Exercises to Lose Belly Fat in 4 Weeks

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The Metabolic Syndrome in HIVinfected Individuals

A constellation of laboratory and physical abnormalities, termed the metabolic syndrome, is associated with increased risk of cardiovascular morbidity and mortality (Table 2). This syndrome is seen in 24 of the US population overall its prevalence is increasing in the US. The metabolic syndrome encompasses disturbances in glucose, insulin, and lipid metabolism, associated with abdominal obesity. The presence of the metabolic syndrome roughly doubles cardiovascular disease mortality. In other studies, the risk for cardiovascular disease with metabolic syndrome is even higher. The metabolic syndrome may be even more common in HIV-infected individuals there are many possible reasons. HIV infection on its own may exacerbate many of the manifestations of the metabolic syndrome, particularly elevation in serum triglycerides this was seen in HIV-infected individuals prior to the advent of antiretro-viral therapy. In addition, many HIV-infected individuals smoke (50 vs. 25 in the US...

Dysmetabolic Metabolic Syndrome Syndrome X

The original definition of syndrome X, by Reaven (20), emphasized insulin resistance. The dysmetabolic syndrome consists of insulin resistance in association with dyslipidemia, obesity (particularly with excess visceral fat), hypertension, and often IGT or type 2 diabetes. This constellation of abnormalities is associated with an accelerated onset of atherosclerosis (18,122). Patients with syndrome X have a 20-40 incidence of type 2 diabetes and probably an even greater association with IGT (123). The obesity in the abdomen tends to be deep or visceral adiposity, which is associated with accelerated atherosclerosis and coronary artery disease (104). The presence of visceral fat in this syndrome is an example of the fact that not all forms of obesity are functionally the same and that different forms can pose different health risks. Patients with fat distributed in subcutaneous regions around the gluteofemoral areas and upper abdomen are at much less risk for complications such as...

HIVSpecific Diseases Lipodystrophy

Lipodystrophy was identified and characterized by Carr and colleagues in 1998. In addition to laboratory abnormalities associated with the metabolic syndrome, there can also be subcutaneous lipodystrophy, which can involve either fat accumulation in the abdomen, neck and upper back, (Figure 1) or lipoatrophy, involving the extremities and the face (Figure 2), and they can both be seen together. The lipoatrophy in the face is highly recognizable and can be stigmatizing. There is deepening of the nasolabial folds and loss of subcutaneous tissue in the temples and cheeks. Lipodystrophy has been associated with treatment with thymidine nucleoside analog-based (stavudine or zidovu-dine) regimens, and co-administration of a thymidine analog with some protease inhibitors may further accelerate fat loss. Studies investigating thymidine-sparing regimens typically show normal limb fat mass and lower incidence of clinical lipoatrophy, even over prolonged follow-up. Figure 1 Lipodystrophy - fat...

Clinical manifestation

Skin changes facial plethora striae ecchymoses and purpura telangiectasias skin atrophy hirsutism and male pattern balding in women increased lanugo facial hair steroid acne acanthosis nigricans Central obesity increased adipose tissue in the face (moon facies), upper back at the base of neck (buffalo hump), and above the clavicles

Higher Level Data Analysis Unsupervised And Supervised Learning

To date, the higher level computational analysis of gene expression data has centered on two approaches (10). Unsupervised learning, or clustering, involves the aggregation of a diverse collection of data into clusters based on different features in a data set. For example, one could divide a group of people into clusters based on any combination of eye color, waist size, or height. Similarly, one can gather data about the various expressed genes in a collection of tumor samples and then cluster the samples as best as possible into groups based on the similarity of their aggregate expression profiles. Alternatively, one could cluster genes across all samples, to identify genes that share similar patterns of expression in varying biologic contexts. Such approaches have the advantage of being unbiased and allow for the identification of structure in a complex data set without making any a priori assumptions. However, because many different relationships are possible in a complex data...

Impaired glucose tolerance is a disease

Components of the Metabolic Syndrome Abdominal obesity (waist circumference) Overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated body mass index (BMI). Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the metabolic syndrome. Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased, e.g., 94-102 cm (37-40 in.). Such patients may have a strong genetic contribution to insulin resistance, and they should benefit from changes in life habits, like men with categorical increases in waist circumference. prevent or delay the progression of IGT to type 2 diabetes underscores the need for early diagnosis (1). The accelerated heart disease in IGT probably stems from the presence of insulin resistance and its associated...

