The origin of intermuscular adipose tissue and its pathophysiological implications.

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66(shc), mitochondrial ROS production, PKCß) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

Nonalcoholic fatty liver disease, adiponectin and insulin resistance in dipper and nondipper essential hypertensive patients.

OBJECTIVE: The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial, and the presence of insulin resistance is recognized as the pathophysiological hallmark of this condition. Arterial hypertension is referred as an insulin-resistant state, and insulin resistance may substantially contribute to the cardiovascular risk in this disorder. We examined the inter-relationship between insulin sensitivity, adiponectin levels, and NAFLD in hypertensive patients with different circadian blood pressure profiles. METHODS: Eighty never-treated patients with essential hypertension were selected for having a nocturnal decrement of blood pressure that was at least 10% (dippers, n=47) or less than 10% (nondippers, n=33) of daytime values. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for hepatic disease. The two groups were similar as to sex, age, and BMI. Abdominal fat distribution and NAFLD were assessed by ultrasonography. RESULTS: Hepatic steatosis was detected in 57.5% of all patients. Nondippers showed a higher prevalence of NAFLD than dippers (81.8 vs. 40.4%, P<0.005). Insulin and the homeostasis model of assessment index were higher (P<0.001) and adiponectin was lower (P<0.001) in nondippers than in dippers, whereas no difference was found in regional fat, liver enzymes, and other metabolic parameters. At multivariate analysis, factors independently associated with nondipping were insulin (P<0.05) and adiponectin (P<0.01) with the homeostasis model of assessment index being of borderline significance. CONCLUSION: In the absence of major risk factors for the development of NAFLD, a high prevalence of liver steatosis was associated with insulin resistance and low adiponectin levels in essential hypertensive patients with a nondipping profile.

Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization.

BACKGROUND: Free fatty acids (FFAs) acutely stimulate but chronically impair glucose-stimulated insulin secretion from beta-cells. The G protein-coupled transmembrane receptor 40 (GPR40) mediates both acute and chronic effects of FFAs on insulin secretion and plays a role in glucose homeostasis. Limited information is available on the effect of GPR40 genetic abnormalities on insulin secretion and metabolic regulation in human subjects. STUDY DESIGN AND RESULTS: For in vivo studies, we screened 734 subjects for the coding region of GPR40 and identified a new single-nucleotide mutation (Gly180Ser). The mean allele frequency was 0.75%, which progressively increased (P < 0.05) from nonobese subjects (0.42%) to moderately obese (body mass index = 30-39.9 kg/m2, 1.07%) and severely obese patients (body mass index > or = 40 kg/m2, 2.60%). The relationship between the GPR40 mutation, insulin secretion, and metabolic alterations was studied in 11 Gly/Ser mutation carriers. In these subjects, insulin secretion (insulinogenic index derived from oral glucose tolerance test) was significantly lower than in 692 Gly/Gly carriers (86.0 +/- 48.2 vs. 183.7 +/- 134.4, P < 0.005). Moreover, a case-control study indicated that plasma insulin and C-peptide responses to a lipid load were significantly (P < 0.05) lower in six Gly/Ser than in 12 Gly/Gly carriers. In vitro experiments in HeLa cells cotransfected with aequorin and the mutated Gly/Ser GPR40 indicated that intracellular Ca2+ concentration increase after oleic acid was significantly lower than in Gly/Gly GPR40-transfected cells. This fact was confirmed using fura-2 acetoxymethyl ester. CONCLUSIONS: This newly identified GPR40 variant results in a loss of function that prevents the beta-cell ability to adequately sense lipids as an insulin secretory stimulus because of impaired intracellular Ca2+ concentration increase.

The metabolic syndrome in primary aldosteronism.

Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder.

Rational error in internal medicine.

Epistemologists have selected two basic categories: that of errors committed in scientific research, when a researcher devises or accepts an unfounded hypothesis, and that of mistakes committed in the application of scientific knowledge whereby doctors rely on knowledge held to be true at the time in order to understand an individual patient's signs and symptoms. The paper will deal exclusively with the latter, that is to say the mistakes which physicians make while carrying out their day-to-day medical duties. The paper will deal with the mistakes committed in medicine trying also to offer a classification. It will take into account also examples of mistakes in Bayesian reasoning and mistakes of reasoning committed by clinicians regard inductive reasoning. Moreover, many other mistakes are due to fallacies of deductive logic, logic which they use on a day-to-day basis while examining patients in order to envisage the consequences of the various diagnostic or physiopathologic hypotheses. The existence of a different type of mistakes that are part of the psychology of thought will be also pointed out. We conclude that internists often make mistakes because, unknowingly, they fail to reason correctly. These mistakes can occur in two ways: either because he does not observe the laws of formal logic, or because his practical rationality does not match theoretical rationality and so his reasoning becomes influenced by the circumstances in which he finds himself.

