vitro (1 microM - 10 mM) did not affect basal or glucose-stimulated insulin release. 6. These data suggest that CYP1A-like protein expression within the pancreatic islets of Langerhans is inducible and may have a role in the alteration of pancreatic beta-cell secretory responsiveness.     

Effects of hindlimb contraction on pressor and muscle interstitial metabolite responses in the cat

We used the microdialysis technique to measure the interstitial concentration of several putative metabolic stimulants of the exercise pressor reflex during 3- and 5-Hz twitch contractions in the decerebrate cat. The peak increases in heart rate and mean arterial pressure during contraction were 20 +/- 5 beats/min and 21 +/- 8 mmHg and 27 +/- 9 beats/min and 37 +/- 12 mmHg for the 3- and 5-Hz stimulation protocols, respectively. All variables returned to baseline after 10 min of recovery. Interstitial lactate rose (P < 0. 05) by 0.41 +/- 0.15 and 0.56 +/- 0.16 mM for the 3- and 5-Hz stimulation protocols, respectively, and were not statistically different from one another. Interstitial lactate levels remained above (P < 0.05) baseline during recovery in the 5-Hz group. Dialysate phosphate concentrations (corrected for shifts in probe recovery) rose with stimulation (P < 0.05) by 0.19 +/- 0.08 and 0.11 +/- 0.03 mM for the 3- and 5-Hz protocols. There were no differences between groups. The resting dialysate K+ concentrations for the 3- and 5-Hz conditions were 4.0 +/- 0.1 and 3.9 +/- 0.1 meq/l, respectively. During stimulation the dialysate K+ concentrations rose steadily for both conditions, and the increase from rest to stimulation (P < 0.05) was 0.57 +/- 0.19 and 0.81 +/- 0.06 meq/l for the 3- and 5-Hz conditions, respectively, with no differences between groups. Resting dialysate pH was 6.915 +/- 0.055 and 6.981 +/- 0.032 and rose to 7.013 (P < 0.05) and 7.053 (P < 0.05) for the 3- and 5-Hz conditions, respectively, and then became acidotic (6. 905, P < 0.05) during recovery (5 Hz only). This study represents the first time simultaneous measurements of multiple skeletal muscle interstitial metabolites and pressor responses to twitch contractions have been made in the cat. These data suggest that interstitial K+ and phosphate, but not lactate and H+, may contribute to the stimulation of thin fiber muscle afferents during contraction.     

Intracranial and spinal dissemination of an ACTH secreting pituitary neoplasia. Case report and review of the literature

Smoking is associated with insulin resistance, dyslipidaemia and markers of the insulin resistance syndrome. This study investigated adipose tissue lipolysis in situ by subcutaneous microdialysis twice in 10 healthy, male smokers after smoking four cigarettes over 2 h and after the administration of an equal amount of nicotine given as nasal spray (NNS). Glucose and insulin levels, in situ lipolysis and adipose tissue blood flow were studied in the post-absorptive state and after a 75-g oral glucose tolerance test (OGTT). Post-absorptively, acute smoking and NNS increased neither subcutaneous adipose tissue glycerol production nor plasma free fatty acid (FFA) or glycerol levels. After the OGTT, plasma insulin and lactate levels were significantly higher after smoking, whereas FFA levels were higher after NNS. Normal smoking or the administration of a normal dose of NNS caused only minor metabolic changes. Thus, it does not seem likely that increased lipolysis is an important contributor to the dyslipidaemia seen in smokers.