RESUMO
The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."
Assuntos
Tecido Adiposo/fisiologia , Insulina/farmacologia , Lipídeos de Membrana/análise , Músculo Esquelético/fisiologia , Obesidade/fisiopatologia , Fosfolipídeos/análise , Tecido Adiposo/anatomia & histologia , Adulto , Arizona , Biópsia , Glicemia/metabolismo , Índice de Massa Corporal , Calorimetria , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/análise , Técnica Clamp de Glucose , Humanos , Indígenas Norte-Americanos , Insulina/administração & dosagem , Insulina/sangue , Masculino , Lipídeos de Membrana/química , Músculo Esquelético/química , Músculo Esquelético/citologia , Fosfolipídeos/química , Análise de RegressãoRESUMO
Circulating lipids and tissue lipid depots predict insulin sensitivity. Associations between fat oxidation and insulin sensitivity are variable. We examined whether circulating lipids and fat oxidation independently influence insulin sensitivity. We also examined interrelationships among circulating lipids, fat oxidation, and tissue lipid depots. Fifty-nine nondiabetic males (age, 45.4 +/- 2 yr; body mass index, 29.1 +/- 0.5 kg/m(2)) had fasting circulating nonesterified fatty acids (NEFAs) and lipids measured, euglycemic-hyperinsulinemic clamp for whole body insulin sensitivity [glucose infusion rate (GIR)], substrate oxidation, body composition (determined by dual energy x-ray absorptiometry), and skeletal muscle triglyceride (SMT) measurements. GIR inversely correlated with fasting NEFAs (r = -0.47; P = 0.0002), insulin-infused NEFAs (n = 38; r = -0.62; P < 0.0001), low-density lipoprotein cholesterol (r = -0.50; P < 0.0001), non-high-density lipoprotein cholesterol (r = -0.52; P < 0.0001), basal fat oxidation (r = -0.32; P = 0.03), insulin-infused fat oxidation (r = -0.40; P = 0.02), SMT (r = -0.28; P < 0.05), and central fat (percentage; r = -0.59; P < 0.0001). NEFA levels correlated with central fat, but not with total body fat or SMT. Multiple regression analysis showed non-high-density lipoprotein cholesterol, fasting NEFAs, insulin-infused fat oxidation, and central fat to independently predict GIR, accounting for approximately 60% of the variance. Circulating fatty acids, although closely correlated with central fat, independently predict insulin sensitivity. Insulin-infused fat oxidation independently predicts insulin sensitivity across a wide range of adiposity. Therefore, lipolytic regulation as well as amount of central fat are important in modulating insulin sensitivity.
Assuntos
Colesterol/sangue , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Insulina/farmacologia , Lipoproteínas/sangue , Adulto , Idoso , Apolipoproteínas B/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Valores de Referência , Análise de Regressão , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 +/- 1 years). Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 +/- 1%, range 14-44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 +/- 0.3 micromol/g, range 1.3-1.9 micromol/g) and log10M (r = -0.53, P < or = 0.001), MZ (r = -0.44, P = 0.006), and nonoxidative glucose disposal (r = -0.48 and -0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10M, MZ, log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.
Assuntos
Insulina/metabolismo , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Triglicerídeos/análise , Adulto , Arizona , Biópsia , Composição Corporal , Constituição Corporal , Técnica Clamp de Glucose , Humanos , Indígenas Norte-Americanos , Masculino , Músculo Esquelético/patologia , Análise de RegressãoRESUMO
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation in adipose tissue is known to regulate genes involved in adipocyte differentiation and lipid metabolism. However, the role of PPAR-gamma in muscle remains unclear. To examine the potential regulation of genes by PPAR-gamma in human skeletal muscle, we used semiquantitative RT-PCR to determine the expression of PPAR-gamma, lipoprotein lipase (LPL), muscle carnitine palmitoyl transferase-1 (mCPT1), fatty acid-binding protein (FABP), carnitine acylcarnitine transferase (CACT), and glucose transporter-4 (GLUT4) in freeze-dried muscle samples from 14 male subjects. These samples were dissected free of adipose and other tissue contamination, as confirmed by minimal or absent adipsin expression. Between individuals, the messenger ribonucleic acid concentration of PPAR-gamma varied up to 3-fold, whereas LPL varied up to 6.5-fold, mCPT1 13-fold, FABP 4-fold, CACT 4-fold, and GLUT4 up to 3-fold. The expression of LPL (r2 = 0.54; P = 0.003), mCPT1 (r2 = 0.42; P = 0.012), and FABP (r2 = 0.324; P = 0.034) all correlated significantly with PPAR-gamma expression in the same samples. No significant correlation was observed between the expression of CACT and PPAR-gamma or between GLUT4 and PPAR-gamma. These findings demonstrate a relationship between PPAR-gamma expression and the expression of other genes of lipid metabolism in muscle and support the hypothesis that PPAR-gamma activators such as the antidiabetic thiazolidinediones may regulate fatty acid metabolism in skeletal muscle as well as in adipose tissue.
