Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the effect of bezafibrate on insulin sensitivity and insulin secretion in 30 non-obese Japanese type 2 diabetic patients with hypertriglyceridemia (serum triglycerides > 150 mg/dL). Insulin sensitivity was measured with homeostasis model assessment insulin resistance (HOMA-IR) proposed by Matthews et al. HOMA-B-cell function, proposed by Matthews et al validated against minimal model-derived insulin secretion, was used to assess pancreatic insulin function. Twenty-two patients were treated with glibenclimide and the rest were treated with diet alone. All patients were treated with bezafibrate (400 mg/d) for 3 months. There were no changes in diet and the dose of any medications used throughout the study. Fasting glucose, insulin, triglycerides, HDL cholesterol, and total cholesterol levels were measured before and after treatment of bezafibrate. After treatment of bezafibrate for 3 months, serum triglyceride levels significantly decreased from 277 +/- 30 to 139 +/- 9 mg/dL (P <.001) and serum HDL cholesterol levels increased significantly from 45 +/- 2 to 52 +/- 2 mg/dL (P =.003). Serum cholesterol level was unchanged during the study (198 +/- 7 v 201 +/- 7 mg/dL, P =.383). Fasting glucose (163 +/- 8 v 139 +/- 6 mg/dL, P =.006) significantly decreased after the treatment with bezafibrate. HbA1c levels decreased, although not statistically significant (7.50 +/- 0.25 v 7.17% +/- 0.19%, P =.147). On the other hand, fasting insulin (9.3 +/- 0.7 v 7.3 +/- 0.5 microU/mL, P =.010) and HOMA-IR (3.61 +/- 0.24 to 2.53 +/- 0.20, P <.001) levels decreased significantly after the treatment with bezafibrate. In contrast, HOMA-B-cell function did not change during the study (41.4 +/- 5.5 v 41.8 +/- 4.7, P =.478). There was no significant difference in body mass index (BMI) levels before and after the therapy (23.0 +/- 0.4 v 23.1 +/- 0.4 kg/m(2), P =.483). From these results, it can be concluded that bezafibrate reduces serum triglycerides, insulin resistance, and fasting blood glucose levels in non-obese Japanese type 2 diabetic patients.

Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

OBJECTIVE: The aim of the study was to investigate the relationships between remnant-like particle (RLP) cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 86 nonobese Japanese type 2 diabetic patients (72 men and 14 women, aged 40-83 years, BMI 20.1-26.6 kg/m2) were studied. BMI, HbA1c levels, and fasting concentrations of plasma glucose, serum lipids (RLP cholesterol, total cholesterol, HDL cholesterol, and triglycerides), and serum insulin were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The subjects were divided into two groups according to the value of HOMA-IR. Values >2.5 were indicative of the insulin-resistant state, and values <2.5 were indicative of the insulin-sensitive state. RESULTS: The insulin-resistant group had significantly higher RLP cholesterol and triglyceride levels and lower HDL cholesterol levels compared with the insulin-sensitive group. Univariate regression analysis showed that insulin resistance was positively correlated with BMI (r = 0.254, P = 0.019), HbA1c levels (r = 0.278, P = 0.011), RLP cholesterol levels (r = 0.315, P = 0.004), and triglyceride levels (r = 0.332, P = 0.002) and was negatively correlated with HDL cholesterol levels (r = -0.301, P = 0.006) in our diabetic patients. Multiple regression analysis showed that insulin resistance was independently associated with serum triglyceride levels, which explained 13.5% of the variability of insulin resistance in our nonobese Japanese type 2 diabetic patients. CONCLUSIONS: These results indicate that 1) nonobese Japanese type 2 diabetic patients with insulin resistance are characterized by high RLP cholesterol and triglyceride levels, and low HDL cholesterol levels; and 2) the level of serum triglycerides is an independent predictor of insulin resistance in these patients.

Effects of gemfibrozil administration on very low density lipoprotein receptor mRNA levels in rabbits.

