Insulin Action and Its Disturbances in Disease - part 6 pps

294 ADIPOKINES AND INSULIN RESISTANCE 225. Hu, E., Liang, P. and Spiegelman, B. M. (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. JBiolChem271 (18), 10 697–10 703. 226. Matsubara, M., Maruoka, S. and Katayose, S. (2002) Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 147 (2), 173–180. 227. Milan, G., Granzotto, M., Scarda, A., Calcagno, A., Pagano, C., Federspil, G. and Vet- tor, R. (2002) Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes Res 10 (11), 1095–1103. 228. Stefan, N., Bunt, J. C., Salbe, A. D., Funahashi, T., Matsuzawa, Y. and Tataranni, P. A. (2002) Plasma adiponectin concentrations in children: relationships with obesity and insulinemia. J Clin Endocrinol Metab 87 (10), 4652–4656. 229. Yang, W. S., Lee, W. J., Funahashi, T., Tanaka, S., Matsuzawa, Y., Chao, C. L., Chen, C. L., Tai, T. Y. and Chuang, L. M. (2002) Plasma adiponectin levels in overweight and obese Asians. Obes Res 10 (11), 1104–1110. 230. Yamauchi, T., Kamon, J., Waki, H., Murakami, K., Motojima, K., Komeda, K., Ide, T., Kubota, N., Terauchi, Y., Tobe, K., Miki, H., Tsuchida, A., Akanuma, Y., Nagai, R., Ki- mura, S. and Kadowaki, T. (2001) The mechanisms by which both heterozygous peroxi- some proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. JBiolChem276 (44), 41 245–41 254. 231. Combs, T. P., Wagner, J. A., Berger, J., Doebber, T., Wang, W. J., Zhang, B. B., Tanen, M., Berg, A. H., O’Rahilly, S., Savage, D. B., Chatterjee, K., Weiss, S., Larson, P. J., Gottesdiener, K. M., Gertz, B. J., Charron, M. J., Scherer, P. E. and Moller, D. E. (2002) Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 143 (3), 998–1007. 232. Hirose, H., Kawai, T., Yamamoto, Y., Taniyama, M., Tomita, M., Matsubara, K., Oka- zaki, Y., Ishii, T., Oguma, Y., Takei, I. and Saruta, T. (2002) Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51 (3), 314–317. 233. Gustafson, B., Jack, M. M., Cushman, S. W. and Smith, U. (2003) Adiponectin gene activation by thiazolidinediones requires PPARgamma2, but not C/EBPalpha-evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun 308 (4), 933–939. 234. Maeda, N., Shimomura, I., Kishida, K., Nishizawa, H., Matsuda, M., Nagaretani, H., Furuyama, N., Kondo, H., Takahashi, M., Arita, Y., Komuro, R., Ouchi, N., Kihara, S., Tochino, Y., Okutomi, K., Horie, M., Takeda, S., Aoyama, T., Funahashi, T. and Mat- suzawa, Y. (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8 (7), 731–737. 235. Pajvani, U. B. and Scherer, P. E. (2003) Adiponectin: systemic contributor to insulin sensitivity. Curr Diab Rep 3 (3), 207–213. 236. Masaki, T., Chiba, S., Yasuda, T., Tsubone, T., Kakuma, T., Shimomura, I., Funahashi, T., Matsuzawa, Y. and Yoshimatsu, H. (2003) Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in Agouti yellow (A(y)/a) obese mice. Diabetes 52 (9), 2266–2273. 237. Tschritter, O., Fritsche, A., Thamer, C., Haap, M., Shirkavand, F., Rahe, S., Staiger, H., Maerker, E., Haring, H. and Stumvoll, M. (2003) Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism. Diabetes 52 (2), 239–243. 238. Combs, T. P., Berg, A. H., Obici, S., Scherer, P. E. and Rossetti, L. (2001) Endoge- nous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108 (12), 1875–1881. REFERENCES 295 239. Fruebis, J., Tsao, T. S., Javorschi, S., Ebbets-Reed, D., Erickson, M. R., Yen, F. T., Bihain, B. E. and Lodish, H. F. (2001) Proteolytic cleavage product of 30-kDa adipo- cyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98 (4), 2005–2010. 240. Yamauchi, T., Kamon, J., Waki, H., Imai, Y., Shimozawa, N., Hioki, K., Uchida, S., Ito, Y., Matsui, J., Eto, K., Komeda, K., Tsunoda, M., Murakami, K., Ohnishi, Y., Yamamura, K., Ueyama, Y., Froguel, P., Kimura, S., Nagai, R. and Kadowaki, T. (2002) Globular adiponectin protected ob/ob mice from diabetes and apoE deficient mice from atherosclerosis. JBiolChem. 241. Xu, A., Wang, Y., Keshaw, H., Xu, L. Y., Lam, K. S. and Cooper, G. J. (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver dis- eases in mice. J Clin Invest 112 (1), 91–100. 242. Berg, A. H., Combs, T. P., Du, X., Brownlee, M. and Scherer, P. E. (2001) The adipo- cyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7 (8), 947–953. 243. Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P., Carling, D., Kimura, S., Nagai, R., Kahn, B. B. and Kadowaki, T. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated pro- tein kinase. Nat Med 8 (11), 1288–1295. 11 Dietary Factors and Insulin Resistance Jeremy Krebs and Susan Jebb 11.1 Introduction Diet is a critical determinant of the risk of many metabolic diseases. However, while the role of dietary factors in the aetiology of cardiovascular disease and cancer has been extensively explored, less consideration has been given to the development of insulin resistance and diabetes. Recently the global epidemic of type 2 diabetes, following in the wake of the increase in obesity, has focussed attention in this area. There is renewed interest in both the role of dietary factors as a contributor to obesity and the impact of specific dietary constituents on insulin resistance, independent of weight. Putative candidates include each of the macronutrients together with specific micronutrients. However, progress in understanding the relationship between diet and insulin resistance is hampered by the complexity of the relationship, which is difficult to isolate from factors such as genetic background, or other environmental factors such as physical activity. Indeed, there are likely to be complex inter-relationships between these factors, including gene–nutrient–environment interactions. Epidemiological analyses of the problem are hampered by the difficulties in making accurate measurements of exposure (dietary intake) and outcome (insulin resistance). Assessment of habitual diet is notoriously flawed, with a bias towards under-reporting, that is unlikely to apply equally across all foods or nutrients. 1, 2 A variety of methods are used to assess insulin resistance, each offering a slightly different perspective on this metabolic disturbance, including fasting insulin concentration, combinations of fasting insulin and glucose such as the homeostasis model assessment (HOMA) and area under the insulin curve Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly  2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6 298 DIETARY FACTORS AND INSULIN RESISTANCE during an OGTT. In some cases the occurrence of impaired glucose tolerance may be used as a surrogate, albeit very loose, marker of insulin resistance. More sophisticated methods of determining insulin sensitivity such as the intravenous glucose tolerance test with minimal modelling or the hyperinsulinaemic eug- lycaemic clamp are the ‘gold standards’ but are invasive, costly and largely confined to experimental studies. Together the measurement errors in diet and insulin resistance incurred in most epidemiological studies make the interpreta- tion of cross-sectional associations particularly challenging. Testing epidemiological hypotheses in controlled intervention studies has also proved difficult because habitual background diet, physical activity and body composition have important modulating effects on the impact of specific dietary factors on insulin resistance. It is difficult to alter one dietary factor independent of other components of the diet, and short term interventions may not appro- priately reflect a lifetime’s exposure. Thus in many situations it is necessary to study the precise mechanism of action of a nutrient at a cellular or tissue level in order to shed light on its potential role in whole body insulin resistance. This chapter draws on evidence from diverse sources to consider the role of dietary factors in the aetiology of insulin resistance and thus offers a foundation for the development of dietary strategies to prevent or reduce insulin resistance. 11.2 The importance of body fatness Body mass index (BMI) is a strong predictor of the risk of developing type 2 diabetes. 3, 4 The association is particularly marked for more specific mea- sures of body fatness, especially abdominal fat. 5 Adult weight gain increases the risk further (Figure 11.1). More detailed experimental studies using a eugly- caemic clamp have confirmed that weight gain is associated with a deterioration in insulin sensitivity in overweight and obese individuals with either normal or impaired glucose tolerance. 