Insulin Action and Its Disturbances in Disease - part 6 pps

Although this fundamental principle of energy balance lies at the heart of the aetiology of obesity, it oversimplifies the complex inter-relationshipsbetween genetic factors, lifestyle, c

225 Hu, E., Liang, P and Spiegelman, B M (1996) AdipoQ is a novel adipose-specific

gene dysregulated in obesity J Biol Chem 271 (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 tor, R (2002) Resistin and adiponectin expression in visceral fat of obese rats: effect

Vet-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 J Biol Chem 276 (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., 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

Oka-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 J Biol Chem.

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.

as a contributor to obesity and the impact of specific dietary constituents oninsulin resistance, independent of weight Putative candidates include each ofthe macronutrients together with specific micronutrients However, progress inunderstanding the relationship between diet and insulin resistance is hampered

by the complexity of the relationship, which is difficult to isolate from factorssuch as genetic background, or other environmental factors such as physicalactivity Indeed, there are likely to be complex inter-relationships between thesefactors, 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 abias towards under-reporting, that is unlikely to apply equally across all foods

or nutrients.1, 2A variety of methods are used to assess insulin resistance, eachoffering a slightly different perspective on this metabolic disturbance, includingfasting 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

during an OGTT In some cases the occurrence of impaired glucose tolerancemay be used as a surrogate, albeit very loose, marker of insulin resistance Moresophisticated methods of determining insulin sensitivity such as the intravenousglucose tolerance test with minimal modelling or the hyperinsulinaemic eug-lycaemic clamp are the ‘gold standards’ but are invasive, costly and largelyconfined to experimental studies Together the measurement errors in diet andinsulin resistance incurred in most epidemiological studies make the interpreta-tion of cross-sectional associations particularly challenging.

Testing epidemiological hypotheses in controlled intervention studies has alsoproved difficult because habitual background diet, physical activity and bodycomposition have important modulating effects on the impact of specific dietaryfactors on insulin resistance It is difficult to alter one dietary factor independent

of other components of the diet, and short term interventions may not priately reflect a lifetime’s exposure Thus in many situations it is necessary tostudy the precise mechanism of action of a nutrient at a cellular or tissue level

appro-in order to shed light on its potential role appro-in whole body appro-insulappro-in resistance Thischapter draws on evidence from diverse sources to consider the role of dietaryfactors in the aetiology of insulin resistance and thus offers a foundation for thedevelopment 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 increasesthe 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

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 growingevidence 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 freefatty acids, adipokines such as Acrp30, IL-6, TNFα, leptin or resistin or someother as yet unidentified agent.7 These are discussed in detail in Chapter 10.However, it is apparent that normally functioning adipose tissue is requiredfor normal whole body insulin sensitivity This is highlighted by syndromes oflipodystrophy where the relative absence of adipose tissue is also associatedwith insulin resistance.8

Body weight is the integrated product of a lifetime’s dietary intake, offset byenergy needs An excess of energy intake over expenditure over a prolongedperiod of time leads to increases in body fat and ultimately, if unchecked, inobesity Although this fundamental principle of energy balance lies at the heart

of the aetiology of obesity, it oversimplifies the complex inter-relationshipsbetween genetic factors, lifestyle, cultural issues and behavioural patterns thatall 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 thischapter, it is important to remember that dietary factors that impact upon therisk of obesity will, in turn, increase the risk of developing insulin resistance.Epidemiological analyses of the relationship between fat intake and obesityare 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 amongobese individuals More detailed experimental studies demonstrate that subjectsallowed 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 theenergy 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 andassociated improvements in insulin sensitivity.15Fruit and vegetables can help toreduce the energy density of the diet, although specific evidence of a protectiverole 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 increasedmarkedly 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 Thusconsumption of these drinks tends to supplement rather than substitute for foodenergy, increasing the risk of excessive energy intakes.17A 10 week interventionstudy showed consumption of sugar rich beverages was associated with signif-icant weight gain relative to artificially sweetened varieties.18 The role of otherspecific carbohydrate sources in the aetiology of obesity is less clear, althoughevidence favours a protective role of foods with a low glycaemic index.19

Recently research has turned towards the investigation of broader eatinghabits rather than specific foods or nutrients Issues such as the impact offast food,20 snacking,21 portion size,22 food consumed in conjunction with TVviewing23 and family or cultural influences24 may all be important determinants

of the risk of obesity Finally, it is important to note the impact of physicalactivity, both as a determinant of energy needs, but also as an element in innateappetite 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 weightloss.27 Even modest weight losses of 5–10 per cent of initial body weightachieved through diet and lifestyle modification in overweight and obese subjectsare 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 dietaryapproaches, and a corresponding greater improvement in insulin sensitivity Inobese sedentary subjects those using a VLCD achieved a 15 per cent weight lossover 4 months with a 24 per cent improvement in insulin sensitivity measured bythe euglycaemic clamp.29 In a group of 40 obese subjects with type 2 diabetesthe initial use of a VLCD for eight weeks resulted in a mean weight loss of morethan 10 per cent body weight with associated improvements in fructosamine, andreductions in insulin requirements This benefit was maintained at 12 monthsafter ongoing standard weight management advice.30

The adjunctive use of pharmacotherapy, such as sibutramine or orlistat, toachieve greater reductions in energy intake or absorption over and above dietand lifestyle modification alone is associated with greater weight loss comparedwith placebo This translates into greater improvements in insulin sensitivity

