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Understanding Blood Sugar Levels, INSULIN RESISTANCE \u0026 Impact on Chronic Diseases - Dr. Rob LustigFat metabolism and insulin resistance -
Furthermore, marked compensation of other functionally redundant proteins can occur, which could limit the physiological impact of any deletion or defect of fatty acid binding proteins in adipose tissue To date, there has been no demonstrated defect in adipose tissue fatty acid uptake caused by a defect in any of the FFA transport or binding proteins in humans The production of acylation stimulating protein ASP , a proteolytic cleavage product of the third component of complement, is stimulated by hydrolyzed chylomicrons and is an important regulator of adipocyte fatty acid esterification by increasing the activity of diacylglycerol acyltransferase through a PKC-dependent pathway There is controversy in the literature regarding the physiological importance of ASP, because some 67 but not others 68 have described abnormalities of postprandial lipoprotein metabolism in ASP-null mice.
Although a blunted response to ASP in IRS and type 2 diabetes cannot as yet be ruled out, evidence in support of such a defect is currently lacking. ASP levels are increased in obesity 69 , and adipocytes from obese humans remain responsive to ASP Aside from putative intrinsic abnormalities in adipocytes, these two other factors have important bearing on adipose tissue fat storage and release in IRS and type 2 diabetes.
Firstly, because the pool of FFAs in adipocytes is released into the circulation in relation to its size, the greater overall fat mass of adipose tissue in obese individuals will result in an elevation of fatty acid flux to nonadipose tissues, even in the absence of a qualitative abnormality in adipose tissue metabolism sc abdominal fat remains a matter of debate 72 , 74 , Visceral fat cells are more sensitive than sc fat cells to the lipolytic effect of catecholamines and less sensitive to the antilipolytic and fatty acid re-esterification effect of insulin reviewed in Ref.
Furthermore, the venous effluent of visceral fat depots leads directly into the portal vein, resulting in greater FFA flux to the liver in viscerally obese individuals than in those with predominantly sc obesity.
Furthermore, total splanchnic blood supply increases postprandially 79 as might the proportion of lipolysis from splanchnic vs. sc fat because of increased insulin and sympathetic activation after meals.
Thus, the contribution of visceral fat to hepatic FFA uptake and systemic FFA appearance could be more substantial in the postprandial than in the fasting state.
The net result of increased FFA lipolysis and diminished FFA fractional esterification in IRS and type 2 diabetes is diversion of FFAs toward nonadipose tissues such as liver Fig. Extreme examples, at opposite ends of the spectrum, of adipose tissue capacity to take up and store incoming fatty acids are illustrated by the clinical conditions of congenital lipoatrophy and massive obesity.
In humans 80 and animal models of lipoatrophy 81 — 83 , in which there is absence of adipose tissue, nonadipose tissues accumulate cytosolic triglycerides to a massive extent and manifest many of the consequences of extreme insulin resistance.
Furthermore, all aspects of the fatless mouse phenotype are alleviated in a dose-response fashion with surgical implantation of adipose tissue Based on his studies with animal models of lipodystrophy, Shulman 84 has recently proposed that insulin resistance develops because of an imbalance of fat distribution between tissues.
Consistent with this hypothesis is the observation that some massively obese individuals have surprisingly few manifestations of the IRS 85 , Normoglycemic and normolipidemic obese individuals display improved postprandial fat storage compared with lean subjects Presumably, the more efficient adipose tissue fat-storing capacity in these individuals could confer relative protection against lipotoxicity in nonadipose tissues.
Role of fatty acids in overproduction of hepatic VLDL and fatty liver infiltration. In insulin resistance and type 2 diabetes, there is defective esterification and re-esterification of fatty acids in adipose tissue, as well as possibly reduced insulin-mediated suppression of HSL, the rate-limiting enzyme for adipose tissue triglyceride mobilization.
Fatty acid flux from adipose tissue is elevated in these conditions, and FFAs released by lipolysis of plasma triglyceride-rich lipoproteins VLDL and chylomicrons are diverted from adipose tissue to other organs, where they can exert their deleterious effects.
Increased FFA flux to the liver in IRS and type 2 diabetes increases the hepatocyte fatty acid pool size. Esterified fatty acids are either stored as cytosolic triglycerides TG or directed toward VLDL synthesis.
The majority of fatty acids released from the cytosolic triglyceride stores are re-esterified and recycled to the cytosol or secreted in VLDL. A high VLDL production rate raises the plasma VLDL concentration, as well as the concentration of intestinally derived chylomicrons because of competition for removal between chylomicrons and VLDL.
High plasma concentrations of triglyceride-rich lipoproteins VLDL and chylomicrons lead to an increase in the release of FFAs and generation of remnants as a result of lipolysis by LPL. FFAs and remnants of triglyceride-rich lipoproteins contribute to increase the hepatocyte fatty acid pool, thereby setting up a vicious cycle and further driving VLDL production.
There appears to be a reciprocal channeling of fuels between muscle and fat when one or the other tissue becomes preferentially insulin resistant. For example, there is preferential channeling of energy fuels toward fat rather than muscles during fat infusion in Zucker rats, related to down-regulation of muscle and simultaneous up-regulation of adipose tissue transporters and genes involved in glucose and fatty acid uptake and disposal Similarly, mice with targeted disruption of glucose transporter GLUT 4 in muscle and consequent muscle insulin resistance have a redistribution of substrate from muscle to adipose tissue The converse also appears to be true, as down-regulation of GLUT4 and glucose transport selectively in adipose tissue has recently been shown to cause insulin resistance in muscle 91 , perhaps by diverting FFAs and other fuels from adipose to nonadipose tissues, although the mechanism is not currently known.
This concept of adipose tissue acting as a sink to protect other tissues from the toxic effects of excessive exposure to energy substrates is further supported by the finding that overexpression of GLUT4 in adipose tissue in mice is associated with an increase in adipose tissue mass and improved whole-body insulin sensitivity 93 , It is likely that the majority of individuals who fall along the spectrum between lipodystrophy and massive obesity have a genetically determined set point at which adaptive adipose tissue insulin resistance limits further adipose tissue fat accumulation, with consequent spillover of fat to nonadipose tissues Fig.
Positive net energy balance exceeds the buffering capacity of adipose tissue, leading to glucolipotoxicity. Positive net energy balance, resulting from increased calorie intake and reduced energy expenditure, leads to an accumulation of triglyceride in many tissues, particularly in adipose tissue.
The accumulation of triglyceride in adipose tissue leads to increased lipolysis by a mass effect. This, associated with the development of adipocyte insulin resistance, results in net spillover of fatty acids to nonadipose tissue, which further increases extraadipocytic triglyceride storage, leading to many of the typical features that characterize the insulin-resistant state and type 2 diabetes.
Intramyocellular triglyceride IMTG accumulation has been associated with muscle insulin resistance in humans 95 — IMTG is also elevated in lean, glucose-tolerant offspring of two parents with type 2 diabetes mellitus compared with individuals without a family history of diabetes and is associated with lower glucose disposal Somewhat paradoxically, however, triglycerides have also been shown to accumulate in the muscle tissue of highly physically trained athletes As pointed out in a recent review on this topic by Kelley and Goodpaster , muscle triglyceride may not have adverse metabolic consequences in muscle that has the capacity for efficient lipid utilization.
The mechanism accounting for the relationship between muscle triglyceride accumulation and insulin resistance is not known. It remains an open question as to whether muscle triglyceride accumulation is merely a marker or plays a causative role in the insulin resistance. A key issue is whether triglycerides accumulate in muscle tissue of insulin-resistant individuals as a result of a primary defect in fatty acid oxidation, increased total FFA flux to muscle, or due to an imbalance between FFA uptake, esterification, triglyceride lipolysis, and fatty acid oxidation.
Muscle from obese, insulin-resistant individuals and type 2 diabetic patients has been shown to have reduced capacity for uptake and oxidation of fatty acids derived from the plasma FFA pool during fasting and exercise — These changes could perhaps be attributed to defects of fatty acid oxidation at the carnitine palmitoyl-transferase-1 CPT-1 and post-CPT-1 levels Furthermore, weight reduction using low-calorie diets in patients with type 2 diabetes has been shown to reduce plasma FFA flux during fasting but not exercise, without significant change in plasma-derived FFA oxidation or muscle mitochondrial oxidative enzymes , Prolonged pharmacological inhibition of muscle CPT-1 in rats has also been associated with IMTG accumulation and development of insulin resistance These findings have been interpreted to suggest that impaired muscle fatty acid oxidation is the primary defect causing the IMTG accumulation and muscle insulin resistance in patients with obesity, IRS, and type 2 diabetes Impaired muscle FFA oxidation in these conditions could also be the result of excessive chronic exposure to FFA, because the elevation of malonyl-coenzyme A CoA due to energy excess has been associated with reduced muscle fat oxidation through inhibition of CPT-1 , It should be pointed out that the reduction of plasma-derived FFA oxidation seen in patients with obesity and diabetes has been shown by some to occur in association with unaltered or even elevated total fat oxidation and with elevated muscle triglyceride lipolysis , Thus, while the capacity for fat oxidation appears to be reduced, total fat oxidation may be increased because of the mass action effect of increased FFA delivery from plasma and from increased intracellular triglyceride stores.
