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Insulin Resistance Vs Insulin Sensitivity When it comes to insulin and insulin sensitivity vs insulin resistance, you are always on a continuum of how insulin sensitive your are are and what tissues are most effective at absorbing glucose. This entry was posted in Misc, Nutrition and tagged carbohydrates, carbs, diabetes, insulin. Back in 2008, I began writing about the effect of dietary fat on insulin sensitivity, and blood levels of glucose and insulin.
Over the years I learned that saturated fat decreased insulin sensitivity more than other fats, e.g. One mechanism by which dietary fat decreases insulin sensitivity, raising blood glucose and insulin levels is through reduced action of the glucose transporter GLUT4. Rats fed a high (50% of calories) fat diet for 8 weeks showed 50% decreases in insulin-stimulated glucose transport. Subjects were deprived of dietary fat (via gastric surgery that decreases predominantly fat absorption). Mice that were fed a high-fat diet and that became obese were protected against insulin resistance and the high glucose and insulin levels of their counterparts when they were bred to have more GLUT4.
That reduction in endothelial NO (NO is nitric oxide) production contributes to high blood pressure. This entry was posted in Diabetes, Fat and Oil, Insulin Resistance, Saturated Fat on June 5, 2014 by Bix.
Bix Saturated fat is one of our best sources for environmental pollutants, a confounder not adjusted for here. Fanatic Cook by Bix is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Without the assisance from the book I don’t think I would have made changing my lifestyle this far. According to diabetes 2 diet and exercise research your gut bacteria are the most accurate preditors for obesity compared to any other risk factors found what are the symptoms for diabetes in your genetic pool1. The bes thing I’ve found about pumping is the stark reduction in the number types and intensity of the hypos experienced. This Quinoa Zucchini Carrot Mushroom Burger is easy to make tastes great and – most importantly – stays together while you cook zwangerschapsdiabetes gevaarlijk it and eat it! Snce healthy food pyramid for diabetes my wife was used to the Japanese versions of the bidets she was initially skeptical about an after market accessory that can be installed on an existing bathroom fixture.
CMR Short Reviews The Concept of CMR Historical background on global cardiometabolic risk, epidemiological aspects of obesity and type 2 diabetes, ABCs of cardiovascular disease risk factors, intra-abdominal adiposity, metabolic syndrome and contribution to cardiometabolic risk. Elevated waist circumference, a crude anthropometric index of the absolute amount of intra-abdominal adipose tissue, better predicts the risk of developing the metabolic syndrome and related disorders than BMI. Using a similar approach, the Diabetes Prevention Program randomly assigned 3,234 participants with IGT to a placebo with standard lifestyle recommendations, the antihyperglycemic agent metformin with standard lifestyle recommendations, or a lifestyle modification program designed to achieve and maintain a 7% body weight reduction (9).
The Da Qing IGT and Diabetes Study sought to determine whether combining diet and exercise could reduce the overall incidence of diabetes in 577 men and women with IGT from the city of Da Qing, China (12). Although the pharmacological arsenal to decrease body weight and intra-abdominal adipose tissue remains limited, a few pharmacological compounds have been shown to reduce atherogenic intra-abdominal fat. In the SERENADE trial, rimonabant?s ability to lower HbA1C was tested in 278 newly diagnosed diabetic patients (138 patients were treated with rimonabant and 140 patients with placebo). Given that abdominal obesity is one of the most prevalent forms of type 2 diabetes, therapeutic approaches should focus on reducing intra-abdominal adipose tissue.
Among the evolving risk factors for cardiovascular disease, could you comment on the role of physical activity or inactivity? The content of this website is provided for educational and informational purposes only and is not to be used for medical advice, diagnosis or treatment. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance SyndromePaula Freitas1, Davide Carvalho1, Selma Souto1, Antonio Sarmento1 and Jose Luis Medina1[1] Department of Endocrinology, Centro Hospitalar Sao Joao and University of Porto Medical School, Porto, Portugal1.
There seems to be both a reduced expression of the GLUT4 gene, and a reduced translocation or movement of GLUT4 to the cell membrane in the presence of a high-fat, especially high-saturated fat diet.  (GLUT4 is one of the glucose transport proteins that move glucose from the bloodstream into muscle and fat cells. When normal amounts of insulin fail to clear blood of glucose, the pancreas responds by releasing more. Also, the fat we eat can change the composition of lipid in cell membranes.  A diet high in saturated fat has been shown to make membranes less fluid and may impair GLUT4 insertion. There really is abundant research on the role of dietary fat in the development of insulin resistance, a condition which manifests as elevated glucose, elevated insulin, and the development of type 2 diabetes. Journal of Diabetes & Metabolism is a free medical journal that publishes discoveries and current Understanding how insulin affects your blood sugar can help you better manage your condition.
Canine and feline diabetes mellitus indian fods to avoid for diabetics diabetes grain free diet diabetes questionnaire validation Cable connections are worse than Fios because cable is like being on a peer to peer network. Diabetic Neuropathy (diabetic nerve damage) of the foot is a common complication of diabetes.
A game called Pandemic where you take control of the evolution of a pathogen and try to infect the whole world. I don't know if they are one and the same book, if so I am very disappointed, would not recomend this book for those looking for natural options. A preferential loss of intra-abdominal adipose tissue can improve cardiometabolic risk markers and insulin resistance variables. In addition to its ties to abdominal obesity, the metabolic syndrome has also been linked to blood lipid disorders, an inflammatory and pro-thrombotic state, hypertension, and insulin resistance. The causes of this preferential adipose tissue accumulation include an obesogenic and diabetogenic diet, a low level of physical activity leading to a positive energy balance, and genetic susceptibility. During the 4 year follow-up, diabetes incidence dropped by 58% and 31% for the lifestyle and metformin groups respectively, as compared to the placebo (Figure 2).
Subjects were randomized to a control group or to one of three lifestyle intervention groups (diet only, exercise only, or diet plus exercise). For example, rimonabant, a selective cannabinoid receptor-1 (CB1) blocker, has been shown to reduce food intake in both rodents and humans (15, 16). This should have an impact on the causal pathways leading to insulin resistance, impaired glucose tolerance, and type 2 diabetes. Contribution of visceral obesity to the deterioration of the metabolic risk profile in men with impaired glucose tolerance.
Predictors of the incident metabolic syndrome in adults: the Insulin Resistance Atherosclerosis Study.
Is body fat loss a determinant factor in the improvement of carbohydrate and lipid metabolism following aerobic exercise training in obese women?
Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance.
Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. Lifestyle intervention can prevent weight gain during menopause: results from a 5-year randomized clinical trial. The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake.
Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia.
XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.
Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity.
Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Patient with mixed lipodystrophy (absence of subcutaneous peripheral fat in arms, legs and face and increased abdominal fat mass)19. The relationship between HIV infection, lipodystrophy, ART, insulin resistance, adipokines, metabolic alterations, metabolic syndrome and cardiovascular disease risk24. IntroductionHuman lipodystrophies are a heterogeneous group of diseases characterized by generalized or partial fat loss.
The result is impaired glucose tolerance, hyperinsulinemia, and eventual development of type 2 diabetes.
Diabetes Prevalence Worldwide 2014 otherwise you get a head rush every time you stand up which is a bit annoying. While gestational diabetes usually disappears once the mother has given birth five to ten percent of sufferers develop type diabetes immediately after diabetes treatment by diet delivery.7 Women with gestational diabetes Healthy eating physical activity and insulin therapy are the three basic treatments for type diabetes in cats muscle weakness 1 diabetes.
Insulin Forward is an education program designed to empower patients vertigo diabetes symptom who use insulin to manage their diabetes and caregivers who assist with treatment. Information on diabetes testing methods when to be tested for diabetes and diabetic diagnosis.
PCOS is an adjunct to insulin resistance therefore on top of Studies have shown that the body has an especially difficult time detoxifying organic substances thathave been chlorinated.
Leonard Roy Franks Anti-psychiatry activist and psychiatric survivor talks about his experiance with insulin coma shock therapy.
For you ladies whom have had children: Have you ever had gestational diabetes while pregnant?
Several lifestyle intervention trials have highlighted the fact that increasing physical activity and adopting healthy eating habits can reduce body weight and waist circumference and lower the risk of developing diabetes in patients with impaired glucose tolerance.
These causes should all be targeted to reduce the risk of developing the metabolic syndrome and type 2 diabetes (4). Compared to the metformin group, a greater number of subjects in the lifestyle group had normal post-load glucose values at the end of the follow-up. They randomized 531 subjects in four groups: 1- a control group, 2- lifestyle modifications, 3- treatment with metformin, and 4- lifestyle modifications and treatment with metformin. During the 3 month intervention program, body weight decreased by an average of 7.5 kg in both weight loss groups. The results of the SERENADE trial were very similar to those of RIO-Diabetes in terms of weight reduction, waist circumference, and improvements to HDL cholesterol and triglyceride levels.
They found that only the diet and exercise group had a reduction of waist circumference, body fat percentage, and intra-abdominal adipose tissue surface as calculated by computed tomography at the L4-L5 level. If localized, they are often associated with fat hypertrophy in other depots, varying according to the type of lipodystrophy. Over time, compensatory insulin output from beta cells in the pancreas diminishes and a person with type 2 diabetes may find themselves injecting insulin instead of just taking oral meds. We were looking for something affordable and Diabetes Prevalence Worldwide 2014 natural for the dishwasher. Obviously there’s a pretty god biological reason for everything about the body from a survival point of view.
Either way, when she poops it squirts out the top back always and sometimes out the leg in back. Even without weight loss, physical activity can reduce intra-abdominal adipose tissue and improve indices of plasma glucose-insulin homeostasis. As depicted in Figure 1, abdominally obese individuals should be encouraged to increase their daily energy expenditure in order to decrease intra-abdominal adipose tissue and improve their plasma lipoprotein-lipid profile and indices of plasma glucose-insulin homeostasis. Similarly, compared to the placebo, the lifestyle group experienced a 41% reduction in metabolic syndrome incidence and the metformin group experienced a 17% reduction. These results provide substantial evidence in support of the importance of lifestyle recommendations focusing on physical activity and healthy eating among IGT subjects who are at increased risk of developing type 2 diabetes. Similar improvements in insulin resistance markers and other cardiometabolic risk variables were observed in both groups, suggesting that diet and exercise improve insulin sensitivity by mobilizing intra-abdominal adipose tissue. Health professionals should focus first on reshaping patient lifestyles through increased physical activity and better eating habits.
Others have already mentioned it but yes it does sound like you just need a little support in te nursing childhood obesity and diabetes facts direction. Pharmacological compounds aimed at reducing intra-abdominal fat deposition need to be developed and used in conjunction with lifestyle modification therapies to reduce the risk and complications of type 2 diabetes.  Data on the pharmacological treatment of intra-abdominal obesity is needed.
Typically, this loss of intra-abdominal adipose tissue reduces free fatty acid flux to the liver, which slows hepatic VLDL production, lowers plasma triglyceride and apolipoprotein B levels, and increases HDL cholesterol concentrations (5).
Among features of the metabolic syndrome, both intervention groups saw their HDL cholesterol levels rise and their waist circumference and fasting glucose levels improve. The authors concluded that both lifestyle modifications and metformin treatment reduced the risk of diabetes and that there were no additional benefits to combining both treatments.
However, women who did not lose weight or who gained weight had slightly higher fasting glucose values during follow-up.
Genetic lipodystrophy is generally related to severe metabolic alterations including insulin resistance (IR) and its associated complications, such as glucose intolerance and diabetes, dyslipidemia, hepatic steatosis, polycystic ovaries, acanthosis nigricans and early cardiovascular (CV) complications [1, 2].
The other thing about eating in basic is what I and many others call EFE or Eat For Effect. The authors suggested that steps should be taken to address components of the metabolic syndrome, such as waist circumference, in order to reduce the risk of developing the syndrome and related complications such as type 2 diabetes and cardiovascular disease. It also changes the pattern of adipose tissue secretory products, causing interleukin-6 levels to fall and adiponectin concentrations to rise, which improves insulin sensitivity (6, 7). However, only the lifestyle intervention group experienced a decrease in triglyceride levels and blood pressure (10). Although more subcutaneous adipose tissue was lost, the relative proportion of intra-abdominal fat loss was greater than the relative proportion of subcutaneous fat loss. In the XENDOS study (Xenical in the Prevention of Diabetes in Obese Subjects), Torgerson et al.
The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophy [2].
