Different metabolic/obesity phenotypes are differentially associated with development of prediabetes in adults: Results from a 14-year cohort study

BACKGROUND The risk of developing prediabetes based on the metabolic/obesity phenotypes has been poorly investigated.AIM To examine the association of baseline metabolic/obesity phenotypes and their changes over time with the risk of prediabetes development.METHODS In a population-based cohort study, 1741 adults(aged 19 years) with normal blood glucose were followed for 14 years. Anthropometric and biochemical measures were evaluated regularly during the follow-up period. According to body mass index and metabolic health status, participants were categorized into four groups: Metabolically healthy normal weight(MHNW), metabolically healthy obese(MHO), metabolically unhealthy normal weight(MUNW) and metabolically unhealthy obese(MUO). Multivariable Cox regression analysis was used to measure the risk of prediabetes according to the baseline metabolic/obesity phenotype and their changes during the follow-up.RESULTSIn the whole population with a mean(95 CCI for mean) follow up duration of 12.7 years(12.6-12.9), all three MUNW, MHO, MUO groups were at higher risk for developing prediabetes compared to the MHNW group(P = 0.022). The MUNW group had the highest risk for developing prediabetes(hazard ratio(HR): 3.84,95%CI: 1.20, 12.27). In stratified analysis by sex, no significant association was found in men, while women in the MUNW group were at the greatest risk for prediabetes(HR: 6.74, 95%CI: 1.53, 29.66). Transforming from each phenotype to MHNW or MHO was not related to the risk of prediabetes development, whereas transforming from each phenotype to MUO was associated with an increased risk of prediabetes(HR 1; P 0.05).CONCLUSION Our findings indicate that MHO is not a high risk, unless it transforms into MUO over time. However, people in the MUNW group have the greatest risk for developing prediabetes, and therefore, they should be screened and treated.     

Metabolically healthy obesity: Is it really healthy for type 2 diabetes mellitus?

Metabolically healthy obese (MHO) individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome. However, the association between MHO and type 2 diabetes (T2DM) is still controversial. Some studies indicated that MHO is a favorable phenotype for T2DM, but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normal-weight individuals, especially among those who would acquire metabolically unhealthy obesity. This has been supported by finding insulin resistance and low-grade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction. Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO. Here, we reviewed current literature on the relationship between MHO and T2DM, discussed the determinants for the development of diabetes in MHO, and summarized the measures for the prevention of T2DM in MHO.     

Prevalence of NASH/NAFLD in people with obesity who are currently classified as metabolically healthy

BackgroundWhile metabolic health in obesity may confer a protective status, recent studies indicate that nonalcoholic fatty liver disease (NAFLD) or even nonalcoholic steatohepatitis (NASH) may exist in this category of individuals. Although cardiovascular and diabetic risks have been well described, the risk of NAFLD and NASH among this population requires further investigation.ObjectiveOur goal was to compare the prevalence of steatosis, NAFLD, and NASH between individuals with metabolically healthy obesity (MHO) and individuals with metabolically abnormal obesity (MAO) and to identify preoperative risk factors for these conditions in a prospective cohort with morbid obesity scheduled for bariatric surgery.SettingsTertiary referral university hospital in France.MethodsThe prospective cohort included 837 bariatric patients who also had an intraoperative liver biopsy between 2002 and 2015. Obese individuals fulfilling none of the criteria in the strict definition of metabolic syndrome were considered metabolically healthy. Preoperative blood samples and liver pathology examinations were reviewed. Steatosis, NAFLD, and NASH were carefully identified allowing comparison of prevalence and risk factors between the 2 cohorts.ResultsIn total, 149 patients (17.8%) had MHO and the remaining 688 (82.2%) had MAO. The cohort with MHO was significantly younger, had a significantly lower glycosylated hemoglobin, a lower homeostasis model assessment of insulin resistance, and increased C-reactive protein. In individuals with MHO, 44 patients (29.5%) had at least moderate steatosis (>33% macrovesicular steatosis) and 5.4% had NASH. Using logistic regression, waist circumference was positively associated with NASH, whereas body mass index and alanine aminotransferase were significantly associated with severe steatosis (>66%).ConclusionOur study indicates that obese individuals without metabolic syndrome may develop subclinical liver involvement. Therefore, the occurrence of NAFLD and NASH in this population needs further investigation.     

