Dietary models of insulin resistance

    Dietary Models of Insulin Resistance James Deer, Juraj Koska, Marlies Ozias, Peter Reaven PII: DOI: Reference:

S0026-0495(14)00261-3 doi: 10.1016/j.metabol.2014.08.013 YMETA 53083

To appear in:

Metabolism

Received date: Revised date: Accepted date:

12 May 2014 20 July 2014 29 August 2014

Please cite this article as: Deer James, Koska Juraj, Ozias Marlies, Reaven Peter, Dietary Models of Insulin Resistance, Metabolism (2014), doi: 10.1016/j.metabol.2014.08.013

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ACCEPTED MANUSCRIPT Dietary Models of Insulin Resistance James Deer, M.D.a, Juraj Koska, M.D., Ph.Da., Marlies Ozias, Ph.D.a, Peter Reaven, M.Da.

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Phoenix VA Health Care System, Department of Endocrinology, 650 E Indian School Road

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Mail Code 111E, Phoenix, AZ 85012-1892

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Abstract: Insulin resistance is a significant factor in the development of type 2 diabetes mellitus, however the connection between the Western diet and the development of insulin resistance

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has not been fully explained. Dietary macronutrient composition has been examined in a number of articles, and diets enriched in saturated fatty acids, and possibly in fructose, appear

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to be most consistently associated with the development of insulin resistance. However,

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mechanistic insights into the metabolic effects of such diets are lacking, and merit further study.

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Keywords: insulin resistance, dietary composition, carbohydrate, fat

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Abbreviations: interleukin-6, IL-6; interleukin-1β, IL-1β; tumor necrosis factor α, TNF-α; toll-like receptor, TLR; nuclear factor κB, NF-κB; homeostatic model assessment, HOMA; saturated fatty acids, SFA; polyunsaturated fatty acids, PUFA; monounsaturated fatty acids, MUFA; area under the curve, AUC. Disclosures: None Abstract word count: 82 Text word count (including abbreviation list): 3686 Tables: 3 Figures: 0 References: 47

ACCEPTED MANUSCRIPT 1.

Introduction Type 2 diabetes is a significant cause of morbidity and mortality in the United States, as

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well as a burden on the health care system. Diabetes is well known to have detrimental effects

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on both the micro- and macrovasculature; and is the leading cause of new cases of blindness and renal failure, while also being a major risk factor for ischemic heart disease,

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cardiomyopathy, and cerebrovascular disease [1,2]. In addition, individuals with type 2 diabetes

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are at greater risk to develop conditions not directly related to vascular injury including nonalcoholic fatty liver disease [3]. The treatment of diabetes and its complications in the US in

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2012 are estimated to cost $245 billion dollars [4]. Importantly, as diabetes is occurring at increasingly younger ages, the healthcare toll of these complications is escalating.

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Excess caloric intake and obesity are significant contributors to insulin resistance, a major component of the pathophysiology of type 2 diabetes. How obesity contributes to insulin

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resistance remains a topic of active study. One prevailing theory contends that obesity

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promotes inflammatory changes in adipose and other tissues, in turn promoting insulin resistance. Increasing adiposity is associated with an influx of inflammatory cells such as

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macrophages and monocytes in the adipose tissue [5,6]. These cells secrete a variety of inflammatory factors, such as IL-6, IL-1β, and TNF-α, that are capable of blunting insulin signaling [7]. In addition, adipocytes themselves are now recognized as potent producers of bioactive factors (or adipokines) that have autocrine and paracrine actions that can modulate insulin action. However, while obesity itself plays a role in the chronic development of insulin resistance, there are indications that certain dietary macronutrients may aggravate this process and/or promote insulin resistance in the acute and sub-acute time frames. Understanding how dietary composition may contribute to this process is critical to developing strategies to prevent the development of insulin resistance. For example, learning how dietary components initiate or

ACCEPTED MANUSCRIPT modulate underlying insulin resistance might reveal therapeutic targets for prevention of type 2 diabetes. This might also facilitate establishment of valid dietary research models in humans

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that would allow direct testing of these insulin modulating pathways and potential treatment

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targets. Finally, this knowledge would permit clinicians to offer concrete nutritional advice for patients at risk of developing type 2 diabetes.