Heart lipid accumulation in obese non-diabetic rats: effect of weight loss.

BACKGROUND AND AIM: The aim of this study was to investigate lipid content and expression of genes involved in lipid metabolism, in lean and obese non-diabetic rats and in obese rats undergoing food restriction and weight loss. METHODS AND RESULTS: We studied lean and genetically obese Zucker rats (fa/fa). Another group of obese rats were food restricted to lose 20% of initial body weight. We measured expression of genes involved in lipid oxidation and synthesis. Tissue triglyceride content, cell apoptosis and tissue fibrosis were also evaluated. The hearts of obese rats have higher triglyceride content compared to lean controls despite an increased expression of genes involved in fatty acid oxidation (PPAR alpha, PGC-1 alpha, CPT-I, ACO, UCP3). No differences were found in apoptosis and tissue fibrosis between the two phenotypes. Weight loss resulted in a significant reduction in heart lipid content, while the expression of genes involved in fatty acid oxidation remained elevated. CONCLUSION: In contrast to data reported in diabetic rats, pathways of lipid oxidation are increased rather than decreased in insulin-resistant obese rats. Food restriction reduced heart triglyceride content while lipid-oxidizing genes remained elevated, probably as a consequence of lipid oversupply coming from the endogenous source.

The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms.

BACKGROUND: The endogenous cannabinoid system participates in the regulation of energy balance, and its dysregulation may be implicated in the pathogenesis of obesity. Adipose tissue endocannabinoids may produce metabolic and endocrine effects, but very few data are available in human adipose tissue and in primary human fat cells. EXPERIMENTAL DESIGN: We measured expression of type 1 and type 2 cannabinoid receptors (CNR), enzymes of cannabinoids synthesis and degradation in human omental, sc abdominal, and gluteal adipose tissue from lean and obese subjects. Furthermore, we assessed the effect of CNR1 stimulation on glucose uptake and intracellular transduction mechanisms in primary human adipocytes. Then we assessed the reciprocal regulation between CNR1 and peroxisome proliferator-activated receptor-gamma (PPARgamma). Finally, we tested whether leptin and adiponectin are regulated by CNR1 in human adipocytes. RESULTS: We found that most genes of the endocannabinoid system are down-regulated in gluteal fat and up-regulated in visceral and sc abdominal adipose tissue of obese patients. Treatment of adipocytes with rosiglitazone markedly down-regulated CNR1 expression, whereas Win 55,212 up-regulated PPARgamma. Win 55,212 increased (+50%) glucose uptake, the translocation of glucose transporter 4, and intracellular calcium in fat cells. All these effects were inhibited by SR141716 and wortmannin and by removing extracellular calcium. Win 55,212 and SR141716 had no effect on expression of adiponectin and leptin. CONCLUSIONS: These results indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channeling excess energy fuels to adipose tissue in obese humans.

The metabolic syndrome in primary aldosteronism.

Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder.

Clinical and diagnostic aspects of encephalopathy associated with autoimmune thyroid disease (or Hashimoto's encephalopathy).

Encephalopathy associated with autoimmune thyroid disease, currently known as Hashimoto's encephalopathy, but also defined as corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis, is a relatively rare condition observed in a small percentage of patients presenting with autoimmune thyroid disease. It consists of a subacute, relapsing-remitting, steroid-responsive encephalopathy characterised by protean neurologic and neuropsychiatric symptoms, diffuse electroencephalographic abnormalities and increased titres of antithyroid antibodies in serum and/or in cerebrospinal fluid. Most of the cases presenting this neurologic complication are affected by Hashimoto's thyroiditis or, less frequently, by other autoimmune thyroid diseases, chiefly Graves' disease. The pathogenesis of this encephalopathy is still unknown and largely debated, because of extremely varied clinical presentation, possibly referable to different aetiologic and pathophysiologic mechanisms, as confirmed by the two clinical cases we report in this paper. Autoimmune aetiology is, however, very likely in view of the well established favourable response to corticosteroid administration. Both vasculitis and autoimmunity directed against common brain-thyroid antigens represent the most probable aetiologic pathways. Clinical manifestations include consciousness changes, neurologic diffuse or focal signs, headache, and altered cognitive function. Although unspecific, cerebral oedema has also been described. Cerebrospinal fluid examination often discloses an inflammatory process, with a mild increase in protein content and occasionally in lymphocyte count. In this review, clinical criteria for the diagnosis of defined, probable, or possible encephalopathy associated with autoimmune thyroid disease are suggested. Corticosteroid therapy currently allows us to obtain rapid remission of disease symptoms, but adverse outcomes as well as spontaneous remissions have also been reported.