Assuntos
Carnitina Aciltransferases/genética , Proteínas de Transporte/genética , Regulação da Expressão Gênica , Lipase Lipoproteica/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Musculares , Músculo Esquelético/metabolismo , Proteínas de Neoplasias , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor , Idoso , Glicemia/metabolismo , Fator D do Complemento , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos não Esterificados/sangue , Transportador de Glucose Tipo 4 , Humanos , Insulina/sangue , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/genética , Valores de Referência , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Fatores de Transcrição/genética , Triglicerídeos/sangueRESUMO
OBJECTIVE: While the exact regulatory interactions between blood pressure (BP) and obesity are not completely understood, weight loss provides an alternative to pharmacological treatment of hypertension. The intent of this repeated measures study of mild-moderate hypertensive, moderately obese subjects (34 females/18 males) was to determine if the reduction in BP following weight loss could be further affected by modifying the fatty acid (FA) composition of the hypocaloric diet. METHODS: BP, insulin sensitivity (Si), and lipid parameters were assessed before and after a 10-week calorie-restricted period. Subjects were randomized to one of three dietary groups differing in FA composition. Reduced body weight was maintained for a further 4 weeks and body composition assessment, BP and heart rate measurements were repeated. RESULTS: Weight loss (10%) in obese hypertensive subjects resulted in substantial improvements in BP, Si and lipid profile. There was no additional effect on the reduction in BP by the type of FA consumed in the diet. Following weight loss, there was a trend for omega-3 FAs to have a protective effect on fat-free mass loss (compared to omega-6 FA Group and saturated FA Group) and a trend to further enhance Si. There were significant improvements in circulating lipid profiles independent of the dietary FA intervention following the weight loss. The improvements in BP and body composition were maintained during the weight-loss maintenance period. The type of fat consumed had minor differential effects on some of the measured metabolic outcomes. CONCLUSION: These results provide strong support for modest weight loss as a treatment for hypertension.
Assuntos
Gorduras na Dieta/farmacologia , Ácidos Graxos Insaturados/farmacologia , Hipertensão/etiologia , Obesidade/complicações , Obesidade/metabolismo , Redução de Peso , Aldosterona/sangue , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Ácidos Graxos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6 , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Insulina/fisiologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/patologia , Renina/sangue , Redução de Peso/efeitos dos fármacosRESUMO
What is clear from the research thus far is that dietary fat intake does influence insulin action. However, whether the effect is good, bad, or indifferent is strongly related to the fatty acid profile of that dietary fat. The evidence has taken many forms, including in vitro evidence of differences in insulin binding and glucose transport in cells grown with different types of fat in the incubation medium, in vivo results in animals fed different fats, relationships demonstrated between the membrane structural lipid fatty acid profile and insulin resistance in humans, and finally epidemiological evidence linking particularly high saturated fat intake with hyperinsulinemia and increased risk of diabetes. This contrasts with the lack of relationship, or even possible protective effect, of polyunsaturated fats. In particular, habitual increased n-3 polyunsaturated dietary fat intake (as fish fats) would appear to be protective against the development of glucose intolerance. It is reassuring that the patterns of dietary fatty acids that appear beneficial for insulin action and energy balance are also the patterns that would seem appropriate in the fight against thrombosis and cardiovascular disease. Mechanisms, though, still need to be defined. However, there are strong indicators that defining the ways in which changes in the fatty acid profile of membrane structural lipids are achieved, and in turn influence relevant transport events, plus understanding the processes that control accumulation and availability of storage lipid in muscle may be fruitful avenues for future research. One of the problems of moving the knowledge gained from research at the cellular level through to the individual and on to populations is the need for more accommodating research designs. In vitro studies may provide in-depth insights into intricate mechanisms, but they do not give the "big picture" for practical recommendations. On the other hand, correlational studies tend to be fairly blunt instruments, requiring large numbers that are very often not feasible if a greater depth of understanding of the biological processes is to be incorporated. There may be benefit in turning to the clinical case study as a framework for a more comprehensive analysis of the links between dietary fats and insulin action. The real challenge is to keep the depth of analysis rigorous enough to be able to explain and accommodate individual variation (i.e., the diversity of both environmental and genetic backgrounds) while at the same time satisfying the cultural need to provide appropriate overall dietary guidelines. Finally, David Kritchevsky brought to our attention a delightful quote from Mark Twain: "There is something fascinating about science. One gets such a wholesale return of conjecture for such a trifling investment of fact." In the field of dietary fats and the Metabolic Syndrome, this quotation is, unfortunately, apt. Much more research is necessary to define how dietary fats really work to affect insulin action. Well designed, long-term studies in "free range" humans must be undertaken if dietary guidelines for the Metabolic Syndrome are to be based on anything more than a "trifling" amount of "fact."