in obese individuals31, 32 and those with the metabolic syndrome33 and alsoimprovements in glycaemic control in those with type 2 diabetes.34 Bariatricsurgery, 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 majorimprovements in insulin sensitivity and reduced progression to diabetes in obeseindividuals.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 fatmass In highly controlled experimental studies, short term periods of energyrestriction in individuals who are insulin resistant are associated with rapidimprovements in insulin sensitivity, even in the absence of weight loss.37 Theexact 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, areduction in circulating free fatty acids is achieved with acute energy restrictiondue 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 withacute 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 theenergy deficit and extent of weight lost and there is little evidence to support aspecific 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 frequentlyaccompanied by deterioration in insulin sensitivity In otherwise healthy obeseindividuals, a minimum of five per cent long term reduction in body weightappears to be required to maintain improvements in insulin sensitivity.39 How-ever, recent data suggests that there may be residual benefits that reduce, or atleast delay, the development of diabetes in obese subjects with impaired glucosetolerance Two large prospective randomized controlled trials of diet and lifestyleintervention to promote weight loss in individuals at high risk of developing dia-betes have shown a significantly reduced risk with very modest initial weightloss and even smaller long term weight loss In the Finnish diabetes preventionstudy40 intensive dietary and lifestyle advice achieved a mean weight loss of 4.7per cent over 12 months in 522 obese individuals with impaired glucose toler-ance, and significant reduction in 2 hour post-glucose-load insulin concentrationbut not fasting insulin This was followed by variable weight regain over themean 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 reductionwas observed in the Diabetes Prevention Program,41 in a similar group of 3234obese individuals with impaired glucose tolerance, and a mean weight loss of lessthan five per cent body weight after 4 years This implies a longer term metabolicbenefit of even small weight losses, which may encompass benefits on insulinrelease from pancreaticβ-cells as well as those of improved insulin sensitivity.However, as might be expected, greater long term weight losses are associatedwith a greater reduction in risk The Xendos trial42 was a randomized, placebo-controlled trial comparing the adjunctive use of orlistat with intensive diet andlifestyle 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 Thistranslated 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 ofthose with impaired glucose tolerance, those in the intensive lifestyle alone grouphad similar rates of progression to diabetes to those in the intensive lifestylegroup of the Diabetes Prevention Program.41 In these subjects, the additionalweight loss achieved with orlistat further reduced the rate of developing diabetes

by an additional 52 per cent

The impact of lifestyle changes, independent of body weight, are unclear, butthe improvement in insulin sensitivity is probably greater than may be antic-ipated from the small overall weight loss Increases in physical activity areknown to offer a decreased risk of diabetes but certain dietary componentsmay also be significant In each of these studies the dietary recommendationswere based around a low fat, calorie-controlled diet, rich in fruits and vegeta-bles and with an emphasis on unrefined carbohydrates, which is consistent withinternational dietary recommendations for the prevention of cardiovascular dis-ease At present, no comparable long term data showing improvements in thehard 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 tance generally focus on specific nutrients, notably macronutrients (fat, carbo-hydrate, protein and, to a lesser extent, alcohol) or micronutrients (vitamins andminerals) In addition there is growing interest in the role of a range of otherplant-based compounds that are not classical nutrients but that may exert specifichealth benefits, such as flavanoids and phytoestrogens.43 This makes it difficult

resis-to disentangle the health effects of specific nutrients Similar difficulties exist

in the interpretation of many dietary intervention studies Changes in absolutemacronutrient intake have implications for total energy intake, while changes

in the proportion of energy-providing substrates result in changes in more thanone macronutrient Food represents a complex mixture of nutrients and foodsare rarely eaten in isolation, so it may be more appropriate, although more com-plex, to analyse broader dietary patterns However suitable statistical techniquesare 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 beenimplicated in the aetiology of obesity However independent of the effect onbody 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 sensitivityand animal studies consistently demonstrate that high fat diets promote insulinresistance compared with diets high in carbohydrate.44 Although less consis-tent, studies in humans show that high fat diets are associated with higherfasting insulin concentration and reduced insulin sensitivity,45, 46 and in longi-

tudinal studies a higher rate of development of impaired glucose tolerance47 andprogression to type 2 diabetes.48

SPECIFIC DIETARY FACTORS 303

However, it is important to distinguish between different types of fat Thenegative association between fat and insulin sensitivity is predominately driven

by saturated fat In epidemiological studies, a high saturated fat intake hasbeen associated with higher fasting insulin and glucose levels45 and greaterrates of glucose intolerance.47 Specific fatty acid analysis of serum and musclemembrane phospholipids reveals an association between high levels of saturatedfatty acid content and higher fasting insulin, reduced insulin sensitivity andhigher risk of developing type 2 diabetes.49, 50

Monounsaturated fatty acids (MUFAs) are usually considered to have a tral impact on insulin sensitivity However, a recent large intervention studyreplacing saturated fat with monounsaturated fat and with detailed measures ofinsulin sensitivity using an IVGTT showed improvements in insulin sensitivity

neu-in healthy subjects after 3 months.51 However, a post hoc analysis suggestedthat this benefit was only apparent among individuals where the intake of fatwas less than 37 per cent of total energy – highlighting the importance of totalfat content

In epidemiological studies, increases in the proportion of PUFAs in the dietare associated with lower insulin levels, enhanced insulin sensitivity52, 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 was0.75 (95 per cent CI, 0.65–0.88) for the highest versus lowest quintile of PUFAintake.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

further desaturated to form long chain fatty acids This occurs to some extent

the diet in the form of the so-called fish oils, eicosapentanoic acid (EPA) anddecosahexanoic 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 then − 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 tance showed that replacing saturated fat with a combination of short chain (18:2

resis-n − 6) aresis-nd short chairesis-n (18:3 resis-n − 3) PUFA had resis-no effect oresis-n iresis-nsuliresis-n resistaresis-nce

measured by the euglycaemic clamp.55 However, if saturated fat was replacedwith 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 tion for enzymes to further elongate and desaturate shorter chainn − 3 PUFAs

competi-prevents this conversion when combined with a diet rich in short chainn − 6

0 5 10 15 20

refer-PUFAs From this it may be concluded that n − 3 PUFAs are important dietary

determinants of insulin sensitivity, and that the ratio ofn − 6:n − 3 PUFAs and

the chain length of n − 3 PUFAs are also important.

Epidemiological evidence supports a beneficial impact of high dietary intakes

of the long chainn − 3 PUFAs eicosapentanoic acid (EPA) and decosahexanoic

acid (DHA) in reducing insulin resistance and rates of impaired glucose toleranceand type 2 diabetes.47, 56 Intervention studies have shown mixed results, which

may reflect differences in habitual diets of participants, doses of n − 3 PUFAs

used, other dietary components, methodologies used for measuring insulin sitivity or other population characteristics Further research is required to resolvethis uncertainty

sen-Although long chain n − 3 PUFAs represent a small proportion of the total

dietary intake fat, they have specific metabolic functions, which may explain theirpositive effect on insulin sensitivity These fatty acids are preferentially incor-porated into cell membranes, altering membrane fluidity and receptor function.57They have anti-inflammatory properties, by virtue of being substrates for less pro-inflammatory ecosanoids than equivalentn − 6 fatty acids.58 They have a potentlipid modifying effect with consistent reductions in fasting triglycerides of 25–30per cent in a wide range of patient groups.59 They are also natural ligands forPPARγ, and via this or other nuclear receptors may impact on gene expression ofadipocytokines.60Any or all of these features may explain the potentially importantrole for dietary long chainn − 3 PUFAs on insulin sensitivity.

