The Randle Cycle (Glucose-Fatty Acid Cycle)

Also see:
Master List – Ray Peat, PhD Interviews
Ray Peat, PhD on Low Blood Sugar & Stress Reaction
Aldosterone, Sodium Deficiency, and Insulin Resistance
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Diabetes: Conversion of Alpha-cells into Beta-cells
Errors in Nutrition: Essential Fatty Acids
Women, Estrogen, and Circulating DHA
Insulin Inhibits Lipolysis
PUFA Breakdown Products Depress Mitochondrial Respiration
PUFA Decrease Cellular Energy Production
Free Fatty Acids Suppress Cellular Respiration
Commentary on Type 2 Diabetes
Soybean oil causes more obesity than coconut oil and fructose
The common oil that science now shows is worse than sugar
Consumption of Fatty Acids Linked to Type 2 Diabetes
The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner

Quotes by Ray Peat, PhD:
“The antagonism between fat and sugar that Randle described can involve the suppression of sugar oxidation when the concentration of fats in the bloodstream is increased by eating fatty food, or by releasing fats from the tissues by lipolysis, but it can also involve the suppression of fat oxidation by inhibiting the release of fatty acids from the tissues, when a sufficient amount of sugar is eaten.”

“The inhibition of fat oxidation, and supporting sugar oxidation, now seems to be appropriate for preventing or treating any age-related degenerative disease.”

“The protective effects of sugar, and the harmful effects of excessive fat metabolism, are now being widely recognized, in every field of physiology.”

“There is a growing recognition that a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure, and aging, indicates a bad prognosis, but there is no generally recognized explanation for the fact that free fatty acids are harmful. I want to mention some evidence showing that it is the accumulation of polyunsaturated fats in the body that makes them harmful.”

“Simply getting outside the world of compartmentalized diseases, there is an abundance of evidence showing the variety of ways in which cells can fail. Energy is needed for cell maintenance and adaptation, and the type of fuel used to provide the energy is crucial. Fatty acids interfere with the oxidation of glucose, and this effect can be seen in heart failure, immunodeficiency, dementia, as well as in simple stress, diabetes, and many other simple situations (dementia: Montine and Morrow, 2005; Yaqoob, et al., 1994).”

“When the tissues are saturated with those antithyroid fats [PUFA], metabolism slows, especially when any stress, such as cold or hunger, increases the concentration of free fatty acids in the blood stream.”

“The competition between fatty acids and glucose, which has been called the “Randle cycle” for about 50 years, can be applied to the treatment of diabetes and other degenerative/stress problems by adjusting the diet, or by using supplements such as niacinamide and aspirin, which improve glucose oxidation by lowering the free fatty acids in the serum.”

“In the Randle effect (it’s called the “Randle cycle,” but there is no cycle), increasing the amount of fat in the bloodstream decreases the ability of cells to metabolize glucose; glucose tolerance decreases, as in diabetes, except that the response to fat is instantaneous. Respiration decreases, mitochondria retain calcium, which tends to accumulate until it destroys the mitochondria. The calcium, when it is released from the mitochondria, causes excitation to increase. Stimulation without efficient energy production leads to proteolysis and apoptosis or other forms of cell death. Sugars replace carbon dioxide and acetate on lysines. This process is involved in diabetes, Alzheimer’s disease, arthritis, and other degenerative diseases, probably including osteoporosis. Mitochondrial damage tends to increase the production of lactic acid instead of carbon dioxide, and lactic acid can stimulate the inappropriate overgrowth of blood vessels, as occurs in the eyes in diabetes. During stress and aging, free fatty acids appear in the bloodstream in large quantities.”

“The effect of diabetes is to keep the respiratory quotient low, since a respiratory quotient of one corresponds to the oxidation of pure carbohydrate, and extreme diabetics oxidize fat in preference to carbohydrate, and may have a quotient just a little above 0.7. The results of Brown’s and Burr’s experiments could be interpreted to mean that the polyunsaturated fats not only lower the metabolic rate, but especially interfere with the metabolism of sugars. In other words, they suggest that the normal diet is diabetogenic.”

“Estrogen and stress cause increased levels of free fatty acids to circulate. The polyunsaturated fatty acids are immunosuppressive, antithyroid, diabetogenic, inhibit respiration, and promote the actions of estrogen and cortisol.”

