Month: January 2015

The Saturated Fat Studies: Set Up To Fail

Nutritional Facts

· January 7th 2015 ·

The Saturated Fat Studies: Set Up to Fail

How might Big Butter design a study (like the Siri-Tarino and Chowdhury meta-analyses) to undermine global consensus guidelines to reduce saturated fat intake?

Doctor’s Note

Dairy industry campaign to “neutralize the negative image of milkfat”? If you missed my last video, check it out here: The Saturated Fat Studies: Buttering Up the Public.

If that “Doubt is our product” memo sounded familiar, I also featured it in my recent Food Industry Funded Research Bias video. More on how industries can design deceptive studies in BOLD Indeed: Beef Lowers Cholesterol?and How the Egg Board Designs Misleading Studies.

And last but not least, this is the first NutritionFacts.org video featuring the work of professional illustrator Sara Marchetto, who has so kindly offered to donate her talents to forward our mission. I hope you’ll see more of her soon!

If you haven’t yet, you can subscribe to my videos for free by clicking here.

Comment Etiquette

 

Relationship of dietary fat to glucose

Atherosclerosis. 2000 Jun;150(2):227-43.

Relationship of dietary fat to glucose metabolism.

Lichtenstein AH1, Schwab US.

Author information

Abstract

The relationship between dietary fat and glucose metabolism has been recognized for at least 60 years. In experimental animals, high fat diets result in impaired glucose tolerance. This impairment is associated with decreased basal and insulin-stimulated glucose metabolism. Impaired insulin binding and/or glucose transporters has been related to changes in the fatty acid composition of the membrane induced by dietary fat modification. In humans, high-fat diets, independent of fatty acid profile, have been reported to result in decreased insulin sensitivity. Saturated fat, relative to monounsaturated and polyunsaturated fat, appears to be more deleterious with respect to fat-induced insulin insensitivity. Some of the adverse effects induced by fat feeding can be ameliorated with omega-3 fatty acid. Epidemiological data in humans suggest that subjects with higher intakes of fat are more prone to develop disturbances in glucose metabolism, type 2 diabetes or impaired glucose tolerance, than subjects with lower intakes of fat. Inconsistencies in the data may be attributable to clustering of high intakes of dietary fat (especially animal fat) with obesity and inactivity. Metabolic studies suggest that higher-fat diets containing a higher proportion of unsaturated fat result in better measures of glucose metabolism than high-carbohydrate diet. Clearly, the area of dietary fat and glucose metabolism has yet to be fully elucidated.

PMID:
10856515
[PubMed – indexed for MEDLINE]

Obesity and Free Fatty Acids (FFA)

Logo of nihpa

About Author manuscripts Submit a manuscript NIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Endocrinol Metab Clin North Am. Author manuscript; available in PMC Sep 1, 2009.
Published in final edited form as:
PMCID: PMC2596919
NIHMSID: NIHMS71140

Obesity and Free Fatty Acids (FFA)

Guenther Boden, M.D.
Author information ► Article notes ► Copyright and License information ►
The publisher’s final edited version of this article is available at Endocrinol Metab Clin North Am
See other articles in PMC that cite the published article.
Go to:

INTRODUCTION

Obesity is closely associated with (peripheral as well as hepatic) insulin resistance (1) and with a low grade state of inflammation characterized by elevation of proinflammatory cytokines in blood and tissues (2). Both, insulin and inflammation, contribute to the development of type 2 diabetes (T2DM), hypertension, atherogenic dyslipidemias and disorders of blood coagulation and fibrinolysis. All these disorders are independent risk factors for atherosclerotic vascular disease (ASVD) such as heart attacks, strokes and peripheral arterial disease (3).

The reason why obesity is associated with insulin resistance is not well understood. In this chapter, I will review evidence demonstrating that free fatty acids (FFA) cause both insulin resistance and inflammation in the major insulin target tissues (skeletal muscle, liver and endothelial cells) and thus are an important link between obesity, insulin resistance, inflammation and the development of T2DM, hypertension, dyslipidemia, disorders of coagulation and ASVD (Figure 1).

Figure 1

Relationship between obesity, insulin resistance, inflammation and atherosclerotic vascular disease

The central nervous system effects of FFA, including the demonstration that infusion of oleic acid into the third ventricle of rats reduced food intake and hepatic glucose production, are reviewed separately (see Chapter 4).

Go to:

FFA AND INSULIN RESISTANCE

The recognition that adipose tissue not only stores and releases fatty acids but also synthesizes and releases a large number of other active compounds (4) has provided a conceptional framework which helps to understand how obesity can result in the development of insulin resistance. According to this concept, an expanding fat mass releases increasing amounts of compounds such as FFA, angiotensin 2, resistin, TNF-α, interleukin 6, interleukin 1-β and others. Some of these compounds, when infused in large amounts, can produce insulin resistance. However, any substance, in order to qualify as a physiological link between obesity and insulin resistance, should meet at least the following 3 criteria: 1) the substance should be elevated in the blood of obese people; 2) raising it’s blood level (within physiologic limits) should increase insulin resistance and 3) lowering it’s blood level should decrease insulin resistance. So far, only FFA can meet these 3 criteria in human subjects. Plasma FFA levels are elevated in most obese individuals (5); raising plasma FFA levels increases insulin resistance (6) and lowering of FFA improves insulin resistance (7).

