Concepts, controversies, and the role of nutrition

Insulin resistance: Concepts, controversies, and the role of nutrition

John L Sievenpiper


Insulin resistance is a prevalent condition, in which insulin loses its normal physiological action. Since people were first classified as insulin resistant over 60 years ago, one of the main discoveries has been that insulin resistance clusters with other risk factors such as obesity, elevated triglycerides, and low high-density lipoprotein cholesterol, increasing cardiovascular disease risk. Although insulin resistance appears to manifest first in the periphery and then in the liver, other sites, such as the brain and the pancreatic beta-cell, may play pathogenic roles. Factors contributing to insulin resistance at these sites include perturbations in free fatty acids, glucose, and hormone-signalling, some of which may be linked to various genetic polymorphisms. Appropriate nutritional treatment for insulin resistance is controversial. Two main approaches are drawn from diabetes recommendations: i) a high-carbohydrate, low-fat, high-fibre diet emphasizing low glycemic-index foods and ii) sharing calories between monounsaturated fat and complex carbohydrate at the expense of saturated fat. Recent interest in insulin resistance has prompted the development of new guidelines. Promising data have also emerged, showing that a high-carbohydrate, high-fibre, low-fat diet plus exercise programs maintained through intensive counselling can decrease diabetes risk by over 40%. Additional research is required to confirm the sustainability of this approach and sort out the determinants of insulin resistance so that more effective nutritional interventions will result.

(Can J Diet Prac Res 2002; 63:20-32)

La resistance a l’insuline est une condition repandue, selon laquelle cette substance perd son action physiologique normale. Depuis que les premieres personnes ont ete classees comme etant resistantes a l’insuline il y a plus de 60 ans, l’une des principales decouvertes a ete que la resistance a l’insuline se combine a d’autres facteurs de risque tels que l’obesite, des niveaux eleves de triglycerides et des niveaux faibles de cholesterol lie aux lipoproteines de haute densite, accroissant ainsi le risque de maladies cardiovasculaires. Bien que la resistance a l’insuline semble se manifester d’abord en peripherie, puffs dans le foie, d’autres sites, tels le cerveau et les cellules beta du pancreas, peuvent jouer des roles pathogenes. Les facteurs contribuant a la resistance a l’insuline a ces sites sont les perturbations dans les acides gras libres, le glucose et la transmission de l’information hormonale, certains d’entre eux pouvant etre lies a divers polymorphismes genetiques. Le traitement nutritionnel approprie en cas de resistance a l’insuline est un sujet controverse. Deux approches principales s’inspirent des recommandations aux diabetiques: i) une alimentation riche en glucides, a faible teneur en matieres grasses, riche en fibres, qui accorde la priorite aux aliments a faible indice glycemique, et ii) le partage des calories entre les matieres grasses monoinsaturees et les glucides complexes au detriment des matieres grasses saturees. L’interet recent envers la resistance a l’insuline a donne lieu a l’elaboration de nouvelles directives. Des resultats prometteurs ont egalement ete obtenus, entre autres qu’une alimentation riche en glucides et en fibres et faible en matieres grasses, couplee a des programmes d’exercice physique observes grace a un counseling soutenu, peut diminuer de plus de 40 % le risque de diabete. D’autres recherches sont necessaires pour confirmer la perennite de cette approche et pour reperer les determinants de la resistance a l’insuline afin d’ameliorer 1’efficacite des interventions nutritionnelles.

(Rev can prat rech dietet 2002; 63:20-32)


Insulin is the primary anabolic hormone. It is secreted by pancreatic beta-cells and primes the liver, muscles, and adipose tissue for a shift toward energy storage, suppressing endogenous glucose production by the liver and stimulating glucose uptake by peripheral tissue (1,2). In 1936, Himsworth (3) was the first to recognize that defects in the action of insulin may affect these processes. Classifying diabetes cases as insulin sensitive or insensitive, he hypothesized that some cases resulted not from a lack of insulin, but instead from the lack of an “insulin-sensitizing factor” (Figure 1). This latter insufficiency, now attributed to multiple factors, has become termed “insulin resistance” (IR), and the diabetes to which it is related type 2 diabetes mellitus (DM2) (4,5).