And Insulin Sensitivity

In experimental rodent models, ACE inhibition has been shown to enhance glucose transport skeletal muscle and adipose tissue in insulin-resistant obese Zucker rats and spontaneously hypertensive rats (147-150). Angiotensin AT1 receptor antagonism has been shown to improve insulin sensitivity and glucose uptake in skeletal muscle of normotensive diabetic KK-Ay mice (151), partially reduce insulin resistance in Wistar fatty rats (114), and increase 2DG uptake and GLUT-4 expression in skeletal muscle in obese Zucker rats (152). Because insulin resistance and the metabolic syndrome accelerate CVD (153) inhibition of the RAS may improve cardiovascular outcomes, in part, by increasing insulin sensitivity and improving metabolic control.

Insulin resistance is a state of inflammation

In addition to the fact that components of the metabolic syndrome contribute to cardiovascular disease, increasing data suggests insulin resistance is a proinflammatory state in itself. Adipose tissue secretes substances (adipokines) that decrease insulin-mediated glucose uptake and or promote vascular inflammation (Table 3). Adipocytokines circulate at higher levels in obese animals or in humans with increased viceral adiposity. Tumor necrosis factor-a (TNF-a) directly suppresses activation of tyrosine kinase on the insulin receptor, resulting in insulin resistance (22). TNF-a levels are not only high in atherosclerotic vessels, promoting inflammation, but are elevated in damaged myocardium and have been implicated in heart failure (23). Adiponectin (Acrp 30) also arises from fat but, in contrast to TNF-a, is low in the circulation of obese humans and animals, enhances insulin-mediated glucose uptake, and inhibits inflammatory responses (24). Leptin is another substance from fat...

Bilateral Upper Urinary Tract Obstruction

The classic presentation of bilateral upper urinary tract obstruction often differs clinically when compared to unilateral obstruction. Bilateral upper urinary obstruction most commonly occurs on a more chronic basis, related to an extrinsic process that progresses slowly over time. In this scenario, signs and symptoms directly related to the extrinsic process often prompt the workup which ultimately leads to the diagnosis of bilateral obstruction. When bilateral chronic upper urinary tract obstruction progresses to the point of causing symptoms, manifestations of renal failure are also commonplace. A common presentation for acute bilateral upper urinary obstruction is related to bilateral obstructing ureteral or UPJ stones. The tip-off to this diagnosis can be the development of bilateral flank pain in the setting of anuria however, more commonly the bilateral stones will be only partially obstructing and the patient will maintain an adequate urine output. Urgent management of...

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women. The effects of estrogen on lipid parameters are discussed in detail in the first part of this chapter. A number of observational studies have also reported that estrogen improves insulin resistance in postmenopausal women, a factor that is predictive for the development of type 2 diabetes (125,129). Estrogen therapy also appears to prevent central fat distribution, a factor that is strongly associated with insulin resistance (126). Thus, estrogen can potentially prevent the insulin resistance associated with central obesity...

Polycystic Ovary Syndrome and Cardiovascular Risk

PAI-1 concentrations in blood are higher in women with PCOS as compared to those not affected. PAI-1 levels have been shown to be positively correlated with triglycerides, basal insulin and abdominal obesity (193). It was shown that impaired fibrinolysis and particularly the high levels of PAI-1 in selected groups of patients with CHD, is not a consequence of the coronary disease itself but it is rather related to the metabolic risk factors of atherosclerosis (194).

Cytokine and metabolicrelated hormone studies

There is a growing literature suggesting that the links between depressive symptoms and OSA may be associated with obesity and the metabolic syndrome. Although both OSA and depression have independently been shown to be associated with metabolic syndrome and cardiovascular disease 105,106 , it is still poorly understood how these risk factors interact with each other.