FFA levels are elevated in obesity

Plasma FFA levels are usually elevated in obesity because 1) the enlarged adipose tissue mass releases more FFA and 2) FFA clearance may be reduced (8). Moreover, once plasma FFA levels are elevated, they will inhibit insulin’s anti-lipolytic action, which will further increase the rate of FFA release into the circulation (9).

Raising FFA increases insulin resistance

In skeletal muscle, acutely raising plasma FFA, for instance by infusing heparinized lipid emulsions, reduces insulin stimulated glucose uptake (more than 80% of which occurs in skeletal muscle) dose-dependently in all individuals irrespective of gender and age (6,10). Under these conditions, the insulin resistance develops within 2–4 h after plasma FFA levels increase and disappears within 4 h after normalization of FFA levels (11).

In the liver, FFA induced hepatic insulin resistance is more difficult to demonstrate because the liver is more insulin sensitive than skeletal muscle (12). Nevertheless, there is convincing evidence that physiological elevations of FFA, such as seen after a fat rich meal, inhibit insulin suppression of hepatic glucose production (HGP) resulting in an increase in HGP (1). Acutely (1–4 h), this rise in HGP is due to FFA mediated inhibition of insulin suppression of glycogenolysis (13). Longer lasting elevations of FFA, however, are likely to also increase gluconeogenesis.

In endothelial cells, IV infusion of insulin has been shown to increase nitric oxide production resulting in increased peripheral vascular blood flow (14,15). Physiological elevations of plasma FFA produce insulin resistance in endothelial cells by inhibiting the insulin induced increase in nitric oxide and blood flow (16).

Lowering FFA reduces insulin resistance

Chronically elevated plasma FFA levels, as commonly seen in obese diabetic and non-diabetic individuals, also cause insulin resistance. This could be demonstrated by normalizing elevated plasma FFA levels for only 12 h which resulted in normalization of insulin stimulated glucose uptake in obese non-diabetic individuals while improving insulin sensitivity from ~ ¼ to ~ ½ of normal in obese patients with T2DM (7). This suggested that high plasma FFA levels may have been the sole cause for insulin resistance in obese non-diabetic subjects but were responsible for only ~ 1/2 of the insulin resistance in obese patients with T2DM (7). Similar results have been reported in non-diabetic subjects genetically predisposed to T2DM (17).

Mechanisms of FFA Mediated Insulin Resistance

FFA have been shown to produce a defect in insulin stimulated glucose transport and/or phosphorylation which is caused by a defect in insulin signaling (10,18). Plasma FFA can easily enter cells where they are either oxidized to generate energy in the form of ATP or re-esterified for storage as triglycerides (TG). Not surprisingly, therefore, raising blood FFA levels result in intracellular (intramyocellular or intrahepatocellular) accumulation of triglycerides (19). For reasons that are not well understood, raising plasma FFA levels also results in accumulation of several metabolites involved in FFA re-esterification including longchain acyl-CoA and diacylglycerol (DAG) (20). DAG is a potent activator of conventional and novel protein kinase C isoforms (21). In addition to PKC, several other serine/threonine kinases including IKK-β and c-Jun NH2-terminal kinase (JNK) can also be activated by acutely raising plasma FFA levels (22,23). Exactly, how these kinases are activated by FFA is not clear but may include FFA mediated generation of reactive oxygen species (ROS) (24), activation of the Toll like receptor 4 (TLR4) pathway (25) or endoplasmic reticulum stress (23). Once activated, one or several of these serine/threonine kinases can interrupt insulin signaling by decreasing tyrosine phosphorylation of the insulin receptor substrate 1 or 2 (IRS 1/2) (26). This will inhibit the activity of the IRS/PI3 kinase/Akt pathway which controls most of insulin’s metabolic actions including glucose uptake, glycogen synthesis, glycogenolysis and lipolysis (27). The IRS/PI3 kinase/Akt pathway is also important for the activation of endothelial nitric oxide synthase (NOS) and the production of nitric oxide (NO). In addition, FFA can reduce NO production through a second mechanism, namely, by stimulation of NAD(P)H oxidase. This has been shown to occur in a PKC dependent manner, and will lead to increased production of reactive oxygen species (ROS) and a decrease in NO (24) (Figure 2).