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There has been extensive work in cell lines [8,9] and animals which highlight possible

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macronutrients and cell signaling pathway contributions to insulin resistance. Mice and rats fed a high fat diet develop insulin resistance [10-12], and a variety of mechanisms have been

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hypothesized. For example, high fat diets have been associated with increased skeletal muscle diacylglycerol and ceramide levels and activation of the pro-inflammatory toll-like receptor (TLR)

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4/nuclear factor κB (NF-κB) pathways, [10-12], each of which has been linked with diminished insulin action. The formation and accumulation of diacylglycerols and ceramides in tissue from

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increased concentrations of certain dietary free fatty acids [13,14] may alter insulin signaling through activation of several pathways, including protein kinase C, MAP kinase, and NF-κB

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activation, all potentially resulting in modulation of insulin signaling and decreased PI3K/Akt

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phosphorylation and activation. In vitro and in vivo saturated fatty acids in particular have been shown to directly or indirectly activate TLR 2 and 4, which can alter insulin action via activation of multiple inflammatory pathways [10-14]. In addition, high fat diets may induce insulin resistance through enhancing intracellular free fatty acid accumulation and generation of reactive oxygen species, resulting in, among other events, the activation of inflammatory pathways such as NF-κB [15]. Studies have also supported the concept that carbohydrate excess, possibly through transient increases in blood glucose or cellular glucose flux and/or hormonal alterations to these glucose peaks, may contribute to insulin resistance. For instance, cultured human monocytes in a high glucose milieu increase the secretion of inflammatory IL-6 and IL-1β and surface

ACCEPTED MANUSCRIPT expression of TLR 2 and 4 [16]. Additionally, rat and mouse models suggest that fructose enriched diets promote insulin resistance through accumulation of hepatic diacylglycerols and

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advanced glycation end products [17,18]. The concept of glycemic index, a measurement of

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how rapidly carbohydrate sources result in blood sugar changes (a higher index reflects more rapid rises in blood glucose), has also been explored in animal models, and the combination of

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a high fat and high glycemic index diet was found to provoke insulin resistance in mice [19].

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All of these data provide important insights regarding possible dietary mechanisms in the development of insulin resistance. However, there are limitations in extrapolating data from cell

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culture and animal studies to the influence of diet on insulin resistance in humans. Translation of cell culture experiment data is inherently complicated, as the cells in such experiments are

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often exposed to substances at far higher concentrations than is realistic, and/or in isolation in a non-physiologic milieu. In addition, while animal models can provide hypotheses about the

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nature of insulin resistance in humans, differences in physiology require that these hypotheses be tested and confirmed in humans. Moreover, while the diet and environment can be tightly

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controlled in animals, variation in dietary compliance, physical fitness and activity all complicate

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these studies in humans. These inherent difficulties make nutritional studies exceedingly challenging to conduct and interpret. The focus of this review will be to examine the state of literature pertaining to dietary effects on insulin resistance in humans, including mechanistic insights which may be drawn from these studies and identifying the gaps in current knowledge.

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Study Characteristics The studies discussed in this review were identified through extensive searches for

human dietary trials affecting insulin resistance published in English within the PubMed database. The majority of these studies included non-diabetic subjects, while a smaller number of studies included patients with type 2 diabetes. Most diets studied were designed to be

ACCEPTED MANUSCRIPT eucaloric and weight neutral; however, most failed to report on whether weight change was avoided. Of the studies that did report on weight change, most, but not all, found that subjects’

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weights remained stable. Additionally, the mean BMI for a majority of the studies was less than

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30. Most studies provided the intervention diets to their participants to reduce concerns about subject adherence. There were also a variety of methods used to assess insulin resistance.

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The most common methods of assessment used were fasting insulin measurements or calculated estimates of insulin resistance, such as HOMA-IR, but more rigorous techniques like

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hyperinsulinemic-euglycemic clamps were only reported in a few studies. The duration of study

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diets varied widely, ranging from single test meals up to 6 months. Although inflammation pathways are believed to be important mediators of dietary induced insulin resistance, only three studies performed any assessment of inflammatory markers.

Similarly, only one study

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examined tissue lipid intermediates and none of the studies assessed ceramide metabolism as

Effect of Carbohydrates

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3.

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part of investigations into potential mechanisms.

As seen in Table 1, four studies reported on the effects of variation in glycemic load

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(derived from the glycemic index and carbohydrate amount) on insulin resistance, while seven additional studies examined the effects of varying the proportion of calories taken in as carbohydrates [20-30]. The duration of exposure to the test diets in these studies varied from 6 days to 12 weeks and the percentage of carbohydrate in the test diets ranged from 20-65%. Of these studies, one failed to report on weight change [22], while four reported no change in weight [20, 24-25, 27], and the remaining studies noted either weight increases or decreases on at least one test diet [21, 23, 26, 28-30]. As illustrated in the Table and noted below there was substantial heterogeneity among the main findings in the studies, with 3 studies reporting that diets enriched in carbohydrates or containing high glycemic loads increase insulin resistance, and the other 5 reporting no effect. Brynes et al. illustrated the difficulty of preparing the diets

