Plasma glucagon, insulin and glucose responses to intravenous arginine infusion in the rat

Plasma glucagon (IRG), insulin and glucose responses to intravenous arginine infusion in the rat were studied. Three doses of arginine hydrochloride were infused into fasted rats: 0.2 gm/kg b.w., 0.5 gm/kg b.w., and 1 gm/kg b.w. The 0.2 gm/kg dose did not result in significant elevation of plasma IRG or insulin. Both the 0.5 and 1 gm/kg doses produced a significant increase in glucagon and insulin levels within 5 minutes of starting the infusion. The 1 gm/kg dose was most effective in stimulating secretion of both hormones. This dose produced a 250% rise in the plasma IRG compared to 80% peak rise with the 0.5 gm/kg dose (p less than .01) and 1055% rise in insulin levels compared to a peak level of 225% above baseline with the 0.5 gm/kg dose (p less than .001). These results demonstrate the effectiveness of intravenous arginine in the stimulation of glucagon and insulin secretion in the rat.     

Plasma free fatty acid transport during prolonged glucose consumption and its relationship to plasma triglyceride fatty acids in man

Plasma free fatty acid (FFA) transport in human subjects has been studied during the course of prolonged ingestion of different amounts of glucose. Compared with the fasting state, hypocaloric glucose intake resulted in marked suppression of net transport of FFA with no change in (fractional) turnover rate. There was no further suppression of net transport of FFA when the intake was increased to isocaloric or hypercaloric levels, but there was a significant increase in the (fractional) turnover rate, indicating an enhancement of clearance mechanisms. During the 20-24-hr period of fasting after isocaloric glucose consumption, the (fractional) turnover rate quickly fell to that found in the fasting individual, whereas net transport remained suppressed for much longer. This suggested that ingestion of glucose maintains an influence on lipolysis longer than on esterification. During this period of fasting after glucose administration, the contribution of plasma FFA to circulating triglyceride fatty acids increased with time and was positively and significantly correlated with the changes in the net transport of plasma FFA.     

Impaired hemorrhage tolerance in the obese Zucker rat model of metabolic syndrome.

As obese Zucker rats (OZR) manifesting the metabolic syndrome exhibit enhanced vascular adrenergic constriction and potentially an enhanced adrenergic activity vs. lean Zucker rats (LZR), this study tested the hypothesis that OZR exhibit an improved tolerance to progressive hemorrhage. Preliminary experiments indicated that, corrected for body mass, total blood volume was reduced in OZR vs. LZR. Anesthetized LZR and OZR had a cremaster muscle prepared for in situ videomicroscopy and had renal, splanchnic, hindlimb, and skeletal muscle perfusion monitored with flow probes. Arterial pressure, arteriolar reactivity to norepinephrine, and tissue/organ perfusion were monitored after either infusion of phentolamine or successive withdrawals of 10% total blood volume. Phentolamine infusion indicated that regional adrenergic tone under control conditions differs substantially between LZR and OZR, whereas with hemorrhage OZR exhibit decompensation in arterial pressure before LZR. Renal, distal hindlimb, and skeletal muscle perfusion decreased more rapidly and to a greater extent in OZR vs. LZR after hemorrhage. In contrast, hemorrhage-induced reductions in splanchnic perfusion in OZR lagged behind those in LZR, although a similar maximum reduction was ultimately attained. With increasing hemorrhage, cremasteric arteriolar tone increased more in OZR than LZR, and this increase in active tone was entirely due to an elevated adrenergic contribution. Norepinephrine-induced arteriolar constriction was greater in OZR vs. LZR under control conditions and during hemorrhage, with arterioles from OZR demonstrating early closure vs. LZR. These results suggest that a combination of reduced blood volume and elevated peripheral adrenergic constriction contribute to impaired hemorrhage tolerance in OZR.     

Wild blueberry (Vaccinium angustifolium) consumption improves inflammatory status in the obese Zucker rat model of the metabolic syndrome

The metabolic syndrome (MetS) is a major public health problem in the United States. Chronic inflammation is a critical component of the MetS, leading to dramatically increased risk of type II diabetes and cardiovascular disease.This study investigates the ability of a wild-blueberry-enriched diet to improve the proinflammatory status associated with MetS in the obese Zucker rat (OZR). Circulating levels of key inflammatory markers and their expression in the liver and abdominal adipose tissue were examined in OZR and its genetic control, the lean Zucker rat (LZR), after feeding a control or an 8% wild blueberry diet (WB) for 8 weeks from age 8 to 16 weeks.In the OZR, WB consumption resulted in decreased plasma concentrations of tumor necrosis factor (TNF)-α (?25.6%, P<.05), interleukin (IL)-6 (?14.9%, P<.05) and C-reactive protein (CRP) (?13.1%, P<.05) and increased adiponectin concentration (+21.8%, P<.05). Furthermore, expression of IL-6, TNF-α and nuclear factor (NF)-kB was down-regulated in both the liver (?65%, ?59% and ?25%, respectively) and the abdominal adipose tissue (?64%, ?52% and ?65%), while CRP expression was down-regulated only in the liver (?25%). In the abdominal adipose tissue, similar trends were also observed in LZR following WB treatment, with decreased liver expression of NF-kB, CRP, IL-6 and TNF-α (?24%, ?16%, ?21% and ?50%) and increased adiponectin expression (+25%).Results of this study suggest that wild blueberry consumption exerts an overall anti-inflammatory effect in the OZR, a model of the metabolic syndrome.     