Diabetes and Insulin Resistance

In humans, type 2 diabetes has been associated with decreased levels of adiponectin (14). In several studies, adiponectin has a negative correlation with fasting glucose, insulin, and insulin resistance and a positive association with insulin sensitivity, independent of BMI (9,14,44). One study demonstrated that adjusting for central obesity renders the negative correlation between adiponectin and insulin resistance no longer significant, suggesting that adiponectin may mediate the relationship between central obesity and insulin resistance (19). In studies involving Pima Indians, Japanese people, and Europeans, subjects with lower adiponectin were more likely to develop type 2 diabetes, independent of adiposity parameters (45-47). In contrast, type 1 diabetic patients have elevated adiponectin levels compared to nondiabetic individuals, and chronically administered insulin does not have an effect on adiponectin levels (48).

Female Sexual Dysfunction

Female sexual dysfunctions (FSD) include persistent or recurrent disorders of sexual interest desire, disorders of subjective and genital arousal, orgasm disorder, pain and difficulty with attempted or completed intercourse. The scientific knowledge on sexual dysfunction in women with diabetes is rudimentary. Sexual dysfunction was observed in 27 of women with type 1 diabetes. FSD was not related to age, BMI, HbAlc, duration of diabetes, and diabetic complications. However, FSD was related to depression and the quality of the partner relationship (71). Recently, the prevalence of FSD in premenopausal women with the metabolic syndrome was compared with the general female population. Women with the metabolic syndrome had reduced mean full female sexual function index score, reduced satisfaction rate, and higher circulating levels of C-reactive protein (CRP). There was an inverse relation between CRP levels and female sexual function index score (72).

High Fat Diets and Obesity Possible Influence of n3 PUFAs

The peptide hormone insulin is produced in the pancreas and secreted in proportion to the degree of adiposity. Similar to leptin, insulin levels are correlated with amount of abdominal fat (Porte et al., 1998 Woods et al., 1996 Woods, Figlewicz Lattemann, Schwartz, & Porte, 1990 Woods et al., 1998). It is transported into the brain where it acts to decrease food intake and body weight (Schwartz, Figlewicz, Baskin, Woods, & Porte, 1992 Woods et al., 1996). High insulin resistance is a characteristic of obesity, hypertension, and non-insulin-dependent diabetes mellitus. There is an inverse relationship between insulin action and triglyceride content. With the ingestion of fat, insulin secretion is increased. Insulin stimulates fatty acid synthase, an enzyme that catalyzes all reactions involved in lipogenesis, and thereby results in the accumulation of triglycerides (Sul, Latasa, Moon, & Kim, 2000). Monounsaturated fatty acids (such as oleate) and saturated fatty acids (such as...

Modified LDL Antibodies and LDLContaining Immunocomplexes

As suggested by recent reports showing that common carotid and femoral IMT are directly related to the levels of IgG oxLDL antibodies and inversely related to the levels of IgM oxLDL antibodies (196). Also of interest is the fact that the levels of IgG oxLDL and MDA-LDL antibodies are associated with the metabolic syndrome and smoking (197).

Abnormalities in the fibrinolytic system

Another well-recognized contributor to augmented activity of PAI-1 in diabetes is the adipocyte. PAI-1 may be released directly from an increased mass of adipose tissue, particularly visceral fat, and that may account, in part, for the association between obesity and impaired fibrinolysis (293-295). However, abnormal concentrations of cytokines such as TGF-P and TNF-a, may also contribute to augment PAI-1 expression in adipocytes (296). Other cytokines including IL-1 and -6 have also been implicated as agonists for PAI-1 synthesis (297). Another factor likely to influence PAI-1 expression in diabetes is the renin-angiotensin system (RAS) because PAI-1 synthesis is augmented

Crystal structures molecular modeling and rational design

Miranda, P.J., DeFronzo, Ralph, Califf, Robert M. and Guyton, John R., Metabolic syndrome Definition, pathophysiology, and mechanisms. Am. Heart J., 149, 33-45 (2004). 6. Mensah, G.A., Mokdad, A.H., Ford, E., Narayan, K.M., Giles, W.H., Vinicor, F., and Deedwania, P.C., Obesity, metabolic syndrome, and type 2 diabetes emerging epidemics and their cardiovascular implications. Cardiol. Clin., 22, 485-504 (2004). 7. Paoletti, R., Bolego, C., Poli, A., and Cignarella, A., Metabolic syndrome, inflammation and atherosclerosis Vasc Health RiskManag., 2, 193-194 (2006). 8. Bray, G.A., and Bellanger, T., Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine, 29, 109-117 (2006). 9. Ceska, R., Clinical implications of the metabolic syndrome. Diab. Vasc. Dis. Res., 4, S2-4 (2007).