6 The exact mechanism for the link between Weight at 21 year 0 5 10 15 20 25 Relative risk Weight gain since 21 year >11 5–10 <5 <22 22–23 >24 Figure 11.1 Impact of BMI and weight change on the risk of developing diabetes in men (data from reference 3) THE IMPORTANCE OF BODY FATNESS 299 increased fatness and insulin resistance remains unclear, but there is growing evidence of signalling between adipose tissue and insulin-sensitive organs – particularly liver and skeletal muscle – which in part regulates the insulin sensi- tivity of these organs. Potential candidates for this signal include circulating free fatty acids, adipokines such as Acrp30, IL-6, TNFα, leptin or resistin or some other as yet unidentified agent. 7 These are discussed in detail in Chapter 10. However, it is apparent that normally functioning adipose tissue is required for normal whole body insulin sensitivity. This is highlighted by syndromes of lipodystrophy where the relative absence of adipose tissue is also associated with insulin resistance. 8 Body weight is the integrated product of a lifetime’s dietary intake, offset by energy needs. An excess of energy intake over expenditure over a prolonged period of time leads to increases in body fat and ultimately, if unchecked, in obesity. Although this fundamental principle of energy balance lies at the heart of the aetiology of obesity, it oversimplifies the complex inter-relationships between genetic factors, lifestyle, cultural issues and behavioural patterns that all contribute to the risk of an individual becoming overweight. 9, 10 Whilst a detailed discussion of the aetiology of obesity is beyond the scope of this chapter, it is important to remember that dietary factors that impact upon the risk of obesity will, in turn, increase the risk of developing insulin resistance. Epidemiological analyses of the relationship between fat intake and obesity are inconsistent, although the trend suggests that a high fat diet is linked to an increased risk of excess weight. 11, 12 However, such studies are confounded by errors in dietary reporting and post hoc changes in consumption among obese individuals. More detailed experimental studies demonstrate that subjects allowed to eat ad libitum from diets of varying fat content consume more energy on high fat foods. 13 However, this high fat hyperphagia is abolished when the energy density is equalized. 14 Low fat, low energy-dense diets that are associ- ated with a reduction in total energy intake lead to modest weight losses and associated improvements in insulin sensitivity. 15 Fruit and vegetables can help to reduce the energy density of the diet, although specific evidence of a protective role for these foods in the aetiology of obesity is lacking. Data from diverse sources implies an adverse effect of sugar rich soft drinks. Consumption of soft drinks among children and young people has increased markedly over the last 20 years, coinciding with the rapid rise in obesity in devel- oped countries. These have a low energy density, due to their high water content, but their low viscosity reduces their impact on innate satiety signals. 16 Thus consumption of these drinks tends to supplement rather than substitute for food energy, increasing the risk of excessive energy intakes. 17 A 10 week intervention study showed consumption of sugar rich beverages was associated with signif- icant weight gain relative to artificially sweetened varieties. 18 The role of other specific carbohydrate sources in the aetiology of obesity is less clear, although evidence favours a protective role of foods with a low glycaemic index. 19 300 DIETARY FACTORS AND INSULIN RESISTANCE Recently research has turned towards the investigation of broader eating habits rather than specific foods or nutrients. Issues such as the impact of fast food, 20 snacking, 21 portion size, 22 food consumed in conjunction with TV viewing 23 and family or cultural influences 24 may all be important determinants of the risk of obesity. Finally, it is important to note the impact of physical activity, both as a determinant of energy needs, but also as an element in innate appetite control systems. 