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Yup stop learning for 4 years and then anywhere from 3-7 years after that of definitely not learning. In medicine an injection is a method of putting liquid into the body with a hollow needle and a syringe. Right now there’s no cure pathogenesis diabetes type 2 for diabetes so people with type 1 diabetes will need treatment for the rest of their lives. My only concern is that the diabetes chart normal range mmol construction of the casing diabetes testing supplies video is almost identical to the first one I had. Find a: enrique iglesias tour reviews billy ray cyrus is gonna be a grandfather apocalypse bruce willis youtube.
Personally I think there are a lot of people in this group that just haven’t given themselves permission to be OK with themselves chill out and put fat loss Is Your Low Carb Diet Making you Metabolically Inflexible?
Each milliliter of LANTUS (insulin glargine injection) contains 100 Units (3.6378 mg) insulin glargine. During pregnancy, maternal hormones, including estrogens, induce a decrease in insulin sensitivity in peripheral tissues. 16.Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
36.Mortality after 16 years for participants randomized to the Multiple Risk Factor Intervention Trial. 48.Vanhoenacker PK, Heijenbrok-Kal MH, Van Heste R, Decramer I, Van Hoe LR, Wijns W, et al. 64.Scholte A, Schuijf J, Kharagjitsingh A, Dibbets-Schneider P, Stokkel M, van der Wall E, et al. 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.
The relationship between hepatic fat content and plasma resistin concentration before () and after () PIO treatment in type II diabetic patients. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics. Type 2 Diabetes is a chronic condition which means that it is a long-term disease that cannot be cured but that can b managed.
I have burned one of them on the inside a little bit but I assume that is because I don’t know how to use the all the way yet. The Cochrane review compared the effects of synthetic human insulin and natural animal insulins in diabetic patients from 1966 to May 2002 (ref.
Prior to vero star glucose meter Flagyl which again takes out all the flora in your intestines I was allergic to no foods. Definition Of Peripheral Insulin Resistance Guar gum (14) Spirulina (5) Psyllium (7) Evening primrose oil (9) Chlorella (9).
An estimated 246 million people world-wide have diabetes, with a forecasted 380 million by 2025 . Concomitantly, these hormones also produce several adaptive changes in the islet, including increased insulin content and secretion.
Screening for coronary artery disease in patients with type 2 diabetes mellitus: An evidence-based review. Coronary artery disease (CAD) is often asymptomatic in these patients until the onset of myocardial infarction (MI) or sudden cardiac death.
Mortality from coronary heart disease in sub­jects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. Inflammation in diabetes mellitus: Role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. Platelet perturbations in diabetes: Implications for cardiovascular disease risk and treatment. Association between multiple cardiovascular risk factors and the early development of atherosclerosis. Should we screen for occult coronary artery disease among asymptomatic patients with diabetes? Identifying high risk asymptomatic diabetic patients who are candidates for screening stress singlephoton emission computed tomography imaging. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: A systematic review. Microalbuminuria as a predictor of a drop in glomerular filtration rate in subjects with non Insulin dependant Diabetes Mellitus and Hypertension. Urinary albumin excretion as a predictor of diabetic retinopathy, neuropathy and cardiovascular diseases in NIDDM.
Screening and management of microalbuminuria in patients with diabetes mellitus: Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease. Cardiovascular disease, mortality, and retinal microvascular characteristics in type 1 diabetes: Wisconsin epidemiologic study of diabetic retinopathy.
The impact of diabetes on survival following myocardial infarction in men vs women: The Framingham Study. Dobutamine stress echocardiography in patients with diabetes mellitus: Enhanced prognostic prediction using a simple risk score.
Aspirin for primary prevention of cardiovascular events in people with diabetes: A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation.
Prediction of cardiovascular events in clinically selected high-risk NIDDM patients: Prognostic value of exercise stress test and thallium- 201 single-photon emission computed tomography.