Furthermore, net fat oxidation is not reduced in obese individuals in response to elevation of plasma FFAs using iv infusion of heparin and lipid emulsion In addition, weight loss secondary to fat malabsorption after bariatric surgery in morbidly obese individuals corrects both the low respiratory quotient and insulin resistance seen in these individuals, suggesting that improvement in insulin resistance with correction of obesity is associated with reduction of lipid oxidation relative to carbohydrate oxidation Because plasma FFA delivery itself, as well as glucose delivery and plasma insulin levels, may determine the rate of muscle FFA oxidation — , these factors should also be carefully controlled for in in vivo experiments before drawing any conclusion regarding the presence of a primordial defect in muscle FFA oxidation in patients at risk for or with established type 2 diabetes.
Skeletal muscle has a high fractional extraction of FFAs in the postabsorptive state, and lipid oxidation accounts for the majority of its energy production Some studies in humans have suggested that muscle fatty acid binding and transport proteins may be altered in obesity and type 2 diabetes.
Skeletal muscle cytoplasmic fatty acid binding protein FABP content has been shown to be reduced together with reduced in vivo muscle plasma FFA uptake and oxidation in obese type 2 diabetic patients , but not in glucose-tolerant obese subjects The skeletal muscle expression of another FAT protein, FATP-1, was found to be reduced in obese women with or without type 2 diabetes, but not in men 51 , 66 , , and their potential role in intramyocellular triglyceride accumulation and insulin resistance remains unclear.
Despite the fact that the efficiency of skeletal muscle FFA uptake and utilization in the postabsorptive state has been shown to be impaired in obese patients with type 2 diabetes , and in nondiabetic individuals with visceral obesity , we need to be cautious in interpreting this observation to mean that total h fatty acid flux to muscle is reduced in insulin resistance and type 2 diabetes.
Experimental evidence suggests that excessive FFA delivery to muscle from the circulation can be a source of muscle triglyceride accumulation — An extramuscular defect of fatty acid metabolism could contribute to the intramyocellular triglyceride accumulation and the skeletal muscle lipotoxic effects seen in obesity and type 2 diabetes.
It has been proposed that gain-of-function mutations of FABP-2, a FABP highly expressed in the small intestine, could result in postprandial lipid abnormalities, insulin resistance, and diabetes A common polymorphism of the intestinal FABP2 gene A54T that results in higher affinity of FABP2 for long-chain fatty acids in vitro has been associated with an increased prevalence of insulin resistance or diabetes in some populations — but not in others — In vivo , this polymorphism has been inconsistently associated with increased total body fat oxidation and a small elevation of plasma FFA levels in different populations , , The association with higher postprandial triglyceride and lipoprotein excursion has also been found in some , but not all studies , Although increased intestinal absorption of FFA has been postulated to be the cause of these abnormalities, this has not yet been convincingly demonstrated in humans It is therefore likely that A54T polymorphism of the FABP2 gene could play some role in abnormal FFA metabolism and be linked with the development of insulin resistance and type 2 diabetes by an unknown mechanism in some populations, such as the Pima Indians, but not in others.
Unger and colleagues — have proposed that the physiological role of the hyperleptinemia that accompanies caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing up-regulation of lipogenesis and by increasing fatty acid oxidation. These researchers argue convincingly against the conventional view that the physiological role of leptin is to prevent obesity during overnutrition.
Leptin has been shown to be antilipogenic in some tissues and up-regulates fatty acid oxidation Leptin-deficiency states, including lipodystrophic syndromes, are associated with massive nonadipose tissue fat accumulation due to increased lipogenesis and reduced fatty acid oxidation , with adverse consequences of nonadipose tissue lipid overaccumulation.
Adenoviral-mediated leptin overexpression in normal rats is antilipogenic and up- regulates β-oxidation Transgenic overexpression of leptin rescues the insulin resistance and diabetes in a mouse model of lipoatrophic diabetes In humans, hyperleptinemia characterizes obesity, insulin-resistant states, and type 2 diabetes, suggesting that leptin resistance, not leptin deficiency, may be involved in the pathophysiology The reduction of plasma leptin concentration after bariatric surgery in morbidly obese individuals occurs independently of the reduction of fat mass but correlates with the reduction of plasma insulin levels, suggesting that resistance to leptin and insulin are closely linked in humans Although leptin resistance could play a role in extra-adipose tissue fat deposition and lipotoxicity, it could also be a consequence of elevated fatty acid availability to tissues , Elevated plasma FFA could lead to relative suppression of leptin release by the adipose tissue, contributing to impaired leptin signaling in insulin-resistant states Nevertheless, the important role of leptin in regulating rates of lipogenesis and fatty acid oxidation illustrates that factors in addition to fat spillover from adipose to nonadipose tissues may regulate the magnitude of triglyceride accumulation in nonadipose tissues in states of caloric overload.
Recently the adipocyte-derived hormone adiponectin has been shown to reverse insulin resistance associated with both lipoatrophy and obesity Decreased expression of adiponectin was shown to correlate with insulin resistance in mouse models of insulin resistance.
Insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. Adiponectin reduced the triglyceride content of muscle and liver in obese mice by increasing the expression of fatty acid oxidation and energy dissipation in muscle.
Adipose tissue storage, release of fatty acids, and its control by insulin are grossly abnormal in IRS well before the development of type 2 diabetes. In the postabsorptive period, basal lipolysis is elevated and suppression by insulin diminished.
In the postprandial period, there is likely to be a net diversion of fat away from adipose tissue depots and toward nonadipose tissues. FFA efflux from an enlarged and lipolytically active visceral fat depot plays a major role in the elevation of fatty acids, which are then free to exert their biological effects in nonadipose tissues.
This phenotype is hypothesized to be characterized by low oxidative or fat oxidative capacity and a tendency toward a positive energy balance With current high-calorie, high-fat diets and sedentary lifestyle, such a thrifty genotype would accumulate excess tissue triglyceride stores, despite resistance to glucose disposal As indicated in Fig.
In addition, adipose cells could adaptively limit further fat accumulation by becoming insulin resistant, thereby diverting fat to nonadipose tissues. Perhaps a corollary of the thrifty genotype theory is that those whose adipocytes are able to most effectively protect themselves against ongoing caloric overload, i.
Perhaps the accumulation of adipose tissue represented an evolutionary disadvantage to those engaged in hunter-gatherer lifestyles. Cytosolic triglyceride accumulation in nonadipose tissues such as muscle and liver is linked to the development of insulin resistance as these tissues also attempt to protect themselves from energy overload.
Insulin resistance imposes a chronic stress on pancreatic β-cells, which may fail to hypersecrete insulin, as the same mechanisms that lead to insulin resistance may ultimately result in β-cell dysfunction and damage see Fig.
The hypertriglyceridemia of IRS and type 2 diabetes is primarily due to VLDL overproduction, with reduced VLDL clearance playing a role in some instances, particularly when there is marked insulin deficiency or poor glycemic control in type 2 diabetes Some of the other prominent features of the dyslipidemia of IRS and type 2 diabetes, such as low high density lipoprotein cholesterol and small, dense LDL particles, may be secondary to VLDL overproduction, as we have previously reviewed , Hepatic VLDL production is primarily substrate driven, with the most important regulatory substrates being FFAs FFAs are taken up by the liver in proportion to their delivery rate , Hepatic fractional extraction of FFA, however, is not affected in type 1 diabetic patients or in depancreatized dogs In the liver, depending on the nutritional and hormonal state of the organism, fatty acids are either predominantly oxidized or are esterified to form triglycerides, which are then either stored in the cytosol or secreted in VLDL.
The production rate of apolipoprotein B apo B is an important regulatory step in VLDL production, but the apo B transcription and translation rate does not regulate the pathway under most physiological conditions — Regulation of apo B occurs primarily at the posttranslational level, either during its translocation into the endoplasmic reticulum lumen or its rate of degradation.
Protection against proteolysis is critically dependent on neutral lipid availability and is facilitated by a number of chaperone proteins and microsomal transfer protein [MTP ]. MTP catalyzes the transfer of lipids to the apo B molecule and is an important factor involved in the assembly of apo B-containing lipoproteins , Primary rat hepatocytes, incubated in vitro with high concentrations of insulin for 3 d, no longer respond to insulin suppression of VLDL apo B secretion and secrete higher basal levels of VLDL apo B FFAs have been shown to directly stimulate hepatocyte VLDL triglyceride synthesis and secretion in HepG2 cells — and cultured hepatocytes , Although it is generally believed that the rate of apo B secretion is determined by the extent of its intracellular degradation, several studies have shown that protection from degradation is insufficient to drive apo B secretion in the absence of available core lipoprotein lipids.
