Manuel T. Velasquez

Getting to the heart of the matter: osteoarthritis takes its place as part of the metabolic syndrome.

Purpose of reviewLabeling osteoarthritis as a degenerative arthritis is a misnomer. It is now clear that an active genetic and proteomic profile suggests inflammation. The cytokine milieu is similarly inflammatory and neatly parallels that found in the metabolic syndrome. Recent findingsImportant cellular changes in the osteoarthritis lesion include not only chondrocytes but also macrophages. Important catabolic mediators of osteoarthritis include metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motif, a disintegrin and a metalloprotease, interleukin (IL)-1β, IL-17, IL-18 and tumor necrosis factor alpha. The striking finding that hand osteoarthritis in older women is linearly correlated to their degree of atherosclerosis suggests that a connection between osteoarthritis and atherosclerosis exists independently of putative overuse factors directly related to obesity. Therefore, it is not surprising that oxidative stress, endothelial dysfunction, and leptin dysregulation all characterize the osteoarthritis lesion. Better understanding of vitamin D metabolic effects and the Wnt, frizzled, secreted frizzled-related protein, Dickkopf, and low-density lipoprotein receptor-related protein gene families are promising regarding osteoarthritis genesis and therapeutics. SummaryCurrent information suggests that osteoarthritis shares a similar biochemical and inflammatory profile to the metabolic syndrome. Mounting evidence exists to call attention to the fact that osteoarthritis deserves a seat at the Metabolic Syndrome ‘table’ of disorders.

Review of hyperuricemia as new marker for metabolic syndrome

Hyperuricemia has long been established as the major etiologic factor in gout. In recent years, a large body of evidence has accumulated that suggests that hyperuricemia may play a role in the development and pathogenesis of a number of metabolic, hemodynamic, and systemic pathologic diseases, including metabolic syndrome, hypertension, stroke, and atherosclerosis. A number of epidemiologic studies have linked hyperuricemia with each of these disorders. In some studies, therapies that lower uric acid may prevent or improve certain components of the metabolic syndrome. There is an association between uric acid and the development of systemic lupus erythematosus; the connection between other rheumatic diseases such as rheumatoid arthritis and osteoarthritis is less clear. The mechanism for the role of uric acid in disorders other than gout is not well established but recent investigations point towards systemic inflammation induced by urate, as the major pathophysiological event common to systemic diseases, including atherosclerosis.

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

Role of angiotensin-converting enzyme inhibition in glucose metabolism and renal injury in diabetes

The role of angiotensin-converting enzyme (ACE) inhibition in glucose metabolism and renal injury in diabetes has been extensively investigated in diabetic humans, as well as in animal models of diabetes. Accumulated data indicate that ACE inhibitors have either no adverse effect on glucose control or insulin sensitivity or may even improve them. ACE inhibitors also appear to have neutral or positive effects on lipid metabolism. The variability of results between studies may relate to differences in experimental design, the degree of glycemia or insulin resistance, potassium balance, and dose or duration of ACE inhibitor treatment, among others. In contrast, ACE inhibitors have proved effective in limiting proteinuria and retarding renal function loss in insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) patients. In rats with experimental or spontaneous diabetes, ACE inhibitors also reduce proteinuria and limit glomerular as well as tubulointerstitial damage, independent of their effects on systemic arterial pressure. How ACE inhibitors limit renal injury in diabetes is not entirely clear, but hemodynamic and nonhemodynamic mechanisms may be involved. Increasing evidence suggests that the intrarenal renin-angiotensin system (RAS) may be altered or activated in the diabetic kidney. Such activation may be specifically inhibited by ACE inhibitors and may explain the superiority of this class of agents over other antihypertensive agents in reducing proteinuria and slowing the progression of diabetic nephropathy.

Potential effects of lignan-enriched flaxseed powder on bodyweight, visceral fat, lipid profile, and blood pressure in rats.

