Running endurance in 27-h-fasted humans

Nine male marathon runners were exercised to exhaustion to determine the effects of a 27-h fast on endurance performance. Each subject completed two exercise tests at the same treadmill speed (set at 70% maximal O2 uptake), one following a 27-h fast and one 3 h after a preexercise meal, in random order. Fasting caused a 44.7 +/- 5.8% (SE) decrease in endurance performance (P less than 0.01). Blood, muscle, psychological, and ventilatory data were examined to determine the cause of the decreased performance. Fasting caused significant increases in O2 uptake (9.3 +/- 2.0%), heart rate (8.4 +/- 2.4%), and rating of perceived exertion, ventilation, and psychological fatigue, evident within the first 60 min of exercise. There were no differences in plasma glucose or epinephrine levels. Muscle glycogen degraded at the same rate (0.482 +/- 0.146 vs. 0.470 +/- 0.281 mumol.g-1.min-1 in the nonfasted and fasted tests, respectively) despite lower respiratory exchange ratio and elevated free fatty acid levels, which may partially explain the elevated O2 uptake. Lactate, insulin, and norepinephrine were all increased in the fasted test (P less than 0.05). The increase in norepinephrine (r = 0.79, P less than 0.01), the diameter of type I muscle fibers (r = 0.70, P less than 0.05), and ending insulin levels (r = -0.88, P less than 0.01) were correlated with endurance time in the fasted state. Fatigue in endurance running for 27-h fasted humans appears to be related to a combination of physiological, psychological, metabolic, and hormonal changes.     

Effects of fat adaptation and carbohydrate restoration on prolonged endurance exercise.

We determined the effect of fat adaptation on metabolism and performance during 5 h of cycling in seven competitive athletes who consumed a standard carbohydrate (CHO) diet for 1 day and then either a high-CHO diet (11 g. kg(-1)x day(-1) CHO, 1 g x kg(-1) x day(-1) fat; HCHO) or an isoenergetic high-fat diet (2.6 g x kg(-1) x day(-1) CHO, 4.6 g x kg(-1) x day(-1) fat; fat-adapt) for 6 days. On day 8, subjects consumed a high-CHO diet and rested. On day 9, subjects consumed a preexercise meal and then cycled for 4 h at 65% peak O(2) uptake, followed by a 1-h time trial (TT). Compared with baseline, 6 days of fat-adapt reduced respiratory exchange ratio (RER) with cycling at 65% peak O(2) uptake [0.78 +/- 0.01 (SE) vs. 0.85 +/- 0.02; P < 0.05]. However, RER was restored by 1 day of high-CHO diet, preexercise meal, and CHO ingestion (0.88 +/- 0.01; P < 0.05). RER was higher after HCHO than fat-adapt (0.85 +/- 0.01, 0.89 +/- 0.01, and 0.93 +/- 0.01 for days 2, 8, and 9, respectively; P < 0.05). Fat oxidation during the 4-h ride was greater (171 +/- 32 vs. 119 +/- 38 g; P < 0.05) and CHO oxidation lower (597 +/- 41 vs. 719 +/- 46 g; P < 0.05) after fat-adapt. Power output was 11% higher during the TT after fat-adapt than after HCHO (312 +/- 15 vs. 279 +/- 20 W; P = 0.11). In conclusion, compared with a high-CHO diet, fat oxidation during exercise increased after fat-adapt and remained elevated above baseline even after 1 day of a high-CHO diet and increased CHO availability. However, this study failed to detect a significant benefit of fat adaptation to performance of a 1-h TT undertaken after 4 h of cycling.     

Increased plasma apoA-IV level is a marker of abnormal postprandial lipemia: a study in normoponderal and obese subjects.