Addition of oleate can rescue the protected apo B polypeptides and induce their lipidation and extracellular secretion in some but not all model systems. It has also been previously suggested that oleate treatment of HepG2 cells facilitates translocation of newly synthesized apo B across the endoplasmic reticulum membrane, which in turn reduces early degradation However, whether or not this protection of early degradation stimulates apo B extracellular secretion appears to differ among cell types.
In HepG2 cells , , , a rat hepatoma cell line , and freshly isolated rabbit hepatocytes , exogenous oleate significantly stimulates apo B secretion. In contrast, this is not the case in McArdle H cells and primary rat , , hamster , or human hepatocytes, although oleate may increase the stability of apo B.
Overall, the effect of oleate on the stability and secretion of apo B appears to be dependent on the cell type primary vs. Because FFAs entering the hepatocyte are predominantly re-esterified and enter a cytoplasmic pool before secretion in VLDL, the size of the cytoplasmic triglyceride pool, rather than the availability of extracellular oleic acid, correlates with VLDL secretion Although it is well recognized that plasma FFAs stimulate VLDL production and are an important source of VLDL triglyceride fatty acids — , an important contribution to the hepatocyte fatty acid pool also comes from three sources other than plasma FFAs: 1 de novo lipogenesis DNL , 2 cytoplasmic triglyceride stores, and 3 intracellular lipolysis of lipoproteins taken up directly by the liver Fig.
Hepatic re-esterification of plasma FFAs contributes the majority of fatty acids to VLDL triglycerides , with sources such as DNL, hepatic triglyceride stores, and lipoprotein remnants contributing somewhat less , The contribution to VLDL triglycerides from plasma FFAs is lower in hypertriglyceridemic than in normotriglyceridemic individuals Chronic hyperinsulinemia and carbohydrate ingestion stimulate the production of newly synthesized fatty acids [DNL — ], by stimulating the activity of lipogenic enzymes in the liver and by increasing the transcription of the genes for fatty acid synthase and acetyl-coenzyme A carboxylase [ACC , ].
Recent studies suggest that the mechanism by which insulin and perhaps glucose stimulate transcription of these lipogenic enzymes is by increasing transcription of sterol-regulatory element-binding protein-1c SREBP-1c , a member of a family of regulated transcription factors Despite down-regulation of the IRSmediated insulin signaling pathway in insulin-resistant states, there appears to be up-regulation of SREBP-1c and chronic stimulation of DNL and reduced fatty acid oxidation in the liver , , which can in turn enhance intracellular availability of triglyceride, promoting fatty liver and driving VLDL assembly and secretion.
Even with carbohydrate feeding, which usually stimulates DNL, newly synthesized fatty acids account for the minority of VLDL-triglyceride fatty acids , — Nevertheless, even though DNL may not be a quantitatively significant contributor to VLDL triglyceride production, it appears to be an important marker of the relative rate of fatty acid re-esterification vs.
oxidation , and there is a well-established correlation between the rates of DNL and the secretion of VLDL Elevation of malonyl-CoA, which is the product of acetyl-CoA carboxylase, the rate-limiting enzyme in hepatic DNL, inhibits CPT-1 activity, thus resulting in diversion of fatty acids from an oxidative to a re-esterification pathway , Conditions associated with high rates of DNL, such as high carbohydrate ingestion, hyperglycemia, and hyperinsulinemia, are invariably associated with a shift in cellular metabolism from lipid oxidation to triglyceride esterification, increasing the availability of liver triglyceride for VLDL synthesis and secretion.
In accordance with the notion that the total capacity to secrete VLDL correlates with the rate of DNL , , hyperglycemia in the presence of constant FFA availability increases VLDL production in humans There is debate about the quantitative contribution of cytosolic triglyceride stores to VLDL triglyceride production, but it does appear that the majority of FFAs esterified upon entering the hepatocyte enter this storage pool, at least temporarily, before their incorporation into VLDL — This intracellular triglyceride storage depot likely serves as a buffer, providing temporary disposal of potentially toxic FFA when their delivery to the liver exceeds its oxidative and VLDL secretory capacity.
It also provides a means of regulating VLDL production in the face of widely fluctuating plasma FFA concentrations. Stored triglyceride turns over fairly rapidly, but only a minor proportion of the released fatty acids are used for VLDL assembly, the remainder being recycled back into the storage pool Fatty acids released from lipolysis of stored triglycerides appear to be preferentially channeled into re-esterification rather than oxidative pathways The cytosolic triglyceride droplets are not incorporated into VLDL en bloc across the endoplasmic reticulum membrane, but first have to be hydrolyzed Hydrolysis of cytosolic triglycerides appears to be partial, to the level of diacylglycerol, followed by remodeling of some of its acyl chains, before re-esterification to form secretory triglyceride Hydrolysis may also proceed to monoglyceride and FFA.
The lipase involved in this process and the details of its regulation are not yet known The partitioning of re-esterified triglycerides between secretory and storage cytosolic pathways can be acutely regulated and is a potentially important site for the regulation of VLDL secretion , Secretion of the esterified fatty acids as VLDL triglycerides is limited by the availability of a number of factors other than the hepatocyte triglyceride pool size per se , including cholesteryl esters, apo B synthesis and translocation across the endoplasmic reticulum membrane, phospholipids, rate-limiting enzymes such as MTP, etc.
Fatty liver frequently coexists with obesity, type 2 diabetes, and metabolic features of IRS and responds to their amelioration — The capacity of the liver to esterify and store incoming fatty acids as cytosolic triglycerides appears to be quite considerable under metabolic conditions when triglyceride synthesis exceeds the combination of hepatic fatty acid oxidation and VLDL-triglyceride secretion Postlipolysis remnants of triglyceride-rich lipoproteins, taken up by receptor-mediated mechanisms, are hydrolyzed in hepatic lysosomes, thereby contributing to the intracellular fatty acid and cholesteryl ester pool and stimulating VLDL secretion in a fashion similar to that of FFAs , The quantitative contribution of fatty acids derived from remnant uptake is not known but could be quite substantial, particularly in the postprandial state.
A self-perpetuating cycle is thus set up, in which elevated FFAs drive VLDL secretion, and FFAs derived from the elevated circulating pool of triglyceride-rich lipoproteins positively feed back on VLDL production by further increasing the FFA pool in the hepatocyte Fig.
The preceding discussion has emphasized the importance of fatty acid availability in the hepatocyte in driving VLDL production. Nevertheless, increased FFA availability per se is not sufficient to explain the high VLDL production rates seen in IRS and type 2 diabetes. The role of resistance to insulin action in the hepatocyte and chronic hyperinsulinemia per se in facilitating VLDL synthesis and secretion has been the focus of intense investigation for many years , , There is still not widespread agreement regarding the acute effects of insulin on VLDL production, but the majority of studies have demonstrated that insulin acutely inhibits VLDL production, shown in both in vitro , , and in vivo experiments in fasting humans , — The nutritional state of the organism, fed or fasted, has recently been shown to modify the acute effect of insulin on VLDL production , perhaps due to a switch in fatty acid partitioning in the hepatocyte , , The acute inhibitory effect of insulin on VLDL production in fasting individuals appears to be independent of the profound FFA suppression induced by hyperinsulinemia in vivo , although this has been disputed by others Chronically insulin-resistant hyperinsulinemic, obese humans and those with type 2 diabetes are resistant to the acute inhibitory effect of insulin on VLDL production , , in keeping with similar findings in hepatocytes derived from fructose-fed and insulin-resistant rats , , For example, we recently found that VLDL secretion rate in healthy individuals is not predicted by the sensitivity of insulin-mediated suppression of plasma FFA concentration in the postabsorptive state but appears to be much more dependent on body mass index We have recently shown in the fructose-fed hamster, an animal model of insulin resistance whose lipoprotein physiology has a number of similarities to that of humans, and in vitro in cultured hamster hepatocytes, that hepatic VLDL-apo B overproduction is associated with whole-body insulin resistance and attenuated hepatic insulin signaling — Fructose feeding was associated with hyperinsulinemia, enhanced MTP expression in the liver, increased intracellular apo B stability, and facilitated assembly of apo B-containing lipoproteins leading to VLDL oversecretion Induction of insulin resistance was accompanied by a considerable rise in hepatic VLDL-apo B and VLDL-triglyceride production.
Although there was an increase in total apo B secretion, the apo B fraction secreted as VLDL was more prominently enhanced in fructose-fed hamsters, suggesting an increase in both the number of VLDL particles and the proportion secreted as VLDL. Enhanced apo B secretion appeared to be caused by increased intracellular stability of apo B, elevated levels of MTP, and enhanced assembly of VLDL particles, with no apparent changes in apo B translocational status in the endoplasmic reticulum.