Examination and investigation of patients with PCOS and secondary amenorrhoea

One should be aware of the possibility of Cushing's syndrome in women with stigmata of the PCOS and obesity as it is a disease of insidious onset and dire consequences additional clues are the presence of central obesity, moon face, plethoric complexion, buffalo hump, proximal myopathy, thin skin, bruising and abdominal striae (which alone are a common finding in obese individuals). Acanthosis nigricans is a sign of profound insulin resistance and is usually visible as hyperpigmented thickening of the skin folds of the axilla and neck it is associated with PCOS and obesity (Fig. 39.1).

Women Interested in Fertility

Weight loss counseling is also important. It has been reported that weight loss of 5-7 of body weight will improve menstrual function (64-66). In a randomized trial, weight loss was associated with decrease in total testosterone and insulin levels, and four of six women had documented ovulation (67). In contrast, none of the five women in the control group ovulated. In another study, women with PCOS were placed on a low-calorie diet and randomized to placebo versus metformin (65). After 6 mo, the women in the metformin arm of the study had greater reduction of body weight (mean 9.7 kg) and abdominal fat and a decrease in serum fasting insulin (40 ), testosterone (35 ), and leptin levels. In addition, they had a significant improvement in menstrual irregularity. abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000 85 2767-2774.

Health consequences of polycystic ovary syndrome

Women with PCOS have a greater truncal abdominal fat distribution as demonstrated by a higher waist hip ratio. The central distribution of fat is independent of BMI and associated with higher plasma insulin and triglyceride concentrations, and reduced HDL (high-density chole-strol) concentrations. From a practical point of view, if the measurement of waist circumference is greater than 88 cm, there will be excess visceral fat and an increased risk of metabolic problems. Thus there is evidence that insulin resistance, central obesity and hyperandrogenaemia have an adverse effect on lipid metabolism, yet these are surrogate risk factors for cardiovascular disease. However, Pierpoint et al. 16 reported the mortality rate in 1028 women diagnosed as having PCOS between 1930 and 1979. All the women were older than 45 years and 770 women had been treated by wedge resection of the ovaries. Seven hundred and eighty-six women were traced the mean age at diagnosis was 26.4 years and average...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Data on HRT in postmenopausal women with diabetes are scarce but are of major importance, because these women are characterized by hyperandrogenicity, insulin resistance, and dyslipidemia and are at a higher risk for developing CHD. Evidence from the available data suggest that short-term unopposed oral estradiol has a beneficial effect on glucose homeostasis, lipid profile, and other components of the metabolic syndrome, which may be compatible with a reduced risk of CHD. The addition of a progestogen may attenuate some of these favourable effects. On the other hand, HRT consisting of continuous combined transdermal 17 -estradiol and oral norethisterone, reduces plasma triglycerides and cholesterol concentrations, factor VII activity and von Willebrand factor antigen levels without concomitant changes in adiposity and glycemic control. These effects, allied with favorable effects on CRP and potential beneficial effects on vascular reactivity, suggest that this regimen may hold...

Genotype To Phenotype Correlations

The genetic defect is in the PRKAG2 gene which encodes for the gamma subunit of the kinase AMPK. AMP-activated protein kinase is a sensor of the body's ATP level. AMP-activated protein kinase is activated by an increase in the ratio of AMP to ATP. AMP-activated protein kinase increases the availability of ATP by increasing glucose absorption, inhibiting glycogen synthesis, increasing fatty acid oxidation, and decreasing fatty acid synthesis. The phenotype consistently observed in addition to WPW syndrome is excess glycogen in the myocytes of the heart. 10 Hypertrophy of the heart is also observed in a percentage of the patients. Several genetic animal models expressing either the R302Q mutation 8 or the mutation N488I 9 as a transgene have been generated. All of them have the preexcitation syndrome and excessive myocardial glycogen phenotype. The model expressing the R302Q mutation has the preexcitation syndrome, increased cardiac glycogen, and inducible supraventricular reentry...