“It’s the prolonged shock-like state that contributes to the degenerative diseases, which typically begin with a sort of diabetes, an inability to use glucose for energy because of the accumulation of too much of the wrong kind of fat.”

If diabetes means that cells can’t absorb or metabolize glucose, then any cellular function that requires glucose will be impaired, despite the presence of glucose in the blood. It is the intracellular absence of glucose which is problematic, rather than its extracellular excess.”

“On the organismic level, it explains why estrogen mimics “shock,” releasing histamine and activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn’t use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids, which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body’s ability to oxidize glucose.”

“In 1963, P.J. Randle clearly described the inhibition of glucose oxidation by free fatty acids. Later, when lipid emulsions came into use for intravenous feeding in hospitals, it was found that they blocked glucose oxidation, lowered the metabolic rate, suppressed immunity, and increased lipid peroxidation and oxidative stress.”

“On a diet lacking the “essential” unsaturated fatty acids, Benhamou (1995) found that nonobese diabetic mice didn’t develop diabetes, that is, the unsaturated fats themselves, without obesity, are sufficient to cause diabetes.”

“But when cells are exposed to PUFA, their ability to use glucose is blocked, increasing their exposure to these fat.”

“Sugar, by reducing the level of free fatty acids in the body, actually tends to protect against these toxic effects of the PUFA. Diabetes, like cancer, has been known for a long time to be promoted by unsaturated oils in the diet, rather than by sugar. The seed oil industry has been more effective than the sugar industry in lobbying and advertising, and the effects can be seen in the assumptions that shape medical and biological research.”

“Diabetics typically have elevated lactate, which shows that glucose doesn’t have a problem getting into their cells, just getting oxidized. Sugars, if they are consumed in quantities beyond the ability to metabolize them (and that easily happens in the presence of PUFA) are converted into saturated fatty acids, which have antistress, antiinflammatory effects. Many propaganda experiments are set up, feeding a grossly excessive amount of polyunsaturated fat, causing sugar to form fat, specifically so they can publish their silly diet recommendations, which supposedly explain the obesity epidemic, but the government figures I cited show that vegetable fat consumption has increased, sugar hasn’t. My articles have a lot of information on the mechanisms, such as the so-called ‘Randle cycle,’ in which fatty acids shut down the ability to oxidize sugar. Polyunsaturated fats do many things that increase blood sugar inappropriately, and my articles review several of the major mechanisms. Several years ago, medical people started talking about the harmful effects of insulin, such as stimulating fat production, so ‘insulin resistance’ which keeps a high level of insulin from producing obesity would seem to be a good thing, but the medical obesity culture really isn’t thinking very straight. One factor in the ‘insulin resistance’ created by PUFA involves estrogen—chronic accumulation of PUFA in the tissues increases the production of estrogen, and the polyunsaturated free fatty acids intensify the actions of estrogen, which acts in several ways to interfere with glucose oxidation.”

High free fatty acids in the blood impair glucose oxidation. Muscle glycogen synthesis is also negatively affected. High free fatty acids are found in the diabetics, the insulin resistant, the obese, and AIDS patients. Anything that promotes the release of fatty acids into the blood is a factor to consider in diabetes progression or correction (i.e. estrogen, stress, growth hormone, exercise, adrenaline, cortisol, serotonin, lactic acid, low thyroid, malnutrition, darkness).

Lancet. 1963 Apr 13;1(7285):785-9.
The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA.

Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E578-91. Epub 2009 Jun 16.
The Randle cycle revisited: a new head for an old hat.
Hue L, Taegtmeyer H.
In 1963, Lancet published a paper by Randle et al. that proposed a “glucose-fatty acid cycle” to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

Br J Nutr. 2007 May;97(5):809-13.
In appreciation of Sir Philip Randle: the glucose-fatty acid cycle.
Sugden MC.
The coordinated regulation of metabolic fuel selection is crucial to energy homeostasis. Philip Randle and his colleagues developed the fundamental concept of interplay between carbohydrate and lipid fuels in relation to the requirement for energy utilisation and storage. Their insight has fashioned current understanding of the regulation of metabolism in health and disease, as well as providing a springboard for research into the roles of lipid derivatives in insulin resistance and, at the transcriptional level, lipid-regulated nuclear hormone receptors.