The Relationship between Childhood Parental Loss and Metabolic Syndrome in Obese Subjects

The increasing global trend of obesity is a fundamental contributor to the growing prevalence of metabolic syndrome, a cluster of medical abnormalities including impaired glucose and lipid metabolism, obesity and hypertension. Results from animal and human investigations have shown that early life stress can result in weight gain and metabolic changes. Our aim is to investigate whether a particular type of an early adverse event, i.e. parental loss during childhood, is associated with the development of metabolic syndrome in severely obese subjects. One hundred thirty‐five consecutive obese patients who were seeking bariatric surgery were assessed for metabolic syndrome according to the Adult Treatment Panel (ATP) III criteria. Information regarding the experience of parental separation or bereavement before the age of 17 was collected with the use of a semi‐structured interview. In our population, 31.1% of the subjects met the criteria for metabolic syndrome. No significant differences in demographic factors, health habits or psychiatric diagnosis were found between patients with and without coexisting metabolic syndrome. After adjusting for age and gender, multivariate logistic regression analysis revealed that both childhood loss of a parent and a body mass index (BMI) value greater than 50 were significant predictors of metabolic syndrome. This study provides preliminary evidence linking childhood parental loss to risk factors for the development of metabolic syndrome. Copyright © 2011 John Wiley & Sons, Ltd.     

Obesity Alters Adipose Tissue Macrophage Iron Content and Tissue Iron Distribution

Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe^hi, and the remaining ATMs are referred to as MFe^lo. In lean mice, ~25% of the ATMs are MFe^hi; this percentage decreases in obesity owing to the recruitment of MFe^lo macrophages. Similar to MFe^lo cells, MFe^hi ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe^hi ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe^hi iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe^hi ATM phenotype and their reduced capacity to handle iron.     

Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk

The adipose tissue has become a central focus in the pathogenesis of obesity-mediated cardiovascular and metabolic disease. Here we demonstrate that adipose sphingolipid metabolism is altered in genetically obese (ob/ob) mice. Expression of enzymes involved in ceramide generation (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) and ceramide hydrolysis (ceramidase) are elevated in obese adipose tissues. Our data also suggest that hyperinsulinemia and elevated tumor necrosis factor (TNF)-alpha associated with obesity may contribute to the observed increase in adipose NSMase, ASMase, and SPT mRNA in this murine model of obesity. Liquid chromatography/mass spectroscopy revealed a decrease in total adipose sphingomyelin and ceramide levels but an increase in sphingosine in ob/ob mice compared with lean mice. In contrast to the adipose tissue, plasma levels of total sphingomyelin, ceramide, sphingosine, and sphingosine 1-phosphate (S1P) were elevated in ob/ob mice. In cultured adipocytes, ceramide, sphingosine, and S1P induced gene expression of plasminogen activator inhibitor-1, TNF-alpha, monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine. Collectively, our results identify a novel role for sphingolipids in contributing to the prothrombotic and proinflammatory phenotype of the obese adipose tissue currently believed to play a major role in the pathogenesis of obesity-mediated cardiovascular and metabolic disease.     

Divergent Effects of Obesity on Bone Health

Historically, obesity was thought to be advantageous for maintaining healthy bones due to the greater bone mineral density observed in overweight individuals. However, recent observations of increased fracture in some obese individuals have led to concern that common metabolic complications of obesity, such as type 2 diabetes, metabolic syndrome, impaired glucose tolerance, insulin resistance, hyperglycemia, and inflammation may be associated with poor bone health. In support of this hypothesis, greater visceral fat, a hallmark of insulin resistance and metabolic syndrome, is associated with lower bone mineral density. Research is needed to determine if and how visceral fat and/or poor metabolic health are causally associated with bone health. Clinicians should consider adding a marker metabolic health, such as waist circumference or fasting plasma glucose concentration, to other known risk factors for osteoporosis and fracture.     