Women Not Interested in Fertility

Metabolic Syndrome The metabolic syndrome seen in women with PCOS is associated with hyper-lipidemia, early-onset diabetes, and hypertension and macrovascular coronary artery syndrome. This underscores the importance of early intervention and treatment. Lifestyle modifications including weight loss and nutritional and exercise counseling remain the mainstay of therapy. In a recent multicenter, randomized, prospective trial sponsored by the NIH, intensive lifestyle modifications in individuals with impaired glucose tolerance reduced the risk of progressing to diabetes by 58 , and metformin reduced the risk of diabetes by 31 over a follow-up period of 3 yr (60 see also Chapter 5). Similar results for lifestyle changes were reported in the recent Finnish Diabetes Prevention Study (61). However, it is still unclear whether and how this applies to specific populations of women with PCOS.

Conclusion

Over the last 15 years, it has become established that insulin is a vascular hormone. Insulin's vascular actions extend beyond its effect to increase skeletal muscle blood flow and glucose uptake. Current data suggest that insulin modulates vascular tone, and vascular smooth muscle cell proliferation and migration via the release of NO and other yet unidentified mechanisms. Thus, insulin's effects on the vascular system may be important to prevent or delay the progression of CVD. The metabolic syndrome affects the vascular system at multiple levels. Resistance to the vascular actions of insulin may explain, at least in part, the abnormalities associated with the metabolic syndrome. The altered state of the vascular system in the metabolic syndrome may contribute to the higher rates of hypertension and macrovascular disease. Future research assessing the interaction between insulin's effect on the vasculature and newly discovered adipocytokines and other vasoactive hormones will better...

Dyslipidemia

Recent findings have shown that small, dense LDLs, and excess triglyceride-rich remnants, which are highly atherogenic, are increased in the insulin-resistant states (105). Hyperinsulinemia and central obesity, which are commonly accompanied by insulin resistance and type 2 diabetes can lead to an overproduction of very low-density lipoproteins (VLDLs) (106). VLDL particles contain a number of apolipoproteins and triglycerides. Increased free fatty acid and glucose levels can increase VLDL output from the liver, and elevated triglyceride levels can inhibit apoB degradation, resulting in increased secretion of VLDL. Lipoprotein lipase (LPL) activity in decreased in diabetic patients because insulin is a major regulator of LPL activity. Because LPL is necessary for the breakdown of chylomicrons and triglycerides and results in decreased clearance of VLDL, decreases in LPL activity are one of the causes for the increase in VLDLs. A decrease in LDL levels results in more glyceride-rich...

Studies in humans

Several studies have been performed in subjects with various diseases that might be suspected to be consequences of HPA axis activation over prolonged periods. Conditions with increased cortisol secretion due to tumours (such as Cushing's syndrome) or with elevated exposure to glucocorticoids due to therapeutic interventions are followed by insulin resistance, abdominal obesity, hypertension, dyslipidaemia, osteoporosis, cognitive impairments and immune deficiencies (Seeman & Robbins 1994). These are consequences of elevated glucocorticoid exposure where the mechanisms are essentially known.

Discussion

Veldhuis This area presents a lot of challenges to me. One of the difficulties I'm having as an endocrinologist with the testosterone theory, is that I don't see this syndrome X (metabolic syndrome) appearing across puberty in boys. At this stage their testosterone goes up 10 30-fold, but they get just mild insulin resistance. This makes me wonder whether insulin resistance is a marker for some other activity in Bj rntorp I know what you are saying. The problem with these studies as I see them is that people lump obesity into one pot. You have to separate central obesity and peripheral obesity.

Praderwilli Syndrome

Excessive or rapid weight gain on weight-for-length chart (excessive is defined as crossing two centile channels) after 12 months but before 6 years of age central obesity in the absence of intervention. 3. Excessive eating (hyperphagia, obsession with food) with central obesity if uncontrolled. 2. Excessive eating (hyperphagia, obsession with food) with central obesity if uncontrolled.