The potential effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder (LEFP) on bodyweight, visceral fat, lipid profile, adipokines, and blood pressure were investigated using rats, divided into four groups (n=8); a normal control diet (NC), a normal control diet with 0.02% LEFP (NCL), a high-fat and high-fructose diet (HFD), or a high-fat and high-fructose diet with 0.02% LEFP (HFDL). Liver, heart, kidney, adipose tissues, and blood were collected following 12-weeks on the diets. The average body weight of the HFD group was significantly higher than those of the NC, NCL, and the HFDL groups (P<0.05). Also, the average weights of kidneys from the HFD and HFDL groups was higher than those of the NC and NCL groups (P<0.05), although not significantly different in the weights of livers and hearts. The visceral fat weight was significantly higher in rats in the HFD group, but notably reduced in the HFDL fed rats (P<0.05). Accordingly, plasma leptin increased significantly in rats fed the HFD diet, higher than rats fed the HFDL diet. Also, the rats in the HFDL group showed improved lipid profile, compared to the rats in the HFD group (P<0.05). Furthermore, a significant reduction in blood pressure was observed in the rats of the HFDL group compared to the HFD group (P<0.05). These data suggest that the LEFP supplementation may provide beneficial effects such as the reduction of bodyweight and fat accumulation, the lipid profile improvement, and blood pressure control.

Leptin and Its Relation to Obesity and Insulin in the SHR/N-corpulent Rat, A Model of Type II Diabetes Mellitus

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p<0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r=0.73, p<0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r=0.54, p<0.05). There was also a significant positive.correlation between plasma leptin and plasma insulin in the entire group (r=0.70, p<0.01). However, this relationship was significant only for lean rats but not for obese rats (r=0.59, p<0.05 for lean rats, and r=0.23, p=NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r=0.75, p<0.05), total cholesterol (r=0.63, p<0.05), and triglyceride (r=0.67, p <0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p<0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r=0.73, p<0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r=0.54, p<0.05). There was also a significant positive.correlation between plasma leptin and plasma insulin in the entire group (r=0.70, p<0.01). However, this relationship was significant only for lean rats but not for obese rats (r=0.59, p<0.05 for lean rats, and r=0.23, p=NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r=0.75, p<0.05), total cholesterol (r=0.63, p<0.05), and triglyceride (r=0.67, p <0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.

Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non—insulin-dependent diabetes mellitus and hypertension

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen synthesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and lean rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.

Urea and protein carbamylation in ESRD: surrogate markers or partners in crime?

Protein carbamylation may result from chronic exposure to elevated levels of urea in patients with chronic kidney disease. Carbamylation could cause conformational changes in proteins resulting in alterations in binding sites and disturbances in cellular functions. Elevated levels of carbamylated protein has been shown to be associated with increased risk of death from cardiac causes in patients with end-stage renal disease. The precise mechanism by which carbamylated proteins mediate toxicity in uremia needs further investigation.

CommentaryUrea and protein carbamylation in ESRD: surrogate markers or partners in crime?

Protein carbamylation may result from chronic exposure to elevated levels of urea in patients with chronic kidney disease. Carbamylation could cause conformational changes in proteins resulting in alterations in binding sites and disturbances in cellular functions. Elevated levels of carbamylated protein has been shown to be associated with increased risk of death from cardiac causes in patients with end-stage renal disease. The precise mechanism by which carbamylated proteins mediate toxicity in uremia needs further investigation.

Ambulatory Blood Pressure in Chronic Kidney Disease: Ready for Prime Time?

Hypertension is common in patients with chronic kidney disease (CKD) and is the most important modifiable risk factor for CKD progression and adverse cardiovascular events in these patients. Diagnosis and successful management of hypertension are critically dependent on accurate blood pressure (BP) measurement. This is most relevant to CKD patients, in whom BP control is difficult to achieve and in whom early antihypertensive treatment is imperative to prevent kidney and cardiovascular complications. Accumulated data indicate that ambulatory blood pressure monitoring (ABPM) is better in detecting hypertension than office BP measurement. ABPM is also a superior prognostic marker compared with office BP and has successfully identified hypertensive CKD patients at increased risk. Additionally, ABPM provides information on circadian BP variation and short-term BP variability, which is associated with cardiovascular and renal outcomes. This paper reviews the evidence for the usefulness of ABPM in detection and management of hypertension in CKD patients and discusses our current understanding of the pathophysiology of altered circadian BP rhythm and variability in CKD and the role of abnormal BP patterns detected by ABPM in relation to outcomes in CKD. In addition, this Review examines the emerging role of antihypertensive chronotherapy to tailor BP management to the circadian BP pattern abnormality detected by 24-hour ABPM.