Carbohydrate

Changes in the proportion of dietary fat frequently lead to reciprocal changes

in carbohydrate, since protein intake tends to remain broadly constant in most

SPECIFIC DIETARY FACTORS 305

Western diets Diets proportionally higher in carbohydrate tend to be associatedwith a reduced risk of obesity and hence decreased risk of diabetes,61 but it isnot easy to ascertain whether this reflects the disadvantageous effects of highfat diets or a specific positive benefit of carbohydrate Recently, the conceptthat low carbohydrate diets may be linked to enhanced weight loss has receivedmuch public attention, but there is little scientific evidence for any novel effect

A systematic review of low carbohydrate diets concluded that weight loss wasrelated to the energy deficit and diet duration rather than to the carbohydratecontent per se.62 A 1 year trial of a low carbohydrate diet versus a low fat dietfound that although initial weight losses were greater in the low carbohydrategroup this was not sustained and after 1 year there was no significant differ-ence between the two groups.63 In practice, a low carbohydrate diet reducesenergy intake since it is difficult to replace calories from carbohydrate fromother sources Indeed, low carbohydrate diets can also reduce fat intake sincethe two co-exist in many foods such as cakes and biscuits, or carbohydrate mayact as a vehicle for added fat, e.g bread and butter

However, over and above these putative effects on body weight there isgrowing interest in the possibility that different types of carbohydrate may

be associated with specific effects on insulin resistance, independent of bodyweight These metabolic properties are particularly associated with specific fea-tures of certain carbohydrate foods, such as their chemical structure, e.g fibrecontent, the degree of processing, e.g wholegrain, or the metabolic effects, e.g.glycaemic index

1 Fibre Epidemiological studies suggest that high fibre diets are associated

with a reduced risk of type 2 diabetes.64 The mechanism of action is notclear, although fibre may attenuate the glycaemic response to ingested car-bohydrate, possibly by its physical effect in the gut, where it tends to slowthe absorption of nutrients, thus reducing the demand for insulin Alterna-tively, fibre and indigestible carbohydrate may be fermented by the colonicbacteria, producing short chain fatty acids These may enter the portal circu-lation, increase hepatic glucose oxidation, decrease FFA release and increaseinsulin clearance.65

The relative effects of soluble and insoluble fibre remain unclear In a crossoverstudy in 14 subjects with type 2 diabetes, increased cereal fibre reduced meanglucose concentration with no effect on insulin levels, suggesting an improve-ment in insulin sensitivity.66In contrast, in 22 healthy postmenopausal womeninsulin sensitivity measured by an IVGTT was no different whether subjectswere taking high fibre rye bread or white wheat bread.67 However, insulinsecretion measured from the IVGTT was increased with the high fibre ryebread, suggesting an effect of fibre onβ-cell function Another study compar-ing whole kernel rye bread, wholemeal rye bread (high in soluble fibre), darkdurum wheat pasta and white wheat bread in a test meal with equivalent total

carbohydrate content demonstrated no difference in rate of gastric emptying

or glucose response, but lower insulin responses to each of the higher fibreproducts compared with white wheat bread The total fibre content of each wasdifferent, but resulted in similar effects on insulin response The authors con-cluded that the structural and compositional properties of the fibre are moreimportant that the total quantity.68

2 Whole grains In western countries the majority of grain products consumed

are refined, with average consumption of wholegrain foods as low as oneserving per day in the United States.69 Epidemiological studies show a pro-tective effect of diets rich in wholegrain foods on insulin sensitivity70and riskfor type 2 diabetes.71 In the Framingham offspring study cohort, there was

an inverse relationship between wholegrain consumption and fasting insulinconcentration, which remained significant after adjustment for BMI.70 In theHealth Professionals Follow-Up Study, the adjusted relative risk of develop-ing type 2 diabetes over 12 years was 0.58 comparing the highest and lowestquintiles of wholegrain intakes.71 Experimental studies have also demon-strated benefits of whole grains on insulin sensitivity In a cross-over study

in 11 obese subjects insulin sensitivity, measured by the euglycaemic clamp,improved after six weeks on a diet rich in whole grains compared withrefined grains This effect was deserved in the absence of any change inbody weight.72

The mechanism for any protective effect of whole grains remains uncertain.The refining process modifies the nutritional composition of grains, reducingmagnesium, vitamin E and fibre content In the Framingham study and theHealth Professionals Follow-Up Study, individual adjustment for intake ofmagnesium and insoluble fibre attenuated the inverse relationship with fastinginsulin and risk for developing type 2 diabetes respectively, suggesting thatthese components may be important,70, 71 although they did not appear toexplain the full association

Of further interest is the observation that, when stratified for BMI, the tective effect of whole grains on fasting insulin may be limited to those with

pro-a BMI grepro-ater thpro-an 30 kg/m2.70 This may be related to higher fasting insulinlevels in the more obese individuals, but also raises the intriguing possi-bility of an interaction between dietary factors and phenotype, where lowwholegrain consumption may be particularly disadvantageous in the obese

3 Glycaemic index (GI) There is increasing interest in the concept of

gly-caemic index (GI) – a physiological classification that describes the impact

of a known quantity of available carbohydrate on blood glucose followingingestion This is of particular relevance to the consideration of insulin resis-tance since there is a high correlation between the glycaemic response and theinsulin response (with just a few exceptions, notably dairy products, whichinduce a disproportionately high insulin response)