Implications

The fact that obesity is not only intimately associated with insulin resistance and that obese subjects have variable components of the metabolic syndrome, but that obesity is a state of vascular inflammation, now shifts the paradigm to suggest that obesity is a major disease, not just a predisposing factor to diabetes, hypertension, and cardiovascular and other chronic diseases. One approach therefore, is to pursue weight loss aggressively in all obese subjects, but successful weight loss been shown to be extremely difficult (46). It may be useful to target early subjects at high risk for diabetes and cardiovascular disease by defining their inflammatory state. Table 5 lists the chronologic order of changes that occur in obesity ultimately resulting in coronary artery disease as assessed by specific testing. Visceral obesity is more commonly associated with cardiovascular endpoints, so identifying fat distribution may be a first step in identification of high-risk patients. In some...

Regulation

The interplay between insulin and leptin regulation of glucose and lipid homeostasis is well known and forms the basis for the complexities of the metabolic syndrome-associated phenotypes. As discussed above, recent findings in both diabetic and Zucker rats, may indicate that these hormones may also have a concerted effect on protein peptide homeostasis in part through the modulation of PepT1 expression. In terms of a classical biochemistry view, it would appear obvious and essential that the three major sources of nutrients (lipid, carbohydrates, and protein) would be subject to coordinate regulation.

Adiponectin ADPN

The adipocyte derived factor ADPN is an insulin sensitivity activator, and is correlated to retinal redox stress and remodeling in metabolic syndrome and T2DM. Low levels of serum ADPN levels were found to be correlated with the severity of retinopathy60. Insulin-sensitizing agents reduce pathological retinal microvessel formation through ADPN mediated modulation of tumor necrosis factor alpha (TNFa) production61. ADPN' s effect on diabetic retinopathy is not clear. However, ADPN induces eNO production by stimulating phosphorylation and activation of eNOS. ADPN inhibits specific binding of oxidized LDL and its uptake by macrophages. ADPN possesses anti-inflammatory properties and thus may negatively modulate the process of atherogenesis62' 63.

With diabetes

Healthy postmenopausal women undergo changes in lipoprotein and carbohydrate metabolism and in the pattern of body fat distribution similar to those of patients with diabetes. In fact, a picture resembling the metabolic syndrome emerges with the menopause (12). Replacement therapy with estrogen can improve the adverse impact of meno Postmenopausal women with diabetes are at risk of dyslipidemia, central obesity, hypertension, and accelerated atherosclerosis, all of which can contribute to an increased risk of CVD (127). Thus, postmenopausal women with diabetes could benefit from a reduced risk of CVD with the use of HRT. However, whether HRT confers cardiovascular protection in postmenopausal women with diabetes is currently unknown and remains an issue for further clinical research. An attempt is made in this section to shed some light in this issue based on current evidence. This is preceded by a brief review of the effects of estrogen on risk factors for diabetes and the metabolic...

Energetics

The highest mass-specific rates of oxygen consumption known for any locomotor muscle. Mitochondrial densities within flight muscle fibers are correspondingly high, ranging in some insects to values as high as 45 of the total muscle volume. Energy during flight is derived almost entirely from the oxidation of chemical fuels anaerobic pathways are absent from flight muscles. Metabolic fuels diffuse from the hemolymph surrounding muscle fibers to the point of oxidation within mitochondria, whereas bulk movement of hemolymph within the body cavity transports fuels from the abdominal fat body to the thoracic musculature. The type and composition of the fuel used in flight (i.e., lipids, carbohydrates, or amino acids) vary with phylogenetic association and may even change with time during a single flight duration in some species. Oxygen influx and carbon dioxide efflux during flight occur primarily via diffusion within tracheal pathways, but may be augmented by convective motion. For...

Insulin

However, although it is clear that administration of exogenous insulin do not lead to an increase in macrovascular disease, hyperinsulinemia syndromes like the insulin resistance syndrome, particularly when associated with central obesity, are definitively associated with accelerated development of macrovascular disease. Although the insulin resistance syndrome, characterized by glucose intolerance and hyperinsulinemia, is associated with several cardiovascular risk factors including dyslipidemia, hypertension, and dysfibrinolysis, the increased risk for macrovascular disease cannot be fully explained by the hypertension and dyslipidemia. It is likely that endothelial dysfunction, an important player in determining increased risk for macrovascular disease is involved.