ACCEPTED MANUSCRIPT for, and conducting, a study of this nature [21]. They examined 17 men with at least one risk factor for cardiovascular disease, including type 2 diabetes. The subjects in this crossover

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design spent 24 days on each of four test diets with a minimum 3 week washout period between

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diet periods. The high glycemic index diet (glycemic index values ranging from 88-118), contained 50-54% of calories from carbohydrate and 31-34% of the calories from fat. The low

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glycemic index diet (glycemic index values were 68-69), contained 51-52% of calories from carbohydrates and 32-35% of calories from fat. The high fat diet contained foods with a

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glycemic index range from 70-86, with 28-30% of calories from carbohydrates, and 54-63% of

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calories from fat (15-34% of that from saturated fatty acids, SFA). The high sucrose diet had a glycemic index range of 75-92, with 50-57% of calories from carbohydrates, and 30-35% of calories from fat. They reported that the high glycemic index diet increased HOMA-IR by 31%,

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compared with a decrease of 20-61% for the other diets, suggesting that this intervention

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appeared to increase insulin resistance. However, this study was hampered by weight increases on the high fat, high glycemic index and high sucrose test diets, and weight loss in the

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low glycemic index group, complicating efforts to separate the effect of diet from the weight changes. A separate study of 21 women with polycystic ovarian syndrome that used a low

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glycemic index test diet for 3 months and avoided weight change came to similar conclusions [27]. The test diet in this study was compared to each participant’s baseline diet (glycemic index of 54.7) and had a mean glycemic index of 48.6. Twelve weeks on the low glycemic index diet resulted in increases in calculated HOMA2-IS (i.e.,a change towards greater insulin sensitivity), from 61.1% during the pre-intervention diet period to 72.8% following the low glycemic index diet. Surprisingly, these differences in HOMA2-IS values were significant despite only modest differences in glycemic index values between the diets. Several studies focused specifically on the effect of greater dietary fructose ingestion on insulin resistance. For example, a study by Faeh et al., evaluated 3 grams/kg/day fructose

ACCEPTED MANUSCRIPT supplementation in addition to an isocaloric diet, and found that fructose addition resulted in significant hepatic insulin resistance compared with the isocaloric diet alone, with no change in

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peripheral insulin sensitivity [24]. The view that fructose intake may influence development of

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insulin resistance has been further strengthened by studies from Aeberli et al., which found that supplementation of an isocaloric diet with fructose sweetened beverages over 3 weeks

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decreased suppression of hepatic glucose production during an euglycemic clamp relative to supplementation with glucose sweetened beverages [30]. However, not all studies found

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changes in glucose metabolism resulted from alterations in carbohydrate intake. For example, a

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study of 14 nonobese men on an isocaloric diet with varying percentage of sucrose intake failed to show any difference in glucose disposal or endogenous glucose production over 6 weeks [25]. Similarly, a separate study compared different weight loss strategies (portion control, low

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glycemic index, and low energy density test diets) failed to show any difference in HOMA-IR

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after 12 weeks [23]. Furthermore, three studies which used gold standard clamp techniques failed to find a difference in whole body glucose disposal from changes in carbohydrate content

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as a percent of total calories [24, 25, 26]. Overall, the data for alterations in dietary carbohydrate modulating insulin resistance are conflicting. However, given the potentially

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negative effects on hepatic insulin sensitivity resulting from high fructose diet studies in these few smaller human studies and many animal models, additional investigation of these diets using larger numbers of subjects with more careful measurements of insulin resistance are needed.

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Effects of Saturated Fatty Acids Ten studies examined the effects of diets enriched in SFA on the development of insulin

resistance (Table 2) [31-40]. Eight of these found that SFA intake ranging from 9-67% of total calories was associated with increased insulin resistance [31-33, 35-39]. The duration of the test diets ranged from single test meals to 3 months. The longest and largest study of SFA

ACCEPTED MANUSCRIPT dietary enrichment was conducted by Vessby et al. in nondiabetic adult men and women [37]. This study included 162 subjects who were provided isocaloric test diets for 3 months with 37%

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of total calories from fat with one test diet containing 17% of calories from SFA and the other

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containing 23% of calories from MUFA. The SFA enriched diet, compared with the MUFA enriched diet, resulted in a significant decrease in the insulin sensitivity index following an IV

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glucose tolerance test (-12.5% versus +8.8%, respectively). Consistent with this study finding, Xiao et al. demonstrated increased insulin resistance in overweight and obese men (mean BMI