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Gorduras na Dieta/metabolismo , Resistência à Insulina , Insulina/metabolismo , Animais , Gorduras na Dieta/administração & dosagem , HumanosRESUMO
Long-chain polyunsaturated fatty acids (LCPUFAs), including docosahexaenoic acid ([DHA] 22:6 n-3), are important components of cell membranes. Low levels of DHA and other LCPUFAs in skeletal muscle membrane phospholipid are associated with insulin resistance and obesity in adults. These findings may be influenced by both dietary and genetic factors. This study aimed to investigate the interrelationships between the type of infant feeding, skeletal muscle phospholipid fatty acid (FA) composition, and glucoregulation in young children. Skeletal muscle biopsies and fasting blood samples were obtained from 56 normally nourished young children (35 males and 21 females) aged less than 2 years (mean +/- SE, 0.76 +/- 0.06) undergoing elective surgery. The dietary history was taken, and muscle phospholipid FA composition was analyzed. Subgroups of totally breast-fed and age-matched formula-fed infants were compared. Breast-fed infants (n = 13; age, 0.54 +/- 0.06 years) had a significantly higher percentage of DHA (3.63% +/- 0.22% v 1.84% +/- 0.11%, P < .0001) and total percentage of LCPUFAs (30.24 +/- 0.87% v 25.17% +/- 0.86, P < .0001) in muscle phospholipids compared with the formula-fed group (n = 12; age, 0.59 +/- 0.08 years). The totally breast-fed group had lower plasma glucose levels than the formula-fed group (4.7 +/- 0.2 v 5.4 +/- 0.2 mmol/L, P < .02). Consistent with these findings, further analysis of a group of 39 children who had either never or not recently been breast-fed showed significant inverse correlations between fasting plasma glucose and the percentage of both DHA (r = -.47, P < .003) and total LCPUFAs (r = -.38, P < .05). The results of this study show that (1) breast-feeding increases LCPUFA levels in skeletal muscle membrane and (2) early development of relatively higher levels of LCPUFAs in the phospholipid of skeletal muscle, influenced both by type of feeding and by genetic predisposition, is associated with lower fasting plasma glucose. Early changes in skeletal muscle membrane phospholipid FA saturation may play a role in the subsequent development of diseases associated with insulin resistance.
