Insulin response and changes in composition of non-esterified fatty acids in blood plasma of middle-aged men following isoenergetic fatty and carbohydrate breakfasts

It was previously shown that a high plasma concentration of non-esterified fatty acids (NEFA) persisted after a fatty breakfast, but not after an isoenergetic carbohydrate breakfast, adversely affecting glucose tolerance. The higher concentration after the fatty breakfast may in part have been a result of different mobilization rates of fatty acids. This factor can be investigated as NEFA mobilized from tissues are monounsaturated to a greater extent than those deposited from a typical meal. Twenty-four middle-aged healthy Caucasian men were given oral glucose tolerance tests (OGTT), and for 28 d isoenergetic breakfasts of similar fat composition but of low (L) or moderate (M) fat content. The composition of NEFA in fasting and postprandial plasma was determined on days 1 and 29. No significant treatment differences in fasting NEFA composition occurred on day 29. During the OGTT and 0-1 h following breakfast there was an increase in plasma long-chain saturated NEFA but a decrease in monounsaturated NEFA (mug/100 mug total NEFA; Pg/100 mug total NEFA; P<0.05), expressed as an increase in 18:1 and decreases in 16:0 and 17:0 in treatment M relative to treatment L (P<0.05). Serum insulin attained 35 and 65 mU/l in treatments M and L respectively during this period. Negative correlations were found between 16:0 in fasting plasma and both waist:hip circumference (P=0.0009) and insulin response curve area during OGTT (within treatment M, P=0.0001). It is concluded that a normal postprandial insulin response is associated with a rapid change in plasma saturated:monounsaturated NEFA. It is proposed that this change is the result of a variable suppression of fat mobilization, which may partly account for a large difference in postprandial total plasma NEFA between fatty and carbohydrate meals

Effects of high- and low-fat meals on the diurnal response of plasma lipid metabolite concentrations in healthy middle-aged volunteers

Three experiments were conducted in healthy middle-aged volunteers (six males and six females in Expt 1, six males and two females in Expt 2 and twelve males in Expt 3) with a mean BMI of 27 kg/m(2) to determine whether there is a difference between morning and afternoon dietary fat clearance and utilization, and to determine in what way the fat and starch contents of the meal influence postprandial blood lipid metabolites over 4.5 h. Over 4 days in Expt 1 each subject received isoenergetic, high-carbohydrate (L, 5.5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a high fat lunch (MM) in a randomized and balanced arrangement. Each evening a standard meal was given. The following effects were significant (P < 0.05): plasma triacylglycerol (TAG) responses were greater following RI meals; plasma TAG concentrations were greater in the afternoon than in the morning, following two meats of the same composition, although the postprandial incremental response was less following lunch than following breakfast and peak responses were reached much earlier than after breakfast; a low-fat breakfast, or fasting at breakfast time, delayed the peak TAG response to a M lunch. The plasma concentrations of nonesterified fatty acids (NEFA) and of free glycerol were higher in the afternoon following M meals at breakfast and lunch, especially in males. This response was reduced, by the L breakfast preceding the M lunch. Two M meals in succession lowered plasma HDL-cholesterol concentration. In Expt 2 each subject received a very low-fat (VL) breakfast, followed by a lunch of the same composition. Each of these meals was followed, 110 min from the start of eating, by an infusion of Intralipid 10 % emulsion at the rate of 1 ml/kg body weight over 60 s. Clearance rates of Intralipid were faster in the afternoon than in the morning (P = 0.024). In Expt 3 twelve subjects were randomly allocated to either treatment MM or LM meal patterns, as given in Expt 1. These were given daily for a period of 17 d, during which the change in fasting plasma TAG concentration was similar in both treatments. On days 1, 16 and 17 responses were measured to the M lunch and to a glucose tolerance test (GTT), conducted 2 h 17 min after lunch. The post-lunch responses confirmed those found in Expt 1; but immediately following the glucose dose there was an abrupt increase in plasma TAG that was greater in treatment LM than in treatment MM (P = 0.025), whereas plasma NEFA concentration decreased rapidly in both treatments at that time (P = 0.00066)

Diurnal trends in responses of blood plasma concentrations of glucose, insulin, and C-peptide following high- and low-fat meals and their relation to fat metabolism in healthy middle-aged volunteers