Biochem Soc Trans. 2003 Dec;31(Pt 6):1115-9.
The glucose-fatty acid cycle: a physiological perspective.
Frayn KN.
Glucose and fatty acids are the major fuels for mammalian metabolism and it is clearly essential that mechanisms exist for mutual co-ordination of their utilization. The glucose-fatty acid cycle, as it was proposed in 1963, describes one set of mechanisms by which carbohydrate and fat metabolism interact. Since that time, the importance of the glucose-fatty acid cycle has been confirmed repeatedly, in particular by elevation of plasma non-esterified fatty acid concentrations and demonstration of an impairment of glucose utilization. Since 1963 further means have been elucidated by which glucose and fatty acids interact. These include stimulation of hepatic glucose output by fatty acids, potentiation of glucose-stimulated insulin secretion by fatty acids, and the cellular mechanism whereby high glucose and insulin concentrations inhibit fatty acid oxidation via malonyl-CoA regulation of carnitine palmitoyltransferase-1. The last of these mechanisms, discovered by Denis McGarry and Daniel Foster in 1977, provides an almost exact complement to the mechanism described in the glucose-fatty acid cycle whereby high concentrations of fatty acids inhibit glucose utilization. These additional discoveries have not detracted from the important of the glucose-fatty acid cycle: rather, they have reinforced the importance of mechanisms whereby glucose and fat can interact.

Can J Appl Physiol. 1998 Dec;23(6):558-69.
The role of glucose in the regulation of substrate interaction during exercise.
Sidossis LS.
Glucose and fatty acids are the main energy sources for oxidative metabolism in endurance exercise. Although a reciprocal relationship exists between glucose and fatty acid contribution to energy production for a given metabolic rate, the controlling mechanism remains debatable. Randle et al.’s (1963) glucose-fatty acid cycle hypothesis provides a potential mechanism for regulating substrate interaction during exercise. The cornerstone of this hypothesis is that the rate of lipolysis, and therefore fatty acid availability, controls how glucose and fatty acids contribute to energy production. Increasing fatty acid availability attenuates carbohydrate oxidation during exercise, mainly via sparing intramuscular glycogen. However, there is little evidence for a direct inhibitory effect of fatty acids on glucose oxidation. We found that glucose directly determines the rate of fat oxidation by controlling fatty acid transport into the mitochondria. We propose that the intracellular availability of glucose, rather than fatty acids, regulates substrate interaction during exercise.

Am J Physiol. 1989 Jun;256(6 Pt 1):E747-52.
Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia.
Felley CP, Felley EM, van Melle GD, Frascarolo P, Jéquier E, Felber JP.
The present study was designed to assess the role of hyperglycemia (150 mg/dl) vs. euglycemia (90 mg/dl) on glucose metabolism in vivo during the infusion of a triglyceride emulsion (Intralipid). Seven young healthy volunteers were studied on four occasions using the hyperinsulinemic clamp technique, twice during euglycemia and twice during hyperglycemia, without or with Intralipid. Glucose oxidation (O) was calculated from continuous respiratory exchange measurements, and glucose storage (S) was obtained as the difference between total glucose disposal (M) and O. Two-way analysis of variance with interaction term demonstrated 1) a significant increase for M with hyperglycemia and a decrease with Intralipid; no interaction, and 2) in euglycemia, O/M and S/M occurred in one-to-one ratios; on the other hand, during 150-mg/dl hyperglycemia, the ratio dropped roughly to 1:2. Intralipid had no effect on the ratio, and no interaction could be observed. These results suggest the existence of physiological regulatory mechanisms by which 1) the rise in plasma free fatty acid inhibits both oxidative and nonoxidative glucose disposal, and 2) the rise in glycemia stimulates predominantly nonoxidative glucose disposal.

Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):142-8.
Free fatty acids and insulin resistance.
Delarue J, Magnan C.
PURPOSE OF REVIEW:
Dysregulation of free fatty acid metabolism is a key event responsible for insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle of Randle, preferential oxidation of free fatty acids over glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. However, other mechanisms are now described to explain the molecular basis of insulin resistance.
RECENT FINDINGS:
Recent studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver, may activate a serine kinase cascade leading to defects in insulin signalling and glucose transport. Inflammation and oxidative stress are also potent mechanisms which could lead to a state of insulin resistance. Finally, modulation of transcription by free fatty acids through their binding to peroxisome proliferator-activated receptors could also contribute to impaired glucose metabolism.
SUMMARY:
The increase in free fatty acid flux resulting from increased lipolysis secondary to adipose-tissue insulin resistance induces or aggravates insulin resistance in liver and muscle through direct or indirect (from triglyceride deposits) generation of metabolites, altering the insulin signalling pathway. Alleviating the excess of free fatty acids is a target for the treatment of insulin resistance.