Plasma apolipoprotein A-IV (apoA-IV) levels are found elevated in hypertriglyceridemic patients. However, the relationship between plasma apoA-IV level and postprandial lipemia is not well known and remains to be elucidated. Thus, our objective was to study the relationship between plasma apoA-IV and postprandial TG after an oral fat load test (OFLT). Plasma apoA-IV was measured at fast and during an OFLT in 16 normotriglyceridemic, normoglucose-tolerant android obese subjects (BMI = 34.6 +/- 2.9 kg/m(2)) and 30 normal weight controls (BMI = 22.2 +/- 2.3 kg/m(2)). In spite of not statistically different fasting plasma TG levels in controls and obese patients, the former group showed an altered TG response after OFLT, featuring increased nonchylomicron TG area under the curve (AUC) compared with controls (516 +/- 138 vs. 426 +/- 119 mmol/l x min, P < 0.05). As compared to controls, obese patients showed increased apoA-IV levels both at fast (138.5 +/- 22.4 vs. 124.0 +/- 22.8 mg/l, P < 0.05) and during the OFLT (apoA-IV AUC: 79,833 +/- 14,281 vs. 68,176 +/- 17,463 mg/l x min, P < 0.05). Among the whole population studied, as among the control and obese subgroups, fasting plasma apoA-IV correlated significantly with AUC of plasma TG (r = 0.60, P < 0.001), AUC of chymomicron TG (r = 0.45, P < 0.01), and AUC of nonchylomicron TG (r = 0.62, P < 0.001). In the multivariate analysis, fasting apoA-IV level constituted an independent and highly significant determinant of AUC of plasma TG, AUC of chymomicron TG, AUC of nonchylomicron TG, and incremental AUC of plasma TG. In conclusion, we show a strong link between fasting apoA-IV and postprandial TG metabolism. Plasma fasting apoA-IV is shown to be a good marker of TG response after an OFLT, providing additional information on post-load TG response in conjunction with other known factors such as fasting TGs.     

Effect of exercise duration on postprandial hypertriglyceridemia in men with metabolic syndrome.

We examined the effect of exercise on postprandial hypertriglyceridemia (PHTG) and insulin resistance in individuals with metabolic syndrome. Subjects were 10 hypertriglyceridemic men with insulin resistance [age = 35.0 +/- 1.8 yr, body weight = 90.7 +/- 3.3 kg, fasting triglyceride (TG) = 2.6 +/- 0.4 mmol/l, peak oxygen consumption ((.)Vo(2peak)) = 36.0 +/- 1.3 ml(-1).kg(-1).min(-1), and homeostatic model assessment of insulin resistance (HOMA-IR)= 3.1 +/- 0.3]. Each participant performed a control trial (Ctr; no exercise) and three exercise trials at 60% of their (.)Vo(2peak) for 30 min (30 min-Ex), 45 min (45 min-Ex) and 60 min (60 min-Ex). All subjects had a fat meal in each trial. In the exercise trials, the subject jogged on a treadmill for a designated duration of 12 h before ingestion of a fat meal. Blood samples were taken at 0 h (before the meal) and at 2, 4, 6, and 8 h after the meal. The plasma TG, area score under TG concentration curve over an 8-h period (TG AUC) after the meal, and HOMA-IR were analyzed. The TG AUC scores in both the 45 min-Ex and 60 min-Ex were 31 and 33% lower, respectively, than Ctr (P < 0.02). There were no significant differences in TG AUC scores between the 30 min-Ex and the Ctr (P > 0.05). There were no trial differences in the fasting plasma glucose concentration (P > 0.05). HOMA-IR values in the 30 min-Ex, 45 min-Ex, and 60 min-Ex trials were lower than the Ctr (P < 0.03), but no significant differences were found in HOMA-IR among the exercise trials. The results suggest that for physically inactive individuals with metabolic syndrome, exercising at moderate intensity for 45 min effectively attenuates PHTG while exercise for 30 min is sufficient to improve insulin action.     

Development of leptin resistance in rat soleus muscle in response to high-fat diets