Control studies showed that insulin resistance induced these changes rather than being direct effects of fructose itself.
More recently, we obtained molecular evidence for impairment of hepatic insulin signaling and insulin resistance, including reduced tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-2, and suppressed activity of PI3K associated with IRS proteins.
Importantly, changes in the insulin signaling pathway coincided with drastic suppression of ER, a cysteine protease previously shown to be associated with apo B in HepG2 cells that has been postulated to play an important role in the degradation of apo B in the endoplasmic reticulum lumen These changes were also accompanied by an increase in the secretion of apo B.
The rate of assembly and secretion of apo B-containing lipoproteins is critically linked with the expression level of MTP as demonstrated in an elegant series of studies in knockout mouse models as well as a model of adenoviral-mediated overexpression Chronic modulation of hepatic apo B secretion in insulin-resistant states may be mediated through changes in expression of MTP.
The promoter region of the MTP gene has an insulin response element, which is negatively regulated by the hormone Thus, it is reasonable to suggest that in insulin-resistant states, there may be a chronic up-regulation of MTP expression and protein levels due to resistance to suppressive effects of insulin on MTP gene expression, leading to hepatic VLDL overproduction.
Based on these recent data, we hypothesize that attenuated insulin signal transduction in hepatocytes causes suppression of ER protease expression, which may contribute to the observed increase in apo B stability.
Furthermore, impairment of hepatic insulin signal transduction may negate a negative regulatory effect of insulin on MTP expression, leading to the overexpression of this key protein, which may further facilitate VLDL assembly and secretion.
Enhanced hepatic FFA flux to the liver, as observed in insulin-resistant states, can provide ample lipid substrate for the high rate of VLDL assembly and secretion. An important additional factor may be up-regulation of SREBP-1c and chronic stimulation of DNL and reduced fatty acid oxidation in the liver , which can in turn enhance intracellular availability of triglyceride and drive VLDL assembly and secretion.
The important factor responsible for up-regulation of SREBP-1c seems to be hyperinsulinemia per se rather than insulin resistance Thus, an interaction between hepatic insulin resistance, hyperinsulemia, increased flux of FFA, and enhanced DNL may be essential to induce the VLDL overproduction state in IRS.
In summary, VLDL overproduction occurs as a result of a composite set of factors, which includes increased flux of fatty acids from extrahepatic tissues to the liver and directly from lipoprotein remnant uptake, increased hepatic de novo fatty acid synthesis, preferential esterification vs.
oxidation of fatty acids, reduced posttranslational degradation of apo B, and overexpression of MTP. These conditions, together with resistance to the normal acute suppressive effect of insulin on VLDL secretion, act in concert to channel fatty acids into secretory and storage rather than degradative pathways.
The increased flux of FFAs to the liver arise from adipose tissue resistance to insulin action, as described above, but we do not know whether the hepatic effects of IRS and type 2 diabetes arise as a result of insulin resistance or hyperinsulinemia per se.
It is possible that the changes in liver metabolism outlined above may be due to both increased and reduced insulin action, with some biochemical pathways in the liver remaining responsive to insulin i. It is well established that FFAs impair glucose metabolism in insulin-sensitive tissues, such as muscle and liver reviewed in Ref.
Recent studies in muscle have shown that there are multiple mechanisms responsible for this impairment Table 1 , but they may be initiated by a single event, i. There is general agreement, as discussed below, that an elevation of FFAs impairs cellular glucose uptake.
Recently, however, controversy has arisen regarding the inhibitory effect of FFAs on glucose oxidation that has been postulated to account for the FFA-mediated inhibition of glucose uptake i.
Although this issue remains unresolved, we will attempt to provide a balanced analysis of existing data. One of the mechanisms whereby FFAs have been postulated to impair glucose metabolism, by substrate competition, was first described by Randle et al.
According to the concept of substrate competition, glucose uptake is limited in tissues that can utilize both FFAs and glucose when the tissue energy needs are satisfied by increased FFA availability. FFA oxidation results in production of acetyl-CoA and reduced coenzymes [dihydronicotinamide adenine dinucleotide NADH and dihydroflavine adenine dinucleotide].
Acetyl-CoA can decrease glucose oxidation by inhibiting pyruvate dehydrogenase. In muscle, glucosephosphate inhibits hexokinase, and the consequent rise in intracellular glucose would ultimately decrease glucose uptake.
In vivo , FFA elevation obtained by Intralipid plus heparin infusion Intralipid is a triglyceride emulsion and heparin activates LPL, thereby hydrolyzing the Intralipid triglycerides to FFAs and glycerol consistently reduced glucose oxidation and decreased glucose uptake in the majority of hyperinsulinemic clamp studies in rats — , dogs — , and humans , — Under the latter conditions, most of the glucose uptake occurs in skeletal muscle.
In addition, leg and forearm balance studies , and studies using positron emission tomography have localized the reduction in whole-body glucose uptake to muscle. In these in vivo studies, the effect of FFA on glucose uptake was studied for a longer time than in in vitro preparations. The results showed that the expected reduction in glucose uptake is delayed , , , and is more often associated with decreased , , , rather than increased , muscle content of glucosephosphate.
Nevertheless, studies in humans based on nuclear magnetic resonance measurements of glucosephosphate , could not detect such an early increase. In addition, FFAs may induce a delayed impairment in glycogen synthesis, which exceeds that expected from the reduction in glucose uptake , It is therefore evident that in muscle, FFAs have effects on glucose metabolism other than or beyond those postulated by the classical Randle cycle i.
Some studies have linked the impairing effects of FFAs on muscle glucose metabolism with increased LCFA-CoA see for Ref. LCFA-CoAs accumulate in the cytosol when increased FFA inflow is associated with malonyl-CoA inhibition of CPT-1 the enzyme that transports fatty acid into the mitochondria for oxidation.
LCFA-CoAs have allosteric effects on purified enzyme preparations such as glycogen synthase ; however, the physiological importance of these effects in vivo in muscle is uncertain. Recent studies by Shulman and colleagues , , however, have also demonstrated that insulin signaling is directly and specifically impaired by FFAs.
By their esterification to diacylglycerol DAG , and perhaps directly, LCFA-CoAs stimulate PKC activity PKC has inhibitory effects on insulin action, due to serine-threonine phosphorylation of the insulin receptor and other intermediates in the insulin signaling cascade PKC can also directly inhibit glycogen synthase In rat skeletal muscle, Intralipid plus heparin infusion increased membrane-bound active PKCθ In addition, transgenic mice with inactivation of PKCθ have recently been shown to be protected from lipid-induced defects in insulin action and signaling in skeletal muscle , suggesting a direct role of PKCθ in the development of fat-induced insulin resistance in skeletal muscle.
Other studies have found that high-fat feeding increased DAG and the percentage of membrane-associated PKCε and θ Overexpression of PKCε, in particular, in skeletal muscle is believed to be causally related to the development of nutritionally induced insulin resistance and diabetes in the sand rat [ Psammomys obesus ], perhaps in part by increasing degradation of the insulin receptor.
Recent studies in muscle cell lines have suggested that ceramides, which can be derived from palmitoyl-CoAs via de novo synthesis, can also inhibit insulin signaling Ref.
LCFA-CoA may also affect GLUT4 translocation by acylating proteins involved in membrane fusion processes , although further studies are required to investigate this mechanism in muscle.
A pathway that has been linked with the FFA-induced impairment of muscle glucose metabolism by some authors but not by others is the hexosamine pathway. This is also an energy-sensing pathway, which is stimulated by increased glucose uptake under conditions of hyperglycemia and hyperinsulinemia.
FFAs could stimulate this pathway via increased fructosephosphate due to FFA-induced inhibition of PFK PFK-1 could be inhibited by citrate or by depletion of xylulosephosphate see Ref.
The mechanism of hexosamine-induced insulin resistance is unknown, although O -glycosylation of insulin signaling molecules or transcription factors may be implicated Another pathway that may be involved in the FFA- induced impairment in glucose metabolism is oxidative stress.
FFAs can directly increase reactive oxygen species ROS via peroxidation reactions and via mitochondrial production FFAs can also indirectly increase ROS via hexosamine biosynthetic products Recent data obtained in collaboration with Dr.
Fantus University of Toronto and co-workers suggests that iv infusion of N -acetyl- l -cysteine NAC , an antioxidant, abolishes hyperglycemia and glucosamine-induced insulin resistance and prevents, in part, FFA-induced insulin resistance in rats Infusion of reduced glutathione, an antioxidant, partially prevented FFA-induced insulin resistance in humans The biochemical mechanisms of oxidative stress-induced insulin resistance are unknown; however, it is well known that ROS can affect both signal transduction and gene expression, perhaps via redox modification of critical molecules.