Figure 2

Potential mechanisms of FFA-induced insulin resistance and inflammation

FFA may also interfere with insulin stimulation of glucose transport by modulating glucose transporter (Glut) gene transcription and mRNA stability (28,29)

Go to:

FFA AND INFLAMMATION

Obesity is associated with elevated levels of proinflammatory cytokines and chemokines in the circulation and in tissues (2). As mentioned, the adipose tissue produces and releases a large number of cytokines and chemokines (collectively called adipokines) (4), some of which are proinflammatory. Recent studies have shed some light on the reasons for the increased release of proinflammatory cytokines in obesity. In one study, mice fed a high fat diet for 3 months developed low grade hepatic inflammation which was associated with increased production and secretion of several proinflammatory cytokines (30). This suggested that the inflammatory state was caused either by a component of the diet or by a substance released from the enlarged adipose tissue. FFA are good candidates for both possibilities because they are elevated in most obese individuals both during a fat meal (31) and under basal and postprandial conditions (5).

The recent demonstration that acute elevation of plasma FFA, in addition to producing peripheral and hepatic insulin resistance, also activated the proinflammatory NFκB pathway (20) resulting in increased hepatic expression of several proinflammatory cytokines including TNF-α, IL1-β, IL6 and an increase in circulating MCP-1 (22), supported the notion that FFA is a primary link between obesity or high fat feeding and the development of inflammatory changes (Figure 2). In this context, the increase in circulating MCP-1 in response to an acute rise in plasma FFA is particularly interesting because MCP-1 is well established to regulate macrophage recruitment to sites of inflammation (32). The rise in plasma MCP-1 levels, therefore, may explain the recent observation of macrophage infiltration into the adipose tissue of obese animals (33).

The early events leading from a rise in circulating FFA to activation of the NFκB pathway are not clear but include several possibilities. First, as discussed, an increase in plasma FFA results in intramyocellular accumulation of DAG and activation of several PKC isoforms (20,22). Gao et al. have recently shown that the FFA mediated activation of IKK (a kinase involved in the activation of NFκB) in fat cell was PKC dependent (34). Thus, DAG mediated PKC activation may be an upstream effector of NFκB activation. Second, some recent evidence suggests that FFA mediated activation of IKK and NFκB may be, at least partially, mediated by the Toll like receptor-4 (TLR-4) (25). The TLR-4 pathway, which is essential for the development of innate immunity to pathogens, triggers production of inflammatory cytokines (35). Thus, it appears that sensing of excess nutrients such as FFA and sensing of infectious pathogens, may use the same signaling pathway and result in the same downstream effects, i.e., inflammation. Third, obesity and FFA have been shown to induce endoplasmic reticulum stress which can result in activation of IKK, JNK and inflammatory responses (36) and lastly, several G protein coupled receptors, including GRP-40 and GRP-120 have been shown to bind FFA (37,38). There is as yet, however, no evidence that these receptors are involved in any of the FFA activities discussed here.

Go to:

FFA AND THE METABOLIC SYNDROME

The increase in the metabolic syndrome (also called the insulin resistance syndrome) is mainly driven by the worldwide increase in obesity. Not surprisingly, therefore, obesity associated and fatty acid mediated insulin resistance is intimately connected with all major components of this syndrome, i.e., T2DM, hypertension and atherogenic dyslipidemia as well as other components that have not yet been formally included in the metabolic syndrome complex such as disorders of blood coagulation and fibrinolysis.

Type 2 diabetes (T2DM)

FFA mediated insulin resistance will result in the development of T2DM unless the insulin resistance is compensated by oversecretion of insulin. There is increasing evidence that FFA stimulate insulin secretion, acutely and chronically, and that FFA induced insulin resistance is compensated by FFA mediated oversecretion of insulin in obese but otherwise healthy individuals (39). However, in pre-diabetic individuals (subjects with inherited predisposition to develop T2DM including first degree relatives of patients with T2DM) this compensation fails and the consequence of FFA induced insulin resistance will be T2DM (17,39). This explains why only ~ 50% of all obese, insulin resistant individuals, namely those who are unable to compensate, will d1evelop T2DM during their lifetime (40).

Hypertension

FFA induced insulin resistance also reduces endothelial production of nitric oxide through PKC dependent activation of NAD(P)H oxidase, resulting in increased production of ROS (see page 5 and ref. 24). Nitric oxide deficiency decreases vasodilatation and promotes the development of hypertension.

Atherogenic Dyslipidemia

Obesity and insulin resistance are associated with increased production of VLDL-TG. A major factor for this is believed to be the increased flux of FFA to the liver in combination with insulin resistance associated hyperinsulinemia. The precise mechanism of this insulin resistance driven hepatic VLDL overproduction remains, however, uncertain (41).

Disorders of coagulation and fibrinolysis

Hyperinsulinemia, the hallmark of insulin resistance, is now recognized to create a procoagulant state in diabetic and non-diabetic individuals by increasing circulatory levels of tissue factor procoagulant activity, increased generation of thrombin, elevated plasma levels of coagulation factors VII and VIII and activation of platelets (42,43).