Direct evidence for leptin resistance in peripheral tissues such as skeletal muscle does not exist. Therefore, we investigated the effects of different high-fat diets on lipid metabolism in isolated rat soleus muscle and specifically explored whether leptin's stimulatory effects on muscle lipid metabolism would be reduced after exposure to high-fat diets. Control (Cont, 12% kcal fat) and high-fat [60% kcal safflower oil (n-6) (HF-Saff); 48% kcal safflower oil plus 12% fish oil (n-3)] diets were fed to rats for 4 wk. After the dietary treatments, muscle lipid turnover and oxidation in the presence and absence of leptin was measured using pulse-chase procedures in incubated resting soleus muscle. In the absence of leptin, phospholipid, diacylglycerol, and triacylglycerol (TG) turnover were unaffected by the high-fat diets, but exogenous palmitate oxidation was significantly increased in the HF-Saff group. In Cont rats, leptin increased exogenous palmitate oxidation (21.4 +/- 5.7 vs. 11.9 +/- 1.61 nmol/g, P = 0.019) and TG breakdown (39.8 +/- 5.6 vs. 27.0 +/- 5.2 nmol/g, P = 0.043) and decreased TG esterification (132.5 +/- 14.6 vs. 177.7 +/- 29.6 nmol/g, P = 0.043). However, in both high-fat groups, the stimulatory effect of leptin on muscle lipid oxidation and hydrolysis was eliminated. Partial substitution of fish oil resulted only in the restoration of leptin's inhibition of TG esterification. Thus we hypothesize that, during the development of obesity, skeletal muscle becomes resistant to the effects of leptin, resulting in the accumulation of intramuscular TG. This may be an important initiating step in the development of insulin resistance common in obesity.     

Postprandial lipemia in young men and women of contrasting training status.

This study compared the postprandial triacylglycerol (TAG) response to a high-fat meal in trained and untrained normolipidemic young adults after 2 days' abstinence from exercise. Fifty-three subjects (11 endurance-trained men, 9 endurance-trained women, 10 sprint/strength-trained men, 11 untrained men, 11 untrained women) consumed a meal (1.2 g fat, 1.1 g carbohydrate, 66 kJ per kg body mass) after a 12-h fast. Venous blood samples were obtained in the fasted state and at intervals until 6 h. Postprandial responses were the areas under the plasma or serum concentration-vs.-time curves. Neither fasting TAG concentrations nor the postprandial TAG response differed between trained and untrained subjects. The insulinemic response was 29% lower in endurance-trained men than in untrained men [mean difference -37.4 (95% confidence interval -62.9 to -22.9) microIU/ml x h, P = 0.01]. Responses of plasma glucose, serum insulin, and plasma nonesterified fatty acids were all lower for endurance-trained men than for untrained men. These findings suggest that, in young adults, no effect of training on postprandial lipemia can be detected after 60 h without exercise. The effect on postprandial insulinemia may persist for longer.     

Involvement of intestinal alkaline phosphatase in serum apolipoprotein B-48 level and its association with ABO and secretor blood group types

Serum levels of intestinal alkaline phosphatase (IAP), a protein implicated in transcellular transport of chylomicrons, vary among ABO blood groups. In rat enterocytes, IAP is associated with chylomicron secretion, but the rat expresses only blood group A. It is not known whether chylomicron secretion may be affected in humans who express multiple blood group types. Serum samples from 40 healthy subjects were obtained after overnight fast and 3h after a high-fat meal, and assayed for IAP and apolipoprotein B-48 (apoB-48), both proteins exclusive to intestine, although only apoB-48 is found in chylomicrons. The two proteins were greater in subjects without blood antigen A (B and O) than in those with this antigen (A and AB); 2.4- and 4.7-fold for IAP and 1.5- and 2.0-fold for apoB-48 before and after the meal, respectively. Moreover, IAP and apoB-48 levels were strongly correlated in the subjects with the secretor phenotype (r > 0.81). These results indicate that IAP is strongly involved in chylomicron formation and fatty acid metabolism might change among ABO blood type. In addition, ABO blood type classification in apoB-48 measurement would improve the diagnostic value in the evaluation of metabolic syndrome.     

Effects of fasting on insulin action and glucose kinetics in lean and obese men and women