Effects of 12 Weeks of Combined Exercise Training on Visfatin and Metabolic Syndrome Factors in Obese Middle-Aged Women

Visfatin is a highly expressed protein with insulin-like functions located predominantly in visceral adipose tissue and has been linked to obesity and increased health risks. The purpose of this study was to examine the effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women. Subjects were randomly assigned to either a training (n = 10) or control (n = 10) group. The training group exercised for 1 hour, 3 days per week during the 12 week supervised training program. The training program included 3 sets of 10 repetition maximum (10RM) resistance exercise as well as aerobic exercise at an intensity of 60-70% of their heart rate reserve (HRR). The control group was asked to maintain their normal daily activities. Two-way (group X time) repeated measured analysis of variance revealed no significant main effects, but there was a significant group X time interaction for the following variables: body weight (p < 0.01), percent body fat (% fat) (p < 0.01), waist hip ratio (WHR) (p < 0.01), diastolic blood pressure (DBP) (p < 0.05), fasting glucose level (p < 0.01), triglyceride levels (TG) (p < 0.01), high density lipoprotein cholesterol levels (HDL-C) (p < 0.05), and visfatin (p < 0.01). In conclusion, the 12 week combined resistance and aerobic training program used in this study was very effective for producing significant benefits to body composition and metabolic syndrome factors, as well as lowering visfatin levels in these obese middle-aged women.

Key points

• Recent studies have linked visfatin to obesity and increased health risks.
• The study was done to investigate the effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women.
• The exercise program used in this study was found to be very effective for lowering visfatin levels in obese middle-aged women.

Key words: Metabolic syndrome, combined resistance, aerobic exercise, visfatin     

The perils of portliness: causes and consequences of visceral adiposity

Although an individual's total fat mass predicts morbidities such as coronary artery disease and diabetes, the anatomical distribution of adipose tissue is a strong and independent predictor of such adverse health outcomes. Thus, obese individuals with most of their fat stored in visceral adipose depots generally suffer greater adverse metabolic consequences than similarly overweight subjects with fat stored predominantly in subcutaneous sites. A fuller understanding of the biology of central obesity will require information regarding the genetic and environmental determinants of human fat topography and of the molecular mechanisms linking visceral adiposity to degenerative metabolic and vascular disease. Here we attempt to summarize the growing body of data relevant to these key areas and, in particular, to illustrate how recent advances in adipocyte biology are providing the basis for new pathophysiological insights.     

Omentin plasma levels and gene expression are decreased in obesity

Central obesity and the accumulation of visceral fat are risk factors for the development of type 2 diabetes and cardiovascular disease. Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in human adipocytes. To determine the impact of obesity-dependent insulin resistance on the regulation of two omentin isoforms, gene expression and plasma levels were measured in lean, overweight, and obese subjects. Omentin 1 was shown to be the major circulating isoform in human plasma. Lean subjects had significantly higher plasma omentin 1 levels than obese and overweight subjects. In addition, higher plasma omentin 1 levels were detected in women compared with men. Plasma omentin 1 levels were inversely correlated with BMI, waist circumference, leptin levels, and insulin resistance as measured by homeostasis model assessment and positively correlated with adiponectin and HDL levels. Both omentin 1 and omentin 2 gene expression were decreased with obesity and were highly correlated with each other in visceral adipose tissue. In summary, decreased omentin levels are associated with increasing obesity and insulin resistance. Therefore, omentin levels may be predictive of the metabolic consequences or co-morbidities associated with obesity.     

Small-Molecule Inhibitors of PKR Improve Glucose Homeostasis in Obese Diabetic Mice

Obesity and metabolic diseases appear as clusters, often featuring high risk for insulin resistance and type 2 diabetes, and constitute a major global health problem with limited treatment options. Previous studies have shown that double-stranded RNA–dependent kinase, PKR, plays an important role in the nutrient/pathogen-sensing interface, and acts as a key modulator of chronic metabolic inflammation, insulin sensitivity, and glucose homeostasis in obesity. Recently, pathological PKR activation was also demonstrated in obese humans, strengthening its prospects as a potential drug target. Here, we investigate the use of two structurally distinct small-molecule inhibitors of PKR in the treatment of insulin resistance and type 2 diabetes in cells and in a mouse model of severe obesity and insulin resistance. Inhibition of PKR reduced stress-induced Jun NH₂-terminal kinase activation and insulin receptor substrate 1 serine phosphorylation in vitro and in vivo. In addition, treatment with both PKR inhibitors reduced adipose tissue inflammation, improved insulin sensitivity, and improved glucose intolerance in mice after the establishment of obesity and insulin resistance. Our findings suggest that pharmacologically targeting PKR may be an effective therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.     