It is known that both oxidative stress and the glucosamine pathway can induce PKC activation. Perhaps linked to FFA-induced oxidative stress and PKC activation is the activation of IκB kinase β IKK-β , a serine-threonine kinase that phosphorylates the insulin receptor and IRSs, thus inhibiting their tyrosine kinase phosphorylation.
The latter pathway has recently been implicated in FFA-induced inhibition of insulin signaling and action, because high-dose salicylate, an inhibitor of IKK-β , prevented FFA-induced insulin resistance in skeletal muscle in vivo , and IKK-β-knockout mice did not exhibit altered skeletal muscle insulin signaling and action after lipid infusion , Also perhaps linked to oxidative stress and to synthesis of ceramides is the induction of inducible nitric oxide iNOS in muscle, which has recently been implicated in insulin resistance in the high-fat-fed rat By activating all the signaling pathways described above, FFA can indirectly influence gene expression FFAs and their eicosanoid derivatives can also directly affect gene expression by binding to PPARs These nuclear receptors induce genes of peroxisomal and mitochondrial fatty acid oxidation , thus potentially up-regulating the Randle cycle.
Paradoxically, however, PPAR activation increases muscle insulin sensitivity, presumably because of induction of uncoupling proteins, which dissipate intracellular energy and reduce intracellular triglycerides.
This may be viewed as a protective mechanism whereby fat accumulation tends to be self-limited. Fat accumulation also depends on the type of fatty acid.
n-3 fatty acids, which preferentially activate PPARs, are associated with less muscle fat accumulation and increased insulin sensitivity compared with saturated fatty acids Fatty acid activation of PPARγ in the adipocyte, perhaps by increasing adipocyte insulin sensitivity and by stimulating adipogenesis, may also indirectly improve muscle insulin sensitivity in vivo by modulating a fat-derived signaling molecule or FFA flux from adipose to muscle tissue Most of the in vivo literature regarding the effect of FFA on hepatic glucose metabolism refers to the acute effect of Intralipid and heparin on glucose production.
Intralipid plus heparin increases FFA as well as glycerol, which is a gluconeogenic precursor, and in almost all of the studies, a glycerol control was not performed. However, glycerol infusion had negligible effects on glucose production in both dogs and humans , whereas we have shown that direct infusion of FFA oleate can increase glucose production during low-dose insulin clamps in dogs In a number of studies, which were mostly conducted at basal insulin levels, Intralipid plus heparin increased gluconeogenesis but not glucose production, consistent with a compensatory reduction in glycogenolysis — This decrease in glycogenolysis may have been due, in part, to small changes in portal insulin concentrations induced by FFA stimulation of insulin secretion or to FFA-induced changes in plasma glucose However, a compensatory reduction in glycogenolysis was also found in studies in which basal insulin and glucose levels were clamped This is consistent with an intrahepatic autoregulatory mechanism, which has mainly been attributed to glucosephosphate stimulation of glycogen synthase and inhibition of phosphorylase Hepatic autoregulation may break down, as evidenced by the increase in basal glucose production induced by Intralipid plus heparin in other studies , The breakdown of autoregulation is facilitated under hyperinsulinemic clamp conditions , , , , , presumably because, at hyperinsulinemia, glycogenolysis is already maximally suppressed.
It is also possible that, as is the case in muscle, FFAs eventually impair insulin signaling, leading to an increase of both glycogenolysis and gluconeogenesis and perhaps also to a decrease of hepatic glucose uptake The latter is currently controversial , The effect of FFA on hepatic glucose production during hyperinsulinemic clamps, however, is more controversial than the effect of FFA on peripheral glucose uptake, as in some studies , , , Intralipid plus heparin failed to increase glucose production.
The negative results could be explained, in part, by the high rate of insulin infused, which completely suppressed glucose production, independent of FFA , , In addition, in most studies, plasma glucose-specific activity was not maintained constantly during the clamp, which leads to an underestimation of glucose production, particularly in the early non-steady-state periods of the clamp Due to this methodological problem, the time course of the effect of FFA on glucose production could not be accurately estimated in most studies , , although there is some suggestion that it might be more rapid than the time course of the effect of FFA on peripheral glucose uptake , , Some of the mechanisms that have been implicated in the FFA-induced impairment of hepatic glucose metabolism are shown in Table 1.
The classical Randle hypothesis has been expanded to include FFA-induced stimulation of gluconeogenesis. As is the case with FFA-induced inhibition of glycolysis, this pathway is also related to FFA oxidation. Acetyl-CoA derived from FFA oxidation stimulates pyruvate carboxylase, and the increased NADH is necessary to produce glyceraldehydephosphate from 1,3 bisphosphoglycerate.
Citrate-induced inhibition of PFK-1 which reduces glycolysis has been demonstrated in the perfused rat liver and in isolated hepatocytes exposed to FFA In the liver, in contrast to muscle, the increased content of glucosephosphate from reduction of glycolysis and stimulation of gluconeogenesis should not affect glucose uptake because liver glucokinase, unlike muscle hexokinase, is not inhibited by glucosephosphate.
However, translocation of glucokinase [ i. As is the case with muscle, FFA oxidation might be inadequate to fully account for the FFA-induced changes in glucose metabolism in liver. In addition, in the high-fat-fed rat, the resistance of glucose production to insulin was not ameliorated by inhibitors of FFA oxidation LCFA-CoAs accumulate in liver, when increased FFA exposure is combined with inhibition of fatty acid oxidation due to elevated malonyl-CoA Numerous allosteric effects of LCFA-CoA on purified hepatic enzyme preparations, including an inhibition of glucokinase , inhibition or stimulation of glucosephosphatase , inhibition of glycogen synthase , and stimulation of glycogen phosphorylase , have been described; however, the physiological importance of these effects in vivo is uncertain.
LCFA-CoAs stimulate PKC in hepatocytes Phosphorylation by PKC can directly influence enzyme activity [for example, PKC reduces hepatic glycogen synthase activity ] and impair hepatic insulin signaling.
Accordingly, hepatic triglyceride content, which is proportional to cytosolic LCFA-CoA, seems to correlate with hepatic insulin resistance Our recent data show that in liver, FFAs increase glucose production in the basal state and induce hepatic insulin resistance. The increase in basal glucose production is not progressive over time and is associated with increased hepatic citrate content Hepatic insulin resistance is progressive over time and is associated with a progressive increase in PKCδ membrane translocation Little is known about the role of the hexosamine pathway and of oxidative stress in the FFA-induced insulin resistance in the liver.
However, transgenic mice with selective overexpression of glutamine-fructose amidotransferase in the liver the rate-limiting enzyme for increasing flow through the hexosamine pathway show hepatic insulin resistance Furthermore, studies in collaboration with Dr.
Fantus suggest that the antioxidant NAC partially prevents FFA-induced hepatic insulin resistance in rats. In the liver as well as in muscle, FFAs induce enzymes of FFA oxidation, including CPT-1 , an effect mediated by PPARs In addition, in the liver, polyunsaturated fatty acids repress ACC gene expression by inhibiting SREBP-1 This could also contribute to the establishment of a chronic Randle cycle by decreasing malonyl-CoA, which inhibits CPT PPAR response elements have been shown on genes of enzymes that are not involved in the Randle cycle, such as phosphoenolpyruvate carboxykinase and glucokinase In addition, glucosephosphatase mRNA and protein are induced by Intralipid infusion in vivo , an effect that may be PPAR dependent Paradoxically, however, the predominant effect of PPAR activation is to increase rather than decrease hepatic insulin sensitivity, presumably by limiting fat accumulation.
In the liver, PPAR-independent effects account for the repression of glycolytic and lipogenic enzymes by n-3 and n-6 fatty acids the mechanism is through inhibition of SREBP-1 and by fatty acyl-CoA [the mechanism is through inhibition of hepatocyte nuclear factors ]. These effects may also improve hepatic glucose metabolism by limiting fat overload.
In summary, increased provision of FFAs in a setting of increased energy availability leads to insulin resistance, thus preventing further intracellular accumulation of energy substrates. It is unclear whether this response is entirely maladaptive or also provides some advantage in terms of avoidance of massive obesity and perhaps avoidance of cell toxicity from tissue fat overload, at least in cardiac muscle and liver The trade-off is a tendency to increased circulating energy substrates fat and glucose and compensatory hyperinsulinemia.
Hepatic insulin resistance and hyperinsulinemia in a setting of elevated FFA influx to the liver lead to increased production of VLDL particles reviewed in Ref.