25 These issues have been recently reviewed. 26 The importance of obesity as a determinant of insulin resistance is confirmed by the striking improvements that can be seen in insulin resistance with weight loss. 27 Even modest weight losses of 5–10 per cent of initial body weight achieved through diet and lifestyle modification in overweight and obese subjects are related to improved insulin sensitivity. 28 The magnitude of the improvement in insulin resistance is largely related to the extent of weight loss. For example, very low calorie diets (VLCD), providing <800 kcal/day, are able to facilitate greater weight loss, at least in the short term, than more conservative dietary approaches, and a corresponding greater improvement in insulin sensitivity. In obese sedentary subjects those using a VLCD achieved a 15 per cent weight loss over 4 months with a 24 per cent improvement in insulin sensitivity measured by the euglycaemic clamp. 29 In a group of 40 obese subjects with type 2 diabetes the initial use of a VLCD for eight weeks resulted in a mean weight loss of more than 10 per cent body weight with associated improvements in fructosamine, and reductions in insulin requirements. This benefit was maintained at 12 months after ongoing standard weight management advice. 30 The adjunctive use of pharmacotherapy, such as sibutramine or orlistat, to achieve greater reductions in energy intake or absorption over and above diet and lifestyle modification alone is associated with greater weight loss compared with placebo. This translates into greater improvements in insulin sensitivity in obese individuals 31, 32 and those with the metabolic syndrome 33 and also improvements in glycaemic control in those with type 2 diabetes. 34 Bariatric surgery, such as gastric bypass or gastric banding, leading to marked decreases in energy intake, results in weight losses of up to 50 per cent body weight. This is considerably greater than that achieved with other methods, leading to major improvements in insulin sensitivity and reduced progression to diabetes in obese individuals. 35, 36 It should be noted that changes in total energy intake have important effects on insulin sensitivity independent of the effect of changes in body weight or fat mass. In highly controlled experimental studies, short term periods of energy restriction in individuals who are insulin resistant are associated with rapid improvements in insulin sensitivity, even in the absence of weight loss. 37 The exact mechanism for this sudden change is not clear, but is likely to be related to changes in nutrient flux or possibly to gut-related hormones. In particular, a reduction in circulating free fatty acids is achieved with acute energy restriction due to reduced dietary fat intake and reduced adipocyte lipolysis. High levels of THE IMPORTANCE OF BODY FATNESS 301 circulating free fatty acids have been linked to insulin resistance via impairment of insulin-mediated glucose uptake and reductions in free fatty acid levels with acute energy restriction reversing this effect. 8, 38 Thus, in the acute phase of weight loss, the improvement in metabolic risk factors is largely related to the energy deficit and extent of weight lost and there is little evidence to support a specific benefit of any one dietary regimen over another. However, in the phase of weight-loss maintenance, diet composition may become more important. Weight loss achieved with diet and lifestyle modification, pharmacother- apy or surgery is often followed by some weight regain, which is frequently accompanied by deterioration in insulin sensitivity. In otherwise healthy obese individuals, a minimum of five per cent long term reduction in body weight appears to be required to maintain improvements in insulin sensitivity. 