In 1988, Reaven built on the concept of human disease secondary to IR (6). He suggested that IR underlies not just diabetes but also a constellation of risk factors that increase the risk of cardiovascular disease (CVD). These include hyperinsulinemia, high blood pressure (BP), elevated triglycerides, and low high-density lipoprotein cholesterol (HDL-C). He termed this cluster syndrome X. Others, however, had already linked insulin-resistant conditions such as obesity, diabetes, and gout much earlier (7), and since Reaven reintroduced the concept, it has continued to be renamed and redefined. This review discusses IR in the context of this evolving syndrome, examining its definition prevalence, sequelae, pathophysiology, mechanisms, genetics. nutritional treatment, and relevance to practice.


The definition of IR is complex. It is described as the inability of insulin to exert a normal physiological effect in target tissue (2). Complexity in its definition relates to how and in which tissue compartment it is measured. The gold standard measurement is the euglycemic-hyperinsulinemic clamp, in which insulin is clamped at a hyperinsulinemic level, while glucose is infused simultaneously to maintain euglycemia. Higher glucose infusion rates indicate higher whole-body insulin sensitivity (8,9). The addition of tritiated glucose allows for differentiation of peripheral and hepatic insulin sensitivity (9). Other techniques include:

* the insulin-modified frequent-sampling intravenous glucose-tolerance test (FSIVGTT), in which an IV glucose bolus is administered and followed by insulin with measurement of plasma glucose disappearance (10);

* the homeostasis-model assessment (HOMA), in which fasting plasma glucose and insulin are used in a derived equation (9-12); and

* various 75-g oral glucose-tolerance test (75g-OGTT) models, in which plasma glucose and insulin during the test are used in derived equations (9,11,13).

Different interpretations are possible from these techniques. Because it is derived from only fasting values, the HOMA reflects more hepatic than whole-body sensitivity to insulin. In contrast, the FSIVGTT- and OGTT-derived models represent more of a composite of the two (9).

Complexity in defining the syndrome related to IR results from its continuous redefinition (Table 1). Most describe it as having the four traditional features of syndrome X with the addition of obesity (especially abdominal obesity) (14-16), while others have now expanded its definition to include hemostatic factors, such as plasminogen-activator inhibitor-1 (PAI-1) (17), low-density lipoprotein (LDL)-apolipoprotein B (18,19), uric acid (20), and/or microalbuminuria (21). To unify the concept, the World Health Organization (WHO) recently renamed the syndrome the “metabolic syndrome,” and proposed a standard definition that includes the presence of DM2, impaired glucose tolerance (IGT), or normal glucose tolerance (NGT) with IR, together with any two of the following: obesity, low HDL-C, high triglycerides, high BP, and microalbuminuria (21).


Estimates of IR prevalence are reported as a function of diabetes prevalence. In the Botnia Study cohort of Finnish and Swedish adults, investigators used the euglycemic hyperinsulinemic clamp to estimate that IR exists in 25% of those with NGT, 59% of those with impaired-fasting-glucose (IFG) and/or IGT, and 88% of those with DM2 (22). This finding agrees with those of the Northern Italian Bruneck Study cohort (23) and the San Antonio Heart Study cohort (24), in which the HOMA indicated that IR existed in 84% and 82.4% of those with DM2, respectively. These estimates suggest the prevalence of IR would be over 30% in Canadian adults (25). As there is an approximately 15-fold difference in diabetes prevalence worldwide (26), this prevalence will vary considerably across populations.

A range of prevalence also likely exists for the syndrome related to IR. The syndrome has been measured in different populations with different assumptions about the prevalence of various features. Using the syndrome X definition, Reaven estimated that it is present in approximately 30% of people (6). In contrast, the prevalence of syndrome X was calculated to be as low as 3% for men and 3.4% for women in a large Italian probability sample (27). The latest estimates, using the WHO definition for the metabolic syndrome (21) in the Botnia study cohort, suggest that it is present in approximately 10%, 50%, and 80% of those with NGT, IGT, and DM2, respectively (22). These latter estimates suggest that it would be present in over 17% of Canadian adults (25).