Obesity, insulin resistance and T2DM are also associated with impaired fibrinolysis (44). Plasma concentrations of plasminogen activator inhibitor 1 (PAI-1), which is the primary inhibitor of fibrinolysis, are increased in obese insulin resistant individuals and in patients with T2DM (45,46). PAI-1 downregulates fibrinolysis by inhibiting the production of plasmin and thus promotes thrombosis. PAI-1 is synthesized in endothelial cells and hepatocytes and is present in platelets and in plasma (Reviewed in ref.47). In vitro, PAI-1 secretion is stimulated by insulin in human adipocytes and by FFAs in hepatocytes. Hence, elevated plasma FFA levels, via producing insulin resistance and hyperinsulinemia (with or without hyperglycemia), promote a state of increased tendency for thrombosis (see above) and decreased ability to lyse blood clots. Together, this increases the risk for acute vascular events.

FFA and matrix metalloproteinases

Smoking, together with the established, insulin resistance related risk factors for ASVD such as T2DM, hypertension, atherogenic dyslipidemia and disorders of blood coagulation and fibrinolysis probably cannot completely explain the obesity/insulin resistance related ASVD risk (48). This suggests that there may be other ways by which insulin resistance can increase this risk. Indeed, one such risk factor may be increased activity of several matrix metalloproteinases (MMPs). MMPs are enzymes with proteolytic activities against connective tissue proteins such as collagen, proteoglycans and elastin. They control degradation and remodeling of extracellular matrix. There is accumulating evidence that MMP-2, MMP-9 and MT-MMP play important roles in the development and progression of heart attacks, strokes, peripheral arterial disease and aortic aneurysms (49–52). We have recently found that acutely increasing plasma levels of FFA, particularly when combined with hyperinsulinemia, strongly increased the activities of MMP-2, MMP-9 and MT-MMP in rat aorta (53). As mentioned, FFA also promote the release of proinflammatory cytokines which are known to be potent stimulators of MMP synthesis and release (49). Thus, the combination of increased MMP activity and inflammatory cytokines may lead to progression of atherosclerotic lesions and contribute to the increased risk for cardiovascular disease in obese insulin resistant individuals.

Go to:

FFA AS TARGET FOR THERAPY

Because insulin resistance is at the core of several serious health problems associated with obesity, insulin resistance should be a major focus of therapy. Whereas weight loss through diet and exercise is clearly the most desirable way to reduce insulin resistance in obese people, neither diet and exercise programs nor presently available pharmacological approaches have been very successful. As pointed out above, elevated plasma FFA levels are responsible for much of the insulin resistance in obese individuals. Therefore, normalizing plasma FFA levels can be expected to improve insulin sensitivity. In support, we have shown that normalization of plasma FFA levels overnight with Acipimox, a nicotinic analog, normalized insulin resistance in obese, non-diabetic subjects and improved insulin resistance in obese patients with T2DM (7). Nicotinic acid or longacting nicotinic acid analogs effectively lower plasma FFA levels. Unfortunately, their use is associated with a rebound of plasma FFA to very high levels (54), which makes this class of drugs unsuitable for the longterm control of plasma FFA. Thiazolidinediones (TZD) lower plasma FFA levels longterm and without rebound. They do this primarily by stimulating fat oxidation through a coordinated induction of genes in adipose tissue related to FFA uptake, binding, β-oxidation and oxidative phosphorylation (55). However, TZD mediated lowering of plasma FFA levels is modest, ranging from < 10% to approximately 20% in most studies (56,57). Moreover, this class of drug has several unwanted effects which limits their use (58). Fibrates, another class of lipid lowering drugs also lower plasma FFA levels modestly and without rebound primarily by stimulating fat oxidation in the liver (59). As both classes of drugs work in different organs (TZDs in fat and fibrates in the liver) and through different mechanisms (TZDs through activation of PPAR-γ and fibrates through activation of PPAR-α), their use in combination produces greater decreases in plasma FFA levels as well as greater improvements in insulin sensitivity than the use of either drug alone (60).

Lowering of plasma FFA, in addition to improving insulin sensitivity, may also prevent activation of the proinflammatory and proatherogenic NFκB pathway and thus may reduce the incidence of atherosclerotic vascular problems. Thus, the challenges for the future include the prevention or correction of obesity and elevated plasma FFA levels through methods that include decreased caloric intake and increased caloric expenditure, development of easy, fast and reliable methods to measure FFA in small blood samples (comparable to portable blood sugar monitoring devices) and development of efficient pharmacological approaches to normalize increased plasma FFA levels.

Go to:

SYNOPSIS

Plasma FFA levels are elevated in obesity. FFA cause insulin resistance in all major insulin target organs (skeletal muscle, liver, endothelial cells) and have emerged as a major link between obesity, the development of the metabolic syndrome and atherosclerotic vascular disease. Mechanisms through which FFA induce insulin resistance involve intramyocellular and intrahepatic accumulation of diacylglycerol and triglycerides, activation of several serine/threonine kinases, reduction of tyrosine phosphorylation of the insulin receptor substrate 1/2 (IRS 1/2) and impairment of the IRS/phosphatidylinositol 3 kinase pathway of insulin signaling. FFA also produce low grade inflammation in skeletal muscle, liver and fat through activation of the nuclear factor-κB and the c-Jun NH2 terminal kinase (JNK) pathways, resulting in release of proinflammatory and proatherogenic cytokines. In addition, FFA contribute to cardiovascular events by promoting a prothrombotic state by reducing fibrinolysis and by activating platelets and arterial matrix metalloproteinases (Figure 3).

