THE PPARGC1A - GLY482SER POLYMORPHISM (RS8192678) AND THE METABOLIC SYNDROME IN A CENTRAL ROMANIAN POPULATION.

BACKGROUND: The peroxisome proliferator-activated receptor-γ co-activator 1-α (PPARGC1A), a key transcription factor involved in the control of metabolism and energy homeostasis, is an important biological and positional candidate of the metabolic syndrome. Association studies of its polymorphisms, however, yielded inconsistent sometimes conflicting results, pointing to important ethnic differences, which call for replication in various populations. OBJECTIVE: In order to study its most common - potentially functional - polymorphism Gly482Ser (rs8192678), we carried out a case-control study in a central Romanian population. MATERIAL AND METHODS: Two hundred and ninety six patients affected by the metabolic syndrome diagnosed according to the International Diabetes Federation proposed criteria and 166 middle-aged control subjects have been investigated. Genotyping was done by PCR-RFLP, using the restriction enzyme MspI. RESULTS: While the G(Gly)/A(Ser) allele frequencies (66.89/33.11 vs. 71.68/28.31 %) and GG/GA/AA genotype distribution (45.27-43.24-11.48 vs. 54.21-34.93-10.84 %) differed in the metabolic syndrome and control group, the risk of developing the metabolic syndrome did not reach the limit of statistical significance (OR=1.43; p=0.06, CI 95%: 0.97-2.09). Metabolic parameters in the two study groups did not show significant differences according to the genotype (p>0.05). CONCLUSION: rs8192678 could be a functional polymorphism contributing to the development of the metabolic syndrome, but probably its effect is minor, and might depend on gene-gene and gene-environment interactions. Clarification of very small effects would require larger sample sizes.

Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial.

AIMS: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination. METHODS: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1:1:1:1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight. RESULTS: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (-0.52 vs. -0.30%, p = 0.0106 and -0.65% vs. -0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated. CONCLUSIONS: Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen.

Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders.

Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP-15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP-15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment.

Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial.

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and beta-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

Exposure to a novel stimulus reduces anxiety level in adult and aging rats.

Male Wistar rats aged 3, 15 and 24 months were isolated and housed individually for 72 h prior to being subjected to inanimate objects (two objects per rat, each 1.5 cm in diameter and 4 cm in length, made of surgical gauze). Following the exposure to the objects, rats were subsequently tested in an elevated plus-maze. The inanimate objects induced locomotor activity, chewing and transportation of the object. This changed to social interaction and play-like behavioral activity in rats of all ages that were kept in small groups with a latency of 1 to 2 min. One hour after the start of exposure, the animals were tested in the elevated plus-maze to measure anxiety behavior. It was found that all age groups spent significantly more time in the open arm of the elevated plus-maze than the corresponding controls. Latencies to first entry into open arms were also significantly lowered. The number of entries to the open or to the dark arm, however, did not show statistical difference, indicating that the novel object-induced activity failed to exert influence on gross motor activity in the elevated plus-maze. In conclusion, the stimulation elicited by the exposure to novel stimulus (inanimate objects) resulted in a significant reduction of anxiety level both in adult and in aging rats.

Inhibitory effect of postpartum lesions or cuts in median raphe nucleus on maternal behavior in female rats.

In order to clarify the role of the median (MRN) and dorsal (DRN) raphe nuclei in regulating maternal care (retrieving and licking behavior), radiofrequency lesions or microknife cuts were made in postpartum rats on the day after delivery. Animals were housed individually without pups after the operation. One week after the surgery, maternal behavioral test was carried out daily for 3 days using pups of 2-6 days age. The results demonstrated that rats with MRN lesions or ventral horizontal cuts of the MRN showed extremely low incidence of the maternal behavior, as compared to those in control and sham-operated groups. DRN-lesions or dorsal cuts of the MRN had no effect. In locomotor activities measured by the infrared sensor system, there was no difference between the groups. This suggest that the MRN but not DRN plays a critical role in regulating retrieving and licking behaviors and ventral outputs are involved in this function in postpartum rats.

Ultrastructural localization of Hsp-72 examined with a new polyclonal antibody raised against the truncated variable domain of the heat shock protein.