Indications are that these prevalence figures are rising in North America. Recent data published by the U.S. Centers for Disease Control show that two core features of the syndrome, obesity and diabetes, are increasing: obesity (BMI>30kg/m^sup 2^) in those aged 18-29 (28) and diabetes in those aged 30-39 (29) increased by approximately 70% from 1990 to 1998.


Consequences of this high and increasing prevalence are potentially very serious. Long before diabetes becomes manifest, the clustering of metabolic abnormalities is believed to exert an additive effect on the atherosclerotic process (30). The result is that CVD risk appears to increase linearly with the number of risk factors (27). This becomes especially evident once diabetes has developed. The Insulin Resistance Atherosclerosis Study (31) showed that people with diabetes have significantly greater intimal media thickness of the common carotid artery, a surrogate CVD marker (32). More definitive data indicate that people with diabetes are at equal or greater risk for myocardial infarction (MI), stroke, and subsequent mortality than are those without diabetes who have had a prior MI (33,34). That is, their risk for cardiovascular events is the same as the risk for people with established coronary heart disease (CHD). The predisposing risk is so profound that approximately 75% of people with diabetes will die from CVD complications (35).


There are two main sites of IR: peripheral tissue and the liver. In the earliest phases of IR, even before the development of manifest IGT, most of the IR appears to be concentrated in the peripheral tissue, the site responsible for approximately 70-90% of glucose disposal following a carbohydrate load (36). Insulin resistance at this site results in postprandial hyperglycemia with compensatory postprandial hyperinsulinemia. Most of this resistance has been attributed to decreased insulin-stimulated muscle glycogen synthesis in humans (37, 38). Possible mediators include defects in glycogen synthase, hexokinase, and glucose transport by glucose transporter-4 (GLUT-4) (38). The best evidence suggests that this last locus is the most important. Using a novel ^sup 13^C-^sup 31^P-nuclear magnetic-resonance (NMR) spectroscopy technique, investigators recently demonstrated that glucose transport is the rate-limiting step in insulin-stimulated glycogen synthesis

in DM2 (39). The specific site of this defect is considered to lie in the insulin-signalling pathway that regulates the translocation of intracellular GLUT-4 to the cell membrane in muscle and adipose tissue (Figure 2). Phosphoinositide 3-kinase (PI3K) activation and steps downstream have received the greatest attention (2,40).

Loss of insulin sensitivity in the liver is believed to develop at latter stages of IR, and to correlate more strongly than postprandial hyperglycemia with fasting hyperglycemia and compensatory fasting hyperinsulinemia in DM2 (36). This fact does not preclude an earlier involvement of the liver in DM2 pathogenesis. The liver remains an important site for glucose clearance and storage, accounting for up to 30% of disposal, and is the principal site for gluconeogenesis and insulin clearance (36,41). An exciting new line of research, in which insulin-receptor knockout models are used in mice, also suggests that the liver may have a greater role in whole-body insulin sensitivity. Researchers have noticed that while mice with a muscle-specific insulin-receptor knockout were able to maintain the same fasting and postprandial glycemia and sensitivity to exogenous insulin as control mice (42), those with a liver-specific knockout in another study were not (1).

Other sites involved in IR may include the pancreatic beta-cell and the brain. Applying the same gene-knockout technique, investigators observed that a beta-cell-specific insulin-receptor knockout produced an insulin-secretory defect similar to that observed in DM2 (43). In a subsequent study (44), a central nervous system (CNS)-specific insulin-receptor knockout resulted in mild IR, elevated fasting insulin, hypertriglyceridemia, and increased body fat. This knockout also increased food intake in female knockout mice and diet-sensitive obesity in both genders. This occurred despite a concomitant increase in leptin, a protein encoded by the obese gene in adipocytes that is thought to signal decreased obesity and ingestive behavior. This finding suggests that IR may also lead to CNS leptin resistance, contributing to weight gain.