To elucidate the regulation of very low density lipoprotein (VLDL) receptor gene expression, we administered to rabbits for 14 days gemfibrozil, a fabric acid derivative and a lipid lowering drug that is also included among peroxisome proliferators. VLDL receptor mRNA levels were examined by Northern blot analysis. The VLDL receptor mRNA levels in retroperitoneal adipose tissue and in gastrocnemius muscle were increased 6.9-fold and 3.7-fold, respectively, with gemfibrozil treatment, but no marked changes were observed in the heart, the organ in which VLDL receptor is most highly expressed. In the liver, VLDL receptor mRNA was not detected either before or after gemfibrozil administration. Lipoprotein lipase (LPL) and long-chain acyl coenzyme A synthetase (ACS) mRNA levels were also increased in parallel in adipose tissue. The enhanced expression of VLDL receptor mRNA may contribute to the increase of triglyceride-rich lipoprotein catabolism in peripheral tissues such as adipose tissue and muscles.

99mTc-MIBI accumulation in the parathyroid autograft in a patient with recurrent hyperparathyroidism.

A case with recurrent hyperparathyroidism secondary to chronic renal insufficiency is reported. The patient had undergone total parathyroidectomy and autotransplantation of parathyroid tissue five years ago. Bone scintigraphy clearly demonstrated skeletal involvement of secondary hyperparathyroidism and 99mTc-methoxyisobutylisonitrile scintigraphy clearly demonstrated a hyperfunctioning parathyroid autograft.

Inhibitory effects of (4-alkoxy-2, 3, 6-trimethylphenyl) glycopyranosides on histamine release induced by antigen-antibody reaction.

The inhibitory effects of newly synthesized 4-alkoxy-2, 3, 6-trimethylphenyl D-glycopyranosides on histamine release induced by antigen-antibody reaction were examined. Among the compounds tested, 4-hexoxy-2, 3, 6-trimethylphenyl alpha-D-mannopyranoside exhibited the strongest inhibitory effect. Furthermore, 4-hexoxy-2, 3, 6-trimethylphenyl alpha-D-glucopyranoside and alpha-D-galactopyranoside markedly inhibited antigen-induced histamine release, and their activities were more potent than those of the corresponding beta-anomers. These results suggest that these compounds may possess excellent anti-allergic activities.

Immunoreactive corticotropin-releasing hormone levels in discrete hypothalamic nuclei of genetically obese Zucker rats.

The levels of immunoreactive corticotropin-releasing hormone (ir-CRH) were measured in discrete hypothalamic nuclei and the median eminence of obese Zucker rats and their lean littermates. More than 90% of total hypothalamic ir-CRH was detected in the median eminence in both obese and lean rats. Though ir-CRH levels in the paraventricular nucleus of obese rats tended to be lower than those of their lean littermates, no significant difference of ir-CRH levels was observed in any hypothalamic nuclei studied between obese and lean rats. However, ir-CRH levels in the median eminence of obese rats were significantly lower than those of their lean littermates (5263 +/- 438 pg/tissue vs. 7050 +/- 473 pg/tissue, P < 0.05). These results suggest that the hypoactive hypothalamic CRH tonus would play some role in the phenotypic expression of obesity in the genetically obese Zucker rats.

Pro-opiomelanocortin messenger RNA levels in anterior pituitaries of female Wistar fatty rats.

We have studied pro-opiomelanocortin (POMC) gene expression by quantifying the POMC mRNA contents in anterior pituitaries of female Wistar fatty rats, a strain obtained by transfer of the fa gene in Zucker rat to Wistar Kyoto rat, in an attempt to understand the role of ACTH synthesis in altered ACTH and corticosterone secretion in these rats. Five- and 12-week-old female Wistar fatty rats and their lean littermates were examined. Plasma ACTH levels were significantly higher in fatty rats than in lean rats (5 weeks: 114.5 +/- 17.5 pg/ml vs. 54.3 +/- 12.4 pg/ml; 12 weeks: 83.8 +/- 12.3 pg/ml vs. 51.7 +/- 6.8 pg/ml; P < 0.01). There was no significant difference between 5-week-old fatty rats and lean rats in POMC mRNA contents nor in POMC/beta-actin ratios in anterior pituitaries. Twelve-week-old fatty rats, however, had significantly higher POMC mRNA contents and also higher POMC/beta-actin ratios in anterior pituitaries than those in lean littermates (P < 0.01, approximately three-fold difference between lean and obese rats). These data suggest that the difference in POMC mRNA contents between lean and obese rats becomes apparent as they grow and develop obesity and the elevated POMC mRNA levels are at least partly responsible for the increased ACTH secretion in 12-week-old fatty rats.

Immunoreactive corticotropin-releasing hormone levels in the hypothalamus of female Wistar fatty rats.