Figure 3

Summary of relation between obesity, FFA and ASVD
Go to:

ACKNOWLEDGEMENTS

We thank Maria Mozzoli, BS and Karen Kresge, BS for technical assistance and Constance Harris Crews for typing the manuscript.

This work was supported by National Institutes of Health grants RO1-DK-68895, RO1-HL-733267 and RO1-DK-066003.

Go to:

Footnotes

Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Go to:

REFERENCES

1. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997;46:3–10. [PubMed]
2. Tataranni PA, Ortega E. A Burning Question. Does an adipokines-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes? Diabetes. 2005;54:917–927. [PubMed]
3. Bray GA. Medical consequences of obesity. J Clin Endocrinol Metab. 2004;89:2583–2589. [PubMed]
4. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548–2556. [PubMed]
5. Reaven GM, Hollenbeck C, Jeng C-Y, et al. Measurement of plasma glucose, free fatty acid, lactate and insulin for 24 h in patients with NIDDM. Diabetes. 1988;37:1020–1024. [PubMed]
6. Boden G, Chen X, Ruiz J, et al. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest. 1994;93:2438–2446. [PMC free article] [PubMed]
7. Santomauro ATMG, Boden G, Silva M, et al. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes.1999;48:1836–1841. [PubMed]
8. Bjorntorp P, Bergman H, Varnauskas E. Plasma free fatty acid turnover in obesity. Acta Med Scand.1969;185:351–356. [PubMed]
9. Jensen MD, Haymond MW, Rizza RA, et al. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest. 1989;83:1168–1173. [PMC free article] [PubMed]
10. Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest. 1995;96:1261–1268. [PMC free article] [PubMed]
11. Boden G, Jadali F, White J, et al. Effects of fat on insulin stimulated carbohydrate metabolism in normal men. J Clin Invest. 1991;88:960–966. [PMC free article] [PubMed]
12. Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981;240:E630–E639. [PubMed]
13. Boden G, Cheung P, Stein TP, et al. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol. 2002;283:E12–E19. [PubMed]
14. Baron AD. Insulin resistance and vascular function. J Diabetes Complications. 2002;16:92–102.[PubMed]
15. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles for insulin receptor, PI3-kinase and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells.Circulation. 2000;101:L1539–L1545. [PubMed]
16. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–1239. [PMC free article] [PubMed]
17. Cusi K, Kashyap S, Gastaldelli A, et al. Effect on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E1775–E1781. [PubMed]
18. 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;103:253–259. [PMC free article][PubMed]
19. Boden G, Lebed B, Schatz M, et al. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001;50:1612–1617.[PubMed]
20. Itani SI, Ruderman NB, Schmieder , et al. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α Diabetes. 2002;51:2005–2011.[PubMed]
21. Farese R. In: Diabetes Mellitus: a Fundamental and Clinical Text. LeRoith D, Taylor SI, Olefsky JM, editors. Philadelphia: Lippincott; 2000. pp. 239–251.
22. Boden G, She P, Mozzoli M, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes. 2005;54:3458–3465. [PubMed]
23. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes. 2005;54:S73–S78. [PubMed]
24. Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49:1939–1945. [PubMed]
25. Shi A, Kokoeva V, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–3025. [PMC free article] [PubMed]
26. Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem.2002;277:50230–50236. [PubMed]
27. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature.2001;414:799–806. [PubMed]
28. Long SD, Pekala PH. Regulation of Glut4 gene expression by arachidonic acid. Evidence for multiple pathways, one of which requires oxidation to prostaglandin. E J Biol Chem. 1996;271:1138–1144.[PubMed]
29. Armoni M, Harel C, Bar-Yoseph F, et al. Free fatty acids repress the Glut4 gene expression in cardiac muscle via novel response elements. J Biol Chem. 205;280:34786–34795l. [PubMed]
30. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–1830. [PMC free article] [PubMed]
31. van Oostrom AJ, van Dijk H, Verseyden C, et al. Addition of glucose to an oral fat load reduces postprandial free fatty acids and prevents the postprandial increase in complement component 31–3. Am J Clin Nutr. 2004;79:5–10. [PubMed]
32. Rollins BJ, Walz A, Baggiolini M. Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood. 1991;78:1112–1116. [PubMed]
33. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808. [PMC free article] [PubMed]
34. Gao Z, Zhang X, Zuberi A, et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Molecular Endocrinology. 2004;18:2024–2034. [PubMed]
35. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–145. [PubMed]
36. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–461. [PubMed]
37. Hirasawa A, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR 120. Nat Med. 2005;1:90–94. [PubMed]
38. Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003;422:173–176. [PubMed]
39. Boden G. Free fatty acids and insulin secretion in humans. Current Diabetes Reports. 2005;5:167–270.[PubMed]
40. Benjamin SM, Valdez R, Geiss LS, et al. Estimated number of adults with prediabetes in the US in 2000: opportunities for prevention. Diabetes Care. 2003;26:645–649. [PubMed]
41. Bamba V, Rader DJ. Obesity and atherogenic dyslipidemia. Gastroenterology. 2007;132:2181–2190.[PubMed]
42. Boden G, Rao AK. Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood coagulation. Current Diabetes Reports. 2007;7:223–227. [PubMed]
43. Boden G, Vaidyula VR, Homko C, et al. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: Effects of insulin and glucose. J Clin Endocrinol Metab.2007;92 0000-0000, in press. [PubMed]
44. Vague P, Juhan-Vague I, Aillaud MF, et al. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism. 1986;35:250–253. [PubMed]
45. Pannacciulli N, De Mitrio R, Giorgino R, et al. Effect of glucose tolerance status on PAI-1 plasma levels in overweight and obese subjects. Obes Res. 2002;10:717–725. [PubMed]
46. Festa A, D’Agostino R, Jr, Tracy RP, et al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes. 2002;51:1131–1137. [PubMed]
47. Sobel BE, Schneider DJ. Platelet function, coagulopathy, and impaired fibrinolysis in diabetes. Cardiol Clin. 2004;22:511–526. [PubMed]
48. Hennekens CH. Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation. 1998;97:1095–1102. [PubMed]
49. Newby AC. Dual role of matrix metalloproteinases (Matrixins) in intimal thickening of atherosclerotic plaque rupture. Physiol Rev. 2005;85:1–31. [PubMed]
50. Galis ZS, Sukhova GK, Lark MW, et al. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493–2503. [PMC free article] [PubMed]
51. Pasterkamp G, Schoneveld AH, Hijnen DJ, et al. Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteinases 1, 2 and 9 in the human coronary artery.Atherosclerosis. 2000;150:245–253. [PubMed]
52. Longo GM, Xiong W, Greiner TC, et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest. 2002;110:625–632. [PMC free article] [PubMed]
53. Boden G, Song W, Pashko L, Kresge K. In vivo effects of insulin and free fatty acids on matrix metalloproteinases in rat aorta. Diabetes. 2007 in press. [PubMed]
54. Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest. 1999;103:365–372. [PMC free article] [PubMed]
55. Boden G, Homko C, Mozzoli M, et al. Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients. Diabetes. 2005;54:880–885. [PubMed]
56. Ghazzi MN, Perez JE, Antonucci TK, et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM: the Troglitazone Study Group. Diabetes. 1997;46:433–439. [PubMed]
57. Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128:176–185. [PubMed]
58. Boden G, Zhang M. Recent findings concerning thiazolidinediones in the treatment of diabetes. Expert Opin Investig Drugs. 2006;15:243–250. [PubMed]
59. Staels B, Fruchart J-C. Therapuetic roles of peroxisome proliferator-activated receptor agonists.Diabetes. 2005;54:2460–2470. [PubMed]
60. Boden G, Homko C, Mozzoli M, et al. Combined use of rosiglitazone and fenofibrate in patients with type 2 diabetes. Prevention of fluid retention. Diabetes. 2007;56:248–255. [PubMed]