Cost-effectiveness of Screening for Coronary Artery Disease in Asymptomatic Patients with Type 2 Diabetes and Additional Atherogenic Risk Factors. Noninvasive coronary angiography by 320-row computed tomography with lower radiation exposure and maintained diagnostic accuracy: comparison of results with cardiac catheterization in a head-to-head pilot investigation. Diagnostic performance of multidetector CT angiography for assessment of coronary artery disease: Meta-analysis.
64-Slice computed tomography angiography in the diagnosis and assessment of coronary artery disease: Systematic review and meta-analysis. Diagnostic accuracy of 320-row multidetector computed tomography coronary angiography in the non-invasive evaluation of significant coronary artery disease. Risk stratification in uncomplicated type 2 diabetes: Prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Coronary artery disease: Improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance and adenosine stress magnetic resonance perfusion. Myocardial viability studies using fluorine - 18- FDG SPECT: A comparison with fluorine - 18- FDG PET.
Impact of diabetes on the risk stratification using stress single-photon emission computed tomography myocardial perfusion imaging in patients with symptoms suggestive of coronary artery disease. Prevalence and predictors of an abnormal l stress myocardial perfusion study in asymptomatic patients with type 2 diabetes mellitus.
On behalf of the Global Dialogue Group for the Evaluation of Cardiovascular Risk in Patients with Diabetes. Screening for left ventricular hypertrophy in patients with type 2 diabetes mellitus in the community. Carotid intimal medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.
Prognostic value of cardiac autonomic neuropathy independent and incremental to perfusion defects in patients with diabetes and suspected coronary artery disease. 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. Definition Of Peripheral Insulin Resistance healthy diabetic smoothie recipes effects of bad diabetes control The picture for this item should be changed to only one item and not three.
Many People are walking around in the world with Diabetes damaging their bodies and they don’t even know it or heed the warning symptoms. While some people have a predisposition to insulin resistance carrying excess weight and obesity are two of the major risk factors of developing insulin resistance. Unless you underwent traumatic injury or can’t breathe it can wait for an appointment. People with type 2 diabetes can also develop ketoacidosis If you think you have DKA test for ketones using urine strips or your glucose meter.
Eating a diabetes diet of light meals often throughout the day that are high in complex carbohydrates, protein, raw fruits and vegetables high in fiber and low in fat is good for a diabetic. Similarly, several studies in mice have shown that EDCs may act as xenoestrogens and induce both insulin resistance and functional changes to the islets of Langerhans. Ruling out stenosis in patients at low-to-intermediate risk for coronary artery disease tops the list, but coronary CT angiography has a much broader role to play. The potential of myocardial perfusion scintigraphy for risk stratification of asymptomatic patients with type 2 diabetes. If localized, they are often associated with fat hypertrophy in other depots, varying according to the type of lipodystrophy. I absolutely hate the Daily Mail… Early Symptoms Of Diabetes Type 2 diabetic medicine journal website. Alcohol use carries diabetes uk donations many health risks a significant danger among them is developing type 2 diabetes. If the adaptive response compensates for the decreased insulin sensitivity, glucose levels will be maintained within the physiological range (euglycemia). However if someone is interested in actually cutting down on medications or insulin or perhaps reversing diabetes I would recommend using Dr.
The numerous supporting photographs and illustrations really deepened my understanding of how to perform the exercises and of the rationale of how they relate to musculoskeletal structure, function and movement. However, if β-cell function fails to compensate insulin resistance, glucose levels will become dysregulated and, eventually, type 2 diabetes mellitus will develop. CVD in diabetic patients is more severe, more complex, and results in higher complication rates than in patients without diabetes.
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]. Christine D: Heard a lot type 2 diabetes leaflet about cinnamon helps with blood sugar levels. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophy [2]. Depending on your body type you’ll find diabetic foot care icd 9 that certain injection sites work better than others.
Preventive Services Task Force (USPSTF) recommends lower blood pressure targets for persons with diabetes and high blood pressure, to reduce the risk of CVD events. Lipodystrophies have been reported in the medical literature for more than 100 years [2, 3].