SPECIFIC DIETARY FACTORS 307

There is concern that a high carbohydrate intake increases insulin tion to maintain glucose homeostasis, resulting in higher postprandial insulinlevels.73 However, the glycaemic index of the carbohydrate, or other compo-nents of the meal, will modulate the effect on insulin release The possibility

secre-of effects secre-of glycaemic index on both insulin secretion and uptake lights the complexities of this theory The glycaemic index measures andranks the impact of carbohydrates on postprandial plasma glucose The GIdepends largely on the rate of digestion and absorption of carbohydrates.From this it can by shown that many ‘complex’ carbohydrates induce a gly-caemic response nearly as high as that of pure glucose This suggests thatthe traditional classification of simple versus complex carbohydrate based onchemical composition may not be especially useful

high-In epidemiological studies, low dietary glycaemic load (GI/total drate) has been associated with reduced rates of developing type 2 diabetes

carbohy-In a cohort of 65 173 women in the Nurses’ Health Study over a six yearperiod the relative risk was 1.37 of developing diabetes in the highest quin-tile of glycaemic load compared with the lowest quintile after adjusting forintake of cereal fibre64 (Figure 11.3) Wolever and Bolognesi examined theeffect of both the amount and source of carbohydrate consumed on postpran-dial glucose and insulin responses to mixed meals of varying total energy,fat, protein and carbohydrate content, in eight subjects without diabetes.74The amount of carbohydrate alone was not significantly related to the meanglucose and insulin responses However, amount of carbohydrate combinedwith glycaemic index explained approximately 90 per cent of the variability

of the glucose and insulin responses This apparent effect on insulin ity may depend on the underlying individual level of insulin resistance In asmall study of seven healthy, lean, insulin-sensitive young men, no improve-ments were seen with a low GI diet compared with a high GI diet in a 30

sensitiv-0 0.5

1 1.5

2 2.5

High (>165)

Medium Low

(<143)

High (>5.8 g)

Medium Low (<2.5 g)

day randomized crossover study.75 However, in a group of 30 patients withadvanced cardiovascular disease those randomized to a low GI dietary inter-vention over 4 weeks had improvements in insulin sensitivity compared withthose on a high GI diet.76

However, these classification systems are not mutually exclusive and there is

no comprehensive definition that neatly accounts for the health effect of bohydrates In epidemiological analyses it may be more useful to focus oncertain foods or on overall eating patterns, using techniques such as or principalcomponent analysis Meanwhile, intervention studies need to use well defineddietary prescriptions, which if successful can be translated into public healthrecommendations

car-Protein

Across diverse diets the proportion of protein in the diet remains relativelystable, with a reciprocal relationship between fat and carbohydrate dominatingmost changes in dietary intake There is relatively little data on the effects ofprotein on insulin sensitivity In a group of overweight insulin-resistant subjects,replacing carbohydrate with protein from meat, poultry and dairy food in acalorie reduced diet (high protein diet, 27 per cent energy protein, 44 per centcarbohydrate and 29 per cent fat, versus low protein diet, 16 per cent protein,

57 per cent carbohydrate, 27 per cent fat) had no effect on overall weight lossbut had a beneficial effect on glycaemic response, suggesting improved insulinsensitivity.77

There is evidence from studies in rats that the source of dietary proteinmay have differential effects on insulin sensitivity In rats fed a high fat diet,

in which the protein source was casein, fish (cod) protein or soy protein, thehigh fat feeding led to severe insulin resistance, which was prevented by fishprotein, and to a lesser degree by soy protein compared with casein.78However,highly controlled intervention studies testing the impact of differing dietaryprotein content or source employing euglycaemic clamp or IVGTT methods ofmeasuring insulin sensitivity in humans are lacking This therefore remains anarea requiring additional research

Alcohol

Epidemiological studies remain equivocal on the relationship between alcoholconsumption and type 2 diabetes, with the impact being dose related The NursesHealth Study79 and US Male Health Professionals Study80 both suggest a pro-tective role for modest alcohol intake (less than 21 standard drinks per week),but the Atherosclerosis Risk in Communities Study (ARIC) suggest that menconsuming over 21 standard drinks per week have an increased risk.81 Data

SPECIFIC DIETARY FACTORS 309

from the British Regional Heart Study suggests a U-shaped relationship betweenalcohol consumption and risk of type 2 diabetes.82 Thus the effects of alcoholmay be different according to level of consumption and are confounded bydifferences in body weight, body fatness and blood lipids Intervention studiesspecifically examining the impact of alcohol on insulin sensitivity are limited.One crossover study in overweight women showed no effect of 10 weeks of mod-est red wine intake on insulin sensitivity, measured by an IVGTT, or glucosehomeostasis.83

Micronutrients

There has been relatively little systematic investigation into the effects of specificvitamins and minerals on insulin sensitivity Epidemiological analysis revealsseveral candidates, but in each case the evidence for specific physiologicaleffects is limited

Vitamin E

Vitamin E is a fat-soluble vitamin with antioxidant properties Increased tive stress has been linked with insulin resistance, raising the possibility thatdietary antioxidants may have beneficial effects Two cohort studies have exam-ined the relationship between vitamin E status and risk of type 2 diabetes.One study showed that low levels of vitamin E were associated with a 3.9-fold increased risk of developing type 2 diabetes over four years.84 The other,

oxida-a nested coxida-ase control study, showed thoxida-at subjects with high levels of vitoxida-amin

E had a 39 per cent lower risk of type 2 diabetes compared with those withlow levels.85 However, this association was lost when adjusted for cholesterol,smoking, BMI and hypertension In healthy non-diabetic individuals, insulinsensitivity measured by an IVGTT was positively related to plasma vitamin Econcentration and inversely related to lipid hyperoxide concentrations, suggest-ing a role in insulin sensitivity.86 However, this relationship was not seen in asimilar study after adjustment for other factors known to affect insulin sensi-tivity such as degree of obesity and level of physical activity.87 Together thisdata suggests that vitamin E intake and status may reflect a generally healthylifestyle rather than independent metabolic effects

Magnesium

Large epidemiological studies have shown an association between low sium intake and the risk of type 2 diabetes in both men and women with arisk ratio for those in the upper quintile compared with the lower quintile ofmagnesium intake of about 0.7 after adjustment for BMI, smoking and physicalactivity.64, 69, 88 Cereal fibre is an important dietary source of magnesium andadjustment for fibre intake attenuates this relationship