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= 31.8) receiving multiple 136 kcal palm oil fat loads at regular intervals over a 24 hour period,

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as assessed with a hyperglycemic clamp [35]. The principal drawback of this study was its small size (n = 7). The remaining studies which found effects of saturated fatty acids on insulin resistance varied in duration from a single test load up to 6 weeks, and were similarly varied in

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methods of assessing insulin resistance, ranging from findings of increased postprandial insulin

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to suppression of hepatic glucose production during a euglycemic clamp [31-33, 36, 38-39]. A crossover study by Fasching et al. did not find a difference in insulin resistance when comparing

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an SFA enriched diet to diets enriched in PUFA, MUFA, or carbohydrates [34]. The duration of exposure to each test diet was 1 week and included a 2 week washout phase. The failure to

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detect an SFA effect may have been a consequence of comparing hypercaloric diets; each diet included a standard 2000 kcal diet supplemented with 800 kcal of the specific macronutrient being tested. No weight changes were reported, but perhaps the expected 1-3 pound change during each hypercaloric phase partially obscured differences between diet-groups. Additionally, the sample size was small, with only 8 participants, providing low statistical power to detect significant group differences. Although both fructose and SFA enriched diets have been studied for their potential to induce insulin resistance, there appears to be a paucity of research regarding a diet enriched in both macronutrients. A study from Lecoultre et al., compared hypercaloric diets with various

ACCEPTED MANUSCRIPT degrees of fructose, glucose, and saturated fat supplementation, which found that overfeeding with 3-4 g/kg/day of fructose decreased hepatic insulin sensitivity, while saturated fat

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supplementation failed to alter hepatic insulin sensitivity [40].

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In summary, most studies of SFA enriched diets have demonstrated increased insulin resistance. Importantly, the observed blunting of insulin action on glucose metabolism with SFA

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enriched diets was reported regardless of the duration of exposure to the test diet, with several

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such studies indicating that even short-term diets may induce insulin resistance. A more acute diet approach may have several unique advantages, as it allows investigators to study

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development of insulin resistance in the absence of possibly confounding weight change, and may allow investigation of the earliest possible mechanistic changes (e.g., changes in tissue

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lipid intermediates or inflammation) before chronic or compensatory secondary events occur. An acute induction of insulin resistance model could also accelerate testing therapeutic targets

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and interventions by allowing testing to occur quickly and more reliably in a series of short cross-over studies. However, it is possible that SFA induced acute changes in insulin action

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could result from unique mechanisms, such as alteration in microvascular recruitment and

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delivery of insulin and glucose to skeletal muscle [41]. Although this would have important implications, it may not fully replicate tissue signaling events and consequences of long-term high fat diets. Further research into the effects of SFA, alone and in conjunction with fructose supplementation, on the development of insulin resistance are clearly needed. Particular attention should also be paid to possible tissue changes in generation of lipid intermediates and their consequences on inflammatory and insulin signaling pathways thought to play a role in insulin resistance.

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Effects of Polyunsaturated Fatty Acids Out of seven studies that included a PUFA enriched diet [31, 34, 42-46], two

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demonstrated a decrease in insulin resistance, when compared with diets without PUFA

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supplementation (Table 3) [42, 45]. However, both of these studies utilized low calorie diets and reported weight loss. Krebs et al. reported on the longest PUFA trial (24 weeks), which was also

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associated with the largest mean weight loss [42]. The test diet included a base caloric intake

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of 800 kcal, supplemented with 5 grams of n-3 PUFA or a placebo consisting of a mixture of linoleic and oleic acids, compared with no dietary intervention. Both the PUFA and placebo oil

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test diets resulted in weight loss (-10.2kg and -11.3kg, respectively), while the control group had an increase in weight of 0.3kg. Both the PUFA and placebo oil arms were found to have

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decreased insulin resistance, as determined by insulin AUC calculations following an oral glucose tolerance test. However, despite marked variation in weight loss, there was no

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difference in the HOMA determination between the three diets, and there was no difference

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between the two groups which lost weight. Based on this, it appears that the effects of the intervention would most likely be attributable to the observed weight loss, rather than the use of

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PUFA supplementation. In the second study, Derosa et al. used a parallel arm design to compare a hypocaloric diet (600 kcal/d deficit) supplemented with 3g/d PUFA with a hypocaloric diet supplemented with a placebo comprised of sucrose, mannitol and mineral salts over 6 months in 157 men and women with dyslipidemia [45]. The base diet derived 50% of its calories from carbohydrate, and 30% from fat, with 6% of those calories from SFA. Weight loss was reported in both groups (-1.6kg for PUFA vs. -2.2kg for placebo). Insulin resistance was assessed with a euglycemic clamp, and glucose uptake was found to be significantly increased in the PUFA supplemented subjects compared with baseline. However, there was no difference in glucose uptake when PUFA supplementation was compared to placebo. In the other five studies, PUFA enriched diets did not affect insulin resistance, regardless of the type of PUFA