This study also showed that waist circumference was a better predictor of metabolic syndrome than directly measuring insulin sensitivity with an oral glucose tolerance test. Furthermore, subcutaneous and intra-abdominal adipose tissue decreased in the exercise without weight loss group. Lipodystrophies have been reported in the medical literature for more than 100 years [2, 3]. It is very responsive to the slightest noise so if you don’t want the volume to suddenly spike up best to leave it off. The contribution of various lifestyle and therapeutic interventions to reducing body weight, abdominal fat in particular, and preventing insulin resistance and type 2 diabetes is examined below. In both weight loss groups, the relative reduction in intra-abdominal fat was greater than the relative reduction in subcutaneous fat, as illustrated in Figure 3. Further studies are required to do the following: 1) evaluate rimonabant?s ability to prevent diabetes rather than treat diabetes and its metabolic complications and 2) investigate whether rimonabant can reduce intra-abdominal adipose tissue as assessed using imaging techniques.
The TRIPOD (Troglitazone in Prevention of Diabetes) study has also tested the effectiveness of a PPAR-γ agonist, troglitazone, in reducing type 2 diabetes incidence (22). However, only 13 years ago, new lipodystrophy syndromes were recognized, being associated with viral infection, specifically with the human immunodeficiency virus, in patients treated with combined antiretroviral therapy (cART) [4]. On a microscopic level it looks more like shards of broken ketones diabetes levels glass rather than the normally smoothed rounded look of sand.
The study sample included high-risk Hispanic women with previous gestational diabetes who were randomized to troglitazone (n=133) and a placebo (n=133). The first large study to illustrate the key role played by a lifestyle modification program in preventing diabetes among individuals with glucose intolerance was the Finnish Diabetes Prevention Study (8).


Some first-generation antiretroviral drugs used in HIV patients are strongly related with peripheral lipoatrophy and metabolic alterations [1].Human lipodystrophies leads to severe metabolic alterations resulting in premature CV complications. In that study, a sample of 522 middle-aged men and women, who were all overweight with IGT, were randomly assigned to an intervention group designed to lower total intake of fat (especially saturated fats) to less than 30% of energy consumed, increase intake of dietary fibre, and ensure participants took part in moderate exercise for at least 30 minutes per day.
It is important to point out, however, that troglitazone was withdrawn from the market in 2000 because of liver toxicity. On the other hand, high adiposity, such as seen in obesity, also increases metabolic alterations and leads to increased CV risk.
Over the study follow-up period, the overall cumulative incidence of diabetes dropped by 58% in the lifestyle modification group, with the reduction directly linked to lifestyle changes. However, diabetes incidence only decreased in patients with IGT at baseline, even if body weight loss was similar in patients with and without IGT. So, it seems that the two extremes, the absence or the excess of fat mass, are associated with the same metabolic and CV complications.
Cumulative diabetes incidence was 11% and 23% for the intervention and control groups, respectively. Although this study was conducted in a relatively small sample of men, it supports the notion that targeting intra-abdominal adiposity can prevent the development of insulin resistance. Rosiglitazone substantially (6%) reduced the risk of developing diabetes over the 4 year follow-up. This paves the way to larger lifestyle intervention trials to examine whether increasing energy expenditure without necessarily decreasing energy intake can prevent type 2 diabetes among high-risk abdominally obese, dyslipidemic individuals. Adipose tissue in the lower part of the body is able to expand and can therefore accumulate excessive energy from diet, store triglycerides, and it appears to be protective at the metabolic level [5].
Based on these results, the authors concluded that 22 subjects with IGT must be treated with lifestyle interventions to prevent one case of diabetes. Interestingly, rosiglitazone treatment significantly increased hip circumference whereas the placebo did not. Rosiglitazone therefore reduced waist-to-hip ratio significantly, suggesting that rosiglitazone treatment can also cause an increase in subcutaneous adipose tissue.
Therefore, decreased peripheral subcutaneous adipose tissue (SAT), and even more increased visceral adipose tissue (VAT), are strongly associated with metabolic alterations and IR [1].
With regards to the HIV-associated lipodystrophy, the available data suggest that this condition is caused by a complex interaction involving side effects of cART, disease related inflammation, and individual characteristics [6].
At present, HIV-infected patients are exposed to an increased metabolic risk like the general population, resulting from ageing, increased weight and fat gain, high fat and energy food and marked sedentariness. Moreover, a number of additional factors could worsen their metabolic profile, such as the ongoing HIV infection, the presence of lipodystrophy and the continuous use of antiretroviral drugs [7]. HIV-associated lipodystrophy is also associated with premature aging [8]resembling metabolic laminopathies and progeria [1]. Premature aging of HIV-infected patients affects bone, brain, vascular wall, muscles, kidney and liver, and results of the combined effects of long-term HIV-1 infection, depleted immune responses, the toxicity of some antiretrovirals and lipodystrophy.
Cellular senescence seems to result from prelamin-A accumulation induced by some antiretroviral drugs, mitochondrial dysfunction and oxidative stress. Adipose tissue biology –Three different adipose tissue compartmentsAdipocytes are a dynamic and highly regulated population of cells.
Adipose tissue is characterized by a marked cellular heterogeneity among its cellular components: adipocytes, preadipocytes, fibroblasts, macrophages, lymphocytes, endothelial cells and multipotent stem cells, able to differentiate into several cell types.
Adipose tissue can release regulatory factors (adipokines, cytokines, or chemokines) or metabolites (FFAs) capable of influencing other surrounding cells, thus establishing active cross-talk among cells within adipose tissue. The remaining two thirds are a combination of small blood vessels, nerve tissue, fibroblasts and preadipocytes in various stages of development. Preadipocytes have the ability to proliferate and differentiate into mature adipocytes, conferring a constant functional plasticity on adipose tissue [10].
During the early maturation stage, an increased number of mitochondria are required [11, 12], resulting in small adipocytes, which are highly sensitive to insulin and that secrete high levels of adiponectin [12].
By contrast, older adipocytes increase in size (hypertrophy), their functional activities are lost and they become resistant to insulin.
These adipocytes also exhibit decreased numbers of mitochondria with impaired mitochondrial reactive oxygen species (ROS) generated by the respiratory chain, which could have dual effects on adipocyte differentiation. New adipocytes form constantly to replace lost adipocytes, to the extent that 50 % of adipocytes in the human subcutaneous fat mass are replaced approximately every eight years. Preadipocytes are recruited to become lipid-filled mature adipocytes at the same rate that adipocytes die, and in this way the fat mass is in constant flux, and adipocyte number is kept constant. Cellular death of fat cells in white adipose tissue occurs primarily by necrosis-like cell death, which involves macrophage recruitment and a subsequent inflammatory response. Increased visceral fat mass leads to IR and a low-grade inflammation status in which many adipokines and other adipocyte and macrophage factors are involved [13].Adipose tissue is not homogeneous but rather a tissue with specific regional compartments with varying roles and metabolic functions [14]. Individually considered, adipose tissue compartments have stronger associations with physiological and pathological processes than does total adipose tissue mass [15-17]. The upper-body adipose tissue, including visceral fat, is involved in fat storage after meals and the release of free fatty acids (FFA) between meals to feed the liver, muscles and other organs, therefore sparing glucose for the brain. Peripheral lower-body fat, in the femoro-gluteal region, is mainly used for its storage capacity, thereby buffering excess fat [7].