Metabolic Profile in Severely Obese Women is Less Deteriorated than Expected when Compared to Moderately Obese Women

Background: Obesity is well known to be associated with an increased prevalence of metabolic complications. Severe obesity is thus expected to have more important alterations of the metabolic profile than moderate obesity. This study aimed to compare the metabolic profile of pre- and postmenopausal severely obese women with moderately obese women. Methods: First, the metabolic profile of pre- (n=165) and postmenopausal (n=43) severely obese women (body mass index (BMI) ≥40 kg/m²) was compared to that of pre- (n=52) and postmenopausal (n=35) moderately obese women (BMI of 30-40 kg/m²). Thereafter, pre- and postmenopausal severely obese women were divided into two subgroups according to the presence/absence of a dysmetabolic profile. We used for comparison, a group of pre- and postmenopausal moderately obese women without a dysmetabolic profile. Results: The metabolic profile of pre- and postmenopausal severely obese women was less deteriorated than expected when compared to moderately obese women. Moreover, severely obese women with or without a dysmetabolic profile displayed comparable or even lower plasma levels of cholesterol, HDL and LDL-cholesterol, and a lower cholesterol/HDL-cholesterol ratio than moderately obese women (P≤0.05). After menopause, the metabolic profile of severely obese women, dysmetabolic or not, was similar to that of moderately obese women. Blood pressure was, however, higher in severely obese women compared to moderately obese women, only before menopause (P≤0.0001). Conclusion: These results indicate that despite their large accumulation of adipose tissue, most of the severely obese women had a metabolic profile less deteriorated than expected, when compared to moderately obese women.     

The FTO Obesity Gene. Genotyping and Gene Expression Analysis in Morbidly Obese Patients

BACKGROUND: Obesity has emerged as one of the most serious public health concerns in the twenty-first century. the fat mass and obesity associated gene (FTO) has been found to contribute to the risk of obesity in humans. Our aims in this study were to investigate the association of rs9939609 single nucleotide polymorphism (SNP) of the FTO gene with different obesity-related parameters, to assess the FTO gene expression in subcutaneous and visceral adipose tissues from morbidly obese and its correlations with other adipocytokine gene expressions. METHODS: The association between the rs9939609 FTO gene variant and obesity related parameters in 75 obese/morbidly obese adult patients and 180 subjects with body mass index (BMI) < 30 kg/m(2) (control group) was examined. Gene expression analyses: subcutaneous adipose tissue samples were obtained from 52 morbidly obese and five subjects with BMI < 30 kg/m(2). Visceral adipose tissue was also obtained from 35 morbidly obese patients. Weight, height, BMI, SBP, DBP, fasting glucose, lipid profile, proinsulin, insulin, leptin, and adiponectin (RIA) of patients were also obtained. Insulin resistance by HOMA(IR). rs9939609 of FTO genotyping using allele discrimination in real-time PCR. Genomic study of RNA extraction of adipose tissue and real-time PCR (RT-PCR) of adipocytokines and a housekeeping gene were quantified using TaqMan probes. Relative quantification was calculated using the DeltaDelta Ct formula. RESULTS: The minor-(A) allele frequency of rs9939609 FTO gene in the whole population was 0.39. A strong association between this A allele and obesity was found, even after age-sex adjustment (p = 0.013). We found higher levels of FTO mRNA in subcutaneous adipose tissue from morbidly obese than in the control group (p = 0.021). FTO gene expression was lower in visceral than in subcutaneous adipose depot. However, this finding did not reach the level of statistical significance. A negative correlation between subcutaneous FTO gene expression and serum triglyceride levels and a positive correlation with leptin, perilipin, and visfatin gene expressions was found. In the visceral adipose tissue, these positive correlations were statistically significant only for perilipin. CONCLUSIONS: Our results show: (1) A strong association between rs9939609 SNP of the FTO gene variant and obesity in Spanish morbidly obese adult patients; (2) positive correlations between FTO mRNA and leptin, perilipin, and visfatin gene expressions in subcutaneous adipose tissue; (3) FTO and perilipin gene expressions were positively correlated in visceral fat depot. Overall these results may suggest a role of FTO in the regulation of lipolysis as well as in total body fat rather in fat distribution patterns.     

