Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25)

IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S(i)] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K(ITT)] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S(i) and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S(i), sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.     

Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation

Lipin-alpha and -beta are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin-alpha and -beta mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, demonstrated higher levels of intramyocellular lipids (IMCLs), and expressed approximately 50% lower levels of lipin-alpha and -beta. In addition, there was a strong inverse correlation between adipose tissue lipin expression and muscle IMCLs but no evidence for an increase in muscle lipid oxidation. After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (Si) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005). Lipin expression in skeletal muscle, however, was not related to obesity or insulin resistance. Hence, high adipose tissue lipin expression is found in insulin-sensitive subjects, and lipin-beta expression increases following treatment with pioglitazone. These results suggest that increased adipogenesis and/or lipogenesis in subcutaneous fat, mediated by the LPIN1 gene, may prevent lipotoxicity in muscle, leading to improved insulin sensitivity.     

Reduction of hyperornithinemia with a low protein,low arginine diet and pyridoxine in patients with a deficiency of ornithine-ketoacid transaminase (OKT) activity and gyrate atrophy of the choroid and retina

Five patients with gyrate atrophy of the choroid and retina showed a 60% or greater decline in plasma ornithine levels during a five week trial of a low protein (10–15 g/day), low arginine (0.50–0.75 g/day) diet supplemented with essential amino acids and pyridoxine administration. These declines in plasma ornithine levels were seen in Patients 1–4 with the pyridoxine non-responsive variant and in Patient 5 with the pyridoxine responsive variant. No harmful systemic side effects were noted. Patients 1–4 continued on a modified low protein (20–35 g/day), low arginine (1.25–1.75 g/day) diet as tolerated and Patient 5 on pyridoxine alone. After one year no improvement was observed in visual acuities, visual fields, final dark adapted thresholds and full field electroretinograms for four patients. In contrast to the other four patients, Patient 3, with relatively poor control of plasma ornithine levels, showed signs of progression of the chorioretinal atrophy and further reduction of electroretinographic responses. Patients 1–4 continue on the dietary regimen and Patient 5 on pyridoxine alone to determine whether any lowering of plasma ornithine levels will modify the course of their ocular disease.     

Temperature dependent alterations in the cardiac muscarinic receptor conformation

Black widow spider venom (BWSW) elicited a prolonged tonic contraction of guinea-pig ileum which abolished the nicotine-induced contraction; however, the subsequent acetylcholine stimulation was found to be unchanged. These findings indicate a depletion of nerve terminal transmtiters caused by BWSW without a disruption of the muscle contractile mechanism. Following the BWSW-induced contraction, the stimulation to 5-hydroxytryptamine (5-HT) was found to be abolished. This abolishment indicates a mediation of 5-HT-induced smooth muscle contraction in the nerve rather than the muscle.     

Cellular localization of aldolase C subunits in human brain

An antiserum specific for the brain-type aldolase C subunit has been used to investigate the cellular localization of this protein in human brain. Immunoperoxidase labeling at the light microscope level showed heavy staining of Purkinje cells in the cerebellum and of astrocytes in the cerebrum. Faint staining of occasional large neurons in the gray matter of the cerebral cortex was also seen.     

A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives

A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective.