An adipose tissue-independent insulin-sensitizing action of telmisartan: a study in lipodystrophic mice.

Adipose tissue plays an important role in energy balance and metabolism and is the major target for insulin-sensitizing peroxisome proliferator-activated receptor (PPAR) gamma agonists. The angiotensin II type 1 receptor blocker telmisartan, a partial agonist of PPAR-gamma, has been demonstrated to improve insulin sensitivity. However, there is uncertainty about the sites of its action. Here, we demonstrate that treatment with telmisartan (3 mg/kg p.o.) for 7 weeks decreased plasma glucose levels in oral glucose and insulin tolerance tests and the index of the homeostasis model assessment of insulin resistance in A-ZIP/F-1 transgenic mice, an animal model of lipodystrophy. These effects were accompanied by decreases in circulating triglyceride and fatty acid levels. However, this treatment did not affect body weight and plasma adiponectin, leptin, and corticosterone levels. In A-ZIP/F-1 mouse liver the transcripts encoding PPAR-gamma and its downstream lipogenic genes were highly up-regulated, consistent with increased hepatic triglyceride content and lipid droplet accumulation. Telmisartan reversed these effects and also down-regulated mRNAs encoding gluconeogenic genes. Thus, the present findings are consistent with a novel mode of insulin-sensitizing action of telmisartan, involving an adipose tissue-independent pathway. Telmisartan-elicited down-regulation of hepatic expression of PPAR-gamma-regulated lipogenic genes is associated with amelioration of fatty liver.

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet.

AIMS/HYPOTHESIS: We have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity. METHODS: To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 microg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight](-1) h(-1)) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined. RESULTS: Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of alpha2 AMPK activity in skeletal muscle. Pair-feeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction. CONCLUSIONS/INTERPRETATION: This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

Alternative sequences of thyrotropin and free thyroxine assays for routine thyroid function testing. Quality and cost.

BACKGROUND: Current guidelines and practices for thyroid function testing are strongly affected by the usually higher patient billing charges and Medicare reimbursement for thyrotropin (TSH) vs free thyroxine (FT4) tests, despite their comparable direct costs. OBJECTIVE: Due to recently reduced laboratory costs, to reexamine the effectiveness and cost of alternative test sequences. METHODS: Alternative test sequences involve using the TSH test first, followed, if the TSH test result is abnormal, by the FT4 test; the FT4 test first, followed by the TSH test; and doing both tests together. We applied these strategies to consecutive patients referred for any thyroid function test to a health maintenance organization, a multispecialty fee-for-service group, a military hospital, and a commercial laboratory. Effectiveness was determined from a literature review. The cost was determined from direct costs and the distribution of diagnostic categories. RESULTS: The TSH and FT4 tests have similar sensitivities for detecting clinical hyperthyroidism and hypothyroidism. The TSH test detects subclinical function, and it monitors thyroxine treatment better; the FT4 test detects central hypothyroidism, and it monitors rapidly changing function better. Direct costs for both were equal, but charges for the TSH test were higher. The average direct cost per patient, starting with the FT4 test, was $4.61; starting with the TSH test, $5.90; and starting with both tests together, $6.50. Medicare reimbursements correlated poorly with costs. CONCLUSIONS: Starting with the TSH test and reflexing to the FT4 test provides a better first-line all-purpose sequence than the reverse. In managed care settings, the slightly higher direct cost of this approach is offset by greater clinical effectiveness. In fee-for-service settings, cost differences can be nearly eliminated by equalizing TSH and FT4 charges to reflect current direct-cost realities. Obtaining both tests together overcomes the disadvantages of each at a slightly higher direct cost.

Prostate-specific antigen concentration: influence of age and ethnicity.

This pilot study evaluated the influence of age and ethnicity on serum prostate-specific antigen (PSA) concentration in Asian and white men without a clinical diagnosis of prostate cancer. Between October and December 1993, 1260 patients who underwent serum PSA determination (Hybritech Tandem-R assay, San Diego, California) at Straub Clinic & Hospital were retrospectively analyzed. Of these, 885 (70%) men aged 40 to 79 years were either Asian (Chinese, Filipino, Japanese, and Korean) or white and had a serum PSA less than 10.0 ng/ml. The PSA for the entire group was 2.1 +/- 2.0 ng/ml (mean +/- SD). PSA correlated with age (r = 0.31, p = 0.0001) and age accounted for 10% of the variance in serum PSA. Using the regression formula, serum PSA increased 2.5% (0.06 ng/ml) per year of age. The entire study group was about equally divided between whites (49%) and Asians (51%). Nearly three-fourths of the Asian men were Japanese. The mean PSA was very close in the Asian and white groups. There was no direct correlation between serum PSA and ethnicity (r = 0.03; p = 0.3201). Ethnicity contributed 0.1% of the variance in PSA. In conclusion, this preliminary study suggests serum PSA increases with age in Asian and white men without a clinical diagnosis of prostate cancer. No difference was found in PSA between men of Asian and white ethnicity.

Térmicos cervicais: indicaçöes em funçäo das ligas utilizadas / The cervical terminations: indications in function of the alloys used

Neste trabalho säo comparados tipo de térmicos cervicais em funçäo das ligas utilizadas para a confecçäo de próteses parciais fixas em metalo-cerâmicas, discutindo as vantagens e desvantagens clínicas e laboratoriais entre ligas básicas de níquel-cromo e ligas áureas, além das conveniências financeiras que estas possam acarretar. O tipo de preparo utilizado nos E.U.A. difere dos preparos mais utilizados no Brasil, em funçäo da indicaçäo destas ligas

The superiority of antimicrosomal over antithyroglobulin antibodies for detecting Hashimoto's thyroiditis.

BACKGROUND: Antimicrosomal (anti-M) and antithyroglobulin (anti-Tg) antibodies are commonly measured together to detect Hashimoto's thyroiditis. Since this nearly doubles the cost of testing for one antibody, we wished to determine whether significant diagnostic loss would occur if the two tests were replaced by anti-M alone. METHODS: Both tests were performed in 2030 consecutive patients referred by general internists and endocrinologists. RESULTS: With a positive result defined as either test being positive at a 1:100 dilution, anti-M was much more sensitive than anti-Tg. Anti-M was positive in 99% (823/831) of all patients with positive tests, while anti-Tg was positive in 36% (302/831). Anti-M was the only positive test in 64% of all patients with positive tests, while anti-Tg was the only positive test in 1%. With a cutoff point of 1:400 dilution, the results were similar. CONCLUSIONS: Anti-M alone appears sufficient to detect autoimmune thyroid disease at about one half the cost of routinely performing both anti-M and anti-Tg studies. The widespread practice of performing both tests increases the cost without an offsetting diagnostic gain.