Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation

Increased plasma branched-chain amino acid concentrations are associated with insulin resistance, and intravenous amino acid infusion blunts insulin-mediated glucose disposal. We tested the hypothesis that protein ingestion impairs insulin-mediated glucose disposal by leucine-mediated mTOR signaling, which can inhibit AKT. We measured glucose disposal and muscle p-mTOR^Ser2448, p-AKT^Ser473, and p-AKT^Thr308 in 22 women during a hyperinsulinemic-euglycemic clamp procedure with and without concomitant ingestion of whey protein (0.6 g/kg fat-free mass; n = 11) or leucine that matched the amount given with whey protein (n = 11). Both whey protein and leucine ingestion raised plasma leucine concentration by approximately twofold and muscle p-mTOR^Ser2448 by ∼30% above the values observed in the control (no amino acid ingestion) studies; p-AKT^Ser473 and p-AKT^Thr308 were not affected by whey protein or leucine ingestion. Whey protein ingestion decreased insulin-mediated glucose disposal (median 38.8 [quartiles 30.8, 61.8] vs. 51.9 [41.0, 77.3] µmol glucose/µU insulin · mL⁻¹ · min⁻¹; P < 0.01), whereas ingestion of leucine did not (52.3 [43.3, 65.4] vs. 52.3 [43.9, 73.2]). These results indicate that 1) protein ingestion causes insulin resistance and could be an important regulator of postprandial glucose homeostasis and 2) the insulin-desensitizing effect of protein ingestion is not due to inhibition of AKT by leucine-mediated mTOR signaling.     

Hepatic Steatosis as a Marker of Metabolic Dysfunction

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.     

Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects

Data from studies in animal models indicate that certain lipid metabolites, particularly diacylglycerol, ceramide, and acylcarnitine, disrupt insulin action. We evaluated the relationship between the presence of these metabolites in the liver (assessed by mass spectrometry) and hepatic insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp with stable isotope tracer infusion) in 16 obese adults (body mass index, 48 ± 9 kg/m2). There was a negative correlation between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol (r = -0.609; P = .012), but not with intrahepatic ceramide or acylcarnitine. These data indicate that intrahepatic diacylglycerol is an important mediator of hepatic insulin resistance in obese people with nonalcoholic fatty liver disease.     

Intrahepatic fat,not visceral fat,is linked with metabolic complications of obesity

Visceral adipose tissue (VAT) is an important risk factor for obesity-related metabolic disorders. Therefore, a reduction in VAT has become a key goal in obesity management. However, VAT is correlated with intrahepatic triglyceride (IHTG) content, so it is possible that IHTG, not VAT, is a better marker of metabolic disease. We determined the independent association of IHTG and VAT to metabolic function, by evaluating groups of obese subjects, who differed in IHTG content (high or normal) but matched on VAT volume or differed in VAT volume (high or low) but matched on IHTG content. Stable isotope tracer techniques and the euglycemic–hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate. Tissue biopsies were obtained to evaluate cellular factors involved in ectopic triglyceride accumulation. Hepatic, adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0.01), whereas VLDL-triglyceride secretion rate was almost double (P < 0.001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Adipose tissue CD36 expression was lower (P < 0.05), whereas skeletal muscle CD36 expression was higher (P < 0.05), in subjects with higher than normal IHTG. These data demonstrate that IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Furthermore, alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.     

Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects

Preparations containing caffeine and ephedrine have become increasingly popular among sportspersons in recent years as a means to enhance athletic performance. This is due to a slowly accumulating body of evidence suggesting that combination of the two drugs may be more efficacious than each one alone. Caffeine is a compound with documented ergogenicity in various exercise modalities, while ephedrine and related alkaloids have not been shown, as yet, to result in any significant performance improvements. Caffeine-ephedrine mixtures, however, have been reported in several instances to confer a greater ergogenic benefit than either drug by itself. Although data are limited and heterogeneous in nature to allow for reaching consensus, the increase in performance is a rather uniform finding as it has been observed during submaximal steady-state aerobic exercise, short- and long-distance running, maximal and supramaximal anaerobic cycling, as well as weight lifting. From the metabolic point of view, combined ingestion of caffeine and ephedrine has been observed to increase blood glucose and lactate concentrations during exercise, wheareas qualitatively similar effects on lipid fuels (free fatty acids and glycerol) are less pronounced. In parallel, epinephrine and dopamine concentrations are significantly increased, wheareas the effects on norepinephrine are less clear. With respect to pulmonary gas exchange during short-term intense exercise, no physiologically significant effects have been reported following ingestion of caffeine, ephedrine or their combination. Yet, during longer and/or more demanding efforts, some sporadic enhancements have indeed been shown. On the other hand, a relatively consistent cardiovascular manifestation of the latter preparation is an increase in heart rate, in addition to that caused by exercise alone. Finally, evidence to date strongly suggests that caffeine and ephedrine combined are quite effective in decreasing the rating of perceived exertion and this seems to be independent of the type of activity being performed. In general, our knowledge and understanding of the physiological, metabolic and performance-enhancing effects of caffeine-ephedrine mixtures are still in their infancy. Research in this field is probably hampered by sound ethical concerns that preclude administration of potentially hazardous substances to human volunteers. In contrast, while it is certainly true that caffeine and especially ephedrine have been associated with several acute adverse effects on health, athletes do not seem to be concerned with these, as long as they perceive that their performance will improve. In light of the fact that caffeine and ephedra alkaloids, but not ephedrine itself, have been removed from the list of banned substances, their use in sports can be expected to rise considerably in the foreseeable future. Caffeine-ephedra mixtures may thus become one of most popular ergogenic aids in the years to come and while they may indeed prove to be one of the most effective ones, and probably one of the few legal ones, whether they also turn out to be one of the most dangerous ones awaits to be witnessed.     