A number of factors are thought to underlie defects in insulin-stimulated glucose transport in the muscle and liver. Chronic elevation of free fatty acids (FFAs) has been implicated in several studies (2,38). Lipid infusions in humans (45) and rats (46) have been shown to inhibit PI3K activity, leading to decreased insulin-stimulated glucose transport in muscle. Decreased insulin binding and subsequent decreased insulin internalization and recycling have also been observed in isolated hepatocytes incubated with various FFAs (47).

Another pathogenic possibility is the chronic hyperglycemia resulting from IR. This may lead to “glucose toxicity,” in which excess glucose interferes with insulin-stimulated glucose transport. The mechanisms involved have not been well defined. One explanation is that the hexosamine pathway is up-regulated, increasing levels of hexosamine metabolites that may interfere with GLUT-4 translocation (2).

Paracrine factors may also play a role in IR pathogenesis. One example is tumor necrosis factor-alpha (TNF(alpha)). This cytokine, observed to be over-expressed in the muscle and adipose tissue, has been negatively correlated with insulin-stimulated glucose metabolism in obese animals and humans (48,49). Furthermore, it has shown potent inhibitory effects on tyrosine phosphorylation of insulin-receptor substrates (IRSs) in vitro (48). Blocking its effects in humans, however, appears to have no effect on insulin sensitivity (50). Another example is a newly discovered hormone, resistin. Increased expression of resistin was observed in the adipocytes of mice with genetic and diet-induced obesity. Administration of recombinant resistin was shown to impair glucose tolerance and increase IR in mice with diet-induced obesity and to decrease insulin-stimulated glucose transport in cultured adipocytes. Blocking the effects of resistin led to decreased IR in the mice and increased insulin-stimulated glucose transport in adipocytes (51).

Finally, neuroendocrine perturbations may participate in IR pathogenesis. Perturbations in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with the metabolic syndrome. These perturbations are characterized by altered diurnal cortisol kinetics in response to stress (52). One presentation is elevated cortisol, as in Cushing’s syndrome, which is associated with the full syndrome. The other presentation is low cortisol, seen with decreased testosterone levels in men. This latter presentation has been associated with IR and obesity, both of which are reversible with testosterone infusion in the rat and in man (52,53).

An association with decreased HDL-C and increased triglycerides, BP, and diabetes incidence was also reported in men in the Multiple Risk Factor Intervention Trial (54,55).


Several candidate genes emerge from the mechanisms cited above. Most are thought to fit the “thrifty genotype” hypothesis, which proposes that evolving from a harsh environment and unstable food supply causes efficient fat storage; this in turn leads to weight gain, thus predisposing a person to features of the IR syndrome and subsequent DM2 development (48). Genes under investigation include those that code for the beta^sub 3^-adrenergic receptor, which has been linked to increased lipolysis in visceral fat depots. Polymorphisms in the beta^sub 3^-adrenergic receptor gene have been associated with increased IR, hyperinsulinemia, and other features of the metabolic syndrome such as abdominal obesity and hypertension (48).

Those genes that code for various lipases in adipose tissue (hormone-sensitive lipase), endothelium (endothelial lipoprotein lipase), and the liver (hepatic lipase) are also under investigation (48). Such mutations may contribute to the high free fatty-acid flux associated with decreased insulin-stimulated glucose transport. In this regard, overexpression of human lipoprotein lipase has been observed to increase fat oxidation and skeletal muscle citrate (a Krebs cycle intermediate and potent inhibitor of glycolysis) during dormant fasting, resulting in decreased glucose tolerance and lower insulin sensitivity in a transgenic mouse model (56).

Other genes with IR-associated polymorphisms include those that code for glycogen synthase; the IRS isomer, IRS-1; TNF(alpha), and the peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) (48). This last receptor is the target of the new class of insulin-sensitizing diabetes drugs, thiazolidinediones (57), two of which (rosiglitazone and pioglitazone) were approved for use in Canada in 2000. Natural ligands include fatty acids and their derivatives. They have been suggested to be modulators of adipocyte differentiation (48), with thiazolidinedione treatment also shown to down-regulate the expression and secretion of resistin markedly in mouse adipocytes (51). Polymorphisms include a variant that leads to decreased receptor activity associated with increased insulin sensitivity and a low body mass index (48).