Proc Assoc Am Physicians. 1999 May-Jun;111(3):241-8.
Free fatty acids, insulin resistance, and type 2 diabetes mellitus.
Boden G.
Evidence is presented that shows that free fatty acids (FFA) are one important link between obesity, insulin resistance, and type 2 diabetes. Plasma FFA levels are elevated in most obese subjects, and physiological elevations of plasma FFA inhibit insulin-stimulated glucose uptake into muscle. This peripheral insulin resistance is caused by an FFA-induced defect, which develops 3-4 hr after raising plasma FFA, in insulin-stimulated glucose transport or phosphorylation, or both. This resistance is also caused by a second defect, which develops after 4-6 hr, consisting of inhibition of glycogen synthase activity. Whether elevated plasma FFA levels inhibit insulin action on endogenous glucose production (EGP), that is, cause central insulin resistance, is more difficult to demonstrate. On the one hand, FFA increase gluconeogenesis, which enhances EGP; on the other hand, FFA increase insulin secretion, which decreases EGP. Basal plasma FFA support approximately one third of basal insulin secretion in diabetic and nondiabetic subjects and, hence, are responsible for some of the hyperinsulinemia in obese, normoglycemic patients. In addition, elevated plasma FFA levels potentiate glucose-stimulated insulin secretion acutely and during prolonged exposure (48 hr). It is hypothesized that obese subjects who are genetically predisposed to develop type 2 diabetes will become partially “lipid blind,” that is, unable to compensate for their FFA-induced insulin resistance with FFA-induced insulin oversecretion. The resulting insulin resistance/secretion deficit will then have to be compensated for with glucose-induced insulin secretion, which, because of their partial “glucose blindness,” will result in hyperglycemia and eventually in type 2 diabetes.

Endocr Pract. 2001 Jan-Feb;7(1):44-51.
Free fatty acids-the link between obesity and insulin resistance.
Boden G.
OBJECTIVE:
To present evidence that free fatty acids (FFA) are an important link between obesity and insulin resistance.
METHODS:
The role of FFA in peripheral insulin resistance, hepatic insulin resistance, insulin secretion, and type 2 diabetes is discussed.
RESULTS:
Obesity is invariably associated with insulin resistance. In most obese subjects, plasma FFA levels are increased. Physiologic increases in plasma FFA levels cause insulin resistance in both diabetic and nondiabetic subjects by producing several metabolic defects: (1) FFA inhibit insulin-stimulated glucose uptake at the level of glucose transport or phosphorylation (or both); (2) FFA inhibit insulin-stimulated glycogen synthesis; and (3) FFA inhibit insulin-stimulated glucose oxidation. (This last-mentioned defect probably does not contribute to insulin resistance.) FFA probably also cause hepatic insulin resistance, which results in increased rates of endogenous glucose production in relationship to the prevailing degree of hyperinsulinemia. Lastly, FFA support between 30 and 50% of basal insulin secretion and potentiate glucose-stimulated insulin secretion in short-term and long-term settings. The stimulatory action of FFA on b-cells enables obese individuals who do not have a genetic predisposition to develop type 2 diabetes mellitus to compensate for their FFA-potentiated insulin resistance with an increase in FFA-mediated insulin secretion. In contrast, subjects who are genetically predisposed to develop type 2 diabetes may be unable to secrete sufficient amounts of insulin to compensate for their FFA-induced insulin resistance. This situation will lead to an increase in blood glucose concentration and eventually to type 2 diabetes.
CONCLUSION:
FFA have been shown to have an important contributing role in the pathogenesis of insulin resistance in human obesity.

Diabetes. 1997 Jan;46(1):3-10.
Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.
Boden G.
Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3-4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4-6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.

Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):545-9.
Interaction between free fatty acids and glucose metabolism.
Boden G.
PURPOSE OF REVIEW:
The prevalence of obesity and of type 2 diabetes mellitus are increasing at an accelerating rate in the USA and other industrialized countries. Free fatty acids (FFAs) have emerged as a major link between obesity and insulin resistance/type 2 diabetes mellitus. A review of the interaction between FFAs and glucose metabolism is therefore timely and relevant.
RECENT FINDINGS:
Acute and chronic elevations in plasma FFAs produce peripheral (muscle) and hepatic insulin resistance. In skeletal muscle, this process is associated with accumulation of intramyocellular triglyceride and diacylglycerol, and with activation of protein kinase C (the beta and delta isoforms). It is hypothesized that FFAs interfere with insulin signaling via protein kinase C-induced serine phosphorylation of insulin receptor substrate-1. In the liver, FFAs cause insulin resistance by interfering with insulin suppression of glycogenolysis. In the beta cells, FFAs potentiate glucose-stimulated insulin secretion. It is postulated that this prevents the development type 2 diabetes mellitus in the majority (approximately 80%) of obese insulin-resistant people.
SUMMARY:
Elevated plasma FFA levels have been shown to account for up to 50% of insulin resistance in obese patients with type 2 diabetes mellitus. Lowering of FFAs in these patients or interfering with steps in the pathway through which FFAs cause insulin resistance could be a new and promising approach to treat type 2 diabetes mellitus.

Diabetes Care. 1996 Apr;19(4):394-5.
Fatty acids and insulin resistance.
Boden G.
We have demonstrated that physiological elevations in plasma free fatty acid concentrations inhibit insulin-stimulated glucose uptake in a dose-dependent manner in normal control subjects and in patients with NIDDM. Two possible mechanisms were identified: 1) a fat-related inhibition of glucose transport or phosphorylation that appeared after 3-4 h of fat infusion and 2) a decrease in muscle glycogen synthase activity that appeared after 4-6 h of fat infusion. We conclude that elevations of plasma FFAs caused insulin resistance and hence may play a significant role in the pathogenesis of insulin resistance in obesity and NIDDM.

J Clin Invest. 1996 June 15; 97(12): 2859–2865.
Mechanism of free fatty acid-induced insulin resistance in humans.
M Roden, T B Price, G Perseghin, K F Petersen, D L Rothman, G W Cline, and G I Shulman
To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.

Current Opinion in Endocrinology, Diabetes & Obesity: April 2011 – Volume 18 – Issue 2 – p 139–143
Obesity, insulin resistance and free fatty acids
Boden, Guenther
Purpose of review: To describe the role of free fatty acid (FFA) as a cause for insulin resistance in obese people.
Recent findings: Elevated plasma FFA levels can account for a large part of insulin resistance in obese patients with type 2 diabetes. Insulin resistance is clinically important because it is closely associated with several diseases including type 2 diabetes, hypertension, dyslipidemia and abnormalities in blood coagulation and fibrinolysis. These disorders are all independent risk factors for cardiovascular disease (heart attacks, strokes and peripheral arterial disease). The mechanisms by which FFA can cause insulin resistance, although not completely known, include generation of lipid metabolites (diacylglycerol), proinflammatory cytokines (TNF-α, IL-1β, IL-6, MCP1) and cellular stress including oxidative and endoplasmic reticulum stress.
Summary: Increased plasma FFA levels are an important cause of obesity-associated insulin resistance and cardiovascular disease. Therapeutic application of this knowledge is hampered by the lack of readily accessible methods to measure FFA and by the lack of medications to lower plasma FFA levels.

Best Pract Res Clin Endocrinol Metab. 2003 Sep;17(3):399-410.
Nutritional effects of fat on carbohydrate metabolism.
Boden G, Carnell LH.
Obesity is commonly associated with elevated plasma levels of free fatty acids (FFAs). High levels of FFA have emerged as a major link between obesity and insulin resistance/type 2 diabetes (T2DM). Thus, acute and chronic elevations of plasma FFAs produce insulin resistance in skeletal muscle and liver. In skeletal muscle, FFA-induced insulin resistance is associated with accumulation of intramyocellular triglyceride and diacylglycerol, and with activation of protein kinase C (the beta and delta isoforms). It is suggested that FFAs interfere with insulin signalling via PKC-induced serine phosphorylation of the insulin receptor substrate-1. In the liver, FFAs cause insulin resistance by interfering with insulin suppression of glycogenolysis. In beta-cells, FFAs potentiate glucose-stimulated insulin secretion acutely and chronically. It is postulated that this prevents the development of T2DM in most (>80%) obese insulin-resistant people who have FFA-mediated insulin resistance. Elevated levels of FFA also seem to activate a pro-inflammatory and pro-atherogenic pathway (the IkappaB/NFkappaB pathway) and may be responsible, at least in part, for the increase in atherosclerotic vascular disease seen in patients with T2DM. As increased plasma levels account for up to 50% of insulin resistance in obese patients with T2DM, lowering of plasma FFAs could be a new and promising approach to the treatment of T2DM.