ACCEPTED MANUSCRIPT utilized. These studies ranged from 2 to 6 months in duration, and reported weight change from 0kg to +0.8kg. Two of these studies compared PUFA against SFA and MUFA in single test

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meals, and found no significant differences in insulin resistance between MUFA and PUFA

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enriched diets, while reporting increased insulin resistance with SFA diet enrichment. Based on these studies, PUFA enriched diets do not appear to directly affect insulin resistance, outside of

Effects of Monounsaturated Fatty Acids

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6.

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observed effects on weight change.

The six studies which included a MUFA enriched test diet typically compared MUFA to

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SFA calorie replacement while two studies also included comparisons to PUFA enriched diets. The duration of the test diets ranged from single test meals up to 3 months. MUFA enrichment

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in each diet ranged from 15-78% of total calories. In five of the six studies, SFA led to a relative

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increase in insulin resistance compared with MUFA enriched diets. For example, a six week crossover study by Christiansen et al. compared MUFA, SFA, and trans fat enriched diets and

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demonstrated significant increases in postprandial insulin levels on the SFA and trans fat enriched diets, relative to the MUFA diet (77% and 59% higher, respectively) [38]. No weight

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change was reported in any group, and the MUFA test diet had no change in postprandial insulin compared to an isocaloric control diet. In a separate study, as discussed above, Fasching et al. did not find a significant difference in glucose disposal during a euglycemic clamp between PUFA, MUFA, or SFA supplementation during a 1 week hypercaloric intervention [34]. Based on these results, it appears that MUFA diets tend to have minimal, if any, impact on insulin resistance, particularly when compared to the consistent increases seen with SFA-enriched diets.

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Conclusion The studies reviewed suggest that SFA enriched diets, regardless of duration of

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exposure, have the ability to induce insulin resistance. Although further study of SFA diets is

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needed to confirm these data, results to date raise the possibility that SFA-enriched diets may be a uniquely valuable model to study mechanisms of dietary induced insulin resistance and

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elucidate potential protective therapies. Diet enrichment with either MUFA or PUFA appears to

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have a more neutral effect on insulin action, while the effect of changing the percentage of calories in the diet represented by carbohydrates or glycemic index on insulin resistance is less

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clear. Importantly, typical diets are not enriched in only one macronutrient. Studies combining multiple common dietary components are also needed. For example, diets enriched in SFA and

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fructose may be of particular interest as ingestion of these nutrients has been increasing steadily over the past several decades and both individually show capacity to induce insulin

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resistance. It is also important when attempting to translate preclinical work to studies in

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humans to take into consideration during designing and analysis of the study the individual factors (e.g., compliance, fitness, activity level) that may influence dietary responses.

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Currently, there is no clear consensus regarding the predominant underlying mechanisms of diet induced insulin resistance in humans. This is in part a result of limitations of many of the human studies to date. For example, many studies have not used accepted gold standard techniques to measure insulin resistance. Additionally, most human dietary studies have not performed the necessary tissue sampling or other sophisticated tests necessary to provide mechanistic insights into the interaction between dietary modifications and insulin action. For instance, assessment of plasma and tissue lipid intermediates, adipose or skeletal muscle inflammatory markers, and tissue reactive oxygen species and mitochondrial function could be made, in conjunction with measurements of whole body insulin resistance, in order to identify key pathophysiologic events resulting from acute ingestion of an SFA rich fat load.

ACCEPTED MANUSCRIPT Future studies in humans would ideally focus on both careful measurement of the ability of certain diets to induce insulin resistance and the inclusion of tissue or metabolic imaging studies

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to attempt to corroborate findings from animal models of insulin resistance.

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Carbohydrate, Lower-Fat Diet Reduces Fasting Glucose Concentration and Improves β-Cell Function in Individuals with Impaired Fasting Glucose. Metabolism. 2012; 61:358-65. 30. Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, Spinas GA, Berneis K. Moderate Amounts of Fructose Consumption Impair Insulin Sensitivity in Healthy Young Men: A Randomized Controlled Trial. Diabetes Care. 2013; 36:150-6. 31. Robertson MD, Jackson KG, Fielding BA, Williams CM, Frayn KN. Acute Effects of Meal Fatty Acid Composition on Insulin Sensitivity in Healthy Post-menopausal Women. Br J Nutr. 2002; 88:635-40.