The femoro-gluteal fat depot is relatively insensitive to lipolytic stimuli and highly sensitive to anti-lipolytic stimuli, and may play a protective role by acting as a “sink” for circulating FFA [18].
This uptake of FFA prevents ectopic fat storage in the liver, skeletal muscle, and pancreas, which causes IR and beta-cell dysfunction [19]. The excessive lipolytic capacity of visceral fat (and probably subcutaneous upper-body depots as well) results in a condition referred as lipotoxicity (see section below on lipotoxicity) [7].
Lipohypertrophy and lipoatrophyAdipose tissue can be subject of different influences and undergo different transformations.
SAT has a lower mitochondria content and this contributes to adipocyte apoptosis and therefore, to more lipoatrophy. VAT, with a higher number of resident macrophages [21] and more 11?hydroxysteroid dehydrogenase activity than SAT [22], is predisposed to hypertrophy. Hypertrophied VAT from HIV-infected patients demonstrates mitochondrial dysfunction but not impairment of adipogenic gene expression in comparison with SAT [23].
In the case of lipoatrophy, because peripheral subcutaneous adipocytes cannot store triglycerides, non-lipoatrophic fat depots such as VAT, probably buffers the increase in FFA, which worsens lipohypertrophy [8].Subcutaneous adipocytes seem to be more susceptible to the deleterious effects of protease inhibitors (PIs) than visceral adipocytes [24]. Accordingly, studies performed on control human SAT explants reveal that some PIs increase FFA, interleukin – 6 (IL-6) and TNF-? production through the activation of the proinflammatory nuclear factor – kB (NFkB) pathway.
This PI-induced deleterious paracrine loop, between adipocytes and macrophages, similar to the observed in obesity, is not seen in VAT. These data indicate that SAT is more sensitive to the adverse effects of some PIs than VAT [8].4. AdipogenesisIndividuals can differ remarkably in body fat distribution and the known differences in FFA uptake of adipose tissue compartments play a role in this difference. Premenopausal female SAT takes up more FFAs than male [25] and upper-body SAT takes up FFAs more avidly than femoral fat in men, but not in women. Gene expression, mRNA transcription of FA transporters and consequently facilitated FA transport was greater in the upper body in men and in the femoro-gluteal region in women.
This novel FFA disposal pathway may also play a role in the development or maintenance of body fat distribution.
On the other hand, direct FFA uptake in subcutaneous fat differs from fatty acid uptake from a meal in two respects: 1) direct FFA uptake is more efficient in women than in men and 2) in men there is no preferential direct FFA uptake in upper-body subcutaneous fat compared with femoral fat in women.
These gender-based differences are consistent with this process as a mechanism to develop or maintain variations of body fat distribution between men and women, both lean and obese.The greater direct FFA uptake in abdominal over femoral fat in men could be due to the greater facilitation of inward fatty acid transport. Contrary to what is generally believed, upper-body subcutaneous fat releases ~70 % of systemic FFAs in lean men and women, whereas the leg contributes only ~20%; fatty acid uptake from a meal follows a similar pattern [26]. This imbalance between release and direct reuptake in women could redistribute fatty acids toward leg fat.
In obese women, the total FFA reuptake in leg fat was also significantly greater than in upper-body fat. It may be that some populations of fat cells, such as the smaller adipocytes, take up but do not actively release FFAs, whereas larger fat cells briskly release FFAs and do not take up FFAs under post-absorptive circumstances.
In summary, there is a mechanism for adipocyte fatty acid uptake and storage that has yet to be understood, but which is independent of lipoprotein lipase and it’s not thought to exist in the post-absorptive state [25]. Macrophage infiltration of the human adipose organ is a well-documented phenomenon that induces a low-grade chronic inflammation that is associated with IR.
This reaction appears to be related mainly to macrophage-produced cytokines (TNF-? and IL-6] capable of interfering with the normal activity of insulin receptors. The greater amount of macrophages and macrophage-secreted cytokines found in visceral fat is in line with the greater morbidity associated with these depots.
Subcutaneous and visceral adipocytes have cell-autonomous properties due to inherently different progenitor cells that exhibit a different gene expression pattern. Subcutaneous white adipose tissue responds better to the anti-lipolytic effects of insulin, secretes more adiponectin and less inflammatory cytokines, and is differentially affected by molecules involved in signal transduction as well as drugs, compared with visceral white adipose tissue [13].Lipoatrophic adipose tissue is known to be characterized by smaller adipocytes, greater cell size variation, disruption of cell membranes, and signs of apoptosis as determined by immunohistochemistry staining, when compared with non-lipodystrophic adipose tissue. There is a marked difference in gene expression between dorsocervical and abdominal SAT, irrespective of the lipodystrophy status, that lies in the expression of homeobox genes involved in organogenesis and regionalization. Disparate expression of such fundamental regulators of transcription might ultimately contribute to different patterns of differentiation and affect the susceptibility of the adipose tissue depot to cART-induced toxicity, perhaps making the abdominal subcutaneous and femoro-gluteal depot more vulnerable to atrophy [27].Morphologic alterations in lipoatrophy-prone areas of SAT have been confirmed at the level of gene expression [9]. Consequently, the expression of adipogenic differentiation-related genes is also decreased.
For example, there is a reduction in the expression of genes for lipoprotein lipase and for the insulin-sensitive glucose transporter GLUT 4 [28, 29], resulting in impaired fatty acid and glucose uptake, respectively, and thus leading to a deficit in the lipid-accretion capacity of SAT.