The development of insulin resistance in the obese individual could impair the ability to appropriately adjust metabolism to perturbations in energy balance. We investigated a 12- vs. 48-h fast on hepatic glucose production (R(a)), peripheral glucose uptake (R(d)), and skeletal muscle insulin signaling in lean and obese subjects. Healthy lean [n = 14; age = 28.0 +/- 1.4 yr; body mass index (BMI) = 22.8 +/- 0.42] and nondiabetic obese (n = 11; age = 34.6 +/- 2.3 yr; BMI = 36.1 +/- 1.5) subjects were studied following a 12- and 48-h fast during 2 h of rest and a 3-h 40 mUxm(-2)xmin(-1) hyperinsulinemic-euglycemic clamp (HEC). Basal glucose R(a) decreased significantly from the 12- to 48-h fast (lean 1.96 +/- 0.23 to 1.63 +/- 0.15; obese 1.23 +/- 0.07 to 1.07 +/- 0.07 mgxkg(-1)xmin(-1); P = 0.004) and was equally suppressed during the HEC after both fasts. The increase in glucose R(d) during the HEC after the 12-h fast was significantly decreased in lean and obese subjects after the 48-h fast (lean 9.03 +/- 1.17 to 4.16 +/- 0.34, obese 6.10 +/- 0.77 to 3.56 +/- 0.30 mgxkg FFM(-1)xmin(-1); P < 0.001). After the 12- but not the 48-h fast, insulin-stimulated AKT Ser(473) phosphorylation was greater in lean than obese subjects. We conclude that 1) 48 h of fasting produces a marked decline in peripheral insulin action, while suppression of hepatic glucose production is maintained in lean and obese men and women; and 2) the magnitude of this decline is greater in lean vs. obese subjects.     

Association between Myocardial Triglyceride Content and Cardiac Function in Healthy Subjects and Endurance Athletes

Ectopic fat accumulation plays important roles in various metabolic disorders and cardiovascular diseases. Recent studies reported that myocardial triglyceride (TG) content measured by proton magnetic resonance spectroscopy (¹H-MRS) is associated with aging, diabetes mellitus, and cardiac dysfunction. However, myocardial TG content in athletes has not yet been investigated. We performed ¹H-MRS and cardiac magnetic resonance imaging in 10 male endurance athletes and 15 healthy male controls. Serum markers and other clinical parameters including arterial stiffness were measured. Cardiopulmonary exercise testing was also performed. There were no significant differences in clinical characteristics including age, anthropometric parameters, blood test results, or arterial stiffness between the two groups. Peak oxygen uptakes, end–diastolic volume (EDV), end–systolic volume (ESV), left ventricular (LV) mass, peak ejection rates and peak filling rates were significantly higher in the athlete group than in the control group (all P<0.02). Myocardial TG content was significantly lower in the athlete group than in the control group (0.60±0.20 vs. 0.89±0.41%, P<0.05). Myocardial TG content was negatively correlated with EDV (r = −0.47), ESV (r = −0.64), LV mass (r = −0.44), and epicardial fat volume (r = 0.47) (all P<0.05). In conclusion, lower levels of myocardial TG content were observed in endurance athletes and were associated with morphological changes related to physiological LV alteration in athletes, suggesting that metabolic imaging for measurement of myocardial TG content by ¹H-MRS may be a useful technique for noninvasively assessing the “athlete’s heart”.     

Bioavailability of starch and postprandial changes in splanchnic glucose metabolism in pigs

Changes in splanchnic metabolism in pigs were assessed after meals containing slowly or rapidly digested starch. The pigs were fed a mixed meal containing a "slow" native (n = 5) or a "rapid" pregelatinized (n = 5) cornstarch naturally enriched with [(13)C]glucose. Absorption of [(13)C]glucose was monitored by the arteriovenous difference technique, and infusion of D-[6, 6-(2)H(2)]glucose in the jugular vein was used to calculate the systemic appearance of [(13)C]glucose. Arteriovenous balance data obtained during a 12-h study period showed that the fraction of ingested glucose equivalent appearing as glucose in the portal vein was 49.7 +/- 7.2% for the slow starch and 48.2 +/- 7.5% for the rapid starch (P = 0.86). These values, corrected for the gut extraction of circulating [(13)C]glucose, became 66.4 +/- 5.6 and 65. 3 +/- 5.6%, respectively (P = 0.35). Isotope dilution data indicated that systemic appearance of exogenous [(13)C]glucose represented 62. 9 +/- 7.6 and 67.4 +/- 3.0% of the oral load for slow and rapid starch, respectively (P = 0.68). Arterial glucose utilization by the gut increased from 7.3 +/- 0.9 micromol x kg(-1) x min(-1) before the meal to 8.5 +/- 1.6 micromol x kg(-1) x min(-1) during absorption, independently of the nature of the starch. Thus splanchnic glucose metabolism was unaffected by the nature of starch ingested.     