Chromium appears to have an important role in tissue whole body insulin sitivity In subjects with impaired glucose tolerance and raised insulin levels,chromium supplementation improves both insulin levels and glucose tolerance

sen-in patients with low sen-intakes of chromium.89 Similar improvements in glycaemiccontrol are seen with chromium supplements in those with established type 2diabetes,90 although there is no apparent effect on insulin sensitivity in thosewith normal glucose tolerance Although the role of chromium supplements

is not firmly established there is at least a plausible mechanism of action forincreased insulin action via increased insulin receptor expression and increasedactivation of insulin receptor kinase.91

11.4 Summary

Whole body insulin sensitivity is the product of a complex interaction betweengenotype, physical characteristics such as body weight and environmental andbehavioural factors such as diet and physical activity

Obesity is strongly linked to impaired insulin sensitivity, but acute changes

in total energy intake influence insulin sensitivity independently of changes inbody weight or fat mass Specific dietary components may also have inde-pendent effects on insulin sensitivity The balance of evidence suggests that

a high intake of saturated fat reduces insulin sensitivity, but that urated and polyunsaturated fat are neutral or beneficial, at least in the set-ting of moderate total fat intake The effects of carbohydrate are less clear;however, unrefined carbohydrate, with a low glycaemic index, wholegrain andhigh fibre foods appear to have beneficial effects on insulin sensitivity com-pared with more refined carbohydrates There may also be an influence ofspecific micronutrients such as magnesium, chromium and vitamin E; however,the evidence is limited The evidence relating to dietary factors and insulinresistance is mostly drawn from epidemiological analyses with limited evi-dence from intervention studies and supplemented in some cases by biochemicalmechanisms However, more research is needed, especially to identify inter-relationships with specific genotypes as have been elucidated with ApoE andhyperlipidaemia.92

monounsat-Nonetheless there is a rational framework to make dietary recommendations

to reduce the risk of insulin resistance and type 2 diabetes Specifically, dietslow in fat, especially saturated fat, with further substitutions of MUFAs or

n − 3 PUFAs for n − 6 PUFAs and increases in unrefined carbohydrate, fruits

and vegetables This dietary prescription is consistent with strategies to reducethe risk of other non-communicable diseases

REFERENCES 311

References

1 Goris, H C., Westerterp-Plantenga, M S and Westerperp, K R (2000) Undereating and underrecording of habitual food intake in obese men: selective underreporting of

fat intake Am J Clin Nutr 71, 130 – 134.

2 Prentice, A M., Black, A E., Coward, W A., Davies, H L., Goldberg, G R and

Murgatroyd, P R et al (1986) High levels of energy expenditure in obese women.

BMJ 292, 983 – 987.

3 Chan, J M., Rimm, E B., Colditz, G A., Stampfer, M J and Willett, W C (1994) Obesity, fat distribution and weight gain as risk factors for clinical diabetes in men.

Diabetes Care 17, 961 – 969.

4 Colditz, G A., Willett, W C., Rotnitzky, A and Manson, J E (1995) Weight gain as a

risk factor for clinical diabetes mellitus in women Ann Intern Med 122 (7), 481 – 486.

5 Carey, D G., Jenkins, A B., Campbell, L V., Freund, J and Chisholm, D J (1996)

Abdominal fat and insulin resistance in normal and overweight women Diabetes 45,

633 – 638.

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 regulation Am J Physiol Endocrinol Metab 280, E827 – E847.

8 Frayn, K N (2001) Adipose tissue and the insulin resistance syndrome Proc Nutr Soc

60 (3), 375 – 380.

9 Jebb, S A (1997) Aetiology of obesity Br Med Bull 53, 264 – 285.

10 Egger, G and Swinburn, B A (1997) An ecological approach to the obesity epidemic.

BMJ 315, 477 – 480.

11 Bolton-Smith, C and Woodward, M (1994) Dietary composition and fat to sugar ratios

in relation to obesity Int J Obes Relat Metab Disorders 18 (12), 820 – 828.

12 Seidell, J C (1998) Dietary fat and obesity: an epidemiological perspective Am J Nutr

67 (Suppl 3), 546S– 550S.

13 Stubbs, R J., Ritz, P., Coward, W A and Prentice, A M (1995) Covert manipulation

of the ratio of dietary fat to carbohydrate and energy density: effect on food

in-take and energy balance in free-living men eating ad libitum Am J Clin Nutr 62 (2),

330 – 337.

14 Stubbs, R J., Harbon, C G and Prentice, A M (1996) Covert manipulation of the dietary fat to carbohydrate ratio of isoenergetically dense diets: effects on food intake in

feeding men ad libitum Int J Obes 20, 651 – 660.

15 NHLBI Obesity Education Initiative Expert Panel Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults; the evidence report: National Institutes of Health; 1998 September 1998 Report No 98-4083.

16 Mattes, R D and Rothacker, D (2001) Beverage viscosity is inversely related to

postprandial hunger in humans Physiol Behav 74, 551 – 557.

consumption of sugar-sweetened drinks and childhood obesity: a prospective,

observational analysis Lancet 357 (9255), 505 – 508.

18 Raben, A., Vasilaras, T H., Moller, A C and Astrup, A (2002) Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after

10 weeks of supplementation in overweight subjects Am J Clin Nutr 76, 721 – 729.

19 Ludwig, D S., Majzoub, J A., Al-Zahrani, A., Dallal, G E., Blanco, I and Roberts,

S B (1999) High glycaemic index foods, overeating, and obesity Pediatrics 103 (3),

E26.

20 Prentice, A M and Jebb, S A (2003) Fast foods, energy density and obesity – a

possible mechanistic link Obes Rev 4 (4), 187 – 194.

21 Green, S M and Blundell, J E (1996) Effect of fat and sucrose-containing foods on the size of eating episodes and energy intake in lean dietary restrained and unrestrained

females: potential for causing over-consumption Eur J Clin Nutr 50, 625 – 635.

22 Rolls, B J., Morris, E L and Roe, L S (2002) Portion size of food affects energy

intake in normal-weight and overweight men and women Am J Clin Nutr 76, 1207 – 1213.

23 Rennie, K and Jebb, S A (2004) Sedentary lifestyles are associated with being

overweight and consumption of savoury snacks in young people (4 – 18 years) Proc Nutr Soc (in press).