Finally, genes involved in the HPA axis and in CNS regulation are under study. These include genes that code for glucocorticoid receptors, polymorphisms of which have been associated with poor regulation of cortisol secretion and subsequent IR, abdominal obesity, and hypertension (53). Also being studied are genes that code for leptin and its receptors. Polymorphisms in its protein have been associated with fat mass, while those in its receptor have been associated with BP regulation (48,53).


Although IR affects carbohydrate metabolism, it is not considered a disease of carbohydrate consumption. This is evident in the recommendations for the dietary treatment of DM2. In practice, treatment often includes behavioural changes to reduce body weight and increase physical activity. Beyond these principles, there are two main approaches. The first is advocated by the Canadian Diabetes Association (CDA) (58): a diet high in carbohydrate (50-60% of calories), low in total fat (

Each set of guidelines is supported by substantive literature (Table 2). Support for the CDA recommendations comes from prospective epidemiological evidence. This evidence indicates that diets that have a low GI and are high in fibre reduce both the risk for developing diabetes (60,61) and CHD (62). Interventional evidence in people with DM2 shows improved long-term glycemic control (63-69,70-72), serum lipids (63-65,67,73-75), and weight management (68). The high carbohydrate component of this type of diet has, however, been criticized on the grounds that it may adversely affect triglycerides and HDL-C, both of which are important features of the metabolic syndrome (59). The ADA addresses this concern with the high monounsaturated fatty-acid (MUFA) component of their recommended diet. Support for this position comes largely from interventional data indicating that replacing SFAs (76) or carbohydrate (77) with MUFAs improves fasting plasma glucose (77), serum insulin, insulin sensitivity (76), and serum lipids while having no adverse effect on HDL-C (76,77). However, no benefit of MUFA on markers of long-term glycemic control has been reported.

Neither the CDA nor the ADA guidelines address the treatment of IR specifically. The deficiency of guidelines prompted publications by both the American Heart Association (AHA) in 2000 (78) and the National Cholesterol Education Program in their third report (NCEP-III) (79). These guidelines emphasize therapy of individual IR risk factors, such as the hyperglycemia that characterizes IR, and associated risk factors (obesity, dyslipidemia, and hypertension). To achieve nutritional goals, the main recommendation of both organizations is caloric restriction to achieve a healthy weight, with SFA intake reduced to under 7% of calories and cholesterol intake to under 200 mg/day.

Like the CDA, the AHA addresses the consumption of low-GI foods and high levels of dietary fibre. The NCEP-III also recommends increasing daily fibre intake to 20-30 g, with 10-25 g coming from viscous soluble fibre.

The NCEP-III guidelines are similar to the ADA recommendations in that they allow an increase in MUFAs up to 20% of calories, provided total fat is kept within 25-35% of calories and trans fatty acids are kept at a low intake. Other options include an intake of 2 g/day of plant stanols or sterols.

Other promising nutritional interventions are emerging for those with IR In the Da Qing study, people with IGT received a combination of a high-carbohydrate, high-fibre, low-fat diet and exercise (>=65 min/day of mixed intensities) effected through intensive counselling (one session a week for the first month, one session a month for the next three months, and one session every three months thereafter). The study showed 42% less conversion to DM2 in the study group than in controls over six years (80).

Recent data from the Finnish Diabetes Prevention Study (FDPS) and the Diabetes Prevention Program (DPP) support these results (81,82). Both trials reported sustained weight loss and an incredible 58% reduction in the conversion to DM2 following a similar lifestyle intervention involving less exercise (>=30 min/day of moderate intensity). Sustainable improvements were again achieved through intensive counselling programs: seven sessions in the first year and one session every three months thereafter in the FDPS (70), and 16 or more sessions for the first 24 months and one session a month thereafter in the DPP (82).