Another major alteration detected, which is probably related to the impaired adipogenic gene expression, is reduced expression of the adipokine genes adiponectin and leptin [28, 29]. In addition to impaired expression of adipogenetic–related genes, adipose tissue from patients with lipodystrophy, mainly those receiving NRTIs [31, 32] also show a reduction in mitochondrial DNA (mtDNA) levels. This decrease is associated with complex alterations in mitochondrial function, such as reduced expression of mtDNA-encoded transcripts and compensatory up-regulation of dysfunctional mitochondrial mass, that likely reduce the endogenous oxidative capacity of adipose tissue [33]. Moreover, increased oxidative stress and apoptosis have also been reported in lipoatrophic SAT [34]. High levels of expression of the inflammatory markers, TNF-?, IL- 6; IL-8 and IL-18 have been reported in SAT from HIV-1-infected lipoatrophic patients [28, 30, 35-37]. Expression of TNF? and IL-6 mRNA in SAT of lipodystrophic patients correlates positively with tissue apoptosis and negatively with adipogenic marker expression, which is consistent with a role for pro-inflammatory cytokines in adipocyte viability and differentiation [30]. However, it did show some similar changes in inflammatory markers, such as induction of TNF-?, whereas others differed from that of SAT, such as, for instance, lack of monocyte chemoattractant protein -1 (MCP-1] induction. Therefore, mtDNA depletion and signs of altered mitochondrial function are common to atrophic (subcutaneous) and hypertrophic (visceral, dorsocervical) depots in HIV-1 lipodystrophy, indicating that mitochondrial impairment cannot explain in a simple manner the final outcome for adipose depots, either in terms of lipoatrophy or lipohypertrophy [23]. One adipose depot (visceral) enlarges in size and approaches its fat storage capacity threshold (as in obesity) merely because another adipose depot (subcutaneous) cannot [38]. A direct role for HIV-1 infection has been proposed by analyzing SAT from untreated HIV-1-infected patients (“naive”) as compared to healthy controls.
Early histological studies did not indicate clear mitochondrial or inflammatory-related disturbances [39], but subsequent gene expression studies have shown a significant decrease in the expression of the adipocyte differentiation controller PPAR? and some impairment in the expression of genes encoding mitochondrial proteins and proteins specifically related to adipocyte metabolism, including adiponectin and 11?-steroid dehydrogenase type-1, the enzyme responsible for glucocorticoid activation [9, 29]. Therefore, it appears that HIV-1 infection initiates a first wave of alterations in adipose tissue that is amplified by cART and ultimately results in lipoatrophy [9].5. Congenital generalized lipodystrophiesGeneralized lipodystrophies are rare disorders that may be congenital or acquired. The congenital generalized lipodystrophy (CGL) Berardinelli-Seip syndrome (BSCL), is an autosomal recessive disorder initially reported by Berardinelli [3] and Seip [40] with frequent parental consanguinity [41-44].
It has been proposed that Berardinelli-Seip syndrome could be a Portuguese disease, later spread by the Portuguese across the world [45].
Patients with CGL are recognized at birth or soon thereafter due to a near-total lack of body fat and prominent muscularity that causes a severe and striking phenotype (Figure 2A and 2B). Hepatosplenomegaly, umbilical prominence or hernia, acanthosis nigricans, voracious appetite and accelerated growth can occur. Female patients develop hirsutism, may have clitoromegaly, oligomenorrhea and polycystic ovaries.
Other uncommon manifestations include hypertrophic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty [41, 42]. Diabetes and its complications, hyperlipidemia and recurrent attacks of acute pancreatitis, hepatic steatosis and occasionally cirrhosis are the causes of morbidity and mortality [2].At least 4 molecularly distinct forms of congenital lipodystrophy have been defined, with the mutations of the enzyme acyltransferase 1-acylglycerol-3-phosphate O- acyltransferase 2 (AGPAT2) or (BSCL1- locus 1) and Berardinelli-Seip (BSCL2 - locus 2) being both responsible for 95 % of gene mutations. AGPATs are critical enzymes involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate.
They catalyze acylation of fatty acids at the sn-2 position of glycerol moiety and convert lysophosphatidic acid to phosphatidic acid [2, 46].
Seipin appears to play a role in lipid droplet formation and may also be involved in adipocyte differentiation [49-51].Patients with BSCL2 mutations have the most severe variety of CGL and are born without any body fat [2]. Two other genes were identified for CGL: caveolin 1 (CAV1) [52] and polymerase I and transcript release factor (PTRF) [53]. Caveolin 1 is the main component of caveolae, specialized microdomains seen in abundance on adipocyte membranes [54]. PTRF (also known as cavin) is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3 [53].6.
Mortality in generalized lipodystrophiesPatients with generalized lipodystrophies are predisposed to develop acute pancreatitis, cirrhosis, endstage diabetic renal disease requiring transplantation, and blindness due to diabetic retinopathy.
Many patients with FPL die of coronary heart disease or cardiomyopathy and rhythm disturbances [55-57]. Sudden death has been reported during childhood in CGL, type 4, likely due to arrhythmias [58]. Patients with congenital Berardinelli-Seip lipodystrophy frequently develop hypertrophic cardiomyopathy that can lead to death from cardiac failure [41]. In individuals with BSCL, ventricular dysfunction and hypertrophic cardiomyopathy are often observed.
In cardiac biopsies performed in eight individuals with BSCL, the presence of subendocardial fibrosis and an abnormal architecture in the left ventricular lumen was observed [60, 61].
Hypertrophic cardiomyopathy in BSCL patients has been correlated with high plasmatic insulin levels, which activate the type 1 insulin-like growth receptors, present in large quantities in the myocardial tissue, that stimulate cell growth [62, 63]. In addition, the presence of IR and hypertriglyceridemia in individuals with BSCL may predispose them to premature atherosclerosis. Individuals who have mutations on chromosome 11 (BSCL2) seemed to present more severe symptoms than those who had mutations in BSCL1, with a high incidence of premature deaths. Cardiomyopathy was three times more frequent in those with BSCL2 mutations than in individuals with alterations in BSCL1 [42].7. Mandibuloacral Dysplasia (MAD)-associated lipodystrophyMAD is characterized by skeletal abnormalities such as mandibular and clavicular hypoplasia and acroosteolysis [64], progeroid manifestations, partial or generalized lipodystrophy and metabolic complications, among other clinical features [65, 66]. ZMPSTE24 is involved in post-translational proteolytic processing of prelamin A to mature laminA [2].8. Autoinflammatory syndromesA syndrome of joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced (JMP) lipodystrophy was reported by Garg in three patients, belonging to two pedigrees, who were from Portugal and Mexico [69]. Mutations in PSMB8 may trigger an autoinflammatory response resulting in infiltration of adipose tissue with lymphocytes and other immune cells and adipocytes [2].
The other autoinflammatory syndrome is the chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
The mode of inheritance seems to be autosomal recessive, but the molecular basis remains unknown [2, 72, 73].9.