24 Campbell, K and Crawford, D (2001) Family food environments as determinants of preschool-aged children’s eating behaviours: implications for obesity prevention policy.

A review Aust J Nutr Dietet 58, 19 – 25.

25 Saris, W H (1998) Fit, fat and fat free: the metabolic aspects of weight control [Review;

50 refs] Int J Obes 22 (Suppl 2), S15 – S21.

26 Jebb, S A and Krebs, J D Lifestyle determinants of obesity In: Kumar, S and

Barnett, A H., eds Obesity and Diabetes New York: Wiley (in press).

27 Pi-Sunyer, F X (1993) Short-term medical benefits and adverse effects of weight loss.

Ann Intern Med 119 (7), 722 – 726.

28 Goldstein, D J (1992) Beneficial health effects of modest weight loss Int J Obes 16,

397 – 415.

29 Goodpaster, B H., Kelley, D E., Wing, R R., Meier, A and Thaete, F L (1999) Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.

Diabetes 48, 839 – 847.

30 Dhindsa, P., Scott, A R and Donnelly, R (2003) Metabolic and cardiovascular effects

of very-low-calorie diet therapy in obese patients with type 2 diabetes in secondary

failure: outcomes after 1 year Diabet Med 20, 319 – 324.

31 Davidson, M H., Hauptman, J., DiGirolamo, M., Foreyt, J P., Halsted, C H and

Heber, D et al (1999) Weight control and risk factor reduction in obese subjects treated

for 2 years with orlistat: a randomized controlled trial JAMA 281 (3), 235 – 242.

32 James, W P., Astrup, A., Finer, N., Hilsted, J., Kopelman, P and Rossner, S et al.

(2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial STORM Study Group Sibutramine Trial of Obesity Reduction and Maintenance.

Lancet 356 (9248), 2119 – 2125.

33 Reaven, G., Segal, K., Hauptman, J., Boldrin, M and Lucas, C (2001) Effect of assisted weight loss in decreasing coronary heart disease risk in patients with syndrome

orlistat-X Am J Cardiol 87 (7), 827 – 831.

34 Finer, N., Bloom, S R., Frost, G S., Banks, L M and Griffiths, J (2000) Sibutramine

is effective for weight loss and diabetic control in obesity with type 2 diabetes:

a randomised, double-blind, placebo-controlled study Diabetes Obes Metab 2 (2),

105 – 112.

35 Sjostrom, C D., Lissner, L., Wedel, H and Sjostrom, L (1999) Reduction in incidence

of diabetes, hypertension and lipid disturbances after intentional weight loss induced by

bariatric surgery: the SOS intervention study Obes Res 7 (5), 477 – 484.

36 Friedman, J E., Dohm, G L., Leggett-Frazier, N., Elton, C W., Tapscott, E B and

Pories, W P et al (1992) Restoration of insulin responsiveness in skeletal muscle of

morbidly obese patients after weight loss Effect on muscle glucose transport and glucose

transporter GLUT4 J Clin Invest 89 (2), 701 – 705.

REFERENCES 313

37 Weinsier, R L., James, L D and Darnell, B E (1992) Lipid and insulin concentrations

in obese postmenopausal women: seperate effects of energy restriction and weight loss.

Diabetes Obes Metab 4 (6), 379 – 387.

40 Tuomilehto, J., Lindstrom, J., Eriksson, J G., Valle, T T., Hamalainen, H and

Ilanne-Parikka, P et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle

among subjects with impaired glucose tolerance N Engl J Med 344, 1343 – 1350.

41 Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type

2 diabetes with lifestyle intervention or metformin N Engl J Med 346, 393 – 403.

42 Torgerson, J S et al (2004) XENDOS: a randomised study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients Diabetes Care

27 (1), 155 – 161.

43 Goldberg, G., ed (2003) Plants: Diet and Health, British Nutrition Foundation Oxford:

Blackwell.

44 Storlien, L H., Pan, D A., Kriketos, A D and Baur, L A (1993) High fat diet-induced

insulin resistance Lessons and implications from animal studies Ann NY Acad Sci 683,

82 – 90.

45 Marshall, J A., Bessesen, D H and Hamman, R F (1997) High saturated fat and low starch and fibre are associated with hyperinsulinaemia in a non-diabetic population: the

San Luis Valley Diabetes Study Diabetologia 40 (4), 430 – 438.

46 Lovejoy, J and DiGirolamo, M (1992) Habitual dietary intake and insulin sensitivity in

lean and obese adults Am J Clin Nutr 55 (6), 1174 – 1179.

47 Feskens, E J., Virtanen, S M., Rasanen, L., Tuomilehto, J., Stengard, J and

Pekka-nen, J et al (1995) Dietary factors determining diabetes and impaired glucose tolerance.

A 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study.

Diabetes Care 18 (8), 1104 – 1112.

48 Marshall, J A., Hoag, S., Shetterly, S and Hamman, R F (1994) Dietary fat predicts conversion from impaired glucose tolerance to NIDDM The San Luis Valley Diabetes

Study Diabetes Care 17 (1), 50 – 56.

49 Storlien, L H., Pan, D A., Kriketos, A D., O’Connor, J., Caterson, I D and Cooney,

G J et al (1996) Skeletal muscle membrane lipids and insulin resistance Lipids 31

(Suppl.), S261 – S265.

50 Vessby, B., Aro, A., Skarfors, E., Berglund, L., Salminen, I and Lithell, H (1994) The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol

esters Diabetes 43, 1353 – 1357.

51 Vessby, B., Unsitupa, M., Hermansen, K., Riccardi, G., Rivellese, A A and Tapsell,

L C et al (2001) Substituting dietary saturated for monounsaturated fat impairs insulin

sensitivity in healthy men and women: the KANWU Study Diabetologia 44 (3),

312 – 319.

52 Feskens, E J., Loeber, J G and Kromhout, D (1994) Diet and physical activity as

determinants of hyperinsulinemia: the Zutphen Elderly Study Am J Epidemiol 140 (4),

350 – 360.

