Obesity Metabolic Disorders Research Articles

The illusion of prostate-specific antigen decline in patients with metabolic syndrome and insulin resistance

Studies have shown that PSA is negatively associated with obesity as a result of hemodilution or metabolic effect. Hemodilution could be the main reason for low PSA levels in obese men. However, the intrinsic metabolic effects such as insulin resistance (IR) or metabolic syndrome (MS) on PSA level have not been clearly evaluated although obesity is closely tied to MS and IR.We regarded MS and IR as the pathophysiological cornerstone of metabolic disorder in obesity and analyzed the relationships among MS, IR, and PSA levels, and plasma volume by using the concept of PSA mass, the total circulating PSA protein. PSA mass did not change depending on the severity of the obesity, MS or IR. Even the group with both MS and IR, which could be the most metabolically disturbed in this study, did not have different PSA mass, comparing with the group without any MS or IR. Thus, the decline in PSA level in men with MS or IR can be also explained by increased plasma volume other than any intrinsic metabolic effects.

The illusion of prostate‐specific antigen decline in patients with metabolic syndrome and insulin resistance

What's known on the subject? and What does the study add? Studies have shown that PSA is negatively associated with obesity as a result of hemodilution or metabolic effect. Hemodilution could be the main reason for low PSA levels in obese men. However, the intrinsic metabolic effects such as insulin resistance (IR) or metabolic syndrome (MS) on PSA level have not been clearly evaluated although obesity is closely tied to MS and IR. We regarded MS and IR as the pathophysiological cornerstone of metabolic disorder in obesity and analyzed the relationships among MS, IR, and PSA levels, and plasma volume by using the concept of PSA mass, the total circulating PSA protein. PSA mass did not change depending on the severity of the obesity, MS or IR. Even the group with both MS and IR, which could be the most metabolically disturbed in this study, did not have different PSA mass, comparing with the group without any MS or IR. Thus, the decline in PSA level in men with MS or IR can be also explained by increased plasma volume other than any intrinsic metabolic effects. • To investigate the detailed mechanism of prostate-specific antigen (PSA) decline in metabolic syndrome (MS) and insulin resistance (IR), which lowers the predictive value of the PSA test, we examined the effect of haemodilution and the possibility of an intrinsic metabolic effect. • We analysed 28,315 men who underwent routine check-ups. We compared the age-adjusted mean PSA levels in subjects with and without MS before and after adjusting or stratifying the plasma volume. We analysed changes in PSA level, plasma volume and PSA mass according to obesity grade, number of MS components, IR severity and diagnosis of MS, IR or both using an analysis of covariance. • The PSA levels were lower in the group with MS than in the group without MS (P= 0.001), but this difference disappeared after adjusting or stratifying the plasma volume (P > 0.05 for all). The PSA levels decreased, plasma volume increased, and PSA mass did not change as the number of MS components increased (P= 0.002, P < 0.001, P= 0.55, respectively) or the IR severity increased (P= 0.001, P < 0.001, P= 0.34, respectively). • Similarly, PSA levels were lower, plasma volumes were higher and PSA masses were the same in subjects with MS (P= 0.002, P < 0.001, P= 0.10, respectively), IR (P= 0.018, P < 0.001, P= 0.94, respectively), or both (P= 0.003, P < 0.001, P= 0.86, respectively) than in subjects without those conditions. • The PSA decline in MS and IR may result simply from a haemodilution effect and be unrelated to intrinsic metabolic disturbances. For this reason, PSA levels could be underestimated in patients with MS or IR because of haemodilution.