Do Vegetarians Get Enough Protein?

 

· June 6th 2014 ·

GD Star Rating
loading…

Nutritional quality indices show plant-based diets are the healthiest, but do vegetarians and vegans reach the recommended daily intake of protein?

View Transcript

Fusili with Roasted Vegetables

fuseli

1 large red onion, halved and then sliced
2 red bell peppers, seeded and cut into 1/2 inch strips
2 yellow bell peppers, seeded and cut into 1/2 inch strips
2 green or orange bell peppers, seeded and cut into 1/2 inch strips
4 fresh plum tomatoes, cut in thin wedges

3 cloves garlic, quartered

1 tbsp. chopped fresh thyme leaves
1/2 tsp. ground pepper
1 and 1/2 tbsp. olive oil (or more) or canola oil
10 oz. spiral pasta
1/4 cup packed fresh basil, finely shredded
1 tbsp. grated Parmesan
1/2 cup white wine
Oven 400 degrees.  In large roasting pan, combine onions, peppers, tomatoes, garlic, thyme, pepper and olive oil.  Roast in oven for 40 minutes, tossing vegetables after 20 minutes.  Cook pasta – drain – toss with vegetables, wine, basil and Parmesan.
Serves 4.

How Did Wheat Belly and Grain Brain get it wrong?

Harvard study finds

Republish Reprint

Sarah Knapton, The Telegraph | January 5, 2015 | Last Updated:Jan 5 7:01 PM ET
More from The Telegraph

The humble bowl of oatmeal: It may help keep heart disease at bay and lead to longer lives, a new Harvard study that tracked 100,000 people suggests.