We have studied immunoreactive corticotropin-releasing hormone (CRH) levels in the hypothalamus of female Wistar fatty rats, a strain with the fa gene transferred from the Zucker rat to the Wistar Kyoto rat, in an attempt to understand the role of CRH in the development of obesity. A study was conducted with 5-week- and 12-week-old female Wistar fatty rats and lean littermates. There was no significant difference in hypothalamic CRH levels between lean and obese rats at the age of 5 weeks (1887 +/- 99.6 vs. 1767 +/- 124 pg/tissue; mean +/- S.E.M.). Hypothalamic CRH immunoreactivities, however, were significantly lower in 12-week-old obese rats (2361 +/- 132 pg/tissue) than those in lean littermates (2992 +/- 118 pg/tissue; P less than 0.05). The difference of CRH contents between the lean and obese group becomes apparent as they grow up and develop obesity.

Immunoreactive corticotropin-releasing hormone levels in brain regions of genetically obese Zucker rats.

The levels of immunoreactive corticotropin-releasing hormone (ir-CRH) were measured in discrete brain regions and pituitary of obese Zucker rats and their lean littermates. Ir-CRH levels were lower in the hypothalamus and neurointermediate pituitary but higher in the striatum and cerebellum of obese Zucker rats than those of lean littermates. These results suggest some abnormalities in the CRH regulating system in obese Zucker rats.

Chronic effects of interleukin-1 on hypothalamus, pituitary and adrenal glands in rat.

To assess the chronic effects of interleukin-1 (IL-1) and IL-2 on the hypothalamo-pituitary-adrenal axis in vivo, we administered recombinant human (rh) IL-1 alpha, rhIL-1 beta or rhIL-2 (2.0 micrograms/day) repetitively to adult male rats for 10 days. In rhIL-1 beta-treated rats, adrenocorticotropic hormone-like immunoreactivity (ACTH-LI) of the anterior pituitary appeared to increase first on day 3 followed by an increase of corticotropin-releasing hormone (CRH)-LI both in the hypothalamus and in the adrenal gland after day 7. At the end of the 10-day treatment, wet weights of the adrenal glands of rhIL-1 beta-treated rats increased significantly compared with those of control rats. Plasma ACTH levels in rhIL-1 beta-treated rats at the sampling time continued to be elevated throughout the experimental period. Under the same experimental design, rhIL-1 alpha increased plasma ACTH levels at the sampling time without changes in adrenal weight or in the peptide contents investigated. The same amount of rhIL-2 had no effect on these measured variables during the 10-day treatment. These data indicate that the repetitive administration of IL-1 beta resulted in chronic effects in the hypothalamo pituitary-adrenal axis to increase the activities in these organs during the treatment and, moreover, IL-1 possibly has a positive direct effect on the CRH-containing cells in the adrenal glands.

Expression of the human pro-opiomelanocortin gene introduced into a rat glial cell line.

A fragment of human genomic DNA containing the entire pro-opiomelanocortin (POMC) gene was introduced by transfection into the rat glial cell line C6. Blot analysis using poly(A)-rich RNA from the transformed C6 cells showed several hybridization bands. One band was similar in size (1.2 kb) to the POMC mRNA of human pituitary, while two were larger (2.6 and 2.2 kb) and the fourth smaller (800 bp). S1 nuclease mapping revealed that the POMC transcripts in transformed C6 cells were similar to those in non-pituitary tissues. Immunoreactive ACTH (ir-ACTH) was measurable in both the culture medium and cells. Gel chromatography showed that ir-ACTH in the medium eluted at a position identical to that of so-called big ACTH (approximately 40 kDa) which is found in the plasma of patients with ectopic ACTH syndrome. The human POMC gene could thus be expressed in the non-pituitary rat glial cell line C6, although the transcripts and translation products in C6 cells differ from those in the human pituitary. These results suggest that the transformed C6 cell may be a useful tool for studying the regulation of human POMC gene expression in non-pituitary cells.

Cyclic AMP-responsive region of the human proopiomelanocortin (POMC) gene.

Transcription of the human proopiomelanocortin (POMC) gene is regulated by cAMP. To identify the region in the human POMC gene responsible for this regulation, we constructed chimeric genes containing different portions of the 5'-flanking region of the human POMC gene fused to the structural sequence encoding the bacterial reporter enzyme chloramphenicol acetyltransferase (CAT). The transcriptional activity of the fusion genes introduced into the rat glial cell line C6 was assayed by measuring CAT activity in the cell lysate. Forskolin, an adenylate cyclase-activating agent, stimulated the expression of POMC-CAT fusion genes. Deletion analysis demonstrated that the region between -417 and -97 bp from the transcriptional origin of the human POMC gene was responsible for regulation by cyclic AMP.