39 How- ever, recent data suggests that there may be residual benefits that reduce, or at least delay, the development of diabetes in obese subjects with impaired glucose tolerance. Two large prospective randomized controlled trials of diet and lifestyle intervention to promote weight loss in individuals at high risk of developing dia- betes have shown a significantly reduced risk with very modest initial weight loss and even smaller long term weight loss. In the Finnish diabetes prevention study 40 intensive dietary and lifestyle advice achieved a mean weight loss of 4.7 per cent over 12 months in 522 obese individuals with impaired glucose toler- ance, and significant reduction in 2 hour post-glucose-load insulin concentration but not fasting insulin. This was followed by variable weight regain over the mean 3.2 year follow-up, resulting in a mean 3.5 ± 5.5 kg decrease in weight from baseline. This small long term sustained weight loss was associated with a 58 per cent reduced risk of progression to diabetes. An identical risk reduction was observed in the Diabetes Prevention Program, 41 in a similar group of 3234 obese individuals with impaired glucose tolerance, and a mean weight loss of less than five per cent body weight after 4 years. This implies a longer term metabolic benefit of even small weight losses, which may encompass benefits on insulin release from pancreatic β-cells as well as those of improved insulin sensitivity. However, as might be expected, greater long term weight losses are associated with a greater reduction in risk. The Xendos trial 42 was a randomized, placebo- controlled trial comparing the adjunctive use of orlistat with intensive diet and lifestyle modification in 4193 obese subjects. Subjects randomized to orlistat lost a mean of 6.9 kg compared with 4.1 kg in those on placebo after 4 years. This translated to a 37 per cent reduction (9.0 per cent compared with 6.2 per cent) in the rate of progression to diabetes over the 4 years of the study. In a subset of those with impaired glucose tolerance, those in the intensive lifestyle alone group had similar rates of progression to diabetes to those in the intensive lifestyle group of the Diabetes Prevention Program. 41 In these subjects, the additional weight loss achieved with orlistat further reduced the rate of developing diabetes by an additional 52 per cent. 302 DIETARY FACTORS AND INSULIN RESISTANCE The impact of lifestyle changes, independent of body weight, are unclear, but the improvement in insulin sensitivity is probably greater than may be antic- ipated from the small overall weight loss. Increases in physical activity are known to offer a decreased risk of diabetes but certain dietary components may also be significant. In each of these studies the dietary recommendations were based around a low fat, calorie-controlled diet, rich in fruits and vegeta- bles and with an emphasis on unrefined carbohydrates, which is consistent with international dietary recommendations for the prevention of cardiovascular dis- ease. At present, no comparable long term data showing improvements in the hard clinical endpoint of incident diabetes is available for other, less orthodox, dietary regimens. 11.3 Specific dietary factors Epidemiological investigations into the role of dietary factors and insulin resis- tance generally focus on specific nutrients, notably macronutrients (fat, carbo- hydrate, protein and, to a lesser extent, alcohol) or micronutrients (vitamins and minerals). In addition there is growing interest in the role of a range of other plant-based compounds that are not classical nutrients but that may exert specific health benefits, such as flavanoids and phytoestrogens. 43 This makes it difficult to disentangle the health effects of specific nutrients. Similar difficulties exist in the interpretation of many dietary intervention studies. Changes in absolute macronutrient intake have implications for total energy intake, while changes in the proportion of energy-providing substrates result in changes in more than one macronutrient. Food represents a complex mixture of nutrients and foods are rarely eaten in isolation, so it may be more appropriate, although more com- plex, to analyse broader dietary patterns. However suitable statistical techniques are only just being employed to analyse nutritional data. Fat Fat is the most energy dense of the macronutrients, containing 9 kcal/g (37 kJ/g) compared with 4 kcal/g (16 kJ/g) for carbohydrate or protein, and has been implicated in the aetiology of obesity. However independent of the effect on body weight, both the amount and type of fat have an impact on insulin sen- sitivity. Diets high in fat are associated with impairments in insulin sensitivity and animal studies consistently demonstrate that high fat diets promote insulin resistance compared with diets high in carbohydrate. 