Assuntos
Glicemia/análise , Dieta , Ácidos Graxos/análise , Lipídeos de Membrana/química , Músculo Esquelético/química , Fosfolipídeos/química , Biópsia , Alimentação com Mamadeira , Aleitamento Materno , Colesterol/sangue , Ácidos Docosa-Hexaenoicos/análise , Ácidos Graxos Insaturados/análise , Feminino , Humanos , Lactente , Insulina/sangue , Resistência à Insulina , Masculino , Lipídeos de Membrana/análise , Fosfolipídeos/análise , Análise de RegressãoRESUMO
Muscle plays a major role in insulin-stimulated glucose disposal. There is now a range of evidence in humans and experimental animals demonstrating strong relationships between the fatty acid composition of structural membrane lipids and insulin action. The in vivo work is correlative but the in vitro studies suggest a causal relationship exists. Good insulin action is associated with an increased proportion of n-3 fatty acids, low saturates, a low n-6/n-3 ratio and possibly increased monounsaturates. What is reassuring is that there is a pleasing symmetry with the fatty acid pattern that might lead to decreased thrombosis. There is little argument about saturated fats with a reduction having a range of beneficial effects. However, the n-3 fatty acids might also be a key to amelioration of both insulin resistance and thrombosis. The sites of action of n-3s are multiple: decreased triglyceride and VLDL production; inhibition of thromboxane A2 production, increased thromboxane A3 and decreased platelet aggregation; reduction of triglyceride and VLDL concentration; improved blood rheology and membrane transport; action on the endothelium and proliferation of the intimal cells, and improvement of vascular tone. The data here are now strong and reasonably consistent. Similarly, after initial controversy, the evidence for n-3s playing a beneficial role in insulin action is now accumulating. The n-6 PUFAs are a bit of a worry: while arachidonic acid levels in muscle phospholipid has linked positively to insulin action in our studies, linoleic is negative. Linoleic acid, in high amounts, is known to inhibit the delta6 fatty acid desaturase enzyme and with the competition between n-6 and n-3 fatty acids for the enzymes of desaturation and elongation it does focus on a high n-6/n-3 ratio as a critical factor in both insulin resistance and atherosclerosis.
Assuntos
Ácidos Graxos/metabolismo , Resistência à Insulina/fisiologia , Lipídeos de Membrana/metabolismo , Músculo Esquelético/metabolismo , Trombose/etiologia , Triglicerídeos/metabolismo , Animais , Gorduras Insaturadas na Dieta/metabolismo , Humanos , Lipídeos de Membrana/química , Músculo Esquelético/química , Fosfolipídeos/análise , Ratos , SíndromeRESUMO
OBJECTIVE: This study investigated the contributions of physical fitness and body composition to 24-h fat oxidation in adults under sedentary conditions in a whole-room calorimeter. METHODS: The following measurements were studied in 109 adults (49 male/45 female) at least 36 h after a bout of exercise: 1) aerobic fitness level assessed by VO2max, 2) body composition determined by underwater weighing, 3) resting metabolic rate (RMR) after an overnight fast, and 4) 24-h energy expenditure (EE) and substrate oxidation determined in a whole-room calorimeter. While in the calorimeter, subjects were provided with a diet (15% protein, 30% fat, and 55% carbohydrate) estimated to produce energy balance on a sedentary day and of similar nutritional composition to their daily dietary intake. RESULTS: We found strong negative correlations between VO2max and % body fat in both male and female subjects, but no relationship between VO2max and 24-h EE under the sedentary conditions of this study. In male subjects, VO2max (mL O2 x kg(-1) fat-free mass x min(-1)) was negatively related to fat oxidation (r = -0.397, P < 0.005), and fat oxidation was more closely related to fat mass (r = 0.434, P < 0.0002) than to fat-free mass (r = 0.165, NS). In contrast, none of these relationships were significant in females. CONCLUSION: The results show that in male subjects under sedentary conditions, 24-h fat oxidation is positively related to body fat mass and negatively related to VO2max (the marker used here for level of physical fitness). This supports our hypothesis that regularly active males maintain lower body fat stores as the low contribution to daily fat oxidation from a lower body fat mass is counterbalanced by the high contribution to fat oxidation from daily physical activity. The lack of a relationship between VO2max and 24-h EE under the sedentary conditions of this study suggests that the major effects of physical activity on total daily EE and fat oxidation may occur during and relatively quickly after an exercise bout. Further, these data also suggest that cessation of regular exercise will likely be associated with a high risk of positive fat balance and weight gain.