Two-site immunoradiometric assay for adrenocorticotrophin: a cautionary study about the reactivity to its precursor molecules.

The specificity of a "two-site" immunoradiometric assay (IRMA) has been reevaluated by examining its ability to detect heterogeneous adrenocorticotrophin-like immunoreactivity (ACTH-LI) separated by gel column chromatography. Plasma samples from patients with Addison's disease, Nelson's syndrome and ectopic ACTH syndrome and tissue extract of human anterior pituitary were subjected to ACTH-IRMA and the levels of ACTH-LI were compared with those measured by conventional ACTH-radioimmunoassay (RIA). The level of ACTH-LI measured by IRMA was considerably lower than that measured by RIA in the plasma of a case of ectopic ACTH syndrome and the ACTH-LI did not show a dilution curve parallel with that of the standard. Gel exclusion chromatography revealed that the plasma contained a relatively large quantity of "big ACTH" which was found to be poorly detected by the IRMA. In the plasma of Addison's disease or the extract of pituitary gland in which "big ACTH" constituted a small portion, whole ACTH-LI was apparently diluted in parallel with the ACTH standard, although the "big ACTH" also did not show full parallelism with the ACTH standard in the IRMA. These data suggest that "big ACTH" derived not only from an ectopic ACTH-producing tumour but also from a normal human pituitary gland cannot be detected as well as authentic ACTH by the ACTH-IRMA system. Therefore, samples which contain a relatively large proportion of "big ACTH" in the total ACTH-LI should be carefully evaluated by ACTH-IRMA.

Monoamine metabolism and its responses to food deprivation in the brain of Zucker rats.

Monoamines and their metabolites levels were simultaneously measured by high-performance liquid chromatography in brain regions of lean and fatty Zucker rats when fed ad lib and deprived of food for 72 hr to evaluate each monoamine metabolism. Metabolite/monoamine ratios were shown for brevity to represent its metabolism. 3-Methoxy-4-hydroxyphenylethyleneglycol/noradrenaline ratios were not affected by the phenotype factor but increased in the cortex of fatty rats and reduced in the midbrain of both phenotypes after fasting; the interaction between phenotype and feeding factors was observed in the cortex and hippocampus. 3,4-Dihydroxyphenylacetic acid/dopamine ratios were increased in the cortex of deprived fatty rats and in the medulla-pons of ad lib-fed fatties compared with lean counterparts and also increased in the striatum of lean rats after food deprivation; the interaction was observed in the cortex, midbrain and medulla-pons. Homovanillic acid/dopamine ratios were decreased in the striatum of deprived fatty rats and in the midbrain and medulla-pons of fatty rats whether deprived or not, but the ratios were not significantly changed by fasting; the interaction was observed in the striatum. 5-Hydroxyindoleacetic acid/5-hydroxytryptamine ratios were reduced in the cortex, striatum and medulla-pons of fatty rats in both feeding states and in the midbrain of deprived fatties, and after food deprivation increased in the cortex and midbrain of lean rats and in the hippocampus of both phenotypes; the interaction was observed in the midbrain.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of food deprivation and high fat diet on immunoreactive beta-endorphin levels in brain regions of Zucker rats.

The levels of immunoreactive beta-endorphin (ir-beta-EP) were measured in the brain and pituitary of lean Zucker rats subjected to food deprivation for 72 h and to a high fat diet, and in fatty Zucker rats after food deprivation for 72 h. Ir-beta-EP was increased in the neurointermediate (NI-) pituitary lobe but reduced in the medulla-pons of fatty rats when compared to lean littermates fed ad libitum. Food deprivation decreased ir-beta-EP in the cortex and medulla-pons of lean rats and in the cortex, midbrain and NI-pituitary of fatty rats. In contrast, ir-beta-EP was increased in the anterior pituitary of lean rats and in the striatum of fatty rats after deprivation. The high fat diet produced a decrease in ir-beta-EP in the cortex, midbrain and NI-pituitary with an increase in the striatum and hypothalamus of lean rats. These results suggest that the ir-beta-EP concentration could be differentially affected in different brain regions of Zucker rats by changes in the energy balance.