ACCEPTED MANUSCRIPT 32. Lovejoy JC, Smith SR, Champagne CM, Most MM, Lefevere M, DeLany JP, Denkins YM, Rood JC, Veldhuis J, Bray GA. Effects of Diets Enriched in Saturated (Palmitic),

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Oxidation in Healthy Adults. Diabetes Care. 2002; 25:1283-8.

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Monounsaturated (Oleic), or trans (Elaidic) Fatty Acids on Insulin Sensitivity and Substrate

33. Manco M, Bertuzzi A, Salinari S, Scarfone A, Calvani M, Greco AV, Mingrone G. The

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Ingestion of Saturated Fatty Acid Triacylglycerols Acutely Affects Insulin Secretion and Insulin

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Sensitivity in Human Subjects. Br J Nutr. 2004; 92:895-903.

34. Fasching P, Ratheiser K, Schneeweiss B, Rohac M, Nowotny P, Waldhausl W. No Effect of

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Short-term Dietary Supplementation of Saturated and Poly- and Monounsaturated Fatty Acids on Insulin Secretion and Sensitivity in Healthy Men. Ann Nutr Metab. 1996; 40:116-22.

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35. Xiao C, Giacca A, Carpentier A, Lewis GF. Differential Effects of Monounsaturated,

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Polyunsaturated, and Saturated Fat Ingestion on Glucose-stimulated Insulin Secretion, Sensitivity, and Clearance in Overweight and Obese, Non-diabetic Humans. Diabetologia. 2006;

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49:1371-9.

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36. Bisschop PH, de Metz J, Ackermans MT, Endert E, Pijl H, Kuipers F, Meijer AJ, Sauerwein HP, Romijn JA. Dietary Fat Content Alters Insulin-Mediated Glucose Metabolism in Healthy Men. Am J Clin Nutr. 2001; 73:554-9. 37. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nalsen C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson IB, Storlien LH. Substituting Dietary Saturated for Monounsaturated Fat Impairs Insulin Sensitivity in Healthy Men and Women: the KANWU Study. Diabetologia. 2001; 44:312-9. 38. Christiansen E, Schneider S, Palmvig B, Tauber-Lassen E, Pedersen O. Intake of a Diet High in Trans Monounsaturated Fatty Acids or Saturated Fatty Acids: Effects on Postprandial Insulinemia and Glycemia in Obese Patients with NIDDM. Diabetes Care. 1997; 20:881-887.

ACCEPTED MANUSCRIPT 39. Brøns C, Jensen CB, Storgaard, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B, Vaag A. Impact of Short-term High-fat Feeding on Glucose

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and Insulin Metabolism in Young Healthy Men. J Physiol. 2009; 587(Pt 10):2387-97.

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40. Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P, Boss A, Zwygart K, Le K-A, Bortolotti M, Boesch C, Tappy L. Effects of Fructose and Glucose Overfeeding on Hepatic

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Insulin Sensitivity and Intrahepatic Lipids in Healthy Humans. Obesity. 2013; 21:782-5.

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41. Eggleston EM, Jahn LA, Barrett EJ. Early Microvascular Recruitment Modulates

Diabetes Care. 2013; 36:104-10.

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Subsequent Insulin-Mediated Skeletal Muscle Glucose Metabolism During Lipid Infusion.

42. Krebs JD, Browning LM, McLean NK, Rothwell JL, Mishra GD, Moore CS, Jebb SA. Additive

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Benefits of Long-chain n-3 Polyunsaturated Fatty Acids and Weight-loss in the Management of

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Cardiovascular Disease Risk in Overweight Hyperinsulinaemic Women. Intl J Obes. 2006; 30:1535-44.

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43. Browning LM, Krebs JD, Moore CS, Mishra GD, O’Connell MA, Jebb SA. The Impact of

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Long Chain n-3 Polyunsaturated Fatty Acid Supplementation on Inflammation, Insulin Sensitivity, and CVD Risk in a Group of Overweight Women with an Inflammatory Phenotype. Diabetes Obes Metab. 2007; 9:70-80. 44. Griffin MD, Sanders TAB, Davies IG, Morgan LM, Millward DJ, Lewis F, Slaughter S, Cooper JA, Miller GJ, Griffin BA. Effects of Altering the Ratio of Dietary n-6 to n-3 Fatty Acids on Insulin Sensitivity, Lipoprotein Size, and Postprandial Lipemia in Men and Postmenopausal Women Aged 45-70 y: The OPTILIP Study. Am J Clin Nutr. 2006; 84:1290-8. 45. Derosa G, Cicero AFG, Fogari E, D’Angelo A, Bonaventura A, Romano D, Maffioli P. Effects of n- PUFAs on Postprandial Variation of Metalloproteinases, and Inflammatory and Insulin

ACCEPTED MANUSCRIPT Resistance Parameters in Dyslipidemic Patients: Evaluation with Euglycemic Clamp and Oral Fat Load. J Clin Lipidol. 2012; 6:553-64.