44 Although less consis- tent, studies in humans show that high fat diets are associated with higher fasting insulin concentration and reduced insulin sensitivity, 45, 46 and in longi- tudinal studies a higher rate of development of impaired glucose tolerance 47 and progression to type 2 diabetes. 48 SPECIFIC DIETARY FACTORS 303 However, it is important to distinguish between different types of fat. The negative association between fat and insulin sensitivity is predominately driven by saturated fat. In epidemiological studies, a high saturated fat intake has been associated with higher fasting insulin and glucose levels 45 and greater rates of glucose intolerance. 47 Specific fatty acid analysis of serum and muscle membrane phospholipids reveals an association between high levels of saturated fatty acid content and higher fasting insulin, reduced insulin sensitivity and higher risk of developing type 2 diabetes. 49, 50 Monounsaturated fatty acids (MUFAs) are usually considered to have a neu- tral impact on insulin sensitivity. However, a recent large intervention study replacing saturated fat with monounsaturated fat and with detailed measures of insulin sensitivity using an IVGTT showed improvements in insulin sensitivity in healthy subjects after 3 months. 51 However, a post hoc analysis suggested that this benefit was only apparent among individuals where the intake of fat was less than 37 per cent of total energy – highlighting the importance of total fat content. In epidemiological studies, increases in the proportion of PUFAs in the diet are associated with lower insulin levels, enhanced insulin sensitivity 52, 53 and reduced risk of developing type 2 diabetes. 54 In the Nurses’ Health Study, after 14 years follow-up, the adjusted relative risk for developing type 2 diabetes was 0.75 (95 per cent CI, 0.65–0.88) for the highest versus lowest quintile of PUFA intake. 54 Polyunsaturated fatty acids are classified as essential fatty acids since they must be obtained from the diet and cannot be synthesised in vivo. Linoleic acid (n − 6) and α-linolenic acid (n − 3) classes of PUFA may be elongated and further desaturated to form long chain fatty acids. This occurs to some extent in vivo, but the majority of these long chain n − 3 PUFAs are obtained from the diet in the form of the so-called fish oils, eicosapentanoic acid (EPA) and decosahexanoic acid (DHA). In the average western diet, intake of n − 6 PUFA is considerably greater than that of n − 3 PUFA, and quantitatively small changes in n − 3 can have a considerable effect on the n − 6:n − 3 ratio. There is some debate about the relative importance of n − 3 intake and the n − 6:n − 3 ratio as a determinant of insulin sensitivity. A study in rats fed a high fat diet resulting in insulin resis- tance showed that replacing saturated fat with a combination of short chain (18:2 n − 6) and short chain (18:3 n − 3) PUFA had no effect on insulin resistance measured by the euglycaemic clamp. 55 However, if saturated fat was replaced with long chain n − 3 PUFA, insulin resistance was significantly improved. Moreover, if the rats were fed a diet of saturated fat combined with short chain n − 3 but not short chain n − 6 PUFA, insulin resistance was similarly improved (Figure 11.2). These results suggest an important role for long chain n − 3 PUFAs in improving insulin sensitivity, but further indicate that the competi- tion for enzymes to further elongate and desaturate shorter chain n − 3 PUFAs prevents this conversion when combined with a diet rich in short chain n − 6 [...]