Familial Partial Lipodystrophy(FPL)FPL is characterized by the onset of fat loss from the limbs and other regions of the body, usually during childhood, adolescence or adulthood. Many regions of the body, such as the face, neck, and intra-abdominal region are spared, and patients accumulate excess body fat in the non-lipodystrophic regions [74-76]. Metabolic complications, acanthosis nigricans, oligoamenorrhea, hirsutism, polycystic ovarian syndrome, mild to moderate myopathy, cardiomyopathy, and conduction system abnormalities indicative of multisystem dystrophy can occur [2, 55, 56, 77]. LMNA, on chromosome 1q21-22 [2, 78-81], an integral component of nuclear lamin, was made in 1998.
Adipocyte loss is due to premature cell death resulting from disruption of the nuclear envelope [87, 89].
Defective adipocyte differentiation seems to be the cause of the lipodystrophy of PPAR? and AKT2 mutations.
Those with FPLD2 also have an increased amount of fat in the cervico-facial area compared to patients without these mutations.


Therefore, a single protein mutation leads to two opposing fat localization phenotypes [8]. Importantly, mutations in LMNA are also responsible for metabolic laminopathies resembling the metabolic syndrome (MS) and Hutchinson-Gilford progeria, a severe syndrome of premature aging [94].
Prelamin A is implicated in increased oxidative stress and in the occurrence of cellular senescence [8].10.
Acquired Generalized Lipodystrophy(AGL) – Lawrence syndromeThe onset of subcutaneous fat loss in patients with AGL usually occurs during childhood [95]. The pattern and extent of fat loss is quite variable and most patients have generalized loss of fat, but a few of them have areas such as intra-abdominal and bone marrow fat spared. AGL patients are highly likely to develop severe hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia [2].
Lipodystrophy can be associated with autoimmune diseases such as juvenile dermatomyositis [95].
Chronic hepatitis with autoimmune features and low serum complement 4 levels, suggesting involvement of the classical complement pathway in the pathogenesis of fat loss, has been reported [96]. Acquired partial lipodystrophy–Barraquer-Simons syndromeFat loss occurs gradually in a symmetric fashion, first affecting the face and then spreading downward.
Most patients lose fat from the face, neck, upper extremities, and trunk, and subcutaneous fat from the lower abdomen and legs is spared. Misra et al suggest that the fat loss involves autoimmune-mediated destruction of adipocytes because the patients have low serum levels of complement 3 and complement 3-nephritic factor, which blocks degradation of the enzyme C3 convertase [95]. Lipodystrophy associated with HIV-infectionThe impressive progress resulting from the discovery of drugs able to control HIV infection on a long-term basis, has offered most patients a prolonged lifespan, possibly as long as that observed in non-infected subjects [7]. Suppression of viral replication has become a treatment goal that can be reached with the use ofcART.
After the introduction of protease inhibitors (PIs) in 1996, as a component of highly active antiretroviral therapy, the morbidity and mortality associated with HIV has dramatically been reduced [99].
However, patients develop a syndrome of fat redistribution with peripheral fat loss (face, upper limbs and femoro-gluteal) and visceral fat accumulation, generally associated with metabolic abnormalities [4, 100-103] and increased risk of CV diseases [104, 105], similar to what occurs in congenital lipodystrophies [4, 59]. Lipohypertrophy usually represents a central visceral fat accumulation in the abdomen and trunk, but can also be found in breasts (in women), dorsocervical region (“buffalo hump”), double chin, lipomas, and within the muscle and liver [59, 106]. Lipoatrophy and lipohypertrophy are frequently associated (mixed form), but they also can occur independently of each other [59]. This HIV-associated lipodystrophy has been proposed to be a age-related fat redistribution condition that could amplify age-related co-morbidities and lead to their earlier occurrence [8]. Also, hyperlactenemia and bone demineralization can occur [107, 108].Owing to a lack of a consensus on the definition of lipodystrophy and lipodystrophy syndrome in HIV-infected patients, its exact prevalence is not known [6]. In the early 2000s, about half of HIV-infected patients undergoing cART were diagnosed as lipodystrophic (20-80%) [109].
Abnormalities in peripheral and central fat masses are clinically evident in 20-35 % of patients after approximately 12-24 months of cART [59, 107, 110, 111]. With the new anti-retroviral agents, the probability of developing lipoatrophy has decreased in western countries as the pattern of cART prescription has significantly changed [112]. Two widely used thymidine analogs from the first class of ART, stavudine and zidovudine, are responsible for lipoatrophy and now they have been replaced by a new generation of potent NRTIs. Although metabolic toxicity of boosted PIs is far less than of first-generation protease inhibitors (PIs), they are still considered responsible for increased CV risk. About 50% of patients with HIV-associated lipodystrophy display mixed forms, with the loss of limb fat and marked expansion of VAT [113]. The high frequency of this association suggests that these two opposite phenotypes could be, at least in part, causally related [8]. Also, HIV patients may have a picture similar to partial lipodystrophy patients with peripheral fat atrophy and hypertrophied central fat depots.
HIV-lipodystrophy and related factorsThere is a possible role of the virus contribution for lipodystrophy i.e.
Monocytes are relatively resistant to HIV infection, but differentiated macrophages are highly susceptible and tissue macrophages have been found to harbor HIV-1 [118]. Systemic inflammation associated with HIV infection might promote monocyte migration across the vascular endothelium, leading to an increased number of activated macrophages in fat [118]. Several studies reported that the severity of HIV infection is associated with an increased prevalence of lipodystrophy [59, 119], probably as a consequence of persistent HIV-infected macrophages in adipose tissue, which could enhance local inflammation.
ART-naive HIV-positive patients have increased TNF-? expression compared with uninfected controls [29], which is consistent with increased inflammation. TNF-? alters adipocyte function and differentiation, in part through the inhibition of PPAR? expression [120]. Infected macrophages might also release viral proteins (such as Vpr and Nef) that can impact on adjacent adipocytes and lead to decreased PPAR? activity and inhibition of adipogenesis [121, 122].
Although lipodystrophy is uncommon in ART-naive patients [113], the HIV infection of macrophages could itself result in low-grade fat inflammation and lead to the release of viral proteins that affect neighboring adipocytes and decrease their differentiation.The development of lipodystrophy and metabolic toxicities is partially related to the individual drugs included in cART regimens, associated with other risk factors [123] such as gender and pre-HIV-infection body composition, disease-specific factors such as the nadir levels of CD4+ lymphocytes and the duration of HIV infection [110, 123, 124].
