Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Objectives-Insulin resistance (IR) has been increasingly implicated in the pathogenesis of gout. The lipoprotein abnormalities described in hyperuricaemic subjects are similar to those associated with IR, and insulin influences renal urate excretion. In this study it was investigated whether dietary measures, reported to be beneficial in IR, have serum uric acid (SU) and lipid lowering eVects in gout. Methods-Thirteen non-diabetic men (median age 50, range 38-62) were enrolled. Each patient had had at least two gouty attacks during the four months before enrolment. Dietary recommendations consisted of calorie restriction to 6690 kJ (1600 kcal) a day with 40% derived from carbohydrate, 30% from protein, and 30% from fat; replacement of refined carbohydrates with complex ones and saturated fats with mono-and polyunsaturated ones. At onset and after 16 weeks, fasting blood samples were taken for determination of SU, serum cholesterol (C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Results were expressed as median (SD). Results-At

Objective. To identify factors that regulate glucose metabolism in rheumatoid arthritis (RA).Methods. We evaluated the homeostatic model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-B) in 94 RA patients. We investigated the relationship between characteristics known to affect glucose metabolism in the general population (age, abdominal obesity [waist circumference], hypertension, antihypertensive therapy) as well as characteristics of RA (disease activity, glucocorticoid therapy) and insulin resistance and beta cell function.Results. Patients with high-grade inflammation (high-sensitivity C-reactive protein value >1.92 mg/ liter) (n ‫؍‬ 81) were more insulin resistant than patients with low-grade inflammation (n ‫؍‬ 13), whereas beta cell function was similar in both groups. Insulin resistance and beta cell function were similar in both groups after adjustment for waist circumference. All recorded characteristics except for age were associated with HOMA-IR or/and HOMA-B in univariate analyses. In mixed regression models, abdominal obesity and patient's assessment of disease activity (by visual analog scale) were predictors of insulin resistance. The Disease Activity Score assessed using 28-joint counts for swelling and tenderness, tender joint count, and patient's assessment of disease activity were associated with reduced beta cell function, and the cumulative dose of glucocorticoids was associated with enhanced beta cell function. The cumulative glucocorticoid dose in all study patients was a mean of only 536 mg (95% confidence interval 239-1,173). In patients with high-grade inflammation, age was further associated with impaired beta cell function, whereas use of angiotensinconverting enzyme inhibitors or angiotensin II type 1 receptor blockers was associated with enhanced beta cell function.Conclusion. The modifiable factors of abdominal obesity, antihypertensive therapy, disease activity, and use of glucocorticoids appear to affect glucose metabolism in RA.

Cardiovascular event rates are markedly increased in rheumatoid arthritis (RA), and RA atherogenesis remains poorly understood. The relative contributions of traditional and nontraditional risk factors to cardiovascular disease in RA await elucidation. The present study comprises three components. First, we compared biomarkers of endothelial dysfunction (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy control individuals before and after controlling for traditional and nontraditional cardiovascular risk factors, including highsensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor necrosis factor-α. Second, we investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in the 74 RA patients. Finally, we assessed associations between biomarkers of endothelial dysfunction and ultrasonographically determined common carotid artery intimamedia thickness and plaque in RA. The three biomarkers of endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor necrosis factor-α, were higher in patients than in control individuals (P < 0.0001). Patients were also older, exercised less and had a greater waist circumference, blood pressure and triglyceride levels (P ≤ 0.04). Five patients had diabetes.Differences in endothelial function were no longer significant between patients and controls (P = 0.08) only after both traditional and nontraditional cardiovascular risk factors were controlled for. In the 74 RA patients, IL-6 predicted levels of all three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular risk factors (P ≤ 0.02). VCAM-1 was associated with common carotid artery intima-media thickness (P = 0.02) and plaque (P = 0.04) in RA. Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals. Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals. IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in RA. Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA.

The authors' goal was to document baseline pituitary-adrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare the changes with an equal number of untreated control subjects. At monthly intervals for 4 mo, 24-h urine samples were obtained for determination of free cortisol excretion. In addition, fasting blood samples were analyzed for levels of cortisol, dehydroepiandrosterone sulfate (DHEAS), ACTH, aldosterone, and catecholamines. Other biochemical measurements included growth hormone, prolactin, insulin, glucose, and lipid components. The Maslach Burnout Inventory, General Health Questionnaire- 28, and Zung depression rating scale were completed on each consecutive visit. The most striking finding was the reduction of urine free-cortisol excretion in the patients compared with controls. Initial urinary free cortisol was significantly lower in the patients (mean +/- SEM = 47.2 +/- 11.0 vs 79.0 +/- 6.8 nmol/L, p = 0.02) and remained significantly reduced at 4 mo (mean +/- SEM = 44.0 +/- 6.1 vs 91.1 +/- 8.8 nmol/L, p = 0.0001). There were no significant changes in the other hormonal and biochemical data. We conclude that there is functional hypocortisolism in burnout, which is not immediately restored on stress management intervention despite clinical and psychological improvement.

This managed care model of diabetes care in the context of the South African Private Health Care System achieved long-term improvement in glycaemic control and all-cause hospital admission rates. This may be due to the cost-containment being in the hands of the treating doctor, supported by an annual training programme. This programme is based on an individualized and holistic approach encompassing intensive patient education to facilitate self-empowerment and including prompting for the management of risk factors.

We investigated the prevalence of subclinical hypothyroidism and its association with insulin resistance and other cardiovascular (CV) risk factors in rheumatoid arthritis (RA). We recorded thyroid function tests, insulin resistance markers comprising the Homeostasis Model Assessment for insulin resistance (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and triglycerides/high-density lipoprotein (HDL) cholesterol ratios, and other CV risk factors in 126 patients with RA. Fifteen (12%) were taking thyroxine for hypothyroidism and 14 (11%) had subclinical hypothyroidism (thyrotropin > 4 mU/L and normal free thyroxine levels). Compared to the 97 euthyroid patients, the QUICKI was lower and the HOMA-IR higher in treated (p = 0.031 for both) and subclinical (p = 0.004 for both) hypothyroid cases while the triglycerides/HDL cholesterol ratios were higher in subclinical (p = 0.039) but not in treated hypothyroid (p = 0.365) cases. Treated hypothyroid patients were more often hypertensive (n = 11 [75%]) than euthyroid patients (n = 36 [37%]) (p = 0.008). No other differences in characteristics were found among the three groups. After controlling for potentially confounding variables, subclinical hypothyroidism remained independently predictive of the HOMA-IR and QUICKI (p

In diabetic Africans, in comparison with white patients, the lower prevalence of the metabolic syndrome in men and severe metabolic syndrome in women, and lesser insulin resistance, might contribute to their lower risk of CHD; the higher prevalence in women might contribute to the reversal of the male:female ratio. The TG:HDL-C ratio appears to be a valid estimate of insulin resistance in diabetic Africans.