Postmedia News filesThe humble bowl of oatmeal: It may help keep heart disease at bay and lead to longer lives, a new Harvard study that tracked 100,000 people suggests.

LONDON — A small bowl of porridge each day could be the key to a longer life span, after a major study by Harvard University found that whole grains reduce the risk of dying from heart disease.

Although whole grains are widely believed to be beneficial for health it is the first research to look at whether they have a long-term impact on life span.

Researchers followed more than 100,000 people for more than 14 years monitoring their diets and health outcomes. Everyone involved in the study was healthy in 1984 when they enrolled, but when they were followed up in 2010 more than 26,000 had died.

Those who ate the most whole grains, such as porridge, brown rice, corn and quinoa seemed protected from many illnesses and particularly heart disease.

Oats are already the breakfast of choice for many athletes and dieters, who find the high fibre levels give them energy for longer. But scientists found that for each ounce (28g) of whole grains eaten a day — the equivalent of a small bowl of porridge — the risk of death overall was reduced by five per cent and heart deaths by 9 per cent. “These findings further support current dietary guidelines that recommend increasing whole grain consumption,” said Dr. Hongyu Wu, the lead author, of Harvard School of Public Health.

“They also provide promising evidence that suggests a diet enriched with whole grains may confer benefits towards extended life expectancy.”

The findings remained even when allowing for different ages, smoking, body mass index and physical activity.
Whole grains, where the bran and germ remain, contain 25% more protein than refined grains, such as those that make white flour, pasta and white rice.

Previous studies have shown that whole grains can boost bone mineral density, lower blood pressure, promote healthy gut bacteria and reduce the risk of diabetes. One particular fibre found only in oats, called beta-glucan, is known to lower cholesterol which can help to protect against heart disease.

A bioactive compound called avenanthramide is also thought to stop fat forming in the arteries.

Whole grains are widely recommended in many dietary guidelines because they contain high levels of nutrients such as zinc, copper, manganese, iron and thiamine. They are also believed to boost levels of anti-oxidants.

The new research suggests that if more people switched to whole grains, thousands of lives could be saved each year. Coronary heart disease is Britain’s biggest killer, responsible for around 73,000 deaths in the U.K. each year. Around 2.3 million people are living with the condition and one in six men and one in 10 women will die from the disease.

The Secret’s Out: The Reason Red Meat is So Bad for Our Health

ONEGREENPLANETBUZZ MONSTER

We’ve known red meat isn’t the healthiest choice for a long time now. It’s a leading cause in heart disease, inflammation, cancer, and even digestive problems. While its highly touted by meat-lovers as being a good source of iron, (though we know there are better sources), the truth is, red meat is not a healthy food. But what is it about red meat that’s so bad?

Scientists at the University of California Found The Secret

Researchers at the University of California found that meat triggers a toxic reaction within the body that weakens the immune system due to a natural sugar it contains our bodies can’t digest. Yes, you heard that right – meat actually has a natural sugar, as small as it may be. Known as Neu5Gc, this sugar is a foreign agent to our body that is seen as an invader.

The body launches an immune response as it tries to get rid of it and in the mean time, a host of health problems occur, such as cancer (which is largely a disease of a weak immune system). The unique findings are that other carnivores can eat red meat fine because their bodies actually contain the natural sugar that digests the meat. Our bodies don’t – clearly a sign that we’re not meant to eat it.

Meat and Tumor Production

The sugar, Neu5Gc, is already in the body of other carnivores that consume meat for food. Mice (who don’t contain the sugar as we don’t) were fed meat and actually developed tumors quickly.

“This is the first time we have directly shown that mimicking the exact situation in humans increases spontaneous cancers in mice,” said Dr Ajit Varki, Professor of Medicine and Cellular and Molecular Medicine at the University of California. ”The final proof in humans will be much harder to come by.”

We don’t think we need more proof to go meat-free, do you? Meat has led to a host of negativeenvironmental and health factors for years. Harvard University found that a diet high in red meat raised the risk of breast cancer for women by 22 percent, and found those who regularly ate 5.6oz (160g) of red meat a day had one third higher risk of bowel cancer.

These studies provide more proof that meat really isn’t a healthy choice. If our bodies don’t see meat as a welcomed food, it’s time to stop eating it once and for all.

For tips to go meatless, check out: 13 Meatless Monday Meals for the Beginner Cook.

Lead Image Source: Rpavich/Flickr

More Milk, More Problems

October 30, 2014Health and Nutrition, ,

milk-fracture

Science Contradicts Milk Marketing

This week, another study has illustrated that milk actually has a negative effect on bone health. Researchers in Sweden published findings in the British Medical Journal showing that women who drink milk have a higher incidence of bone fractures—and an increased risk of mortality from heart disease and cancer.