Assuntos
Tecido Adiposo , Metabolismo Energético , Exercício Físico/fisiologia , Gorduras/metabolismo , Aptidão Física/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , OxirreduçãoRESUMO
Skeletal muscle plays a major role in insulin-stimulated glucose disposal. This paper reviews the range of evidence in humans and experimental animals demonstrating close associations between insulin action and two major aspects of muscle morphology: fatty acid composition of the major structural lipid (phospholipid) in muscle cell membranes and relative proportions of major muscle fiber types. Work in vitro and in vivo in both rats and humans has shown that incorporation of more unsaturated fatty acids into muscle membrane phospholipid is associated with improved insulin action. As the corollary, a higher proportion of saturated fats is linked to impairment of insulin action (insulin resistance). Studies in vitro suggest a causal relationship. Among polyunsaturated fatty acids (PUFA) there is some, but not conclusive, evidence that omega-3 (n-3) PUFA may play a particular role in improving insulin action; certainly a high n-6/n-3 ratio appears deleterious. In relation to fiber type, the more highly oxidative, insulin-sensitive type 1 and type 2a fibers have a higher percentage of unsaturated fatty acids, particularly n-3, in their membrane phospholipid, compared to the insulin-resistant, glycolytic, type 2b fibers. These variables, however, can be separated and may act in synergy to modulate insulin action. It remains to establish whether lifestyle (e.g., dietary fatty acid profile and physical activity), genetic predisposition, or a combination are the prime determinants of muscle morphology (particularly membrane lipid profile) and hence insulin action.
Assuntos
Resistência à Insulina , Lipídeos de Membrana/metabolismo , Músculo Esquelético/metabolismo , Animais , Humanos , Fibras Musculares Esqueléticas/metabolismo , Fosfolipídeos/metabolismoRESUMO
One of the key abnormalities of non-insulin-dependent diabetes mellitus (NIDDM) and related diseases of the "Metabolic Syndrome" is impaired insulin action (insulin resistance). Since skeletal muscle plays a major role in insulin-stimulated glucose uptake and whole-body energy expenditure, it is a central player in carbohydrate and lipid metabolism, and hence in the balance between health and disease. This manuscript seeks to describe the evidence both for involvement in insulin resistance of three major muscle variables: membrane lipid composition, storage triacylglycerol and fibre type mixture; and for the interrelationships between these variables. Taken with results provided in other chapters in this volume, the literature described gives insights into the role that certain dietary fats and physical inactivity may play in the development of insulin resistance and hence the disease cluster of the Metabolic Syndrome.
Assuntos
Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Animais , Membrana Celular/metabolismo , Gorduras na Dieta/metabolismo , Glucose/metabolismo , HumanosRESUMO
OBJECTIVE: To investigate levels of components of the alternative pathway of complement, and of two activation products, ASP and Bb, in persons ranging in insulin resistance both fasting and following the consumption of a high-fat, low-carbohydrate meal. SUBJECTS: Healthy controls (n = 17) and normoglycaemic first-degree relatives of patients with type II diabetes (n = 15). MEASUREMENTS: All subjects had normal glucose tolerance. Blood was collected for the measurement of plasma glucose, insulin, triglycerides and free fatty acids. Body composition was assessed with dual energy X-ray absorptiometry (DEXA) and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Basal and postprandial values over 6 h were determined for plasma C3, B, D, Bb and ASP. Basal levels of C1q, C4 and CRP were also determined. RESULTS: Controls did not differ significantly from the relatives of patients with type II diabetes for any metabolic parameter except in their degree of insulin resistance and central fat (kg). Across all subjects, basal levels of C3, but no other complement protein, were correlated with insulin resistance. Native complement proteins, but not ASP or Bb, were correlated with body mass index and the amount (kg) of central fat. Basal levels of C3 and factor B were significantly higher in the relatives group, whereas factor D and the classical pathway proteins C1q and C4 did not differ between the two groups. Postprandially, levels of factor D were significantly reduced in both groups. ASP levels also fell postprandially, the decline achieving significance in the relatives group. CONCLUSIONS: Elevated levels of C3 and factor B in the diabetic relatives group may have resulted from increased synthesis by adipose tissue. There was no evidence of alternative pathway activation in response to a fat meal in terms of ASP or Bb production, or significant consumption of C3 and factor B. These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat.