In insulin-resistant states, peripheral hyperinsulinemia is caused both by insulin hypersecretion and by reduced hepatic extraction of insulin One of the factors that may account for the impaired hepatic insulin extraction in obesity is elevated circulating FFA levels. In the in situ -perfused rat liver, physiological FFA concentrations caused a decline in hepatic insulin extraction We have found that an elevation of circulating FFA from an Intralipid plus heparin infusion decreases hepatic insulin extraction in vivo in dogs In further studies, the impairment in hepatic insulin extraction appeared to be greater when equimolar oleate infusion was given portally vs.
peripherally to selectively elevate the hepatic FFA levels and thus mimic visceral obesity In agreement with our findings, Hennes et al. We have obtained similar findings in humans but only after prolonged Intralipid plus heparin infusion.
On the contrary, others failed to show changes in hepatic insulin extraction after 48 h of Intralipid plus heparin infusion performed during a h hyperglycemic clamp The majority of studies in humans did not show differences in peripheral insulin levels when hyperinsulinemic euglycemic clamps were carried out with or without Intralipid plus heparin infusion see, for example, Refs.
Because insulin was infused peripherally in these studies, however, the impact of the liver on the resultant peripheral insulin levels was less than with physiological portal insulin delivery.
Furthermore, in most of these studies the duration of the Intralipid plus heparin infusion was not long. In rats, the reduction in insulin clearance that we observed during a hyperinsulinemic clamp was greater after 7 h than 2 h of the Intralipid plus heparin infusion Hepatic insulin extraction depends on insulin binding to its receptor.
In isolated rat hepatocytes, low physiological concentrations of FFA reduced insulin binding and degradation in proportion to a decreased receptor number , In addition, FFAs may activate PKC Ref.
In our preliminary studies on isolated rat hepatocytes, PKC inhibition abolished the FFA-induced reduction in insulin binding We are currently determining the isoform of PKC involved. In vivo in rats, the progressive reduction of insulin clearance induced by Intralipid and heparin was associated with a progressive increase in PKCδ translocation , Interestingly, PKC activation has also been implicated in FFA-induced insulin resistance, which would explain the association between impaired insulin extraction and sensitivity The FFA-mediated reduction in hepatic insulin extraction may be viewed as an adaptive mechanism to generate peripheral hyperinsulinemia, and thus, to partially overcome the peripheral insulin resistance induced by FFAs.
This adaptive mechanism could relieve, in part, the stress on pancreatic β-cells imposed by insulin resistance Fatty acids are actively taken up and metabolized by β-cells and can regulate β-cell enzymes, ion channels, and genes , In the latter study , it was demonstrated that more saturated animal fat was far more potent in acutely facilitating insulin secretion in vivo and that the insulinotropic effects of individual fatty acids in a perfused rat pancreas model increased and decreased dramatically with chain length and degree of unsaturation, respectively.
Acute lowering of plasma FFAs with nicotinic acid results in a reduction in basal plasma insulin in both nonobese and obese healthy fasted individuals , and in patients with type 2 diabetes The prevailing FFA concentration also appears to play an important role in maintaining β-cell responsiveness to glucose during fasting The precise mechanisms responsible for the acute effects of FFAs on insulin secretion are still debated.
Intracellular FFAs are rapidly converted to fatty acyl-CoA, which can be oxidized to produce ATP. However, contrary to glucose, ATP generation followed by closure of the K-ATP channels is not the main mechanism of the acute stimulatory effect of FFAs on insulin secretion.
Instead, the key factor appears to be accumulation of cytosolic LCFA-CoA when FFA oxidation is inhibited by glucose-derived malonyl-CoA , , Of note, the acute effect of FFAs on insulin secretion does not appear to be specific for a glucose stimulus, which suggests that final common events in stimulus secretion coupling may be involved Some of these mechanisms PKC activation may be operational in both β-cells and peripheral tissues and thus link insulin resistance and hyperinsulinemia at the cellular level.
These hormones sense dietary nutrients and send appropriate neural signals to the brain specifically the hypothalamus to orchestrate fuel usage for either oxidation into energy or long-term storage. The central hormone involved in this metabolic communication system is insulin.
However, increased inflammation can disturb these complex communication systems eventually leading to metabolic defects obesity, metabolic syndrome, and diabetes.
Insulin is the primary regulator of carbohydrate, fat, and protein metabolism [ 1 — 3 ]. It inhibits lipolysis of stored fat in the adipose tissue and gluconeogenesis in the liver, it stimulates the translocation of the GLUT-4 protein to bring glucose into the muscle cells along with gene expression of proteins required for the optimal cellular function, cellular repair, and growth, and it indicates the metabolic availability of various fuels to the brain.
Therefore keeping insulin within a therapeutic zone is critical for our survival. In the past, access to adequate nutrients was a major concern. Today we have a new concern: Excess nutrient intake. However, even in this regard, insulin plays a primary role in defending the body against potential damage by using the adipose tissue, liver, and skeletal muscle as biological buffers against excess nutrient intake.
This is important since all dietary nutrients are naturally inflammatory since their metabolism into other biological materials or conversion to energy can generate molecular responses that can activate increased inflammation [ 4 ]. This means that the intake of excess nutrients sets the foundation for the generation of excess inflammation.
In the face of increased inflammation, the ability of insulin to orchestrate metabolism becomes compromised. Obesity is different than insulin resistance. Obesity is defined as the excess of body fat. That itself is not necessarily an adverse condition as long as the fat is safely stored in healthy fat cells that respond to insulin.
Insulin resistance is a condition in which cells are no longer responding appropriately to circulating insulin. Although there are many potential molecular causes of insulin resistance, ultimately they are all either directly or indirectly caused by increased inflammation.
The definition of insulin resistance is deceptively simple a condition in which cells are no longer responding appropriately to circulating insulin. Although the molecular mechanism is not fully understood, at the cellular level the strength of insulin signaling from its receptor to its final action is attenuated.
It is also known that certain short-term dietary changes can rapidly reduce insulin resistance before any significant fat loss occurs. This would include stringent calorie restriction to reduce insulin resistance within a matter of days [ 7 ].
Likewise, certain drugs, such as corticosteroids, can rapidly increase insulin resistance [ 8 ]. Furthermore there are various metabolic adaptations to stressors that can induce insulin resistance. These stressors include pregnancy, hibernation, and sepsis [ 1 ].
The increase in insulin resistance in response to these stressors is a method of diverting stored nutrients to address the necessary metabolic adaptation.
Likewise sleep deprivation is another effective way of increasing insulin resistance in the short-term [ 9 ]. However, it is chronic insulin resistance that appears to be directly or indirectly related to diet-induced inflammation. The mechanisms at the molecular level are complex and manifold.
The primary suspects appear to be inflammatory mediators including the inflammatory cytokine tumor necrosis factor alpha TNFα as well as inflammatory protein kinases such as c-JUN N-terminal kinase JNK and the IKK complex [ 10 ]. The JNK pathway is stress-activated and is associated with the presence of M1 activated macrophages [ 12 ].
If the IKK complex is activated by inflammation, it phosphorylates IκB the inhibitor of NF-κB leading to its rapid degradation. Once IκB is degraded, it can no longer prevent the free entry of NF-κB into the nucleus.
Once NF-κB enters the nucleus it causes the expression of additional inflammatory mediators such as cytokines IL-1, IL-6, TNFα, etc.
and enzymes such as COX-2 [ 13 ]. The suggestion that inflammation may be related to insulin resistance came more than a century ago when it was observed that certain anti-inflammatory drugs salicylates and aspirin were effective in reducing the hyperglycemia observed in diabetes [ 14 — 17 ].
It is now known that these drugs are inhibitors of phosphorylation action of the IKK complex [ 18 , 19 ]. Table 1 summarizes the various inflammatory pathways, but the underlying general mechanism of each ultimately appears to be induced through increased inflammation within the cell.
The first three pathways have been discussed extensively in the literature; therefore this review will focus on the latter pathway. Additional molecular mechanisms of insulin resistance include the lipid- overload hypothesis in which there is a build-up of diacylglycerides DAG or ceramides that inhibit the signaling of insulin as well as endoplasmic reticulum ER stress induced by excess calories or oxidative stress induced by the generation of excess free radicals [ 20 — 22 ].
Making these diverse molecular mechanisms of insulin resistance even more complex is that they are operative in some organs and not in others. Insulin resistance can be characterized as a metabolic dysfunction that is often mediated by increased inflammation. Much of that inflammation may be diet-induced via the role of various dietary fatty acids.
In particular, omega-6 and saturated fatty acids especially arachidonic acid AA and palmitic acid can be viewed as pro-inflammatory molecules, whereas omega-3 fatty acids especially eicosapentaenoic acid EPA and docosahexaenoic acid DHA can be viewed as anti-inflammatory molecules.
This is because they have the ability to function as the necessary substrates to generate resolvins as well as binding to specific binding proteins that can decrease insulin resistance in an organ.
The various organs that can be affected by these fatty acid-mediated effects are shown in Fig. In many ways insulin resistance appears to start in the hypothalamus. The hypothalamus acts to match energy intake to energy expenditure to prevent excess accumulation of stored energy [ 23 ]. In particular, satiety signals from the gut are matched to adiposity primarily-leptin and blood primarily-insulin hormonal signals to control food intake [ 24 , 25 ].