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46. Kabir M, Skurnik G, Naour N, Pechtner V, Meugnier E, Rome S, Quignard-Boulangé A,

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Vidal H, Slama G, Clément K, Guerre-Millo M, Rizkalla SW. Treatment for 2 Months with n-3 Polyunsaturated Fatty Acids Reduces Adiposity and Some Atherogenic Factors but Does Not

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Improve Insulin Sensitivity in Women with Type 2 Diabetes: A Randomized Controlled Study.

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Am J Clin Nutr. 2007; 86:1670-9.

47. Levy JC, Matthews DR, Hermans MP. Correct Homeostasis Model Assessment (HOMA)

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Evaluation Uses the Computer Program [letter]. Diabetes Care. 1998; 21:2191-2.

n

BMI (mean )

Weight Change

Results

Healthy adults

80

27.4

None

Low GI: 27% lower postprandial insulin, p<0.01

20

Men with 1+ CVD risk factors

17

29.3

+0.46kg high fat, 0.27kg low GI, +0.84kg high sucrose, +0.43kg high GI

High GI: increased HOMA (+31%, vs -20 to -60% for other diets, p<0.001)

21

Healthy men

8

N.R.

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Corn syrup: associated with higher integrated insulin compared with sucrose (56 vs 38 µUnits/mL, p<0.05)

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Overwei ght and obese adults

15 7

31.8

No difference in HOMA between groups

23

Healthy men

7

N.R. (range 20.225.4)

High fructose: decreased suppression of hepatic glucose production, not reversed by PUFA (28% vs control 44%, p<0.05)

24

Healthy men

14

26.6

None

No differences in glucose uptake or production

25

Overwei ght and obese adults

27

low CHO: 34.5, low fat:

low CHO: -7.4 kg low fat: -6.5 kg

No differences in change in glucose infusion rate or postprandial insulin

26

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Portion control: 3.7kg, low GI: -3.3 kg, low energy density: -4.1kg None

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low CHO: 37.1 low fat: 35.9

low CHO: -6.8 kg low fat: -5.1 kg

Overwei ght and obese adults with NGT or IFG Healthy men

69

NGT: 31.7 IFG: 33.7

-1.64 kg

HOMA2-IS increased vs baseline (61.1% vs 72.8%, p=0.03) Low CHO: HOMA-IR -0.90 +/- 1.45 Low fat: HOMA-IR -0.43 +/0.92 change in HOMA-IR between groups NS after adjustment for weight loss. NGT: 55% CHO increased SI following liquid mixed meal compared with 43%CHO, p<0.05

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28

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Eucaloric, 9 N.R., 80g/d 80g/d fructose: decreased 30 supplement range fructose: -1.8 suppression of hepatic ed with 4020-24 kg compared glucose production during 80g/d with 80g/d euglycemic clamp fructose, 80 glucose compared with 80g/d g/d glucose (59.4% vs. 70.3% glucose, or hepatic suppression, 80 g/d p<0.05) sucrose in beverages (3 wk, crossover) Table 1. Summary of studies testing diets high in carbohydrates. Abbreviations: GI, glycemic index; CVD, cardiovascular disease; PUFA, polyunsaturated fatty acid; CHO, carbohydrate; PCOS, polycystic ovarian syndrome; N.R., not reported; NS, not significant; HOMA, homeostatic model assessment (HOMA-IR=(glucose x insulin)/22.5); HOMA2-IS homeostatic model assessment, 2nd generation (nonlinear computer based model of insulin sensitivity) [46]; NGT, normal glucose tolerance; IFG, impaired fasting glucose; SI, insulin sensitivity index. a

This study utilized a crossover design in which subjects were given an isocaloric diet, with or without a 6 day regimen of fructose supplementation, and with or without a 28 day regimen of PUFA supplementation.

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Weight Chang e

Results

Healthy postmenopau sal women

1 0

25

N.R.

SFA: lower Si (1.38 vs. 1.872.13 for other diets)

Healthy adults

3 1

23.5

None

Normal weight and obese women

1 0

control: 23.0 obese: 45.0

Healthy men

8

22.4

N.R.

Healthy men

7

31.8

Healthy men

6

NGT or IGT

1

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32

N.R.