... insulin OGTT–fasting and post-challenge insulin Fasting and post-challenge plasma insulin None Stratified by sex Analysis presented for quintiles of waist–hip girth ratio (W/H) (continues overleaf ) Inverse relationship in women (r = −.07, p < 0.05 for fasting insulin and r = −0.10, p < 0.0001 for 2 h insulin) Inverse association between PA and W/H ratio Direct association between insulin levels and. .. of action for increased insulin action via increased insulin receptor expression and increased activation of insulin receptor kinase.91 11.4 Summary Whole body insulin sensitivity is the product of a complex interaction between genotype, physical characteristics such as body weight and environmental and behavioural factors such as diet and physical activity Obesity is strongly linked to impaired insulin. .. women Diabetes 45, 63 3 63 8 6 Weyer, C., Hanson, K., Bogardus, C and Pratley, R E (2000) Long-term changes in insulin action and insulin secretion associated with gain, loss, regain and maintenance of body weight Diabetologia 43 (1), 36 46 7 Fruhbeck, G., Gomez-Ambrosi, J., Muruzabal, F R and Burrell, M A (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism... insulin during an OGTT Fasting insulin Measure of insulin resistance Table 12.1 (continued ) Age, fasting glucose, BMI, WHR, sum of skin fold, ethnicity, MABP, smoking, angina Confounders adjusted for Inverse relationship between insulin and activity during leisure time (p < 0.05) but not during work Men: β = −0.0008; p = 0.0027, for METh/week on insulin Women: β = −0.0003; p = 0 .60 27, for METhr/wk on insulin. .. 551 /66 9 Age: 15–24 years Mean BMI (SD): 21.4 (3.0) Nationality: Finnish N (m/f): 819/1159 Age: 35 64 years BMI: Ethnicity: Mexican Hispanics Measure of physical activity N (m/f): 219 Age: 31– 76 years BMI: 28.1 Ethnicity: Hispanics and non-Hispanic Caucasians Participant characteristics OGTT–fasting and post-challenge insulin Fasting insulin OGTT–fasting and post-challenge insulin Measure of insulin. .. oxidation, decrease FFA release and increase insulin clearance .65 The relative effects of soluble and insoluble fibre remain unclear In a crossover study in 14 subjects with type 2 diabetes, increased cereal fibre reduced mean glucose concentration with no effect on insulin levels, suggesting an improvement in insulin sensitivity .66 In contrast, in 22 healthy postmenopausal women insulin sensitivity measured... OGTT–fasting and post-challenge insulin IVGTT Measure of insulin resistance Table 12.1 (continued ) Fasting serum insulin No significant association in the patients, the healthy subjects or when combined Positive relationship between insulin sensitivity and fitness in men (r = 0.44, p < 0.001) and women (r = 0.32, p < 0.001) No association between level of PA and risk of insulin resistance status Direction and. .. leisure-time and occupational activity N (m/f): 63 2/719 Age: 51.8 (12.1) years BMI: 25.5 (4.2) Ethnicity: Hispanics and Non-Hispanic Caucasians Fasting insulin Fasting insulin IVGTT Fasting insulin Age, BMI, SES, smoking, heavy drinking, existing CHD Three-way analysis of covariance adjusted for age Age, sex, ethnicity, clinic, alcohol intake, smoking, energy intake from fat, hypertension (continues... viewpoint strongly against Curr Opin Lipidol 8 (1), 23–27 74 Wolever, T M and Bolognesi, C (19 96) Prediction of glucose and insulin responses of normal subjects after consuming mixed meals varying in energy, protein, fat, carbohydrate and glycemic index J Nutr 1 26 (11), 2807–2812 75 Kiens, B and Richter, E A (19 96) Types of carbohydrate in an ordinary diet affect insulin action and muscle substrates in. .. for age and BMI Stratified by sex and ethnicity (continues overleaf ) Inverse association between self-reported heavy PA and insulin in men only (p < 0.05) Inverse association between fitness and insulin in all strata (p < 0.01) except black women 22% lower insulin levels in women doing regular heavy exercise (p < 0.005) but no difference in men SUMMARY OF FINDINGS FROM OBSERVATIONAL STUDIES IN ADULTS . insulin action via increased insulin receptor expression and increased activation of insulin receptor kinase. 91 11.4 Summary Whole body insulin sensitivity is the product of a complex interaction. (HOMA) and area under the insulin curve Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly  2005 John Wiley & Sons, Ltd ISBN: 0-4 7 0-8 500 8 -6 298 DIETARY FACTORS AND INSULIN RESISTANCE during. determinant of insulin sensitivity. A study in rats fed a high fat diet resulting in insulin resis- tance showed that replacing saturated fat with a combination of short chain (18:2 n − 6) and