Reduced plasma visfatin/pre-B cell colony-enhancing factor in obesity is not related to insulin resistance in humans.

CONTEXT: Visfatin was recently identified as a protein highly expressed and secreted in adipose tissue with insulin-mimetic effect and is a candidate hormone to help explain the association among adipose tissue expansion, insulin resistance, and type 2 diabetes. OBJECTIVE: The objective of the study was to assess expression of visfatin in lean and obese subjects and in sc and visceral adipose tissue and moreover to explore the role of visfatin on insulin resistance in humans. DESIGN: We measured circulating visfatin and its mRNA expression in sc adipose tissue (SAT) in lean and obese subjects. Furthermore, we measured visfatin mRNA in visceral adipose (VAT) and SAT by quantitative RT-PCR. Finally, plasma visfatin and its mRNA in SAT were measured under free fatty acid-induced insulin resistance in healthy subjects. RESULTS: Plasma visfatin and its mRNA in SAT were significantly lower in obese subjects, compared with normal-weight controls. Both circulating visfatin and SAT visfatin mRNA were negatively correlated with body mass index, whereas no correlation was found with homeostasis model assessment. Significantly higher visfatin mRNA was found in VAT of obese subjects, compared with lean controls. Interestingly, visfatin mRNA in VAT was positively correlated with BMI. Elevation of free fatty acid induced a condition of insulin resistance but did not affect either circulating visfatin or its mRNA. CONCLUSIONS: Our findings show that, in human obesity, plasma visfatin is reduced, whereas visfatin mRNA is differentially regulated in SAT and VAT. Visfatin is not related to insulin resistance either as assessed by homeostasis model assessment or during lipid infusion.

A critical reflection on the definition of metabolic syndrome.

The metabolic syndrome (visceral obesity, dyslipidaemia, hyperglycaemia, and hypertension), has become one of the major public-health challenges worldwide. There has been growing interest in this constellation of closely related cardiovascular risk factors. Recently, definition and relevance of this syndrome have been questioned. In the present review we analyze in detail the epistemological issues regarding definition and the methodological approaches to definition of the metabolic syndrome.

Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance.

CONTEXT: The recently discovered hormone resistin is linked to the development of insulin resistance, but direct evidence of resistin levels in humans with nonalcoholic fatty liver disease (NAFLD) is lacking. METHODS: We conducted this study to assess the relationship between serum resistin and NAFLD. We measured serum resistin and biochemical, hormonal, and histological correlates in 28 NAFLD patients, 33 controls, and 30 obese patients [body mass index (BMI), >30 kg/m2] without NAFLD. RESULTS: Resistin and adiponectin expression were measured in sc adipose tissue by quantitative RT-PCR. Resistin was higher in NAFLD patients compared with controls (5.87 +/- 0.49 vs. 4.30 +/- 0.20 ng/ml; P = 0.002) and obese patients (4.37 +/- 0.27 ng/ml; P = 0.002). Increased resistin mRNA was also found in the adipose tissue of NAFLD patients compared with controls and obese subjects. CONCLUSIONS: Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients.

Prevalence and characteristics of the metabolic syndrome in primary aldosteronism.