Butter: Si decreased in lean subjects, butter 0.6 mL/min per kg per pmol/L vs water 2.26 mL/min per kg per pmol/L, p<0.05 No differences in glucose disposal

33

None

SFA: glucose infusion/plasma insulin ratio smaller than all other conditions tested

35

NR (range 21-26)

N.R.

High fat diet: decreased suppression of hepatic glucose production (74% vs 91%, p<0.05)

36

SFA:

None

SFA: Si decreased 10.3%,

37

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31

SFA: overweight subset had decreased Si by 24% vs MUFA, NS

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34

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Subjects

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Study calories, diet compositio n, and (duration) Isocaloric; 50% SFA vs 74% n6PUFA vs 22% n3PUFA vs 72% MUFA (2 meals) Isocaloric; 9% MUFA vs 9% SFA vs 9% TFA (4 wk, crossover) 100g butter vs 100g water (2 test loads)

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17% SFA vs adults 6 26.6 p=0.032 23% MUFA 2 MUFA: (3 mos) 26.3 Isocaloric; Obese adults 1 33.5 None SFA: increased postprandial 38 20% SFA vs with T2DM 6 insulin (19.5 nmol/L per 240 20% MUFA min vs MUFA 10.9 nmol/L per vs 20% TFA 240 min, p<0.05) (6 wks, crossover) Hypercaloric; Healthy men 2 Control: None High fat overfeeding: 39 60% total 6 23.4 increased hepatic glucose calories from Hypercal production vs control (p<0.05) fata vs oric: isocaloric 23.3 control (5 days, crossover) Eucaloric Healthy men 5 22.4 NS 30% SFA: no significant 40 control vs 5 change in hepatic glucose hypercaloric production with 1.5, 3.0, 3.0 and 4.0 g/kg/d fructose: or 4.0g/kg/d decreased hepatic insulin fructose, sensitivity index (80.0% and 3.0g/kg/d 80.6% of control, p<0.01 vs. glucose, or control) 30% SFA (1 wk) Table 2. Summary of studies testing diets high in saturated fatty acids. Abbreviations: SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acid; CHO, carbohydrate; TFA, trans fatty acids; NGT, normal glucose tolerance; IGT, impaired glucose tolerance; T2DM, type 2 diabetes; N.R., not reported; NS, not significant; Si, insulin sensitivity; HOMA, homeostatic model assessment (HOMA-IR=(glucose x insulin)/22.5) Calories from fat were divided evenly between SFA, PUFA, and MUFA.

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Study Subjects n BMI Weight Results Refere calories, (mean) Change nce diet compositi on, and (duration) Hypocaloric women 1 35 PUFA:-10.2 Decreased AUC insulin for 42 (800-900 with 1 kg, both PUFA (32,909 pmol/120 kcal/d), + baseline 6 Placebo oil: min), placebo oil (36,390 5g PUFA insulin >70 -11.3 kg, pmol/120 min) compared to vs placebo pmol/L control diet: control (53,460 pmol/120 vs control +0.3 kg min) diet (24 wks) No diet Women 1 32.8 N.R. PUFA: lower AUC insulin in 43 modificatio with 5 subjects with high sialic acid n, elevated levels (30,747 pmol/L per 120 supplement baseline min) compared to placebo ed with 5g sialic acid (37,081 pmol/L per 120 min), PUFA vs p<0.05 placebo (12 wk, crossover) Isocaloric; Healthy 2 26 +0.8 kg No significant differences in 44 N6:n3 adults 5 HOMA, RQUICKI PUFA 5:1 8 vs 10:1 (6 mos) Hypocaloric Dyslipidemi 1 control: Control: PUFA: increased M (+1.89 45 ; (600kcal c adults 5 27.2 2.2kg μmol/min/kg) compared to deficit) +37 PUFA: PUFA: baseline, NS vs placebo PUFA 3g/d 26.0 1.6kg vs placebo (6 mos) Isocaloric; Postmenop 2 30 None No change in HOMA (80.6% 46 55% carb, ausal 7 PUFA vs 70.6% paraffin, NS) 15% prot, women 30% fat + with T2DM 3g/d fish oil or paraffin oil (2 mos) Table 3. Summary of studies testing diets high in polyunsaturated fatty acids. Abbreviations: PUFA, polyunsaturated fatty acid; T2DM, type 2 diabetes; N.R., not reported; NS, not significant; Si, insulin sensitivity; AUC, area under the curve; HOMA, homeostatic model assessment (HOMA-IR=(glucose x insulin)/22.5); RQUICKI, revised quantitative insulin sensitivity check index (RQUICKI= 1/[log insulin + log glucose + log nonesterified fatty acid].