53 Mayer-Davis, E J., Monaco, J H., Hoen, H M., Carmichael, S., Vitolins, M Z and

Rewers, M J et al (1997) Dietary fat and insulin sensitivity in a triethnic population: the role of obesity The Insulin Resistance Atherosclerosis Study (IRAS) Am J Clin Nutr

65 (1), 79 – 87.

54 Salmeron, J., Hu, F B., Manson, J E., Stampfer, M J., Colditz, G A and Rimm, E B.

et al (2001) Dietary fat intake and risk of type 2 diabetes in women Am J Clin Nutr 73

(6), 1019 – 1026.

55 Storlien, L H., Jenkins, A B., Chisholm, D J., Pascoe, W S., Khouri, S and gen, E W (1991) Influence of dietary fat composition on development of insulin resis- tance in rats Relationship to muscle triglyceride and omega-3 fatty acids in muscle

Krae-phospholipid Diabetes 40 (2), 280 – 289.

56 Adler, A I., Boyko, E J., Schraer, C D and Murphy, N J (1994) Lower prevalence

of impaired glucose tolerance and diabetes associated with daily seal oil or salmon

consumption among Alaska Natives Diabetes Care 17 (12), 1498 – 1501.

57 Simopoulos, A P (1999) Essential fatty acids in health and chronic disease Am J Clin

Nutr 70 (Suppl 3), 560S– 569S.

58 Grimble, R F (1998) Dietary lipids and the inflammatory response Proc Nutr Soc 57

(4), 535 – 542.

59 Harris, W S (1996) n-3 fatty acids and lipoproteins: comparison of results from human

and animal studies Lipids 31 (3), 243 – 252.

60 Chambrier, C., Bastard, J P., Rieusset, J., Chevillotte, E., Bonnefont-Rousselot, D.

and Therond, P et al (2002) Eicosapentaenoic acid induces mRNA expression of

61 Hill, J O and Prentice, A M (1995) Sugar and body weight regulation Am J Clin Nutr

62 (Suppl 1), 264S– 274S.

62 Bravata, D M., Sanders, L., Huang, J., Krumholz, H M., Olkin, I and Gardner, C D.

et al (2003) Efficacy and safety of low-carbohydrate diets A systematic review JAMA

289, 1837 – 1850.

63 Foster, G D., Wyatt, H R., Hill, J O., McGuckin, B G., Brill, C and Mohammed,

B S et al (2003) A randomised trial of a low-carbohydrate diet for obesity N Engl J

Med 348, 2082 – 2090.

64 Salmeron, J., Manson, J E., Stampfer, M J., Colditz, G A., Wing, A L and lett, W C (1997) Dietary fiber, glycemic load, and risk of non-insulin-dependent dia-

Wil-betes mellitus in women JAMA 277 (6), 472 – 477.

65 Thorburn, A., Muir, J and Proietto, J (1993) Carbohydrate fermentation decreases

hepatic glucose output in healthy subjects Metabolism 42, 780 – 785.

66 Karlstrom, B., Vessby, B., Asp, N G., Boberg, M., Gustafsson, I B and Lithell, H.

et al (1984) Effects of an increased content of cereal fibre in the diet of type 2

(non-insulin-dependent) diabetic patients Diabetologia 26, 272 – 277.

67 Juntunen, K S., Laaksonen, D E., Poutanen, K S., Niskanen, L K and nen, H M (2003) High-fibre rye bread and insulin secretion and sensitivity in healthy

Mykka-postmenopausal women Am J Clin Nutr 77, 385 – 391.

68 Juntunen, K S., Niskanen, L K., Liukkonen, K H., Poutanen, K S., Holst, J J and Mykkanen, H M (2002) Postprandial glucose, insulin and incretin responses to grain

products in healthy subjects Am J Clin Nutr 75, 254 – 262.

69 Meyer, K A., Kushi, L H., Jacobs, D R., Slavin, J., Sellers, T A and Folsom, A R.

(2000) Carbohydrates, dietary fiber, and incident type 2 diabetes in older women Am J

71 Fung, T T., Hu, F B., Pereira, M A., Liu, S., Stampfer, M J and Colditz, G A et al.

(2002) Whole-grain intake and the risk of type 2 diabetes: a prospective study in men.

Am J Clin Nutr 76, 535 – 540.

REFERENCES 315

72 Pereira, M A., Jacobs, D R., Jr., Pins, J J., Raatz, S K., Gross, M D and Slavin, J L.

et al (2002) Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic

adults Am J Clin Nutr 75 (5), 848 – 855.

73 Reaven, G M (1997) Do high carbohydrate diets prevent the development or attenuate

the manifestations (or both) of syndrome X? A viewpoint strongly against Curr Opin

Lipidol 8 (1), 23 – 27.

74 Wolever, T M and Bolognesi, C (1996) Prediction of glucose and insulin responses

of normal subjects after consuming mixed meals varying in energy, protein, fat,

carbohydrate and glycemic index J Nutr 126 (11), 2807 – 2812.

75 Kiens, B and Richter, E A (1996) Types of carbohydrate in an ordinary diet affect

insulin action and muscle substrates in humans Am J Clin Nutr 63, 47 – 53.

76 Frost, G (1996) The effect of low-glycaemic carbohydrate on insulin and glucose

response in vivo and in vitro in patients with coronary heart disease Metabolism 45

(6), 669 – 672.

77 Farnsworth, E., Luscombe, N D., Noakes, M., Wittert, G., Argyiou, E and Clifton,

P M (2003) Effect of a high-protein, energy-restricted diet on body composition, glycaemic control, and lipid concentration in overweight and obese hyperinsulinaemic

men and women Am J Clin Nutr 78, 31 – 39.

78 Lavigne, C., Tremblay, F., Asselin, G., Jacques, H and Marette, A (2001) Prevention

of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats Am J

Physiol Endocrinol Metab 281 (1), E62 – E71.

79 Stampfer, M J., Colditz, G A and Willett, W C (1988) A prospective study of

moderate alcohol drinking and risk of diabetes in women Am J Epidemiol 128, 549 – 558.

80 Ajani, U A., Hennekens, C H and Spelsberg, A (2000) Alcohol consumption and risk

of type diabetes mellitus among US male physicians Arch Intern Med 160, 1025 – 1030.