Adiponectin expression and metabolic markers in obesity and Type 2 diabetes

Adiponectin has emerged over the last decade as a key adipokine linking obesity, insulin resistance, and Type 2 diabetes. However, the molecular mechanisms controlling adiponectin expression in adipose tissue are not fully elucidated. Furthermore, increasing evidence indicates that peroxisome proliferator-activated receptor- γ (PPAR-γ) plays an important, and beneficial, role in modulating adiponectin expression. The aim of the present study was to assess the separate role of obesity and Type 2 diabetes in the relationship between endogenous PPAR-γ signaling and adiponectin expression in subcutaneous adipose tissue. Enzyme-linked immuno sor bent assay and real time quantitative PCR analysis were carried out in overweight, obese, and/or diabetic Tunisian patients who underwent an abdominal surgery. These results collectively indicate that circulating levels of adiponectin were decreased in all overweight, obese, and/or diabetic (p<0.001). However, the subcutaneous mRNA expression of adiponectin was reduced only in diabetics (p<0.01) but presents some discrepancies in obese individuals. Moreover, mRNA levels of adiponectin were positively correlated with levels of mRNA encoding PPARγ and its heterodimeric partner retinoid X receptor-α (RXR-α), in both obese and diabetic patients. Our study on Tunisian patients shows impaired regulation of circulating and mRNA adiponectin levels dependent of metabolic disorders in obesity and Type 2 diabetes. The data suggest that subcutaneous adipose tissue may play an important role in modulating adiponectin expression in diabetes and obesity. Moreover, adiponectin mRNA could be potentially regulated by endogenous PPARγ/RXRα-dependent pathways.

Differences in lipogenesis and lipolysis in obese and non-obese adult human adipocytes.

It has been proposed that differences in adipocyte function and/or metabolism between obese and lean individuals may manifest themselves in functional adipose tissue abnormalities that lead to metabolic disorders in obesity. We studied lipogenesis and lipolysis of omental adipocytes from obese (OB) and non-obese (NOB) humans. The specific activity of the lipogenic marker enzyme G3PDH was 50% lower in total adipocytes of OB compared to that of NOB subjects. Omental adipocytes from OB subjects also had lower basal lipolytic levels, and a lower lipolytic response to beta-adrenergic stimulus. Cholesterol depletion of adipocyte plasma membrane using methyl b-cyclodextrin caused a lipolytic effect on adipocytes of both groups together, but when obese and lean subjects were analyzed separately, the response was significant only in the obese. We present evidence of a different lipogenic and lipolytic profile in obese individuals' omental adipocytes, and propose a relevant role of plasma membrane cholesterol, where the impact of its removal in OB and NOB adipocyte lipolysis differs.

Adaptive and maladaptive cortisol responses to pediatric obesity

The recent unprecedented increase of childhood obesity has led to an alarming rise in type 2 diabetes mellitus (T2D) among these children. The process underlying the progression from simple obesity to T2D is not well understood. Cortisol is a candidate factor in the pathogenesis of T2D, as it can exacerbate insulin resistance and provoke other disturbances of the metabolic syndrome. The 24-h integrated concentration (IC) of cortisol is suppressed in non-diabetic obese children compared to lean children. This difference in IC-cortisol is not due to changes in cortisol binding globulin or plasma cortisol to cortisone ratio between groups. In obese individuals, IC-cortisol suppression disappears with age after adolescence, which corresponds with increasing occurrence of T2D and other metabolic disorders of obesity. We consider the IC-cortisol levels of lean insulin sensitive children to be metabolically inappropriate for obese insulin resistant children. Thus, we hypothesize that suppression of IC-cortisol is an important adaptive response to obesity (cortisol adaptive suppression) in childhood that prevents pediatric T2D while failure to suppress IC-cortisol (cortisol suppression failure) exacerbates insulin resistance and contributes to the development of T2D. In further support of this hypothesis is early pilot data suggesting that cortisol suppression failure occurs in obese children with impaired fasting glucose levels. The mechanism(s) underlying cortisol adaptive suppression, how and why these mechanism(s) fail are unknown. Elucidation of these mechanisms may lead to interventions to prevent the development of T2D and its complications in obese individuals.