In spite of the intensive search for the determination of the continuously widening physiological and pathological roles of different stress proteins, their ultrastructural localization at the electron microscopic (EM) level has hardly been examined. As it becomes increasingly evident that the function and physiological effectiveness of stress proteins are highly dependent on their spatial location and their associations with diverse regulator proteins, the demand for morphological studies which can identify their detailed distribution within the cells is evident. The reason for the practical lack of studies carried out at the EM level, lies in the shortage of reagents with suitable specificity and avidity necessary for this type of examination. To create such a reagent, a polyclonal antibody was raised using a recombinant truncated form of the inducible Hsp-72 protein. The antibody was extensively characterized, using different immunochemical methods to determine and verify its specificity, and then it was tried in ultrastructural examinations. Using the new antibody, it was possible to analyze the intracellular distribution of Hsp-72 with the immunogold technique. The localization of Hsp-72 was demonstrated directly at the ultrastructural level in the cytoplasm (especially at the cisterns of the RER), in the nucleus (mainly around the heterochromatic regions) and at both sides of the nuclear envelope close to the membrane pores. Apart from these localizations, Hsp-72 was found in several membrane bordered intracellular structures, which mainly belong to the endosomal-lysosomal system. We provide the first morphological verification of the appearance of Hsp-72 on the surface of the cells. Also novel is the indication, that the stress protein may recycle from the cell surface using a common route which includes coated pits and the endosomal system.

Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle.

To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.

Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects.

Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells from various stresses is the heat-shock response which results in the induction of the synthesis of heat-shock proteins (HSPs or stress proteins). A large body of information supports that stress proteins--many of them molecular chaperones--are crucial for the maintenance of cell integrity during normal growth as well as during pathophysiological conditions, and thus can be considered "homeostatic proteins." Recently emphasis is being placed on the potential use of these proteins in preventing and/or treating diseases. Therefore, it would be of great therapeutic benefit to discover compounds that are clinically safe yet able to induce the accumulation of HSPs in patients with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamine derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboximidoil-chloride maleate, Bimoclomol, facilitates the formation of chaperone molecules in eukaryotic cells by inducing or amplifying expression of heat-shock genes. The cytoprotective effects observed under several experimental conditions, including a murine model of ischemia and wound healing in the diabetic rat, are likely mediated by the coordinate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applications.

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.

Bimoclomol (BRLP-42) ameliorates peripheral neuropathy in streptozotocin-induced diabetic rats.

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of gamma-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.

Identification of trinucleotide repeat-containing genes in human pancreatic islets.

In the search for diabetes genes, the combined approaches of positional cloning with random markers and subsequent evaluation of candidate genes mapping to areas of interest will be increasingly used. For islet candidate genes of unknown function, expressed trinucleotide (triplet) repeats represent a unique subset. It is unlikely that abnormal expansion of expressed islet triplet repeats would be a major cause of diabetes, yet the triplet repeats are frequently polymorphic and can thus be used to map the genes in the human genome. In this study, a human islet cDNA library was screened with (CGG)7 and (CAG)7, and 23 triplet repeats were isolated. Sequencing revealed four known and six novel islet genes containing 4-15 triplet repeats. The four known cDNAs included ferritin, the major iron-binding protein in cells; HSGSA2R, a full-length clone of the alpha-subunit of the G-regulatory protein; HUMSATB1A, a DNA-binding protein expressed predominantly in thymus; and HUMPPA-PRO, a ribosomal protein. The triplet repeats in ferritin and HUMPPAPRO were found to be monomorphic. Characterization of the six unique novel expressed islet triplet cDNAs revealed that they were 0.6-1.5 kb in size, contained 4-15 triplet repeats, and were expressed in islets and all other tissues examined. Four of the novel clones, CGG-isl 10, CGG-isl 11, CAG-isl 6, and CAG-isl 7, were mapped to human chromosomes 19, 16, 12, and 3, respectively, via somatic cell hybrids. One islet cDNA, CAG-isl 7, contained a repeat that was highly polymorphic, with 14 alleles (4-18 triplets) in African-Americans (heterozygosity = 0.86) and 6 alleles (heterozygosity = 0.77) in whites. Northern analysis indicated that the mRNA was abundant in pancreatic islets. A putative full-length clone contained an open reading frame encoding 213 amino acids with a variable number of alanines (4-18) within the COOH-terminal. The gene was uniquely mapped with odds > 1,000:1 on chromosome 3p in Centre d'Etude du Polymorphisme Humain pedigrees. There were no differences in CAG-isl 7 allele frequencies between African-American patients with NIDDM (n = 108) and control subjects (n = 116), nor was expansion above 18 repeats noted. Linkage analysis in 14 nonglucokinase maturity-onset diabetes of the young pedigrees showed a cumulative logarithm of odds score of -33.19 at theta = 0.00. Abnormal expansion was not observed in 20 IDDM patients with one NIDDM parent. While these data suggest no major role for CAG-isl 7 in diabetes, at least four of the six novel islet triplet genes are coexpressed in pancreatic islets and neural tissue, and these genes can now be considered as candidates for diabetes and/or neuropsychiatric diseases.