Diabetes. 1999 Jun;48(6):1270-4.
Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI.
To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.

Eur J Clin Invest. 2002 Jun;32 Suppl 3:14-23.
Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.
Boden G, Shulman GI.
Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.

J Clin Invest. 1994 Jun;93(6):2438-46.
Mechanisms of fatty acid-induced inhibition of glucose uptake.
Boden G, Chen X, Ruiz J, White JV, Rossetti L.
Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

Trends Endocrinol Metab. 2000 Nov;11(9):351-6.
Free fatty acids and pathogenesis of type 2 diabetes mellitus.
Bergman RN, Ader M.
Plasma free fatty acids (FFA) might mediate the insulin resistance and impaired glucose tolerance associated with central obesity. Central adipocytes are resistant to insulin, suggesting that FFA delivery to the liver via the portal vein is increased when visceral triglyceride (TG) stores are increased. Muscle insulin resistance might result from the ‘Randle’ mechanism, from downregulation of the insulin signaling pathway, and/or reduced access of insulin to skeletal muscle owing to changes in blood flow or insulin transport across capillary endothelium. TG storage within muscle might interfere with insulin action, but a causal relationship between myocellular lipid and glucose disposal remains to be demonstrated. Basal levels of FFA appear to be permissive for insulin secretion; however, elevated FFA have a minor effect on insulin secretion in vivo. In humans, prolonged hyperlipidemia engenders an insulin response matched to the degree of insulin resistance, leaving open the question of whether lipotoxicity of islet cells contributes to glucose intolerance and diabetes in humans. Elevated portal FFA might account for overproduction of liver glucose output with visceral adiposity. Additionally, portal FFA might reduce hepatic extraction of insulin, diminishing the necessity of increased beta-cell response to compensate for FFA-driven insulin resistance. Overall, effects of FFA can lead to several components of the insulin resistance syndrome and risk for diabetes. Reduction in FFA might be the appropriate therapy for these disorders.

J Basic Clin Physiol Pharmacol. 1998;9(2-4):205-21.
Central role of the adipocyte in insulin resistance.
Bergman RN, Mittelman SD.
Mechanisms of insulin resistance in subjects at risk for type 2 diabetes remain to be elucidated. Insulin acts slowly in vivo, but rapidly in vitro, suggesting that the pathway insulin traverses from B-cell to insulin sensitive tissue may be altered in diabetes. An important component of that pathway is transport of insulin across the capillary endothelium. Several groups have demonstrated that insulin resistance may result from reduced capillary permeability to insulin–it remains to be determined whether reduced permeability contributes to insulin resistance in any stage leading to type 2 diabetes. Interestingly, the transport of insulin across the endothelial barrier not only limits the rate of insulin to stimulate glucose uptake by skeletal muscle, but appears also to determine the rate at which insulin suppresses liver glucose output. Because the liver circulation is fenestrated, it is not possible that insulin transport into the liver is the rate determining step for suppression of liver glucose output. An alternative hypothesis was considered–that insulin is transported into an extrahepatic tissue. A “second signal” is generated by the extrahepatic tissue, the signal is released into the blood, and the signal in turn controls hepatic glucose output. Several lines of evidence suggest that the second signal is free fatty acids (FFA): 1) There is a strong correlation between FFA and liver glucose output under a variety of experimental conditions. 2) If FFA are maintained at basal concentrations during insulin administration, glucose output fails to decline. 3) If FFA are reduced independent of insulin administration, glucose output is reduced. These three points support the concept that insulin, by regulating adipocyte lipolysis, controls liver glucose production. Thus, the adipocyte is a critical mediator between insulin and liver glucose output. Evidence that FFA also suppress skeletal muscle glucose uptake and insulin secretion from the B-cell supports the overall central role of the adipocyte in the regulation of glycemia. Insulin resistance at the fat cell may be an important component of the overall regulation of glycemia because of the relationships between FFA and glucose production, glucose uptake, and insulin release. It is possible that insulin resistance at the adipocyte itself can be a major cause of the dysregulation of carbohydrate metabolism in the prediabetic state.