Serum sphingomyelin levels are related to the clearance of postprandial remnant-like particles

It is known that sphingomyelin (SM) content is higher in apolipoprotein B-containing particles (BLps) than in high density lipoproteins and that BLp levels, including chylomicrons and their remnant particles, are positively related to atherosclerosis. To evaluate the relationship between serum SM and postprandial remnant particle levels, we determined SM, triglyceride (TG), and cholesterol levels in serum and in remnant-like particles (RLPs) before and 3, 5, 7, and 10 h after a high-fat meal in 31 healthy subjects. We found that serum SM, like serum TG, was increased to its maximum 3 h after fat loading and then gradually decreased to basal levels after 10 h. More important, we determined that SM and TG levels in RLPs were parallel. Serum SM was positively correlated with serum TG (P <0.001), RLP SM (P <0.001), RLP TG (P <0.001), and RLP cholesterol (P <0.001) levels. It is our conclusion that serum SM is a marker for the clearance of RLPs.     

Increased circadian prolactin release is blunted after body weight loss in obese premenopausal women

We recently showed that prolactin (PRL) release is considerably enhanced in obese women in proportion to the size of their visceral fat mass. PRL release is inhibited by dopamine 2 receptor (D2R) activation, and dietary restriction/weight loss are associated with increased dopaminergic signaling in animals. Therefore, we hypothesized that enhanced PRL release in obese humans would be reversed by weight loss. To evaluate this postulate, we measured 24-h plasma PRL concentrations at 10-min intervals in 11 obese premenopausal women (BMI 33.3 +/- 0.7 kg/m2) before and after weight loss (50% reduction of overweight/15% absolute weight loss, using a very low-calorie diet) in the follicular phase of their menstrual cycle. The 24-h PRL concentration profiles were analyzed by a peak detection program (Cluster) and a wave form-independent deconvolution technique (Pulse). Spontaneous 24-h PRL secretion was significantly reduced in obese women [mean daily release, before 128 +/- 24 vs. after weight loss 110 +/- 17 microg/liter distribution volume (Vdl)(-1) x 24 h, P = 0.05]. Body weight loss particularly blunted PRL secretory burst mass (Pulse area, before 230 +/- 28 vs. after weight loss 221 +/- 31 microg/Vdl(-1) x 24 h, P = 0.03), whereas burst frequency was unaffected (no. of pulses, before 11 +/- 1 vs. after weight loss 12 +/- 1 n/24 h, P = 0.69). Thus elevated PRL secretion rate in obese women is significantly reduced after loss of 50% of overweight. We speculate that amelioration of deficit D2R-mediated neurotransmission and/or diminutions of circulating leptin/estrogen levels might be involved in the physiology of this phenomenon.     

Reduced alpha(2)-adrenergic sensitivity of subcutaneous abdominal adipocytes as a modulator of fasting and postprandial triglyceride levels in men

This study examined the postprandial lipemia of two groups of men displaying similar age, body weight, and regional fat distribution, but characterized by either low (n = 11) or high (n = 15) alpha(2)-adrenergic sensitivity of subcutaneous abdominal adipocytes. In addition to fat cell lipolysis, adipose tissue lipoprotein lipase (AT-LPL) as well as postheparin plasma LPL activities were measured in the fasting state. Fasting AT-LPL and PH-LPL activities were similar in both groups. Maximal adipose cell lipolysis induced by isoproterenol (beta-adrenergic agonist) as well as the beta-adrenergic sensitivity did not differ between both groups of men. The selective alpha(2)-adrenergic agonist UK-14304 promoted a similar antilipolytic response in subcutaneous abdominal adipocytes from both groups. However, the alpha(2)-adrenergic sensitivity, defined as the dose of UK-14304 that produced half-maximal inhibition of lipolysis (IC(50)), was significantly different between groups (P < 0.0001). Men with low versus high subcutaneous abdominal fat cell alpha(2)-adrenergic sensitivity showed higher fasting TG levels. In the whole group, a positive relationship was observed between log-transformed IC(50) UK-14304 values of subcutaneous adipocytes and fasting TG levels (r = 0.39, P < 0.05), suggesting that a low abdominal adipose cell alpha(2)-adrenergic sensitivity is associated with high TG levels. After the consumption of a high-fat meal, subjects with low subcutaneous abdominal adipose cell alpha(2)-adrenergic sensitivity showed higher TG levels in total, medium, and small triglyceride-rich lipoprotein (TRL) fractions at 0- to 6-h time points than men with high adipocyte alpha(2)-adrenergic sensitivity (P values ranging from 0.01 to 0.05). Stepwise regression analysis showed that the fasting TG concentration was the only variable retained as a significant predictor of the area under the curve of TG levels in total TRL fractions (73% of variance) among independent variables such as body weight, percent body fat, visceral and subcutaneous abdominal adipose tissue accumulation measured by CT, as well as subcutaneous abdominal fat cell alpha(2)-adrenoceptor sensitivity.Taken together, these results indicate that a reduced antilipolytic sensitivity of subcutaneous abdominal adipocytes to catecholamines may increase fasting TG levels, which in turn play a role in the etiology of an impaired postprandial TRL clearance in men.     