CONTEXT: Patients with hypertension have a high prevalence of concurrent metabolic abnormalities, including obesity, dyslipidemia, and hyperglycemia. Clustering of these cardiovascular risk factors, defined as metabolic syndrome, causes a more pronounced target organ damage. Aldosterone excess has been found to be associated with glucose disorders and may contribute to cardiovascular damage. OBJECTIVE: The aim of our study was to assess the prevalence and the characteristics of the metabolic syndrome in a group of patients with hypertension due to primary aldosteronism compared with patients with essential hypertension. METHODS: The National Cholesterol Education Program Adult Treatment Panel III definition of the metabolic syndrome was used. Eighty-five patients with primary aldosteronism and 381 patients with essential hypertension were studied. Most patients were not receiving antihypertensive therapy during the investigation. RESULTS: Blood glucose and systolic blood pressure were higher (P < 0.05 and P < 0.01, respectively) and duration of hypertension was longer (P < 0.05) in primary aldosteronism than in essential hypertension. The prevalence of metabolic syndrome was higher in primary aldosteronism than in essential hypertension (41.1% vs. 29.6%; P < 0.05). Distribution of single components of the metabolic syndrome other than hypertension showed a higher prevalence of hyperglycemia in primary aldosteronism than in essential hypertension (27.0% vs. 15.2%; P < 0.05). CONCLUSIONS: Our findings confirm a negative effect of aldosterone excess on glucose metabolism and suggest that the recently reported higher rates of cardiovascular events in primary aldosteronism than in essential hypertension might be due to increased prevalence of the metabolic syndrome in the former condition.

Late potentials and ventricular arrhythmias in acromegaly.

BACKGROUND: Sudden death and increased prevalence of ventricular arrhythmias have already been described in acromegaly. Although late potentials (LPs) have been proved to be a new technique in detecting patients at risk for ventricular tachyarrhythmias its use in acromegaly is still unknown. METHODS: We studied 70 acromegalic patients [32 males, 38 females; age 49+/-12 years (mean+/-S.D.)] and 70 control subjects age- and sex-matched [(35 males and 35 females; 46+/-12 years (mean+/-S.D.)]. Besides hormonal tests, we performed the following cardiovascular investigations: ECG, 24-h ECG Holter monitoring, echocardiography, and signal-averaged ECG (SAECG) time-domain analysis. RESULTS: LPs occurrence was significantly higher in acromegalic patients as compared to the control group (22.9% vs. 2.9%; p=0.001). A greater duration of disease in patients with positive LPs compared to negative ones was pointed out (18 vs. 12 years; p=0.024). In the group of acromegalic patients with positive LPs we observed a significant association with premature ventricular complexes (PVCs) detected by means of 24-h Holter ECG recording (13 out of 15 patients: 86.7%; p=0.024). The positivity or negativity of LPs proved to be significantly associated with Lown scale PVC trends recorded by 24-h Holter ECG (p=0.014). In the group of patients with left ventricular hypertrophy a significant and pathological worsening of SAECG signals (QRS, LAS, RMS) was documented. CONCLUSIONS: We observed a higher prevalence of LPs in acromegaly which significantly correlated with Lown scale of PVCs.

Acute adrenal failure as the heralding symptom of primary antiphospholipid syndrome: report of a case and review of the literature.

Acute adrenal failure is a potentially fatal condition if overlooked. Occasionally, acute adrenal insufficiency may ensue from bilateral adrenal haemorrhage in patients with known antiphospholipid syndrome (APS). APS is characterized by recurrent arterial and venous thrombosis, pregnancy complications and detection of autoantibodies to phospholipids. This syndrome may be associated with non-organ specific diseases (e.g. connective tissue disorders) or with malignancies, but it may also appear in isolated form (primary APS). In a very few cases the heralding manifestation is given by adrenal failure. We report here a 63-year-old man presenting with acute adrenal insufficiency as the opening clinical manifestation of an APS. We also carried out a computer-aided search of the literature to identify all cases of primary adrenal failure as the first-recognized expression of a primary APS, a condition that not so infrequently may be tackled by endocrinologists. 20 patients fulfilled the inclusion criteria. The great majority of them were males (75%) with a mean age of 42 years. Abdominal pain was present in 14 patients, followed by fever (13 patients) and hypotension (12 patients). The main morphological findings by computed tomography or magnetic resonance were consistent with bilateral adrenal haemorrhage in 11 patients. Lupus anticoagulant was present in all of the 19 tested patients. Our observations emphasize the importance in the assessment of clotting times, and possibly of antiphospholipid antibodies, in all patients with diagnosis of rapidly progressive adrenal failure and concurrent abdominal pain.

Increased serum resistin in adults with prader-willi syndrome is related to obesity and not to insulin resistance.