Interventions with dietary fibre supplements have also been beneficial in subjects with syndrome X. Consumption of a high-carbohydrate, low-fat diet with cookies containing the novel soluble fibre konjac mannan (obtained from Amorphophallus konjac C. Koch, a plant root indigenous to Asia) for eight weeks significantly improved two features of the syndrome: insulin sensitivity (83) and apolipoprotein-B (84).


Because of the high CVD risk associated with IR, identifying people with this condition is critical. In the absence of insulin data, this identification can be accomplished by recognizing key features of the syndrome, such as IGT/DM2, abdominal obesity, low HDL-C, and high triglycerides.

Once IR has been identified, a compelling case can be made for aggressive treatment that includes intensive counselling programs to promote sustainable weight loss and lifestyle changes. Nutritional goals include a high-carbohydrate (50-60% of calories), high-fibre (25-35 g), low-fat (total-fat =30 min/day of moderate intensity). Combining existing dietary paradigms that include increasing MUFA and low-GI foods would likely be of added benefit. The use of soluble-fibre supplements to achieve adequate fibre intakes may also improve outcomes.

More research is needed before optimal nutritional guidelines for IR can be developed. Whether the lifestyle interventions to prevent DM2 are sustainable and whether their effects prevent or delay DM2 development require clarification. The ability to implement such intensive programs must also be investigated. Furthermore, much remains to be understood about IR. Whether it is the underlying pathogenic factor of the syndrome or simply a comorbidity is unclear (85). Despite the new WHO definition (19), the exact features of the syndrome also remain controversial. In addition, the mechanisms underlying impaired insulin signalling and related genetic polymorphisms must be clarified. Through this scientific progression, successful personalized nutritional treatments should emerge.


John L. Sievenpiper held an Ontario Graduate Scholarship during the writing of this review.

He also received consultation fees from the Canadian Sugar Institute and both he and Vladimir Vuksan have received research and travel funding from MuscleTech Research and Development Incorporated. Vladimir Vuksan has also received honoraria and/or research funding from Mead Johnson Nutritionals, U.S.A.; Kelloggs, U.S.A.; Dicofarm, Italy; Nestle, U.S.A.;


1. Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 2000;6:87-97.

2. Sheppard PR, Kahn BB. Glucose transporters and insulin action. N Engl J Med 1999;341:248-57.

3. Himsworth HP. Diabetes mellitus-its differentiation into insulin sensitive and insulin insensitive types. Lancet 1936;1:127-30.

4. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association. Can Med Assoc J 1998;159 (Suppl 8):S1-29.

5. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20;1183-97.

6. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-1607.

7. Vague J. The degree of masculine differentiation of obesities: a factor– determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20-8.

8. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214-23.

9. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462-70.

10. Hermans MP, Levy JC, Morris RJ, et al. Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes. Diabetologia 1999;42:678-87.

11. Belfiore F, Iannello S, Volpicelli G. Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 1998;63:134-41.

12. Matthews DR, HoskerjP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28 412-9.

13. Mari A, Pacini G, Murphy E, et al. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001;24:539-48.

14. Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989;149:1514-20.

15. Liese AD, Mayer-Davis EJ, Tyroler HA, et al. Development of the multiple metabolic syndrome in the ARIC cohort: joint contribution of insulin, BMI, and WHR Atherosclerosis risk in communities. Ann Epidemiol 1997;7:407-16.

16. Hjermann I. The metabolic cardiovascular syndrome: syndrome X, Reaven’s syndrome, insulin resistance syndrome, atherothrombogenic syndrome. J Cardiovasc Pharmacol 1992;20 (Suppl 8):S5-10.

17. Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993;13:1865-73.

18. Selby JV, Austin MA, Newman B, et al. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 1993;88:381-7.

19. Despres JP. The insulin resistance-dyslipidemia syndrome: the most prevalent cause of coronary artery disease? Can Med Assoc J 1993;148:1339-40.