Prog Clin Biol Res. 1983;111:89-109.
Energy metabolism in trauma and sepsis: the role of fat.
Wolfe RR, Shaw JH, Durkot MJ.
There seems little doubt that there are signals for the increased mobilization of fat in shock, trauma, and sepsis. Whether those signals are reflected by an actual increase in mobilization is dependent on many variables including cardiovascular status. A hypothetical scheme based on our own experiments in the hyperdynamics phases of response to burn injury and to sepsis is presented in Figure 8. According to this scheme, catecholamines stimulate lipolysis in the adipose tissue, resulting in the release of glycerol and FFA into the plasma at increased rates. The glycerol is cleared by the liver and converted into glucose–a process stimulated by, among other things, glucagon. Some of the increased flux of FFA is also cleared by the liver, whereupon the fatty acids are incorporated into VLDL and released again into the plasma. The increased FFA levels also exert a dampening effect on the factors stimulating hepatic glucose production. At the periphery, plasma FFA as well as VLDL fatty acids are taken up at an increased rate. The tissues are attuned to the oxidation of fat, and as a consequence most of the energy production is derived from fat oxidation. The increased fatty acids exert an inhibitory effect on the complete oxidation of glucose, so although glucose may be taken up at an accelerated rate, the relative contribution of glucose oxidation to total energy production may fall. Rather than being completely oxidized, pyruvate is reduced to lactate and released into the plasma at an accelerated rate. The lactate then contributes to the production of glucose in the liver, completing a cyclical process called the Cori Cycle. Although all aspects of this scheme are supported by data highlighted in this paper, it certainly must be an oversimplification of the overall response of substrate metabolism to trauma and sepsis. It is presented for the purpose of highlighting the potential role of fat as a controller of the metabolic response, and to suggest that the enhanced mobilization and oxidation of fat is one of the fundamental responses to stress.

J Physiol. 2013 May 13. [Epub ahead of print]
Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration onInsulin Signaling and Inflammation in Skeletal Muscle from Human Subjects.
Liang H, Tantiwong P, Sriwijitkamol A, Shanmugasundaram K, Mohan S, Espinoza S, Dubé JJ, Defronzo RA, Musi N.
Key points

• Reducing free fatty acids in the circulation gives protection against muscle insulin resistance.

• In the present study, we investigated the mechanism by which free fatty acid reduction improves muscle insulin sensitivity.

• The antilipolytic drug acipimox reduced the plasma concentration of unsaturated and saturated fatty acids in insulin-resistant (obese and type 2 diabetic) subjects.

• The reduction in plasma free fatty acid concentration caused by acipimox led to an improvement in local inflammation and insulin signalling in skeletal muscle.

• The improvements in local inflammation and insulin signalling were more pronounced in obese type 2 diabetic subjects than obese non-diabetic individuals, suggesting that diabetic subjects are more susceptible to the toxic effect of circulating free fatty acids.

Free fatty acids (FFA) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacologic FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signaling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signaling, IκBα protein, c-Jun phosphorylation, inflammatory gene [toll-like receptor (TLR)4 and monocyte chemotactic protein (MCP)1] expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for seven days, and results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signaling in obese and T2DM subjects. Acipimox increased IκBα protein [an indication of decreased IKK-nuclear factor (NF)κB signaling] in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacologic FFA reduction improves insulin signaling in muscle from insulin resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Diabetes. 2014 Aug;63(8):2812-20. doi: 10.2337/db13-1130. Epub 2013 Dec 18.
Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.
Daniele G1, Eldor R1, Merovci A1, Clarke GD1, Xiong J1, Tripathy D1, Taranova A1, Abdul-Ghani M1, DeFronzo RA2.
Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

Diabetes August 2014 vol. 63 no. 8 2611-2612
Improved Mitochondrial Function Is Linked With Improved Insulin Sensitivity Through Reductions in FFA
Bret H. Goodpaster⇑ and Paul M. Coen
“These persuasive data support a link between FFA reduction and improved insulin sensitivity and mitochondrial ATP production. While not proving causality, this study makes an important contribution to our knowledge regarding the potential origins of IR; one that also has therapeutic implications”

PLoS One. 2013 Oct 7;8(10):e77280. doi: 10.1371/journal.pone.0077280. eCollection 2013.
Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart
Clair Crewe, Michael Kinter, Luke I. Szweda
Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.