81 Kao, W H., Puddey, I B and Boland, L L (2001) Alcohol consumption and the risk

of type 2 diabetes mellitus: atherosclerosis risk in communities study Am J Epidemiol

154, 748 – 757.

82 Perry, I J., Wannamethee, S G., Walker, M K., Thompson, A G., Whincup, P H and Shaper, A G (1995) Prospective study of risk factors for development of non-insulin

dependent diabetes in middle-aged British men BMJ 310, 560 – 564.

83 Cordain, L., Melby, C L., Hamamoto, A E., O’Neill, D S., Cornier, M A and

Barakat, H A et al (2000) Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women Metab: Clin

Exp 49 (11), 1473 – 1480.

84 Salonen, J T., Nyyssonen, K., Tuomainen, T P., Maenpaa, P H., Korpela, H and

Kaplan, G A et al (1995) Increased risk of non-insulin dependent diabetes mellitus

at low plasma vitamin E concentrations: a four year follow up study in men BMJ 311

(7013), 1124 – 1127.

85 Reunanen, A., Knekt, P., Aaran, R K and Aromaa, A (1998) Serum antioxidants and

risk of non-insulin dependent diabetes mellitus Eur J Clin Nutr 52 (2), 89 – 93.

86 Facchini, F S., Humphreys, M H., DoNascimento, C A., Abbasi, F and Reaven,

G M (2000) Relation between insulin resistance and plasma concentrations of lipid

hydroperoxides, carenoids and tocopherols Am J Clin Nutr 72 (3), 776 – 779.

87 Facchini, F., Coulston, A M and Reaven, G M (1996) Relationship between dietary vitamin intake and resistance to insulin-mediated glucose disposal in healthy volunteers.

Am J Clin Nutr 63 (6), 946 – 949.

88 Salmeron, J., Ascherio, A., Rimm, E B., Colditz, G A., Spiegelman, D and

Jenk-ins, D J et al (1997) Dietary fiber, glycemic load, and risk of NIDDM in men Diabetes

Care 20 (4), 545 – 550.

89 Anderson, R A., Polansky, M M., Bryden, N A and Canary, J J (1991) al-chromium effects on glucose, insulin, glucagon and urinary chromium losses in

Supplement-subjects consuming controlled low-chromium diets Am J Clin Nutr 54, 909 – 916.

90 Anderson, R A., Cheng, N., Bryden, N A., Polansky, M M., Chi, J and Feng, J (1997) Elevated intakes of supplemental chromium improve glucose and insulin variables

in individuals with type 2 diabetes Diabetes 46, 1786 – 1791.

91 Vincent, J B (2000) The biochemistry of chromium J Nutr 130, 715 – 718.

Kromhout, D (1998) Lipid profiles reflecting high and low risk for coronary heart

disease: contribution of apolipoprotein E polymorphism and lifestyle Atherosclerosis

136 (2), 395 – 402.

to describing this association, and our concentration is on a systematic review ofstudies that have quantified the relationship between activity and/or fitness andinsulin resistance The level of causal inference from these studies varies and,

as in all other areas of epidemiological enquiry, can be assessed by reference tothe classic Bradford Hill criteria.1These include assessment of the strength andconsistency of the association, the degree of dose–response effect and biologi-cal plausibility The demonstration of reversibility in a clinical trial contributesmassively to causal inference and also points the way for preventive efforts

A key question in the context of the design of preventive strategies is whetherthe association of inactivity with insulin resistance is similar in all individuals

If it is, then a population-wide preventive strategy would be most appropriate.However, if sub-populations were demonstrably more at risk of the metabolicconsequences of sedentary living, then targeted prevention would be a logicalstrategy Thus in this chapter we consider the evidence for heterogeneity of asso-ciation between different sub-groups in the population The chapter concludeswith a discussion of major unresolved uncertainties and areas of future enquiry

Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly

 2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6

12.2 Evidence from observational studies of the association

between physical activity and insulin resistance

Rather than only present data from papers that support the theory that cal activity is protective against the development of insulin resistance, we haveelected to undertake a more systematic summary In describing the studies, wehave separated studies in adults (Table 12.1) from those in children and adoles-cents (Table 12.2) We excluded studies with fewer than 50 adult participants

physi-We have only included those studies that have a measure of insulin resistance,either from a euglycaemic hyperinsulinaemic clamp or more indirectly frominsulin measurement at fasting or in an intravenous or oral glucose tolerancetest This focus on insulin measurement excludes those studies where the out-come of interest is related to insulin resistance such as measures of glucosehomeostasis or the metabolic syndrome

12.3 Summary of findings from observational

studies in adults

Table 12.1 shows that a total of 39 cross-sectional studies relating an assessment

of physical activity or fitness to a measure of insulin sensitivity were fied Thirty-four of these studies demonstrated that some dimension of physicalactivity was inversely associated with fasting insulin or other proxy measures

identi-of insulin resistance None identi-of the studies found the association to be in theopposite direction and four of the five inconclusive studies were either small(Ross2(n = 50), Palaniappan et al.3(n = 207), Parker et al.4(n = 358)) or used

a global assessment of activity,5 which may have resulted in non-differentialmisclassification and attenuation of the true association Thus, overall the datasuggests that the finding of an inverse association between activity and insulinresistance is strong and consistent between studies

In 30 of these cross-sectional studies self-reported or interviewer administeredphysical activity questionnaires were used as the main measure of activity Thisconcentration on self-report assessment introduces the possibility of recall bias.This is less likely to be a direct phenomenon than it would be in a study whereindividuals with a diagnostic label were being compared with those without,since people with insulin resistance would tend to be unaware of their condi-tion Direct bias of this nature would be much more likely if people with andwithout diabetes were being compared, for example However, it is more likely

in this context that self-report is biased with respect to obesity, which would

in turn create a bias with respect to the outcome of insulin resistance since therelationship between obesity and insulin sensitivity is so strong Adjustment forobesity whilst removing its effect as a confounder would not deal with the issue

of associated recall bias

SUMMARY OF FINDINGS FROM OBSERVATIONAL STUDIES IN ADULTS 319

SUMMARY OF FINDINGS FROM OBSERVATIONAL STUDIES IN ADULTS 321

SUMMARY OF FINDINGS FROM OBSERVATIONAL STUDIES IN ADULTS 323