Unfortunately, either excess calories or saturated fats especially palmitic acid can cause inflammation in the hypothalamus, leading to resistance to the satiety signaling of both insulin and leptin [ 26 — 28 ]. As a result, satiety is attenuated and hunger increases. The hypothalamus also contains GPR binding proteins that are specific for long-chain omega-3 fatty acids such as EPA and DHA [ 29 ].
Thus the presence of adequate levels of these omega-3 fatty acids in the diet can decrease inflammation within the hypothalamus [ 30 ]. In fact, intracerebroventricular icv injections of omega-3 fatty acids into obese rats decrease insulin resistance [ 29 — 31 ].
Likewise, similar icv injections of anti-TLR-4 and anti-TNFα antibodies also decrease insulin resistance [ 32 ]. High-fat diets HFD , especially those rich in saturated fats, are the standard method to cause diet-induced obesity in animal models. Increased inflammation appears in the hypothalamus within 24 h after beginning a HFD as indicated by increases in JNK and IKK proteins as well as increased expression of TLR-4 receptors and detection of ER stress [ 33 ].
IKK induces inflammation via activation of NF-κB, which inhibits the normal hormonal signaling of leptin and insulin necessary to create satiety. Activation of JNK is often preceded by the increase in ER stress [ 34 ]. This sets up a vicious cycle of increased hunger that eventually leads to the accumulation of excess calories as stored fat in the adipose tissue.
It should be noted that the inflammation in the hypothalamus precedes any weight gain in the adipose tissue [ 35 ]. This also explains why significant calorie restriction can reduce insulin resistance before any significant loss in excess body fat in the adipose tissue.
These experimental observations suggest that the hypothalamus is the central control point for the development of insulin resistance. Excess nutrient intake especially saturated fat can also indirectly cause inflammation in the hypothalamus by activation of the TLR-4 receptors in the microglia in the brain eventually causing inflammatory damage to neurons in the hypothalamus [ 28 ].
It has been shown that with an extended use of a HFD that there is a decrease in the number of neurons responsible for generating satiety signals in the hypothalamus [ 36 ]. HFD diets are also associated with increased production of palmitic acid-enriched ceramides in the hypothalamus.
This would provide still another link to the increased insulin and leptin resistance giving rise to increased hunger as satiety depends on functioning insulin pathways in the hypothalamic neurons [ 37 ].
Besides the presence of the GPR receptors in the hypothalamus, which if activated by omega-3 fatty acids decrease inflammation [ 38 , 39 ], there are other fatty-acid-nutrient sensors in the hypothalamus that can be activated to increase inflammation.
If those fatty acids are rich in palmitic acid the primary product of de novo lipid production in the liver caused by excess dietary glucose , then the HPA axis is activated to release more cortisol thereby increasing insulin resistance [ 40 ].
On the other hand, if the fatty acid being sensed is primarily oleic acid, there will be a reduction in NPY a powerful appetite-inducing hormone expression in the hypothalamus that promotes satiety [ 41 ]. Finally there is the interaction of the hypothalamus with the liver via signaling through the vagus nerve [ 42 ].
This may explain why any inhibition of TNFα or TLR-4 signaling in the hypothalamus also decreases glucose production in the liver. As you can begin to appreciate, the central regulation of appetite control by the hypothalamus is a very complex orchestration of the levels of inflammation and nutrient intake generated by the diet and the sensing of those levels by the hypothalamus.
We often think of obesity as the cause of insulin resistance, yet as described above, the genesis of insulin resistance appears to start in the hypothalamus with a disruption in the normal balance of hunger and satiety signals.
As hunger increases, so does calorie intake. The most effective site for storage of excess fat calories is the adipose tissue including those excess calories from carbohydrates that are converted to fat in the liver.
The fat cells of the adipose tissue are the only cells in the body that are designed to safely contain large amounts of fat. This is why the adipose tissue is extremely rich in stem cells that can be converted to new fat cells to contain large levels of excess energy as triglycerides [ 43 ].
As long as those fat cells are healthy, there are no adverse metabolic effects except excess weight for the person. They have excess body fat but no metabolic disturbances that characterize the manifestation of insulin resistance.
However, fat cells do not have an unlimited capacity to expand. Even though the adipose tissue is highly vascularized, the over-expansion of existing fat cells can create hypoxia, which activates the HIF-1 gene [ 45 , 46 ].
This results in the increased expression of both JNK and IKK thereby creating inflammation within the fat cell [ 47 ]. This inflammation, in turn, creates insulin resistance within the fat cell. In the adipose tissue, insulin is normally an anti-lipolytic hormone as it decreases the activity of hormone-sensitive lipase HSL , which is required to release stored fatty acids [ 48 ].
With the development of cellular inflammation and insulin resistance in the fat cell, higher levels of free fatty acids FFA can leave the fat cell to enter into the circulation and be taken up by other organs, such as the liver and the skeletal muscles that are unable to safely store large amounts of fat.
As described later, this leads to developing insulin resistance in these organs. With increased inflammation in the fat cells, there is also a migration of greater numbers of M1 macrophages into the adipose tissue with a corresponding release of inflammatory cytokines, such as TNFα, which further increases insulin resistance and lipolysis [ 49 , 50 ].
Theoretically, new healthy fat cells could be generated from stem cells within the adipose tissue. However, that process requires the activation of the gene-transcription factor PPARγ [ 53 ].
The activity of this gene-transcription factor is inhibited by inflammatory cytokines, such as TNFα [ 54 ]. On the other hand, the activity of PPARγ is increased in the presence of anti-inflammatory nutrients, such as omega-3 fatty acids and polyphenols [ 55 , 56 ].
Without the ability to form new healthy fat cells, the continued expansion of the existing fat cells eventually leads to cell death and further adipose tissue inflammation caused by incoming neutrophils and macrophages to clean the cellular debris caused by the necrotic fat cells [ 57 ].
As stated earlier, insulin resistance can inhibit the action of HSL due to increased hyperinsulinemia. Ironically, the increased hyperinsulinemia activates the lipoprotein lipase at the surface of the fat cell that hydrolyzes lipoprotein triglycerides to release free fatty acids [ 58 , 59 ].
This also increases the synthesis of fatty-acids-binding proteins that bring the newly released FFA from the lipoproteins into the fat cells for deposition [ 60 , 61 ]. The increase in fatty acid flux into the fat cells also requires greater synthesis of the FFA into triglycerides, but this can lead to ER stress activating the JNK pathway, thus further increasing insulin resistance in the fat cells [ 62 ].
This sets up a vicious cycle in which insulin resistance results in greater hunger via insulin resistance in the hypothalamus with increasing flux of FFA both into and out of the adipose tissue [ 63 ]. The cytokines being released by the pro-inflammatory M1 macrophages being attracted to the adipose tissue due to increasing cellular inflammation only increase this process by accelerating insulin resistance in the fat cells.
This is why obese individuals with insulin resistance have greater levels of both the uptake and release of FFA into and from the adipose tissue.
The increase in lipid influx causes an over-load of the synthetic capacity to make triglycerides, and as a result both DAG and ceramide levels begin to increase, which only further increases insulin resistance in the fat cells [ 64 ].
The speed of the inflammatory changes in the adipose tissue is not as rapid as they are in the hypothalamus. Whereas inflammatory changes can be seen in the hypothalamus within 24 h after beginning a HFD in animal models, it often takes 12—14 weeks to see similar changes in inflammation in the adipose tissue [ 65 ].
If the fat cells cannot expand rapidly enough to store this increasing fatty acid flow, then the excess released fatty acids begin to accumulate in other tissues such as the liver and skeletal muscles, and this begins the process of lipotoxicity that further increases systemic insulin resistance [ 66 ].
It is with the development of lipotoxicity that the real metabolic consequences of insulin resistance begin. The liver can be viewed as the central manufacturing plant in the body.
Raw materials primarily carbohydrates and fats are bought into the body to be processed by the liver and either stored as liver glycogen or repackaged as newly formed triglycerides in the form of lipoproteins.
The liver helps maintain stable glucose levels between meals by balancing glycogenesis glycogen formation and glycolysis of stored glycogen [ 67 ].
Unlike the adipose tissue that can safely store excess fat, the liver cannot. Therefore of the first adverse metabolic consequences of insulin resistance is the build-up of fatty deposits in the liver. This is known as non-alcoholic fatty liver disease or NAFLD.
Another difference between the liver and the adipose tissue is the lack of infiltrating macrophages. Whereas a significant increase is observed in the levels of macrophages in the adipose tissue upon inflammation, it is the internal macrophages Kupfer cells in the liver that become activated.
These activated Kupfer cells can now release cytokines that will further activate NF-κB in the liver cells. Like hypothalamic inflammation, NAFLD can be rapidly generated in animal models within 3 days of starting a HFD [ 69 ].