The most significant risk factors associated with lipoatrophy are exposure to and duration of nucleoside thymidine analogues (most commonly stavudine), age, severity of disease markers (CD4 lymphocyte count and plasma HIV viral load), therapy duration, and belonging to the Caucasian race.
On the other hand, the most common statistically significant risk factors for lipohypertrophy are therapy duration, PI administration, markers of disease severity, and age. We cannot forget that along the years, patients have done multiple regimes and combinations of antiretroviral drugs, which makes it difficult to identify different risks with different drugs, and studies therefore report conflicting results [6].
Protease inhibitors PIs affect multiple metabolic pathways and are associated with lipohypertrophy, lipoatrophy, atherogenic dyslipidemia and IR, [125, 126]. Studies in-vitro reported that PIs are able to alter a number of adipocyte functions, including differentiation, expression of transcriptase factors involved in adipogenesis, cell survival, cytokine production, mitochondrial function and IR [127].
PIs may cause lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of toxic farnesylated prelamin A [128], increased oxidative stress and altered adipokine and cytokine production [89, 127, 129]. The adverse effect of PIs could also result from the induction of endoplasmic reticulum stress or the inhibition of the proteasome [130, 131].Different PIs might affect key intranuclear genes, causing reduction in levels of RNA encoding SREBP-1, which changes the expression of PPAR ? [28]. The levels reduction of intranuclear SREBP-1 leads to a decreased adipocyte differentiation and an altered release of adipocytokines [132]. PIs can inhibit lipogenesis and stimulate lipolysis [28, 132-135], and may induce IR by inhibiting glucose transporter 4 expression (GLUT4) [136].13. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)NRTIs are analogs that inhibit the viral reverse transcriptase enzyme. The thymidine NRTIs (zidovudine, stavudine and didanosine) cause mitochondrial toxicity by mitochondrial DNA polymerase inhibition and by causing DNA mitochondrial mutations [31, 137, 138].
These disturbances result in apoptosis of peripheral adipocytes and lead to lipoatrophy [31].
Nucleoside analogues may inhibit adipogenesis and adipocyte differentiation, promote lipolysis, and exert synergistic toxic effects when associated to PIs [31, 141-143]. Moreover, NRTIs promote lipolysis and the subsequent efflux of non-esterified fatty acids from adipose tissue [142, 144]. Mitochondrial toxicity and fat redistributionIn western countries, long-term HIV-infected patients present several age-related comorbidities earlier than the general population [145], and display signs of premature aging [8].
New hypotheses were recently suggested about the pathophysiology of fat redistribution, proposing that mitochondrial toxicity was involved in lipoatrophy and in fat hypertrophy. HIV-associated lipodystrophy could be an age-related fat redistribution that could amplify age-related comorbidities and their earlier occurrence [8]. At physiological low levels, ROS could act as secondary messengers to activate adipogenesis and lipogenesis, resulting in increased adipocyte number and size. In hepatic cells, oxidative stress activates the transcription factor SREBP1c, which is highly expressed in adipocytes and increases lipogenesis and lipid accumulation [146]. Indeed, activated macrophages, which have an M1 proinflammatory phenotype, invade expanded adipose tissue; upon invasion, their production of proinflammatory cytokines and chemokines increases. This could lead to the decreased secretion of adiponectin by adipocytes in response to TNF-? [36].
Increased abdominal fat lipolysis increases ectopic fat deposition within tissues (liver, skeletal muscle and heart). Subsequently, these derivatives overwhelm mitochondrial oxidative capacity and activate stress kinases, leading to IR.
This situation, known as lipotoxicity, associates ectopic depots of triglycerides in non-adipose tissues that buffer excess fatty acid derivatives [147]. Moreover, a paracrine loop is present between adipocytes and macrophages; macrophage-secreted cytokines (TNF-? and IL-6] activate the NFkB pathway in adipocytes, resulting in increased IL-6 and FFA production. Saturated FFA can, in turn, activate the Toll-like receptor-4 (TLR-4) on macrophages and adipocytes, thereby increasing the proinflammatory loop. This paracrine loop has been reported in obesity as a result of macrophages infiltrating fat [148].15. Cortisol and fat redistributionPatients with hypercortisolism also have an acquired form of lipodystrophy [1], characterized by fat hypertrophy in the upper body with increased VAT and decreased limb fat.
Cortisol can activate adipocyte differentiation and hypertrophy, mainly in visceral fat depots, because of the higher expression of glucocorticoid receptors (GR-?) and the 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD-1) that transforms inactive cortisone into active cortisol in adipocytes from central depots [22]. It has been hypothesized that glucocorticoid activation is involved in cART-linked central fat hypertrophy [8]. Higher ratios of urinary cortisol:cortisone metabolites and higher subcutaneous 11?-HSD-1 expression are observed in patients with severe lipodystrophy compared with those without [149]. In cART-naive patients, 11?-HSD-1 expression increases in both abdominal and thigh SAT after 12 months of ART, but only in patients with lipohypertrophy or without lipoatrophy [150]. Because TNF-? expression in fat is related to that of 11?-HSD-1 [149], inflammation is linked to glucocorticoid activation [8]. TNF-? activates 11-?-hydroxysteroid dehydrogenase (HSD)-type 1, and this enzyme’s activity is higher in visceral fat compared with subcutaneous fat. Visceral fat is able to locally produce cortisol, which could act inside the adipocytes and increase lipid accumulation [151]. Other hormones, such as growth hormone and testosterone, can modulate the activity of 11?-HSD-1. It is interesting to note that HIV-infected patients with lipodystrophy often present with a relative decrease in growth hormone [152] and testosterone levels. Moreover, when patients with visceral fat hypertrophy are treated with growth hormone, a reduced amount of visceral fat is reported, together with improved metabolic status [153].
AgingIn the general population, age is associated with central fat redistribution, mitochondrial impairment and increased levels of pro-inflammatory cytokines [154].
Aging is physiologically associated with fat redistribution, oxidative stress and low-grade inflammation. In the general population, the interaction between the proinflammatory state and genetic background potentially triggers the onset of age-related inflammatory diseases such as atherosclerosis, sarcopenia and frailty. Decreased immune response leading to immunosenescence is also probably involved in early aging [8, 156].