20. Zimmet PZ, Collins VR, Dowse GK, et al. Is hyperinsulinaemia a central characteristic of a chronic cardiovascular risk factor clustering syndrome? Mixed findings in Asian Indian, Creole and Chinese Mauritians. Mauritius Noncommunicable Disease Study Group. Diabet Med 1994;11:388-96.

21. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.

22. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-9.

23. Bonora E, Kiechl S, Willeit J, et al. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 1998;47:1643-9.

24. Haffner SM, Mykkanen L, Festa A, et al. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation 2000;101:975-80.

25. Ekoe JM: Epidemiology of type 2 diabetes mellitus in North America. CJDC 1999;23:43-6.

26. World Health Organization. Prevention of diabetes mellitus: report of WHO study group. Geneva, WHO Technical Report Series, 1994; 844. 27. Trevisan M, Liu J, Bahsas FB, et al. Syndrome X and mortality: a

population-based study. Risk Factor and Life Expectancy Research Group. Am J Epidemiol 1998;148:958-66.

28. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care 2000;23:1278-83.

29. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282:1519-22. 30. Haffner SM, Stem MP, Hazuda HP, et al. Cardiovascular risk factors

in confirmed prediabetic individuals. Does the clock for coronary hear disease start ticking before the onset of clinical diabetes? JAMA 1990;263:2893-8.

31. Wagenknecht LE, D’Agostino RB Jr, Haffner SM, et al. Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness: the Insulin Resistance Atherosclerosis Study. Diabetes Care 1998;21:1812-8.

32. O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22.

33. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339(4):229-34.

34. Mukamal KJ, Nesto RW, Cohen MC, et al. Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction. Diabetes Care 2001;24:1422-7.

35. Bierman EL. George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-56.

36. Defronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 1997;5:177-269.

37. Shulman GI, Rothman DL, Jue T, et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulindependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990;322:223-8.

38. Shulman GI. Cellular mechanisms of insulin resistance in humans. Am J Cardiol 1999;84(lA):3J-lOJ.

39. Cline GW, Petersen KF, Krssak M, et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 1999;341:240-6.

40. Shepherd PR, Withers DJ, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 1998;333:471-90.

41. Ferrannini E, Wahren J, Faber OK, et al. Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am J Physiol 1983;244:E517-27.

42. Bruning JC, Michael MD, Winnay JN, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998;2:559-69.

43. Kulkarni RN, Bruning JC, Winnay JN, et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999;96:329-39.

44. Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289:2122-5. 45. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on

glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999;103:253-9.

46. Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signalling cascade. Diabetes 1999;48:1270-4.

47. Svedberg J, Bjorntorp P, Smith U, et al. Effect of free fatty acids on insulin receptor binding and tyrosine kinase activity in hepatocytes isolated from lean and obese rats. Diabetes 1992;41:294-8.

48. Groop L. Genetics of the metabolic syndrome. Br J Nutr 2000;83(Suppl 1):539-48.

49. Saghizadeh M, Ong JM, Garvey WT, et al. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 1996;97:1111-6.

50. Ofei F, Hurel S, Newkirk J, et al. Effects of an engineered human antiTNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996;45:881-5.

51. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-12.

52. Bjorntorp P, Rosmond R The metabolic syndrome – a neuroendocrine disorder? Br J Nutr 2000;83 (Suppl 1):S49-57.

53. Bjorntorp P. Insulin resistance: the consequence of a neuroendocrine disturbance? Int J Obes 1995;19(Suppl 1):S6-10.

54. Zmuda JM, Cauley JA, Kriska A, et al. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997;146:609-17.

55. Haffner SM, Shaten J, Stern MP, et al. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulindependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;143:889-97.

56. Ferreira LD, Pulawa LK, Jensen DR, et al. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes 2001;50:1064-8.

57. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 2000;133:73-4.

58. Wolever TMS, Barbeau, Charron S, et al. Guidelines for the nutritional management of diabetes mellitus in the new millennium: a position by the Canadian Diabetes Association. CJDC 2000;23:56-69.