The association of aldosterone with obesity-related hypertension and the metabolic syndrome

Overweight and obesity are associated with arterial hypertension. Given the large increase in the obesity prevalence worldwide, the number of obese patients with hypertension is likely to increase substantially in the near future. Overweight and obese patients are exposed to an important metabolic and cardiovascular risk. The understanding of the mechanisms linking obesity to hypertension is important for specific prevention and therapy in this population. There is some evidence that obesity is associated with an increased aldosterone level. To date, 2 mechanisms may explain the interaction of fat tissue with the renin-angiotensin-aldosterone system, and therefore explain, in part, obesity-related hypertension. First, human adipose tissue produces several components of the renin-angiotensin-aldosterone system, mainly adipose tissue-derived angiotensinogen. Second, increased fatty acid production in the obese patient, especially nonesterified fatty acids, might stimulate aldosterone production, independent of renin. A better understanding of these mechanisms might have implications for the management of hypertension in overweight and obese patients. Because aldosterone also is associated with blood glucose and blood lipids, selective aldosterone blockade may represent a particularly attractive therapeutic strategy in obese patients with a clustering of cardiovascular risk factors.     

Pregnancy outcomes after bariatric surgery: maternal, fetal, and infant implications.

Obese women who become pregnant face many health risks, including gestational diabetes, pregnancy-induced hypertension, and pre-eclampsia. These women also have a greater incidence of preterm labor, cesarean sections, and perioperative morbidity. Infants born to obese women have increased rates of macrosomia and congenital anomalies, as well as life-long complications such as obesity and its associated morbidities. With the increase in numbers of weight loss operations being performed in women of child-bearing age, physicians will have to address patient concerns regarding the safety of pregnancy after surgery. Many of the proposed health benefits of weight loss after surgery could translate to decreased rates of complications experienced by obese pregnant women. Case reports and small series have emerged documenting pregnancy courses after bariatric surgery. We reviewed the studies that reported pregnancy outcomes compiled from PubMed and Ovid databases to help draw conclusions regarding the maternal, fetal, and infant safety in women after bariatric surgery. The observations from these studies have shown that the health risks experienced by obese women during pregnancy are reduced after weight loss surgery. Additionally, there does not appear to be any increased risk regarding fetal or infant outcome.     

Obesity, low testosterone levels and erectile dysfunction

Obesity is an important risk factor for many common diseases including cardiovascular disease (CVD), type 2 diabetes, cancer and erectile dysfunction (ED). Adipose tissues produce a number of adipokines and cytokines, which affect endothelial and metabolic function resulting in insulin resistance and the metabolic syndrome (risks factors for CVD). Both ED and metabolic syndrome improve with a reduction in body mass index (BMI). The relationships among obesity, metabolic syndrome, ED, sex hormone-binding globulin (SHBG) and serum total and free testosterone levels are complex and often confusing to the physician. It is known that BMI is inversely proportional to serum total testosterone concentrations; low serum SHBG levels in obesity contribute to the low serum total testosterone. Recent studies show that BMI is also inversely proportional to free testosterone concentration. The characteristic low serum testosterone concentrations observed in obese men are also present in men with the metabolic syndrome and type 2 diabetes mellitus. A small proportion of men with ED have hypogonadism; however, the proportion increases if these men are obese with manifestations of the metabolic syndrome or type 2 diabetes mellitus. ED is a common symptom in patients with type 2 diabetes who also have low testosterone levels. This review describes the relationships between low serum testosterone concentrations and ED in obese patients and those with metabolic syndrome and type 2 diabetes mellitus.     

Diabetic ketoacidosis and rhabdomyolysis following excessive intake of a weight reducing diet

With the awareness of health problems related to obesity, weight reducing diets have become very popular. However, if these meal supplements are not taken as recommended, they can cause considerable harm in high risk individuals. We report a case of a young obese man who developed diabetic ketoacidosis (DKA) followed by rhabdomyolysis and acute renal failure (ARF) after excessive intake of a high carbohydrate containing weight-reducing meal. DKA associated with excessive intake of weight reducing diets has not been reported previously. In people with obesity and insulin resistance improper use of these supplements can cause severe metabolic complications.     