Differences in lipogenesis and lipolysis in obese and non-obese adult human adipocytes

It has been proposed that differences in adipocyte function and/or metabolism between obese and lean individuals may manifest themselves in functional adipose tissue abnormalities that lead to metabolic disorders in obesity. We studied lipogenesis and lipolysis of omental adipocytes from obese (OB) and non-obese (NOB) humans. The specific activity of the lipogenic marker enzyme G3PDH was 50% lower in total adipocytes of OB compared to that of NOB subjects. Omental adipocytes from OB subjects also had lower basal lipolytic levels, and a lower lipolytic response to beta-adrenergic stimulus. Cholesterol depletion of adipocyte plasma membrane using methyl b-cyclodextrin caused a lipolytic effect on adipocytes of both groups together, but when obese and lean subjects were analyzed separately, the response was significant only in the obese. We present evidence of a different lipogenic and lipolytic profile in obese individuals' omental adipocytes, and propose a relevant role of plasma membrane cholesterol, where the impact of its removal in OB and NOB adipocyte lipolysis differs.

Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals

In adipocytes, oxidative stress and chronic inflammation are closely associated with metabolic disorders, including insulin resistance, obesity, cardiovascular disease, and type 2 diabetes. However, the molecular mechanisms underlying these metabolic disorders have not been thoroughly elucidated. In this report, we demonstrate that overexpression of glucose-6-phosphate dehydrogenase (G6PD) in adipocytes stimulates oxidative stress and inflammatory responses, thus affecting the neighboring macrophages. Adipogenic G6PD overexpression promotes the expression of pro-oxidative enzymes, including inducible nitric oxide synthase and NADPH oxidase, and the activation of nuclear factor-kappaB (NF-kappaB) signaling, which eventually leads to the dysregulation of adipocytokines and inflammatory signals. Furthermore, secretory factors from G6PD-overexpressing adipocytes stimulate macrophages to express more proinflammatory cytokines and to be recruited to the adipocytes; this would cause chronic inflammatory conditions in the adipose tissue of obesity. These effects of G6PD overexpression in adipocytes were abolished by pretreatment with NF-kappaB inhibitors or antioxidant drugs. Thus, we propose that a high level of G6PD in adipocytes may mediate the onset of metabolic disorders in obesity by increasing the oxidative stress and inflammatory signals.

Clinical efficacy of metformin against insulin resistance parameters: sinking the iceberg.

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.

Vascular Actions of Insulin in Health and Disease

Insulin has well known metabolic effects. However, depending on the magnitude and duration of the insulin stimulus, this hormone can also produce vasodilation and vascular smooth muscle growth. The association of hyperinsulinemia with the metabolic disorders of obesity and non-insulin-dependent diabetes, as well as with the cardiovascular pathologies of hypertension and atherosclerosis, has led to suggestions that perhaps elevated insulin levels are causally related to these diseases. Alternatively, insulin resistance may develop following an increase in skeletal muscle vascular resistance, with or without hypertension, such that a reduction in skeletal muscle blood flow leads to an attenuated glucose delivery and uptake. These hypotheses are explored in this review by examining the effects of insulin on vascular smooth muscle tissue during both acute and prolonged exposure. An interaction among hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with the insulin resistant state is described whereby insulin resistance can be both a cause and a result of elevated vascular resistance. The association between blood flow and insulin stimulated glucose uptake suggests that therapeutic intervention against the development of skeletal muscle vascular resistance should occur early in individuals generally predisposed to cardiovascular pathology in order to attenuate, or avoid, insulin resistance and its sequelae.

The functional state of the kidneys in obesity (according to the data of radioisotope renoangiography)

Despite the fact that significant advances have been made in the study of obesity [3, 4, 5, 12-17], many aspects of this complex disease remain insufficiently illuminated. In the pathogenesis of metabolic disorders in obesity, the disorder of water-electrolyte metabolism, the mechanisms of which still remain unclear, is largely involved. There is no doubt that the kidneys play an important role in maintaining water-electrolyte balance. The state of the kidneys in obesity has already been studied by a number of foreign researchers [11, 17] using clearance tests and tests generally accepted in nephrology (urinalysis, blood analysis, Zimnitsky test, determination of the residual nitrogen content in the blood). However, these tests can only give an idea of ​​the total activity of the kidneys, without differentiating the functional state of each of them.