An experiment was conducted in twelve healthy middle-aged volunteers, six of each sex, with a mean BMI of 27 kg/m(2) to detect differences between morning and afternoon in postprandial blood glucose, insulin and C-peptide concentrations. These responses were measured following the consumption of isoenergetic meals that were high or low in fat content, at breakfast and at lunch. Over 4d each subject received the high-carbohydrate (L, 5.5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a moderately high-fat lunch (NM), in three Latin squares. Each evening a standard meal was given. Plasma glucose, insulin and C-peptide responses were greater following L than M meals and within both MM and LL treatments insulin and C-peptide responses were greater following breakfast than following lunch. The incremental C-peptide response to a fatty lunch following a fast at breakfast time (MM) was similar to that to a fatty breakfast, but the incremental insulin response for the same comparison was marginally lower at lunch (P=0.06). The relationship of C-peptide and insulin concentrations was assessed. Plasma glucose response to a fatty lunch was increased by a fatty breakfast. The relationships of these metabolic events with fat metabolism are discussed

Effect of breakfast fat content on glucose tolerance and risk factors of atherosclerosis and thrombosis

Twenty-four middle-aged healthy men were given a low-fat high-carbohydrate (5.5 g fat; L), or a moderately-fatty, (25.7 g fat; M) breakfast of similar energy contents for 28 d. Other meals were under less control. An oral glucose tolerance test (OGTT) was given at 09.00 hours on day 1 before treatment allocation and at 13.30 hours on day 29. There were no significant treatment differences in fasting serum values, either on day 1 or at the termination of treatments on day 29. The following was observed on day 29: (1) the M breakfast led to higher OGTT C-peptide responses and higher areas under the curves (AUC) of OGTT serum glucose and insulin responses compared with the OGTT responses to the L breakfast (P < 0.05); (2) treatment M failed to prevent OGTT glycosuria, eliminated with treatment L; (3) serum non-esterified fatty acid (NEFA) AUC was 59% lower with treatment L than with treatment M, between 09.00 and 13.20 hours (P < 0.0001), and lower with treatment L than with treatment M during the OGTT (P = 0.005); (4) serum triacylglycerol (TAG) concentrations were similar for both treatments, especially during the morning, but their origins were different during the afternoon OGTT when the Svedberg flotation unit 20-400 lipid fraction was higher with treatment L than with treatment M (P = 0.016); plasma apolipoprotein B-48 level with treatment M was not significantly greater than that with treatment L (P = 0.086); (5) plasma tissue plasminogen-activator activity increased after breakfast with treatment L (P = 0.0008), but not. with treatment M (P = 0.80). Waist:hip circumference was positively correlated with serum insulin and glucose AUC and with fasting LDL-cholesterol, Waist:hip circumference and serum TAG and insulin AUC were correlated with factors of thrombus formation; and the OGTT NEFA and glucose AUC were correlated. A small difference in fat intake at breakfast has a large influence on circulating diurnal NEFA concentration, which it is concluded influences adversely glucose tolerance up to 6 h later

Modelling of tolerance and rebound in normal and diseased rats

The development of rebound and tolerance is an important consideration when optimizing medical therapy, both with respect to drug dosing and adverse effects. By using quantitative approaches to study these processes, potential risks can be minimized. In this thesis nicotinic acid (NiAc)-induced changes in non-esterified fatty acids (NEFA) were used as a tool to investigate key determinants of tolerance and rebound in normal Sprague Dawley and in obese Zucker rats, a disease model of dyslipidaemia. The aim of the studies was to develop and challenge a model that described tolerance and rebound following different durations, rates and routes of NiAc administration. In normal rats, administration of NiAc resulted in a rapid decrease in NEFA plasma concentration, followed by rebound, the extent of which depended on both the level and duration of drug exposure. Rebound oscillations followed long duration of NiAc exposure. During constant drug exposure, increasing NEFA concentrations indicated tolerance development. The pharmacodynamic characteristics of NiAc-induced changes in NEFA differed in normal and diseased rats, with NEFA baseline concentrations being increased, rebound diminished, and tolerance develop¬ment more pronounced in the diseased animals. The non-intuitive pattern of NiAc-induced changes in NEFA was captured by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment inhibited the formation of response and the last stimulated the loss of response. The model was based on mechanistic principles, mimicking the dual actions of insulin in inhibiting the hydrolysis of triglycerides to NEFA and glycerol, and stimulating the re-esterification of NEFA. In both the normal and diseased rats, the model described the pharmacodynamic characteristics adequately. The concentration-response relationship at steady state was shifted upwards and to the right, and was shallower, in diseased rats compared to normal rats. The extent of such shifts demonstrates the impact of disease at equilibrium in the system. These studies have shown that by eliciting different exposure patterns and taking into account both the washout dynamics of the administered drug and the pharmacodynamic characteristics of normal and diseased animals, a mechanistically-based feedback model was able to tease out important information about tolerance and rebound