Metformin - it's possible that your doctor might decide to give you this oral drug used to treat type 2 diabetes patients. 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].
This means that patients with diabetes have a risk for coronary events similar to that of patients without diabetes who have already had an event. 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. On the other hand, high adiposity, such as seen in obesity, also increases metabolic alterations and leads to increased CV risk. So, it seems that the two extremes, the absence or the excess of fat mass, are associated with the same metabolic and CV complications.
Hyperglycemia causes vascular disturbances, especially endothelial dysfunction, contributed by abnormal nitric oxide biology, increased endothelin and angiotensin 2, and reduced prostacyclin activity.[7] Diabetic dyslipidemia further contributes to the increased atherosclerotic risk. Diabetic dyslipidemia is mainly due to increased low density lipoproteins (LDL), increased apolipoprotein B concentration, increased triglycerides and decreased high density lipoproteins (HDL). 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].
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]. CAD increases with advancing age but often occurs at a younger age in patients with diabetes.
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. The major risk factors identified by the Framingham Risk Score include sex, total cholesterol, HDL cholesterol, blood pressure (or treatment thereof), cigarette smoking, and age. 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]. Previous studies have demonstrated the same association between autonomic neuropathy and risk for adverse cardio vascular events. 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. If there are one or more cardiovascular risk factors, they are considered as at risk, and those having high risk are the ones who already have diabetes with CAD, peripheral arterial disease or CKD.[30] Although diabetes increases relative cardiovascular risk more in females than in males, the absolute risk of cardiovascular events is still higher in men than women. 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]. They range from invasive procedures like coronary arteriography to noninvasive tests like electrocardiogram, echocardiography, treadmill testing, coronary computed tomography (CT) angiography and radionuclide studies. 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]. Echocardiography uses ultrasound beams reflected by cardiovascular structures to produce characteristic lines or shapes caused by normal or altered cardiac anatomy in one, two, or three dimensions by M (motion)-mode, two-dimensional, or three-dimensional echocardiography, respectively. It gives the anatomical and physiological information about the heart without the risk of ionizing radiation or patient discomfort and is well suited for the initial assessment of cardiac diseases. Lipohypertrophy and lipoatrophyAdipose tissue can be subject of different influences and undergo different transformations.
Appreciation of cardiac anatomy and hemodynamics by bedside echocardiography makes a physician's clinical evaluation, including physical examination, more relevant to the care of patients. SAT has a lower mitochondria content and this contributes to adipocyte apoptosis and therefore, to more lipoatrophy. Thus, echocardiography with its reliable noninvasive hemodynamic evaluation and confident delineation of cardiovascular structures has become an important tool for both risk stratification and assessment of cardiac function.Stress echocardiographyThe advent of stress echocardiography has dramatically reduced the clinical necessity for hemodynamic cardiac catheterization.
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].
DSE provides information about Left ventricular (LV) systolic and diastolic function, wall motion abnormalities and assesses for evidence of exercise-induced ischemia. Some studies have also shown exercise echocardiography to be the most cost-effective strategy followed by exercise electrocardiography.
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.
It is based on standard Bruce protocol, and is mainly used to estimate prognosis, determine functional capacity, the likelihood and extent of coronary artery disease, and the effects of therapy.
These data indicate that SAT is more sensitive to the adverse effects of some PIs than VAT [8].4. Dynamic protocols are most frequently used to assess cardiovascular reserve, and those suitable for clinical testing should include a low-intensity warm-up phase.
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. In general, approximately 8-12 minutes of continuous progressive exercise, during which the myocardial oxygen demand is elevated to the patient's maximal level, is optimal for diagnostic and prognostic purposes. 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. The factors that indicate poor outcome include poor exercise capacity <5 metabolic equivalents (METS), exercise induced angina, low peak blood pressure or fall in systolic blood pressure, chrono­tropic incompetence, low heart rate recovery (HRR) at 1-2 minutes after exercise, and ventricu­lar arrhythmias, especially during the recovery phase. 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.
It is performed by direct injection of radiopaque contrast material into the coronary arteries and recording of digital radiographic images.