Diet, obesity, and prostate health: are we missing the link?

Prostate problems, such as benign prostatic hyperplasia, prostatic intra-epithelial neoplasia, prostatitis, and prostate cancer have been recognized as problems largely related to androgens and genetic factors. They affect a large fraction of the elderly population, contributing significantly to morbidity and mortality. Estrogen has also now been recognized as one of the important regulators of prostate growth. Diet, general health, and obesity were disregarded as the causative or complicating factors until very recently. Increasing episodes of prostate problems, complications in overweight/obese individuals, or both have attracted attention toward these contemporary risk factors. Prostate problems are reportedly less frequent or less severe in areas in which a plant-based diet is predominant. Consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. As adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems. Adipose tissue is now known to affect circulating levels of several bioactive messengers and therefore could affect the risk of developing prostate problems in addition to several other well-recognized health problems. Nevertheless, increased plasma volume, excess tissue growth, and fat deposition could affect resection and number of biopsies required, thus adding further complications because of a delayed diagnosis. In short, evidence is gathering to support the influence of diet and obesity on prostate health. In this review article, we have tried to make this connection more apparent using supporting published data.     

Renal and metabolic effects of caffeine in obese (fa/fa(cp)), diabetic, hypertensive ZSF1 rats.

In Western society, the triad of hypertension, metabolic syndrome and obesity (which caries a high risk for renal disease) is increasing, as is the intake of caffeine. However, no information is available regarding the metabolic or renal consequences of caffeine consumption in this complex disease entity. The purpose of this study was to investigate the effects of chronic caffeine consumption on renal function and metabolic status in obese ZSF1 rats, an animal model of obesity, hypertension and the metabolic syndrome. Fifteen, 18-week-old male, obese ZSF1 rats were randomized to drink tap water (Cont, n = 8) or 0.1% solution of caffeine (Caff, n = 7) for 8 weeks. Metabolic and renal function measurements were performed at baseline and after 4 and 8 weeks of treatment. Caffeine treatment significantly (p < 0.05) reduced body weight, food, and fluid consumption and improved insulin sensitivity (fasting insulin 129.6+/-8.1 vs 97.5+/-3.6 microIU/mL; fed insulin 146.3+/-8.5 vs 110.6+/-3.4 microIU/mL; fasting glucose 138.7+/-13.4 vs 145+/-8.0 mg/dL; fed glucose 373+/-19.4 vs 283.3+/-19.6 mg/dL, Cont vs Caff, respectively). After 8 weeks of caffeine treatment, animals were less glycosuric as compared with control group. Area under glucose curves (AUC-glucose) in oral glucose tolerance test did not differ between the two groups (AUC- glucose: 592.5+/-42.7 vs 589.5+/-20.5 mg/dL x h, Cont vs Caff), whereas caffeine treatment significantly decreased AUC of insulin (AUC-insulin: 257.77+/-12.9 vs 198.0+/-5.9 microIU/mL x h, Cont vs. Caff, p<0.05). No differences were found with regard to plasma triglycerides and glycerol levels; however, caffeine significantly increased cholesterol levels after 4 and 8 weeks (2F-Anova, p<0.001). Moreover, caffeine significantly decreased creatinine clearance after 4 and 8 weeks (CrCl, Cont: 3.5+/-0.4, Caff: 2.2+/-0.2 L/kg/day, p<0.05) and increased protein/CrCl ratio (Cont: 323+/-30, Caff: 527+/-33 mg/L/day). Caffeine treatment for 8 weeks tended to increase plasma norepinephrine levels (p<0.06), but the two groups did not differ with regard to plasma renin activity, blood pressure, renal blood flow or and renal vascular resistance. The study indicates that caffeine improves insulin sensitivity but increases plasma cholesterol levels and impairs renal function in obesity with the metabolic syndrome and hypertension. Our results imply that the health consequences of chronic caffeine consumption may depend heavily on underlying pathophysiology process.