Plasma glucagon-like peptide-1 (GLP-1) responses to duodenal fat and glucose infusions in lean and obese men

It has been suggested that obesity is associated with a reduced glucagon-like peptide-1 (GLP-1) response to oral carbohydrate, but not fat. The latter may, however, be attributable to changes in gastric emptying. We have assessed plasma GLP-1 levels in response to these infusions in lean and obese subjects. Seven healthy lean (body mass index (BMI), 19.1-24.6 kg/m(2)) and seven obese (BMI, 31.3-40.8 kg/m(2)) young men received an intraduodenal infusion of glucose and fat for 120 min (2.86 kcal/min) on two separate days. Blood samples for plasma GLP-1 were obtained at baseline and every 20 min during the infusion. Plasma GLP-1 increased during infusion of glucose and fat (P = 0.001), but there were no differences between lean and obese subjects, nor the two nutrients. We conclude that GLP-1 secretion in response to duodenal infusion of glucose and fat is not altered in obese subjects.     

Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome

Aim

The aim of this study was to examine the effects of cholecalciferol on systemic inflammation and memory in the setting of fatty liver disease in rats.

Materials and methods

To induce the development of fatty liver disease, the rats were fed a 35% fructose solution over 8 weeks. Group I (n = 6) was designated as the control group and fed with standard rat chow. Group II (n = 6) was provided with, standard rat chow, and 0.3 μg/kg/day of oral cholecalciferol over a duration of 2 weeks. In addition to standard rat chow, group III (n = 6) and group IV (n = 6) were given 4 mL of the 35% fructose solution per day via oral gavage for 8 weeks. However, group IV was also given 0.3 μg/kg/day of oral cholecalciferol over 2 weeks. After the treatment period, passive avoidance tasks were performed by all groups. The liver and brain were harvested for subsequent biochemical and histopathologic analyses.

Key findings

The development of fatty liver extends the memory latency period of passively avoiding tasks after 1 trial. Moreover, there were increases in brain TNF-α and plasma MDA levels according to two-way analysis of variance. Cholecalciferol supplementation decreased the latency period of passively avoiding tasks in rats with hepatosteatosis, and also significantly reduced brain TNF-α and plasma MDA levels.

Significance

Fatty liver may contribute to the development of systemic inflammation, which affects cognition and causes deficits in memory; however, the anti-inflammatory and antioxidant properties of vitamin D may improve the cognitive function of rats with hepatosteatosis.     

Effect of glucagon on glucose and fatty acid metabolism in goats.

Adult goats of a white breed were injected i.v. with glucagon in doses of 6.25--25 mug/kg. The blood sugar curve rose relatively slowly after the injection after the injection and the maximum increase, which attained 360--400% of the resting value was usually recorded 20-30 min after glucagon administration. The non-esterified fatty acid (NEFA) level rose immediately after injecting glucose. Within 10 min it returned to the initial value and then fell abruptly. No concentration correlation was found between the glucagon dose and the size of the metabolic response.     

Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome

Non-alcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome characterized by dislipidemia and insulin resistance. We hypothesized that ezetimibe, an inhibitor of NPC1L1, improves these metabolic disorders in Zucker obese fatty rats (ZOF). Ezetimibe significantly lowered total cholesterol and triglycerides in ZOF with prominent reduction in the remnant lipoprotein fraction and small dense low density lipoprotein fraction. Moreover, lipid deposition and fibrosis of liver were decreased by ezetimibe. Interestingly, ezetimibe improved insulin and plasma glucose response after intraperitoneal glucose injection. Further, ezetimibe enhanced insulin signaling in cultured hepatocytes. Our results indicate the potential of ezetimibe in treating the metabolic syndrome and NAFLD.     

Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid (TDGA) on glucose and fatty acid oxidation in isolated rat soleus muscle

1. The effect of 2-tetradecylglycidic acid (TDGA), a potent, specific inhibitor of long-chain fatty acid oxidation, on fatty acid and glucose oxidation by isolated rat soleus muscle was studied. 2. TDGA inhibited [1-14C]palmitate oxidation by soleus muscle in a concentration-dependent manner. 3. TDGA inhibited the activity of soleus muscle mitochondrial carnitine palmitoyltransferase A (CPT-A). 4. Added palmitate (0.5 mM) significantly inhibited D-[U-14C]glucose oxidation and, under conditions where TDGA inhibited palmitate oxidation, the oxidation of D-[U-14C]glucose by isolated soleus muscle was significantly stimulated. 5. TDGA stimulation of glucose oxidation was reversed by octanoate, a medium-chain fatty acid whose oxidation is not inhibited by TDGA. 6. When nondiabetic rats were treated with TDGA (10 mg/kg p.o./day x 3 days), fasting plasma glucose was significantly lowered and the ability of isolated contralateral soleus muscles to oxidize palmitate was inhibited while glucose oxidation was significantly stimulated.     

Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model

Background

Obesity is associated with various progressive age-related diseases, including neurological disorders. However, underlying molecular basis for increased risk of neurodegeneration in obesity is unknown. A suitable animal model would immensely help in understanding the obesity-linked neurological problems.

Methods

A spontaneously developed obese rat (WNIN/Ob) which is highly vulnerable for a variety of degenerative diseases was isolated from the existing WNIN stock rats. Ultrastructure of neurons in the cerebral cortex of 12-month old obese rats was evaluated by transmission electron microscopy. qRT-PCR and immunoblotting of ubiquitin C-terminal hydrolases (UCHs), ubiquitin, proteasomal sub-units, markers of ER stress and apoptosis were performed in the cerebral cortex. Proteasome activity was assayed by fluorometric method. Immunohistochemistry was performed for mediators of apoptosis, which was further confirmed by TUNEL assay. These investigations were also carried in high-fat diet-induced obese rat model.

Results

Neurons in the cerebral cortex of 12-month obese rats showed swollen mitochondria, disrupted ER and degenerating axons, nucleus and finally neurons. Results showed altered UPS, existence of ER stress, up-regulation of apoptotic markers and apoptosis in the cerebral cortex of obese rats. It appears that UCHL-1 mediated apoptosis through stabilizing p53 might play a role in neuronal cell death in obese rat. Similar changes were observed in the brain of diet-induced obese WNIN rats.

Conclusion

Altered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions.

General significance

This is the first report to highlight the role of altered UPS in neurodegeneration due to obesity.     

The role of insulin, glucagon and growth hormone in the regulation of plasma glucose and free fatty acid levels in anorexia nervosa

It is well established that glucagon plays an important role in the regulation of fuel supplies as its plasma level increases during the first days of a complete fast. However, it is not certain that glucagon is involved in the adaptation to chronic starvation. In the present study, this problem was investigated by the determination of the changes in the plasma glucagon level elicited by an i.v. glucose tolerance test followed by an i.v. arginine perfusion in 26 self starved patients suffering from anorexia nervosa (AN) and 14 control patients having only minor neurotic disorders. The basal plasma glucagon level tended to be higher in the AN patients than in the controls; but the difference was not statistically significant. Glucagon responses to glucose and arginine observed in the AN patients were not significantly different from those seen in the control patients. In the AN patients, the insulin response to both loads was reduced and the plasma GH level increased paradoxically after the glucose load, whereas it rose normally after the arginine load. It may be concluded that in chronic starvation by AN the regulation of fuel supplies depends mainly on decreased insulin and increased growth hormone secretion. The role of glucagon seems to be of minor importance in this condition.     

Changes in plasma glucose, insulin (IRI), glucagon (IRG) and free fatty acids (FFA) following alanine loading in hyperthyroid patients

The responses of plasma glucose, insulin (IRI), glucagon (IRG) and free fatty acids (FFA) following alanine loading (0.1 g/kg) were observed in 9 control subjects and 7 hyperthyroid patients, before and after restoration of thyroid function to normal. Despite the persistence of impaired glucose response to alanine, the blunted IRI and IRG responses in the hyperthyroid state were improved with a significant reduction in fasting IRI and IRG after treatment. Markedly increased FFA following alanine loading in hyperthyroid patients was reduced after treatment, but the FFA concentration remained greater than in the control subjects. We tentatively conclude that the impaired alpha and beta-cell responses to alanine were temporarily induced by the direct and/or indirect effects of thyroid hormone excess.     

Human glucagon and vasoactive intestinal polypeptide (VIP) stimulate free fatty acid release from human adipose tissue in vitro

Glucagon, vasoactive intestinal polypeptide and secretin are strong stimulators of lipolysis in adipose tissue from laboratory animals. Yet, in human adipose tissue these data could not be confirmed under comparable experimental conditions. Using pH stat titration, an advanced in vitro test system for evaluating lipolysis, it was possible to demonstrate lipolytic activity for glucagon down to a concentration of 10(-8) mol/l. This is comparable to the minimal effective doses in rat adipose tissue and corresponds to the effect of equimolar concentrations of noradrenaline in man. Secretin with an amino acid sequence very similar to glucagon was not lipolytically active, while VIP stimulated free fatty acid release in a concentration of 10(-6) mol/l. Since the minimal effective dose of glucagon is only 30 times greater than the plasma levels a physiological significance of these finding may be suggested. The lipolytic activity of VIP seems to be only of pharmacological interest.