Organic food: nutritious food or food for thought? A review of the evidence

Apparently, one of the primary reasons for purchasing organic food is the perception that it is more nutritious than conventional food. Given the increasing interest towards organic food products, it is imperative to review the existing literature concerning the nutritional value of the produce, and to determine to what extent are consumer expectations met. There are only few well-controlled studies that are capable of making a valid comparison and, therefore, compilation of the results is difficult and generalisation of the conclusions should be made with caution. In spite of these limitations, however, some differences can be identified. Although there is little evidence that organic and conventional foods differ in respect to the concentrations of the various micronutrients (vitamins, minerals and trace elements), there seems to be a slight trend towards higher ascorbic acid content in organically grown leafy vegetables and potatoes. There is also a trend towards lower protein concentration but of higher quality in some organic vegetables and cereal crops. With respect to the rest of the nutrients and the other food groups, existing evidence is inadequate to allow for valid conclusions. Finally, animal feeding experiments indicate that animal health and reproductive performance are slightly improved when they are organically fed. A similar finding has not yet been identified in humans. Several important directions can be highlighted for future research; it seems, however, that despite any differences, a well-balanced diet can equally improve health regardless of its organic or conventional origin.     

Dietary fat and carbohydrate quality have independent effects on postprandial glucose and lipid responses

Purpose

The magnitude of postprandial lipemia is influenced not only by the amount but also the type of fat and carbohydrate consumed. The aim of this study was to evaluate differences in postprandial glucose and lipid responses after a mixed meal containing low- or high-glycemic-index (GI) carbohydrate and three different types of fat varying in the degree of saturation in healthy subjects.

Methods

A randomized, controlled, single-blinded crossover study was conducted in 20 healthy Chinese men. Subjects consumed in random order six experimental isocaloric meals that differed in carbohydrate and fat quality, and contained 40 g of either saturated fat (SFA, butter), monounsaturated fat (MUFA, olive oil) or polyunsaturated fat (PUFA, grapeseed oil), and 50 g of either low-GI (basmati rice) or high-GI (jasmine rice) carbohydrate. Glucose, insulin, c-peptide, triglycerides (TG) and non-esterified fatty acids (NEFA) were measured over 4 h.

Results

For all substrates evaluated, there were no significant interactions between fat and carbohydrate. The incremental area under the curve (iAUC) for TG was significantly lower after the SFA and PUFA meals compared with the MUFA meal, irrespective of GI. No significant difference was found for NEFA iAUC in all treatments. Glucose, insulin and c-peptide iAUCs were significantly lower after ingestion of low-GI than high-GI meals, independent of the type of fat.

Conclusions

A carbohydrate-rich meal (of either low or high GI) that contains butter or grapeseed oil results in lower postprandial TG concentrations relative to olive oil in healthy Chinese males. Glucose, insulin and c-peptide responses, however, are directly dependent on the GI of the meal and not on the degree of saturation of dietary fat.The trial was registered at clinicaltrials.gov as NCT02585427.

     

Effect of the methylenetetrahydrofolate reductase (MTHFR 677C>T) polymorphism on plasma homocysteine concentrations in healthy children is influenced by consumption of folate-fortified foods

ObjectiveTo explore the influence of folate-fortified foods (ready-to-eat [RTE] breakfast cereals or fruit-juice drinks) on the relation between the methylenetetrahydrofolate reductase (MTHFR 677C > T) polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children.MethodsThis was a cross-sectional study by face-to-face interview. A total of 186 sixth-grade students participated from randomly selected primary schools in Volos, Greece. Fasting plasma tHcy, folate, and vitamin B12 were measured. The MTHFR genotypes were determined. Anthropometric data were collected and dietary intake was assessed by two non-consecutive 24-h recalls. Participants were characterized as non-consumers of RTE breakfast cereals or fruit-juice drinks if there was no report of any such food during the 24-h recall interviews; all other children were classified as consumers.ResultsGeometric means for plasma tHcy were higher, whereas plasma folate was lower in non-consumers compared with consumers. The sample was divided by consumption status (yes or no) to explore the significance of each polymorphism depending on consumption status. The association between the genotype and tHcy was restricted to non-consumers (P < 0.05). Specifically, only in children who did not consume RTE breakfast cereals or fruit-juice drinks did the TT genotype carriers exhibit higher tHcy concentrations when compared with C-allele carriers (P < 0.05). In contrast, in consumers, circulating tHcy was similar regardless of genotype.ConclusionThese observational findings support a beneficial effect of RTE breakfast cereals and fruit-juice drinks on lowering plasma tHcy and improving folate status in children. Also, consumption of folate-fortified foods modulates the association of the MTHFR 677C > T polymorphism with tHcy, suggesting that habitual consumption of folate-fortified foods is a practical approach in providing consistent protection to those children who may benefit the most, i.e., carriers of the TT genotype.