This may be due to the direct linkage of the hypothalamus to the liver via the vagal nerve [ 70 ]. Once NAFLD is established, the ability of insulin to suppress liver glucose production is diminished without changes in weight, fat mass, or the appearance of any indication of insulin resistance in the skeletal muscle [ 71 ].
Because of the rapid build-up of fatty acids in the liver, the ability to convert them to triglycerides is also overwhelmed and DAG formation in liver increases [ 67 , 71 ]. This is why the levels of DAG in the liver are the best clinical marker that chronic insulin resistance has begun to develop in that organ.
The primary source of the fatty acids coming to the liver is via the adipose tissue because as the adipose tissue develops insulin resistance, the increased flow of FFA from the fat cells into the blood and therefore into the liver increases [ 72 ].
De novo lipid synthesis of fats from glucose in the liver is a smaller contributor to this increased flux of FFA into the liver [ 73 ]. Furthermore, liver insulin resistance is related only to the fatty acid levels in the liver, not the levels of visceral fat [ 74 ].
This may explain why many normal BMI individuals especially Asians can have high levels of insulin resistance in the liver [ 75 ]. Since the liver also controls cholesterol synthesis, insulin resistance in this organ is reflected in growing dysfunction in lipoprotein synthesis.
In particular, VLDL particles are increased and HDL levels are decreased [ 67 ]. Skeletal muscle represents the key site for glucose uptake. Thus reducing insulin resistance in this organ becomes a primary strategy for managing diabetes. Unlike the adipose tissue where macrophage infiltration is a key indicator of inflammation, there is very little macrophage infiltration observed in skeletal muscle in individuals with insulin resistance [ 77 ].
It appears that cytokines coming from other organs adipose tissue and liver may have the important impact on the development of insulin resistance in the muscle.
However, enhanced signaling through the TLR-4 receptor by saturated fatty acids can reduce fatty acid oxidation of the lipids in the muscle [ 78 ]. In addition, palmitic acid is the preferred substrate for ceramide synthesis [ 79 ].
Whereas ceramide levels are not related to insulin resistance in the liver, they are strongly related to insulin resistance in the muscle [ 80 ].
The skeletal muscle is unique that exercise can overcome insulin resistance in this organ by increasing the oxidation of accumulated fatty acids and enhancing the transport of glucose into the cell [ 81 ].
This suggests that the molecular drivers of insulin resistance can be different from organ to organ. Although the beta cells of the pancreas sense glucose levels in the blood via glucokinase [ 82 ] and secrete insulin in response to those levels, the beta cells of this organ are not normally considered targets of insulin resistance.
However, the beta cells are very prone to toxicity mediated by inflammatory agents. In particular, HETE derived from AA is very toxic to the beta cells [ 83 ]. With the destruction of the beta cells by HETE, the pancreas is no longer able to maintain compensatory levels of insulin secretion to reduce blood-glucose levels and the development of type-2 diabetes is rapid.
Like the pancreas, the GI tract is also not considered a standard target organ for insulin resistance, but it is the first organ in the body for nutrient sensing of molecules that can ultimately affect insulin resistance.
This begins in the oral region. Fatty-acid receptors such as GPR and GPR40 and fatty binding proteins such as CD36 are present in the mouth and line the entire GI tract [ 84 ].
CD36 binds oleic acid and helps convert it into oleylethanolamide OEA [ 85 ]. OEA activates PPARα gene transcription factor to increase satiety and also the expression of the enzyme required for fatty acid oxidation [ 86 ].
Thus the type of fat sensed in mouth and gut provides satiety signals to hypothalamus. The increased satiety lowers the overall caloric intake and reduces development of ER and oxidative stress thus indirectly reducing the development of insulin resistance.
These specific cells sense and respond to specific nutrients by secreting more than 20 different hormones [ 87 ]. The primary hormones secreted by these cells that relate to insulin resistance include CCK from the proximal I-cells and GLP-1 and PYY from the distal L-cells.
CCK is the hormone secreted from the I-cells in response to the fat content in a meal [ 88 ]. This is short-acting hormone and works in association with serotonin to suppress hunger by directly interacting with the hypothalamus via the vagus nerve [ 89 , 90 ].
In animal models being fed a HFD, the satiety signals of CCK to the hypothalamus can become attenuated probably by increased inflammation in the hypothalamus [ 91 ]. CCK can also reduce glucose synthesis in the liver probably through its interaction with the hypothalamus [ 92 ], but only if its hormonal signaling pathway is not being disrupted by inflammation within the hypothalamus.
PYY and GLP-1 are the hormones released by protein and glucose respectively when sensed by the L-cells more distal in the GI tract. Both of these hormones are powerful inducers of satiety [ 93 , 94 ].
It has been shown that PYY responses are lower in obese individuals compared to lean individuals [ 95 ]. Animal models that have increased levels of PYY due to transgenetic manipulation are resistant to dietary induced obesity [ 96 ].
It should be noted that PYY levels rapidly rise after gastric bypass surgery helping to explain the long-term weight loss success of this surgical intervention [ 97 ].
Finally, any mention of the GI tract would not be complete without discussing the microbial composition of the gut. It is known that the microbiota is different in lean and obese individuals [ 98 , 99 ].
The microbial composition also may be a source of low-grade intestinal inflammation especially via endotoxemia mediated by the lipopolysaccharide LPS component of gram-negative bacteria that interacts with the TLR-4 receptor. TNFα is up regulated in the ileum of the GI tract by HFD before weight gain is observed in animal models [ ].
It is also known that a single high-fat or high-carbohydrate meal can induce such endotoxemia during the increased permeability of the gut during digestion [ — ].
Thus a diet that is higher in protein and lower in both carbohydrate and fat should reduce endotoxemia. Any LPS fragments that enter the blood stream are carried by chylomicrons to the lymph system where it can then interact with the TLR-4 receptors in the body to increase TNFα levels that can generate insulin resistance in a wide variety of organs [ ].
Furthermore, it has been demonstrated in animal models that a high-fat diet can initiate insulin resistance via endotoxemia as well as change the composition of the gut microbiota [ , ]. It has also been recently demonstrated that composition of the high-fat diet either rich in saturated fat or omega-3 fats can dramatically alter the composition of the gut microbiome and influence the levels of endotoxemia in animal models [ ].
Insulin resistance is easy to define, but complex to understand at the molecular level. The same is true for inflammation. This leads to a major limitation of this review because of the integral relationship of fatty acids to inflammation especially as precursors to eicosanoids as modulators of inflammation.
In this more limited review, we have tried to focus on the role of fatty acids interactions with specific binding sites in different organs or their synthesis into non-hormonal lipids that may be related to the wide range of the adverse metabolic consequences associated with insulin resistance.
It appears that insulin resistance starts in the hypothalamus causing a disruption in the balance of satiety and hunger signals. This leads to overconsumption of calories.
Although excess calories can be theoretically stored safely in the adipose tissue, as the inflammation increases in this organ and insulin resistance develops in the fat cells, the ability to safely store excess fat is compromised.
One of the consequences of insulin resistance in the adipose tissue is that excess fat is released into the blood stream and is sequestered by other organs liver and skeletal muscles that are not equipped to safely store this excess fat.
This is the start of lipotoxicity. With increased lipotoxicity, the metabolism and energy generation becomes compromised, and the development of chronic diseases diabetes, heart disease, and polycystic ovary syndrome associated with insulin resistance becomes accelerated. The levels of fat in the diet and the composition of those fatty acids in the fat component can have a significant role in the modulation of insulin resistance.
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Amalia Pumpkin Seed Recipes for SnacksMelania GagginiMetabolidm A. Minimize water retention Role of Adipose Tissue Insulin Resistance in the Natural History of Type 2 Diabetes: Metavolism Pumpkin Seed Recipes for Snacks the San Antonio Metabolism Study. Diabetes 1 April ; 66 4 : — In the transition from normal glucose tolerance NGT to type 2 diabetes mellitus T2DMthe role of β-cell dysfunction and peripheral insulin resistance IR is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated.
Fredrik KarpeJulian Pumpkin Seed Recipes for Snacks. DickmannKeith N. All-natural weight loss pills Fatty Acids, Obesity, and Insulin Tesistance Pumpkin Seed Recipes for Snacks for a Reevaluation. Diabetes 1 October ; 60 Fst : — Insuiln is a widespread acceptance resiistance the literature that plasma nonesterified fatty acids NEFAalso called free fatty acids FFAcan mediate many adverse metabolic effects, most notably insulin resistance. Elevated NEFA concentrations in obesity are thought to arise from an increased adipose tissue mass. It is also argued that the process of fatty acid mobilization from adipose tissue, normally suppressed by insulin, itself becomes insulin resistant—thus, lipolysis is further increased, potentially leading to a vicious cycle.
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