Assuntos
Via Alternativa do Complemento , Diabetes Mellitus Tipo 2/imunologia , Gorduras na Dieta/administração & dosagem , Síndrome Metabólica/imunologia , Adulto , Análise de Variância , Composição Corporal , Estudos de Casos e Controles , Complemento C3/análise , Fator B do Complemento/análise , Diabetes Mellitus Tipo 2/genética , Jejum , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Síndrome Metabólica/genética , Período Pós-PrandialRESUMO
AIM/HYPOTHESIS: We determined the effect of exercise training on insulin sensitivity and muscle lipids (triglyceride [TG(m)] and long-chain fatty acyl CoA [LCACoA] concentration) in patients with Type 2 diabetes. METHODS: Seven patients with Type 2 diabetes and six healthy control subjects who were matched for age, BMI, % body fat and VO(2)peak participated in a 3 days per week training program for 8 weeks. Insulin sensitivity was determined pre- and post-training during a 120 min euglycaemic-hyperinsulinaemic clamp and muscle biopsies were obtained before and after each clamp. Oxidative enzyme activities [citrate synthase (CS), beta-hydroxy-acyl-CoA (beta-HAD)] and TG(m) were determined from basal muscle samples pre- and post training, while total LCACoA content was measured in samples obtained before and after insulin-stimulation, pre- and post training. RESULTS: The training-induced increase in VO(2)peak (approximately 20%, p<0.01) was similar in both groups. Compared with control subjects, insulin sensitivity was lower in the diabetic patients before and after training (approximately 60%; p<0.05), but was increased to the same extent in both groups with training (approximately 30%; p<0.01). TG(m) was increased in patients with Type 2 diabetes (170%; p<0.05) before, but was normalized to levels observed in control subjects after training. Basal LCACoA content was similar between groups and was unaltered by training. Insulin-stimulation had no detectable effect on LCACoA content. CS and beta-HAD activity were increased to the same extent in both groups in response to training ( p<0.001). CONCLUSION/INTERPRETATION: We conclude that the enhanced insulin sensitivity observed after short-term exercise training was associated with a marked decrease in TG(m) content in patients with Type 2 diabetes. However, despite the normalization of TG(m )to levels observed in healthy individuals, insulin resistance was not completely reversed in the diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico/fisiologia , Insulina/farmacologia , Músculo Esquelético/metabolismo , Triglicerídeos/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Tecido Adiposo/anatomia & histologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Citrato (si)-Sintase/metabolismo , Técnica Clamp de Glucose , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio , Aptidão Física , Valores de ReferênciaRESUMO
BACKGROUND: The postprandial triglyceride response following a meal high in fat (HFM) has been related to atherogenesis and insulin resistance. We examined the influence of dietary carbohydrate and the accompanying insulin secretory response on the postprandial triglyceride response following a HFM. MATERIALS AND DESIGN: High-fat meals of equal fat content (fat 80 g) containing either 20 g (low) or 100 g (high) of carbohydrate (HFM-LC and HFM-HC, respectively), and therefore not isocaloric (4250 kJ of HFM-LC and 5450 kJ of HFM-HC), were consumed by seven (four male, three female) normolipidaemic subjects (aged 32.9 +/- 3.7 years, BMI 24.7 +/- 1.8 kg m-2). Blood and indirect calorimetry data were collected at 0-4 h. RESULTS: HFM-HC produced a significant rise in plasma glucose (Delta0.54 +/- 0.23 mmol L-1, P = 0.05) at 2 h, while a HFM-LC elicited no mean change from baseline. Following a HFM-LC, the plasma insulin incremental area under the curve (AUC) was significantly lower (31.3 +/- 6.7 vs. 83.2 +/- 11.9 mU l-1 h-1, P < 0.0003) and the postprandial triglyceride response AUC was significantly greater (1.66 +/- 0.36 vs. 1.24 +/- 0.31 mmol L-1 h-1, P < 0.006) compared with a HFM-HC. Plasma free fatty acids were suppressed by 44% (P = 0.04) and 66% (P < 0.0001) at 1 h following HFM-LC and HFM-HC, respectively, compared with baseline. There were no significant differences between the meals in energy expenditure, substrate oxidation rates, or respiratory quotient responses. CONCLUSIONS: By design, the HFMs were not isocaloric but the presence of carbohydrate in a HFM invoked an insulin response that significantly reduced the 4 h postprandial triglyceride response even in healthy, normolipidaemic subjects. This phenomenon may have clinical implications, particularly in relation to insulin sensitivity.