Short-term flexibility of myocardial triglycerides and diastolic function in patients with type 2 diabetes mellitus

Short-term caloric restriction increases plasma levels of nonesterified fatty acids (NEFAs) and is associated with increased myocardial triglyceride (TG) content and decreased myocardial function in healthy subjects. Whether this flexibility of myocardial TG stores and myocardial function is also present in patients with type 2 diabetes mellitus (T2DM) is yet unknown. Myocardial TG content and left ventricular (LV) ratio between the early (E) and atrial (A) diastolic filling phase (E/A) were determined using magnetic resonance (MR) spectroscopy and MR imaging, respectively, before and after a 3-day very low-calorie diet (VLCD) in 11 patients with T2DM. In addition, we studied patients after a 3-day VLCD combined with the antilipolytic drug acipimox. The VLCD induced myocardial TG accumulation [from 0.66 +/- 0.09% (mean +/- SE, baseline) to 0.98 +/- 0.16%, P = 0.028] and a decrease in E/A ratio [from 1.00 +/- 0.05 (baseline) to 0.90 +/- 0.06, P = 0.002]. This was associated with increased plasma NEFA levels (from 0.57 +/- 0.08 mmol/l at baseline to 0.92 +/- 0.12, P = 0.019). After the VLCD with acipimox, myocardial TG content, diastolic function, and plasma NEFA levels were similar to baseline values. In conclusion, in patients with T2DM, a VLCD increases myocardial TG content and is associated with a decrease in LV diastolic function. These effects were not observed when a VLCD was combined with acipimox, illustrating the physiological flexibility of myocardial TG stores and myocardial function in patients with T2DM.     

Comparison of the expression and activity of the lipogenic pathway in human and rat adipose tissue

Lipogenesis is considered less active in human than in rat adipose tissue. This could be explained by different nutritional conditions, namely high-carbohydrate (HCHO) diet in rats and high-fat (HF) diet in humans. Adipose tissue was sampled (postabsorptive state) in rats and humans receiving HCHO or HF diets, ad libitum fed humans, and obese subjects. We measured 1) mRNA concentrations of fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), sterol regulatory element binding protein 1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP), 2) SREBP-1c protein, and 3) FAS activity. FAS, ACC1, ChREBP, and SREBP1-c mRNA concentrations were unaffected by diet in humans or in rats. FAS and ACC1 mRNA levels were lower in humans than in rats (P < 0.05). FAS activity was unaffected by diet and was lower in humans (P < 0.05). SREBP-1c mRNA concentrations were similar in rats and humans, but the precursor and mature forms of SREBP-1c protein were less abundant in humans (P < 0.05). ChREBP mRNA concentrations were lower in humans than in rats. In conclusion, the lipogenic capacity of adipose tissue is lower in humans than in rats. This is not related to differences in diet and is probably explained by lower abundance of SREBP-1c protein. A decreased expression of ChREBP could also play a role.     

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.     

Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men

Context

Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified.

Objective

To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal.

Design

Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5–40.2 kg/m²) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL₁ and VLDL₂) were measured after the fat-rich meal.

Main Outcome Measures

Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.

Results

The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.

Conclusions

In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.     