Lipids

Although there has been some variation in study conclusions, epidemiological and observational studies have generally concluded that low endogenous testosterone levels in men are associated with lipid profiles consisting of decreased high-density lipoprotein (HDL) cholesterol levels and increased total cholesterol, triglycerides and LDL levels compared to normal or higher levels. This is referred to as Hypoandrogen Metabolic Syndrome (HAM) and often accompanies the metabolic syndrome of central obesity and insulin resistance (Kaushik et al. 2010). Multiple studies have reached a similar conclusion and found that men with higher levels of testosterone generally have better lipid profiles including high HDLs and lower triglycerides (Kaushik et al. 2010). Supplementation of testosterone in hypoandrogenesis is generally considered to decrease HDLs and only modestly affect LDLs (Mendelsohn and Karas 2005). Lower testosterone levels in men have also been linked to central adiposity, insulin...

Anovulation

Insulin Pump Overweight Women

Weight loss should be the first line of treatment in obese women with anovulation due to PCOS. Central obesity and high BMI are important predisposing factors for insulin resistance, hyperinsulinaemia and hyperandroge-naemia. Effective treatment of obesity can reverse these

Genetics of PCOS

The PCOS has long been noted to have a familial component 11 . Genetic analysis has been hampered by the lack of a universal definition for PCOS. Most of the criteria used for diagnosing PCOS are continuous traits, such as, degree of hirsutism, level of circulating andro-gens, extent of menstrual irregularity, and ovarian volume and morphology. To perform genetic analyses these continuous variables have to be transformed into nominal variables. Family studies have revealed that about 50 of first-degree relatives have PCOS suggesting a dominant mode of inheritance 12 . Commonly first-degree male relatives appear more likely to have premature baldness and metabolic syndrome. As hyperandrogenism is a key feature of PCOS it is logical to explore the critical steps in steroidogenesis and potential enzyme dysfunction. Some studies have found an abnormality with the cholesterol side chain cleavage gene (CYP11a), which is the rate limiting step in steroidogenesis.

Mechanisms

Additionally, differences in insulin sensitivity between women and men may also explain the higher rates of NO production release in women. Indeed, previous reports have indicated that women display higher insulin sensitivity than men of similar age and body mass index (113) suggesting that sex modulates the association between body fat distribution (central vs peripheral) and insulin sensitivity. Therefore, the enhanced endot-helial function observed in women may be secondary to the higher insulin sensitivity in women than men. Type 2 diabetes with associated central obesity and insulin resistance may obviate this sex advantage in women.

Abbreviations

ACE, angiotension converting enzyme AGE, advanced glycation end-products AR, androgen receptor Akt, serine threonine protein kinase CNV, choroidal neovascularization COX, cyclooxygenase CVD, cardiovascular disease DHEA, dehydroepiandrosterone DHT, dihydrotestosterone DIEP, Diabetes in Early Pregnancy Study E, estrogens E2, 17p-estradiol EDRF, endothelium-derived relaxing factor ETDRS, Early Treatment of Diabetic Retinopathy Study eNOS, endothelial nitric oxide synthase ER, estrogen receptor ERa, estrogen receptor alpha ERp, estrogen receptor beta ERE, estrogen-response element ERK, extracellular signal-regulated kinases FGF, fibroblast growth factor HAM, hypoandrogen metabolic syndrome HDL, high-density lipoprotein HLA, human leukocyte antigen HRT, hormone replacement therapy HSP, heat-shock protein HUVEC, human umbilical endothelial cells IDDM, insulin-dependent diabetes mellitus, type 1 ICAM, inter-cellular adhesion molecule LDL, low-density lipoprotein LH, luteinizing hormone MAPK,...

Classification

Several published studies have also demonstrated the association of fat distribution (in particular central or visceral obesity), with increased risk for the metabolic complications of obesity, such as insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia (15-26). Although the link(s) between visceral obesity and obesity-related comorbidities have not been thoroughly clarified, a number of pathophysiologic mechanisms have been postulated. For example, dysregulation of the hypothalamic-pituitary-adrenal axis could lead to Cushing's disease of the omentum, which would result in visceral obesity as well as an increase in circulating free fatty acid levels (27,28). The increased free fatty acids not only promote hypertriglyceridemia and lipoprotein abnormalities but may also contribute to insulin resistance hyperinsulinemia and glucose intolerance, which in a permissive genetic setting results in type 2 diabetes mellitus (29). Hyperinsulinemia, by altering the...

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