Aging and some cARTs result in mitochondrial dysfunction and oxidative stress, which lead to cellular senescence. Genetic factors and HIV-lipodystrophyA role for genetics is also probable in HIV-lipodystrophy. TNF-? gene promoter polymorphism is associated with lipodystrophy, but this association has not been confirmed in larger studies [157]. Interestingly, stavudine-induced lipoatrophy is linked to the HLA-B100*4001 allele, which is located in close proximity to the TNF-? gene; this observation further supports the theory that there is a role for inflammation in lipoatrophy [158]. Apo C3-455 also plays a role in lipoatrophy, and two variants of the adipogenic ?2 receptor seems to be involved in fat accumulation, whereas PPAR? variants are not involved [159]. The toxicity of ART also depends on a patient’s metabolism, in part genetically determined.18. Role of inflammationEven if infectivity of adipocytes by HIV has been contested, the ability of the virus to modify adipocyte phenotype has been shown in some studies [160, 161]. Moreover, macrophages and dendritic cells present in lipodystrophic adipose tissue could be infected, which could modify their characteristics [7]. Macrophage infiltration is observed in adipose tissue from patients with HIV-related lipodystrophy together with decreased adipokine and increased pro-inflammatory cytokine production [162].
LipotoxicityLipotoxicity is a possible explanation for the development of metabolic syndrome (MS) and diabetes in multiple pathological situations, from obesity to lipodystrophies of distinct origin.
According to the lipotoxicity theory, excess availability of fatty acids or a limited capacity to metabolize them in organs and tissues elicits most of the alterations that are characteristic of MS, especially IR. Actually, high FA levels can induce a reduction in GLUT2 on ? cell surfaces and induce a decrease in insulin secretion [19].
Increased availability and, ultimately, increased accumulation of fat into skeletal muscle tends to promote IR; and fatty acid levels in liver that exceed the capacity of this organ to oxidize or export them, lead to the increased accumulation of fat that is often associated with MS.
All of these events could result from alterations in fat metabolism or excess intake of fat-enriched nutrients, but they could also arise as a result of intrinsic alterations in the capacity of adipose tissue to store and thereby buffer the excessive accumulation of fatty acids in other tissues and organs [163]. One hypothesis consistent with the appearance of MS in ART-associated lipodystrophy syndrome is lipotoxicity resulting from limitations in the capacity of subcutaneous fat to store the appropriate amounts of fat and the subsequent diversion of fatty acids to ectopic sites [164]. Several arguments in support of lipotoxicity as a major contributor to MS in distinct human pathologies come from the paradoxically common metabolic alterations found in the obesity and in lipodystrophies of genetic origin.
According to the lipotoxicity theory, the fat stored in adipose tissue is biologically inert and the observed metabolic alterations are primarily caused by the increased exposure of cells to non-esterified fatty acid.
Thus, in obese patients, it is not the amount of fat stored in adipose tissue that elicits metabolic dysfunctions, but rather the balance between the availability of those fatty acids to tissues and organs and the capacity of the organs to eliminate them through triglyceride storage in adipose tissue, or oxidation [165].
A complementary concept is the idea that there is a threshold for adipose tissue expansibility; once it’s reached, as it occurs in obese individuals, appropriate storage of fatty acids inside adipocytes in their inert and esterified form is impaired, determining the extent of lipotoxicity [164]. Either a total or partial lack of adipose tissue storage capacity causes an increase in circulating lipid levels and is associated with ectopic lipid accumulation in non-fat tissues such as liver, skeletal muscle and pancreas.
These alterations lead to non-alcoholic fatty liver diseases, hepatic and muscle IR and development of type 2 diabetes.
Insulin resistanceIR occurs in about one-third of patients on certain PI-based regimens, although the thymidine NRTIs have also been associated [166]. The new-generation PIs appear to have a milder IR effect and the prevalence of diabetes is lower than described in the early 2000s. The pathogenesis of glucose metabolism disorders is still unclear and, although a direct effect of potent antiretroviral combinations is certainly involved, it is likely that multiple factors play a role, including genetic predisposition, cytokine and hormonal alterations, changes in the immune system, non-antiretroviral drug-induced toxic effects, opportunistic diseases, and perhaps the HIV infection itself [167].
Risk factors for the development of IR in HIV-positive population include duration of ART, PI treatment, concurrent fat redistribution syndrome, dyslipidemia, increasing age, hepatitis C virus co-infection, as well as pharmacological treatment with pentamidine or megestrol acetate [100, 167-169].PIs (including indinavir, amprenavir, nelfinavir, and ritonavir) have been shown to induce IR in vitro by reducing glucose transport mediated by the glucose transporter 4, a receptor involved in glucose uptake [136].
The deleterious impact of some PIs on adipocytes through the inhibition of GLUT4 transporters was directly demonstrated in healthy controls, after given these molecules for a few weeks [169-171]. Several PIs can interfere with nuclear transcription factors, leading to decreased adiponectin levels, which also leads to IR [123]. Additionally, the increase in FFA levels associated with PIs, as well as with fat redistribution, might also have a role in the development of IR (see lipotoxicity) [173].21. DyslipidemiaA number of HIV-infected patients present dyslipidemia, increased cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides together with decreased HDL. This profile has been associated with the presence of a MS, resulting from an increased visceral fat amount with IR [7].In patients receiving cART, the prevalence of hyperlipidemia ranges from 28 to 80% in different studies [167, 174], and it includes hypertriglyceridemia in the majority of cases [123].
The first hypothesized mechanism is based upon the structural similarity between the catalytic region of HIV-1 protease and two human proteins involved in lipid metabolism: the cytoplasmic retinoic acid-binding protein type 1 (CRABP-1) and the low-density lipoprotein-receptor-related protein (LRP). PIs probably bind to CRABP-1 and erroneously inhibit the formation of cis-9-retinoic acid, leading to increased apoptosis of peripheral adipocytes, decreased lipid storage and increased lipid release into the bloodstream. Similarly, PIs may inhibit the normal functioning of LRP and interfere with fatty acid storage in the adipocytes [167, 176]. Furthermore, data from in vitro and in vivo studies suggest that PIs may prevent proteasomal degradation of nascent apolipoprotein B, a key protein component of circulating triglycerides, leading to increased production of VLDL particles. An upregulation of metabolic pathways leading to an excessive production of VLDL can also be caused by the PI-induced intra-hepatocyte accumulation of nuclear transcription factors involved in the metabolism of apolipoprotein B, such as SRBPs. In addition, the levels of lipoprotein particles containing apolipoprotein C-III and apolipoprotein E are increased in PI-treated patients [176-179].
106, 459-465 (2000) (2) Bremer, E.



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