Assuntos
Carboidratos da Dieta/metabolismo , Gorduras na Dieta/metabolismo , Insulina/metabolismo , Triglicerídeos/metabolismo , Glicemia/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Secreção de Insulina , Masculino , Período Pós-PrandialRESUMO
OBJECTIVE: (-)-Hydroxycitric acid ((-)-HCA) is available as a herbal supplement, and promoted as a weight loss agent. It is hypothesized that (-)-HCA can increase fat oxidation by inhibiting citrate lyase, an enzyme which plays a crucial role in energy metabolism during de novo lipogenesis. The indirect inhibition of the cytosolic pool of citrate by (-)-HCA and the subsequent reduction in acetyl coenzyme A and oxaloacetate alters steps in the citric acid cycle that promote fat oxidation. The objective of this study was to determine the effect of (-)-HCA on marker substrates of altered metabolism, as well as on respiratory quotient (RQ) and energy expenditure (EE) in humans, following an overnight fast and during a bout of exercise. HYPOTHESIS OF STUDY: We hypothesized that supplementation with (-)-HCA would result in an increase in fat oxidation and metabolic rate, reflected by an increase in beta-hydroxybutyrate and EE and/or a decrease in RQ. Furthermore, during moderately intense exercise, we hypothesized that (-)-HCA supplementation would increase the rate of lactate conversion to glucose in the liver, with a subsequent reduction of circulating lactate and an elevation of circulating ketone bodies due to the increased partial oxidation of fatty acids (FA) in mitochondria. Studies have examined the fat regulating action of (-)-HCA on steps of the citric acid cycle in rodents showing reductions in body weight and food intake. No studies have investigated the effects of (-)-HCA supplementation in conjunction with a typical daily dietary composition (that is approx 30-35% fat) on metabolic processes which could influence body weight regulation in humans. DESIGN: This was a double blind, placebo controlled, randomized, crossover study involving three days of (-)-HCA (3.0 g/d) or placebo supplementation. The effects of (-)-HCA supplementation on metabolic parameters with or without moderately intense exercise was studied over four laboratory visits. SUBJECTS: Sedentary adult male subjects (n = 10, age: 22-38 y, body mass index (BMI) 22.4-37.6 kg/m2). MEASUREMENTS: Two of the four visits involved no exercise (Protocol A) with and without (-)-HCA treatment, while the remaining two visits included a moderately intense exercise bout (Protocol B; 30 min at 40% maximal aerobic fitness (VO2max) and 15 min at 60% VO2max) with and without (-)-HCA treatment. EE (by indirect calorimetry) and RQ were measured for 150 min following an overnight fast. Blood samples were collected for the determination of glucose, insulin, glucagon, lactate, and beta-hydroxybutyrate concentrations. RESULTS: In a fasted state and following 3 d of (-)-HCA treatment, RQ was not significantly lowered during rest (Protocol A) nor during exercise (Protocol B) compared with the placebo treatment. Treatment with (-)-HCA did not affect EE, either during rest or during moderately intense exercise. Furthermore, the blood substrates measured were not significantly different between treatment groups under the fasting conditions of this study. CONCLUSION: These results do not support the hypothesis that (-)-HCA alters the short-term rate of fat oxidation in the fasting state during rest or moderate exercise, with doses likely to be achieved in humans while subjects maintain a typical Western diet (approx 30-35% total calories as fat).
Assuntos
Fármacos Antiobesidade/farmacologia , Citratos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adulto , Estudos Cross-Over , Método Duplo-Cego , Exercício Físico , Jejum , Humanos , Masculino , Obesidade/enzimologia , OxirreduçãoRESUMO
OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal. DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal. SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20). MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting. RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting. CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.