59. American Diabetes Association. Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care 2000;23(Suppl 1):543-6.

60. Salmeron J, Manson JE, Stampfer MJ, et al. Dietary fibre, glycemic load and risk of non-insulin-dependent diabetes mellitus in women. JAMA 1997;277:472-7.

61. Salmeron J, Ascherio A, Rimm EB, et al. Dietary fibre, glycemic load, and risk of NIDDM in men. Diabetes Care 1997;20:545-50.

62. Liu S, Willett WC, Stampfer MJ, et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2000;71:1455-61.

63. Jenkins DJ, Wolever TM, Buckley G, et al. Low-glycemic-index starchy foods in the diabetic diet. Am J Clin Nutr 1988;48:248-54.

64. Brand JC, Colagiuri S, Crossman S, et al. Low-glycemic index foods improve long-term glycemic control in NIDDM. Diabetes Care 1991;14:95-101.

65. Wolever TM, Jenkins DJ, Vuksan V, et al. Beneficial effect of low– glycemic index diet in overweight NIDDM subjects. Diabetes Care 1992;15:562-4.

66. Fontvieille AM, Rizkalla SW, Penfornis A, et al. The use of low glycaemic index foods improves metabolic control of diabetic patients over five weeks, Diabet Med 1992;9:444-50.

67. Jarvi AE, Karlstrom BE, Granfeldt YE, et al. Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low– glycemic index diet in type 2 diabetic patients. Diabetes Care 1999;22:10-8.

68. Spieth LE, Harnish JD, Lenders CM, et al. A low-glycemic index diet in the treatment of pediatric obesity. Arch Pediatr Adolesc Med 2000;154:947-51.

69 Gilbertson HR, Brand-Miller JC, Thorburn AW, et al. The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type I diabetes. Diabetes Care 2001;24:1137-43.

70. Hjollund E, Pedersen 0, Richelsen B, et al. Increased insulin binding to adipocytes and monocytes and increased insulin sensitivity of glucose transport and metabolism in adipocytes from non-insulindependent diabetics after a low-fat/high-starch/high-fiber diet. Metabolism 1983;32:1067-75.

71. Karlstrom B, Vessby B, Asp NG, et al. Effects of an increased content of cereal fibre in the diet of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1984;26:272-7.

72. Fukagawa NK, Anderson JW, Hageman G, et al. High-carbohydrate, high-fiber diets increase peripheral insulin sensitivity in healthy young and old adults. Am J Clin Nutr 1990;52:524-8.

73. Luscombe ND, Noakes M, Clifton PM. Diets high and low in glycemic index versus high monounsaturated fat diets: effects on glucose and lipid metabolism in NIDDM. Eur J Clin Nutr 1999;53:473-8.

74. Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 2000;342:1392-8.

75. Brown L, Rosner B, Willett WW, et al. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999;69:30-42.

76. Vessby B, Unsitupa M, Hermansen K, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia 2001;44:312-9.

77. Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr 1998;67(3 Suppl):5775-82S. 78. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines:

revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 2000;102:2284-99.

79. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

80. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.

81. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.

82. National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). Diet and exercise dramatically delay type 2 diabetes: diabetes medication metformin also effective.

Accessed Aug 8, 2001

83. Vuksan V, Sievenpiper JL, Owen R, et al. Beneficial effects of viscous dietary fiber from Konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial. Diabetes Care 2000;23:9-14.

84. Vuksan V, Sievenpiper JL, Jenkins DJA, et al. Chronic feeding of Konjac-mannan (KJM) fibre improves postprandial glycemia in insulin resistance. [abstract] FASEB J 2000;14:A727.

85. Yudkin JS. Abnormalities of coagulation and fibrinolysis in insulin resistance. Diabetes Care 1999;33 (Suppl 3):C25-30.

JOHN L. SIEVENPIPER, BASc, MSc; ALEXANDRA L. JENKINS, BSc, RD, CDE; DANA L WHITHAM, BSc, RD, CDE; VLADIMIR VUKSAN, PhD, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON

Copyright Dietitians of Canada Spring 2002

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