According to the study, women who consume three or more glasses of milk per day have a 60 percent increased risk of developing a hip fracture and a 93 percent increased risk of death. And each glass of milk increases mortality risk by 15 percent.

However, this news should not come as a shock to anyone outside of the dairy industry’s advertising department. A 2005 review in Pediatrics showed that milk has no effect on preventing stress fractures in girls. In fact, the research linked higher milk consumption with higher fracture risk.

For strong, healthy bones, it’s important to have enough calcium and vitamin D. However, animal products tend to leech calcium from bones, yet plant foods do not have this effect. One cup of collards has 268 mg of calcium. Spinach has 245 mg in a single cup, while a cup of soybeans has 261 mg. When you take fortified orange juice and fortified tofu into account, it’s easy to obtain more than the daily calcium recommendation of 1,000 mg.

Regardless of what milk marketers would have you believe, vitamin D is not naturally occurring in dairy milk. Last week, we examined a recent Canadian study suggesting that children who consumed dairy milk had higher levels of vitamin D. After reviewing the research, we learned that the dairy milk was fortified—while the plant milks were not. Any fortified non-dairy beverage can provide the necessary nutrients, without the cholesterol and saturated fat found in milk.

The science is there: milk does a body bad. Let’s wipe off the milk mustaches and remove milk from the school lunch line. To learn how you can help get milk out of schools, visitwww.HealthySchoolLunches.org.

Last updated by at October 30, 2014.

Animal Protein as a Carcinogen

By October 29th, 2012 Cancer, Diseases16 Comments

Answer to a Reader’s Question:

Although there are many arguments favoring the nutritional imbalance explanation of cancer, one of the more striking for me was the experimental animal studies discussed in Chapter 3 in my book, The China Study. Namely, aflatoxin is a very potent carcinogen for the rat. However, after the Indian researchers showed that decreasing protein (casein) intake from the usual level of consumption of 20% to 5% completely prevented this very powerful carcinogen to cause cancer, we then began our work (references in our book). We explored that finding in great depth and eventually confirmed their initial observation. That is, simple adjustment of dietary protein (casein) within very normal ranges of protein intake controlled cancer growth and it worked not by one mechanism but by a large array of mechanisms. In other words, we proved this association beyond any doubt.

Further, over the years, this research required a lot of funding and our applications for funding were reviewed by other researchers highly experienced in this field. Every time we got high marks for the quality of the research. Then, when we submitted the results for publication, they were again reviewed by peers and these papers were published in the very best cancer research journals. Among the people who know the most about cancer, our work was entirely convincing.

Very simply, normal adjustment of protein intake was capable of enormously influencing the ability of a chemical carcinogen’s ability to promote cancer. Dietary protein trumped a very powerful carcinogen in a species that was exceptionally sensitive to this carcinogen.

Then we did much the same thing with a cancer caused by a virus, the hepatitis B virus.

If we follow the criteria of determining what is a carcinogen and what is not, these findings should shake up the entire world of cancer research and education because this is the way that other carcinogens (Alar, dioxin, DDT, etc.) also work–except the evidence favoring their carcinogenicity is far less than it is for aflatoxin!

But I was not comfortable taking the usual path of declaring that casein is a carcinogen that was far more powerful than aflatoxin (“the most potent carcinogen ever discovered” according to the people who favor the chemical carcinogen hypothesis). Instead, I was more interested in asking broader questions, involving the role of animal protein based foods in their association with human cancer, as well as to study the comparative associations of aflatoxin consumption and protein consumption in humans–this was the China Study.

I have given this story to many of the very best–and most critical audiences — that I can find (Harvard, Berkeley, Cornell, Emory, Yale, Duke, NIH, etc.) and I get no serious criticism. The only comment that seems to surface more than a few times is ‘I am taking on some very powerful interests and they won’t listen — regardless of the veracity of the evidence’, or words to that effect. In other words, this issue — first narrowly defined but later expanded into a much larger issue — is mostly about politics, economics, personal bias, etc., and not about rational science. Quite honestly, it depresses me because there is so much at stake for human health. Corporate America, who controls the agenda in this health research business, is more interested in their own health than they are in the health of the public!!

Related Posts:

ResearchWhat Does Research Indicate About Animal Protein and “Reproductive” Cancers? animal-v-plantAnimal vs. Plant Protein Dr. T. Colin Campbell's ProvocationsProvocations – Controversial Dairy Protein Questions Dr. T. Colin Campbell's ProvocationsProvocations – Casein is a Carcinogen. Really?

Author:

Dr. T. Colin Campbell has been at the forefront of nutrition research for over forty years. His legacy, the China Project, has been acknowledged as the most comprehensive study of health and nutrition ever conducted. Dr. Campbell is the Jacob Gould Schurman Professor Emeritus of Nutritional Biochemistry at Cornell University. Dr. Campbell also serves as the President of the Board for the T. Colin Campbell Center for Nutrition Studies and is featured faculty in our highly acclaimed, Plant-Based Certificate and our online heart course, Nutrition for a Healthy Heart.