Assuntos
Gorduras na Dieta/sangue , Resistência à Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Período Pós-Prandial , Proteínas/metabolismo , Adiponectina , Adulto , Glicemia/metabolismo , Western Blotting , Gorduras na Dieta/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
AIMS: To examine the relationships between body composition and changes in fasting glycaemia, and in indices of insulin secretion and insulin action over 6 years in females with a family history of Type 2 diabetes with or without prior gestational diabetes ('at risk' group, AR) and control females (control group, C). METHODS: At baseline and at follow-up, an oral glucose tolerance test and dual energy X-ray absorptiometry assessment of body composition were performed. Indices of insulin resistance (HOMA R') and insulin secretion (HOMA beta') were obtained from fasting insulin and glucose concentrations. RESULTS: At baseline, the groups were similar for age, body mass index, fasting levels of plasma glucose and insulin, HOMA R' and HOMA beta'. Despite similar total body fatness, AR had significantly greater waist circumference and central fat (both P < 0.02) compared with C. At follow-up there was a significant increase in central adiposity only in AR, and the fasting plasma glucose (FPG) level was higher in AR compared with C (5.0 +/- 0.2 vs. 4.3 +/- 0.2 mmol/l, P = 0.02). This rise in plasma glucose in AR was related to a decline in HOMA beta' (r = 0.45, P = 0.0065). Both the baseline and the increments in total and central abdominal fat mass were associated with the time-related decline in HOMA beta'. CONCLUSIONS: Six years after initial assessment, AR showed deterioration in FPG levels due predominantly to a decline in insulin secretion index without major change in insulin resistance index. Importantly, baseline body fatness (especially central adiposity), as well as increases in fatness with time, were the major predictors of the subsequent decline of insulin secretion index and the consequent rise in FPG.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Jejum/sangue , Insulina/metabolismo , Adulto , Composição Corporal , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Pessoa de Meia-IdadeRESUMO
Insulin resistance in skeletal muscle is associated with 1) relative increases in the proportion of glycolytic and fast-twitch muscle fibers and decreases in the proportion of more oxidative fibers and 2) a higher proportion of the saturated fatty acids in membrane structural lipids. Exercise is known to improve insulin action. The aims of the current studies were 1) to investigate the relationship between muscle fiber type and membrane fatty acid composition and 2) to determine how voluntary exercise might influence both variables. In sedentary Wistar rats in experiment 1, increased amounts of unsaturated fatty acids were found in the more oxidative insulin-sensitive red quadriceps and soleus muscles, whereas reduced levels of polyunsaturated fatty acids were found in primarily glycolytic white quadriceps muscles. In experiment 2, voluntary running-wheel exercise by adult female rats over 45 days resulted in reduced proportions of type IIb fibers (P = 0.01) and increased proportions of type IIa/IIx fibers (P = 0.03) in extensor digitorum longus muscle. The magnitude of these changes was related to the distance run (r = -0.73, P = 0.04; r = 0.79, P = 0.02, respectively). Exercise significantly increased oxidative capacity, as assessed by the proportion of intensely NADH-stained fibers (P = 0.0004) and citrate synthase (P = 0.003) and hexokinase (P = 0.04) activities. Citrate synthase activity was also increased by exercise in soleus muscle, where, as expected, no fiber type changes were detected. No significant differences in the fatty acid profile of soleus and extensor digitorum longus were found between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Citrato (si)-Sintase/metabolismo , Hexoquinase/metabolismo , Lipídeos de Membrana/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Animais , Ácidos Graxos/metabolismo , Feminino , Membro Posterior , Masculino , Fibras Musculares Esqueléticas/classificação , Oxirredução , Esforço Físico , Ratos , Ratos WistarRESUMO
OBJECTIVES: To investigate the fibre type composition of skeletal muscle in infants and young children and to compare the findings to an adult population. To relate the fibre type profile of skeletal muscle in adults to measures of adiposity. DESIGN: Cross-sectional studies of skeletal muscle fibre composition in infants and adults with measures of adiposity in the adults. SUBJECTS: 21 healthy infants and young children (age: 3-21 months) and 40 healthy adult Australian Caucasians (age: 26-62 y; BMI: 18-48 kg/m2). MEASUREMENTS: Skeletal muscle fibre type composition (by myosin ATPase method) and relative body fatness (BMI, waist circumference and waist/hip ratio (WHR)). RESULTS: Infants and young children had significantly lesser proportions of glycolytic Type 2b fibres (6.2 +/- 1.1%; range 0.3-18.9%) compared with adults (20.5 +/- 1.6%; range 4.9-36.0%) (p < 0.0001). The percentage of Type 2b fibres was directly related to BMI (r = 0.44, p = 0.02), waist circumference (r = 0.49, p = 0.009) and WHR (r = 0.44, p = 0.02) in adults. A significant, direct relationship was also found between the proportion of glycolytic Type 2b fibres and age in the adults (r = 0.45, p = 0.01). CONCLUSION: Skeletal muscle fibre type composition is different in infants and adults and there is an age-dependent increase in Type 2b fibres over the lifespan. An increased proportion of glycolytic Type 2b fibres is associated with obesity in adults. Results support a gene-environment interaction on fibre type composition in human skeletal muscle.