CONTEXT: Determinants of insulin resistance in Prader-Willi syndrome (PWS) are not completely understood. The discovery of several adipokines with relevant effects on insulin resistance and cardiovascular complications of metabolic syndrome offered new tools of investigation of insulin resistance in PWS. OBJECTIVE: The purpose of this study was to measure serum resistin and mRNA in adipose tissue of patients with PWS, those with simple obesity, and healthy controls and correlate resistin levels with anthropometric and biochemical features. DESIGN: Twenty-eight adult PWS patients, 29 obese patients, and 25 healthy controls were studied. Anthropometric variables were measured and fasting serum and plasma were collected for measurement of resistin, adiponectin, leptin, lipid profile, glucose, and insulin. RESULTS: Serum resistin and resistin mRNA expression in adipose tissue was significantly higher in PWS patients, compared with both healthy lean controls and obese patients. Moreover, on regression analysis resistin was significantly correlated with body mass index, whereas no significant association was found between resistin and homeostasis model assessment index. A weak association between resistin and adiponectin was found in the PWS group only. However, on multivariate analysis only the correlation between resistin and body mass index remained significant. CONCLUSIONS: These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.

Plasma adiponectin is decreased in nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and is frequently associated with obesity and metabolic syndrome. The recently discovered hormone adiponectin is produced by adipose tissue, and low plasma adiponectin is considered a key factor in the development of the insulin resistance underlying metabolic syndrome. Animal studies suggest that adiponectin may protect against non-alcoholic steatohepatitis, but direct evidence in humans is lacking. We therefore conducted this study to assess the relationship between plasma adiponectin and nonalcoholic fatty liver disease to explore its role in the pathogenesis of this disease. DESIGN AND METHODS: We measured plasma adiponectin and anthropometric, biochemical, hormonal and metabolic correlates in a group of 17 NAFLD patients with diagnosis confirmed by biopsy, and 20 controls with comparable age, body-mass index and sex. Furthermore we compared plasma adiponectin in patients with simple steatosis and steatohepatitis. RESULTS: Plasma adiponectin was significantly lower in NAFLD patients than controls (5.93+/-0.45 vs 15.67+/-1.60ng/ml). Moreover, NAFLD patients were significantly more insulin resistant while having similar serum leptin. Adiponectin was similar in simple steatosis and in steatohepatitis (6.16+/-0.78 vs 5.69+/-0.49ng/ml). An inverse correlation was observed between adiponectin and homeostatic model assessment (HOMA) of insulin resistance (P = 0.008), while adiponectin did not correlate with serum transaminases and lipid values. CONCLUSIONS: These data support a role for low circulating adiponectin in the pathogenesis of NAFLD and confirm the strict association between reduced adiponectin production by adipose tissue, NAFLD and insulin resistance.

Do oestrogen receptors play a role in the pathogenesis of HIV-associated lipodystrophy?

Epidemiological data show an increased risk of HIV-associated lipodystrophy in women, and sex hormone abnormalities have been reported with highly active antiretroviral therapy (HAART). This study, which demonstrates that oestrogen receptor beta expression is significantly reduced in the subcutaneous adipose tissue of HIV-infected lipodystrophic patients, downregulated by HAART regimens including protease inhibitors (PI), and restored after switching from PI, opens perspectives for the investigation of selective oestrogen receptor modifiers for the management of this syndrome.

Effect of sibutramine on weight management and metabolic control in type 2 diabetes: a meta-analysis of clinical studies.

OBJECTIVE: The aim of this study was to provide a comprehensive meta-analysis of randomized controlled clinical studies on the effects of sibutramine on weight loss and glycemic control in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Controlled clinical trials assessing the effect sizes of sibutramine on weight loss effects on glycemia in obese subjects with type 2 diabetes were identified and reviewed using the Cochrane Library, Medline, EMBASE, and a manual search. RESULTS: Eight placebo-controlled, double-blind, randomized trials of sibutramine were included. After sibutramine treatment, the decrease in body weight and waist circumference was significantly greater than in the placebo group. Fasting blood glucose and HbA(1c) significantly decreased after sibutramine treatment. Treatment benefits were seen in plasma triglycerides and HDL, without significant variations in serum total and LDL cholesterol. No differences in systolic blood pressure between the sibutramine and the placebo groups were seen, while recording of diastolic blood pressure and heart rate showed that sibutramine produced a small increase relative to placebo. CONCLUSIONS: A pharmacological approach in a weight management program for patients with type 2 diabetes may be helpful in glycemic control and in the management of other risk factors. Sibutramine may help improve glucose control because it is conducive to weight loss. The reviewed data on the effect of sibutramine further enforce the recommendations that weight management may be the most important therapeutic task for most obese subjects with type 2 diabetes.