The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

Fasting promotes triglyceride (TG) accumulation in lean tissues of some animals, but the effect in humans is unknown. Additionally, fasting lipolysis is sexually dimorphic in humans, suggesting that lean tissue TG accumulation and metabolism may differ between women and men. This study investigated lean tissue TG content and metabolism in women and men during extended fasting. Liver and muscle TG content were measured by magnetic resonance spectroscopy during a 48-h fast in healthy men and women. Whole-body and hepatic carbohydrate, lipid, and energy metabolism were also evaluated using biochemical, calorimetric, and stable isotope tracer techniques. As expected, postabsorptive plasma fatty acids (FAs) were higher in women than in men but increased more rapidly in men with the onset of early starvation. Concurrently, sexual dimorphism was apparent in lean tissue TG accumulation during the fast, occurring in livers of men but in muscles of women. Despite differences in lean tissue TG distribution, men and women had identical fasting responses in whole-body and hepatic glucose and oxidative metabolism. In conclusion, TG accumulated in livers of men but in muscles of women during extended fasting. This sexual dimorphism was related to differential fasting plasma FA concentrations but not to whole body or hepatic utilization of this substrate.     

高脂饮食诱导的C57BL／6J肥胖小鼠脂肪组织RIP140基因表达水平的研究

目的：探讨高脂饮食致肥胖小鼠脂肪组织RIP140mRNA表达水平的变化及其与胰岛素抵抗的关系。方法：将C57BL／6J雄性小鼠随机分为正常饮食（NFD）组、高脂饮食（HFD）纽分别喂养14周后,测量两组小鼠体重,以NFD组小鼠体重作为对照,选取HFD组中体重大于对照组小鼠平均体重20％的小鼠作为肥胖组小鼠。对照组和肥胖组小鼠取血测甘油三酯（TG）、总胆固醇（TC）、空腹血糖（FBG）、空腹胰岛素水平（FIns）,计算稳态模型胰岛素抵抗指数（HOMA-IR）;采用RT—PCR技术检测两组小鼠附睾脂肪组织RIP140 mRNA的表达水平,并进行统计学分析。结果：HDF组小鼠中有12只符合标准计入肥胖组。肥胖组小鼠TG、TC、FBG、Fins（P〈0．05）,HOMA-1R（P〈0．01）均明显高于对照组;肥胖组小鼠脂肪组织RIP140mRNA的表达高于对照组,差异具有统计学意义（P〈0．05）;相关分析显示小鼠脂肪组织R1P140 mRNA表达水平与TG水平呈正相关（r=0．536,P〈0．05）,与胰岛素抵抗指数呈正相关（r=0．465,P〈0．05）,而与TC、FBG、Fins水平相关分析无统计学意义（P〉0．05）。结论：高脂饮食诱导的肥胖小鼠脂肪组织RIP140 mRNA表达增加,并与胰岛素抵抗程度呈正相关。     

A high-fat diet raises fasting plasma CCK but does not affect upper gut motility, PYY, and ghrelin, or energy intake during CCK-8 infusion in lean men

There is evidence from studies in animals that the effects of both fat and CCK on gastrointestinal function and energy intake are attenuated by consumption of a high-fat diet. In humans, the effects of exogenous CCK-8 on antropyloroduodenal motility, plasma CCK, peptide YY (PYY), and ghrelin concentrations, appetite, and energy intake are attenuated by a high-fat diet. Ten healthy lean males consumed isocaloric diets (~15,400 kJ per day), containing either 44% (high-fat, HF) or 9% (low-fat, LF) fat, for 21 days in single-blind, randomized, cross-over fashion. Immediately following each diet (i.e., on day 22), subjects received a 45-min intravenous infusion of CCK-8 (2 ng.kg(-1).min(-1)), and effects on antropyloroduodenal motility, plasma CCK, PYY, ghrelin concentrations, hunger, and fullness were determined. Thirty minutes after commencement of the infusion, subjects were offered a buffet-style meal, from which energy intake (in kilojoules) was quantified. Body weight was unaffected by the diets. Fasting CCK (P < 0.05), but not PYY and ghrelin, concentrations were greater following the HF, compared with the LF, diet. Infusion of CCK-8 stimulated pyloric pressures (P < 0.01) and suppressed antral and duodenal pressures (P < 0.05), with no difference between the diets. Energy intake also did not differ between the diets. Short-term consumption of a HF diet increases fasting plasma CCK concentrations but does not affect upper gut motility, PYY and ghrelin, or energy intake during CCK-8 infusion, in a dose of 2 ng.kg(-1).min(-1), in healthy males.