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. Coronary arteriography establishes the presence or absence of coronary stenoses, defines therapeutic options, and determines the prognosis of patients with symptoms or signs of ischemic CAD. 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].
It is indicated in patients who show evidence of ischemia on a stress test or for those who continue to be symptomatic in spite of a negative stress test (suspected false negative results).
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 is these images, acquired at high spatial and temporal resolution, that have enabled cardiovascular medicine to enter the CT imaging era.
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.
CT Angiography utilizes intravenous iodinated contrast injection in order to visualize the contrast-filled coronary vessels. 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].
Among the indications of coronary computed tomography angiogram (CCTA) in screening diabetics for CAD, detection of coronary stenosis is the most important.
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. This is especially helpful in patients who are unable to undergo invasive angiography or who are at a high risk for the procedure.
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.
No further screening test is required in those patients in whom a high-quality MSCT shows no coronary stenosis. 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.
It allows a whole heart coverage in one gantry rotation with a slice thickness of 0.5 mm, [46],[50] and a 16-cm craniocaudal coverage can be obtained in a single heart beat, with excellent image quality and demonstration of the entire coronary arteries. 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.
Patient-based analysis has proven the diagnostic accuracy of 320 slice CT angiogram upto 95%, in the detection of more than 50% coronary stenosis. 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. It can be used as a highly sensitive screening modality, that achieves high diagnostic accuracy for the detection of significant CAD.Coronary calcium scoreCoronary calcium score (CCS) on CT can be highly correlated with total coronary atherosclerotic burden and it identifies asymptomatic diabetics at higher risk for inducible ischemia. 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]. The Agatston score for each lesion in each segment of coronary artery is computed as the prod­uct of the area of each lesion with a weighting fac­tor assigned according to the maximum attenuation value of the lesion. 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]. The volume score for each lesion is estimated as the product of the number of voxels containing calcium and the volume of one voxel. 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]. Hence , it may be considered only as a second-line testing modality or for patients who are unable to exercise. 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]. The accuracy of SPECT for myocardial perfusion is approaching that of Positron Emission Tomography (PET) [61] with the emergence of vasodilator stress SPECT myocardial perfusion imaging. This is of enormous value in patients who are unable to complete a symptom limited exercise test due to obesity, PVD or peripheral neuropathy, where therapeutic intervention may be required. 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.
Medical stress test with SPECT imaging assesses myocardial ischemia with sensitivity of 91-96% and specificity of 75-82%. Congenital generalized lipodystrophiesGeneralized lipodystrophies are rare disorders that may be congenital or acquired. The clinical outcome of the patient can be better predicted on the basis of ischemic abnormalities on noninvasive testing, than the presence or absence of angina. 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).
Other modalities of screeningLeft ventricular hypertrophyLeft ventricular hypertrophy (LVH) detected by ECG or echocardiography can be used as a predictor for CAD in asymptomatic diabetics. 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. A diminished ABI is a sensitive indicator of increased risk for future cardiovascular events. 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].
An exercise TMT can be a safe and effective initial screening test in patients who can exer­cise and have a normal baseline ECG. Two other genes were identified for CGL: caveolin 1 (CAV1) [52] and polymerase I and transcript release factor (PTRF) [53]. If, based on the assessment, a tread­mill stress test is not the best study for a particular patient, an imaging study may be considered. Caveolin 1 is the main component of caveolae, specialized microdomains seen in abundance on adipocyte membranes [54]. Screening should also be con­sidered in patients with an abnormal ECG tracing suggestive of ischemia or infarction. If the results of an anatomi­cal study, such as CCS or CCTA, are abnormal, a functional study, such as a nuclear stress or stress echocardiog­raphy study, is recommended to assess for the presence of ischemia.
PTRF (also known as cavin) is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3 [53].6. Coronary arteriography remains the gold standard for identifying obstructive lesions, though it is never used as an initial screening test.
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]. Future studies in this field should aim on use of biomarkers and genetic testing along with the present imaging techniques. 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].

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