Postmarathon paradox: insulin resistance in the face of glycogen depletion.

Acute physical exercise enhances insulin sensitivity in healthy subjects. We examined the effect of a 42-km marathon run on insulin sensitivity and lipid oxidation in 19 male runners. In the morning after the marathon run, basal serum free fatty acid concentration was 2.2-fold higher, muscle glycogen content 37% lower (P < 0.01), glycogen synthase fractional activity 56% greater (P < 0.01), and glucose oxidation reduced by 43% (P < 0.01), whereas lipid oxidation was increased by 55% (P < 0.02) compared with the control study. During euglycemic-hyperinsulinemic clamp, whole body glucose disposal was decreased by 12% (P < 0.01) because of a 36% lower glucose oxidation rate (P < 0.05), whereas the rate of lipid oxidation was 10-fold greater (P < 0.02) than in the control study. After the marathon, muscle glycogen content correlated positively with lipid oxidation (r = 0.60, P < 0.05) and maximal aerobic power (Vo2peak; r = 0.61, P < 0.05). Vo2peak correlated positively with basal lipid oxidation (r = 0.57, P < 0.05). In conclusion, 1) after the marathon run, probably because of increased lipid oxidation, the insulin-stimulated glucose disposal is decreased despite muscle glycogen depletion and the activation of glycogen synthase; 2) the contribution of lipid oxidation in energy expenditure is increased in proportion to physical fitness; 3) these adaptations of fuel homeostasis may contribute to the maintenance of physical performance after prolonged exercise.

[The effect of prolonged acenocoumarol therapy on bone density]. / A tartós acenocumarol kezelés hatása a csonttömegre.

The effect of chronic cumarin treatment on bone mineral content was investigated. Bone mineral density was determined by double photon densitometry (Lunar DPXL). The density data (mean +/- SE) of 45 cardiac patients (age: 57.0 = +/- 6.3 y, body mass index: 26.7 +/- 3.8 kp/m2, cardiac stadium score, according to New York Heart Association: 2-3), had been treated by acenocumarol at least for 2 years (duration of treatment: 75.0 +/- 52 months), were compared to the values of 45 age, body mass index, cardiac status matched patients not treated by anticoagulant. The density values of L2-L4 lumbar regions were lower in the treated group (1.041 +/- 0.17 vs. controlls: 1.13 +/- 0.15 g/cm2, p < 0.05), while no differences in ultradistal ulnar and radial regions were detected. No correlation between bone mineral density and the length, or the dose of the cumarin treatment were observed. This observation suggests the importance of the regular bone densitometry control of cumarin treated patient.

Increased concentrations of glycogen synthase protein in skeletal muscle of patients with NIDDM.

To examine whether changes in the glycogen synthase protein concentration contribute to impaired insulin-stimulated glycogen metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM), muscle biopsies were taken before and after a 4-h euglycemic hyperinsulinemic clamp to measure glycogen synthase activity and glycogen synthase protein concentrations in 14 patients with NIDDM and in 17 control subjects. Nonoxidative glucose metabolism was reduced by 64% in patients with NIDDM compared with control subjects and correlated with insulin-stimulated glycogen synthase activity (r = 0.55, P < 0.05). The concentration of glycogen synthase protein in skeletal muscle was higher in patients with NIDDM than in control subjects (6.75 +/- 0.88 vs. 4.41 +/- 0.50 counts.min-1.micrograms protein-1, P < 0.05), whereas there was no significant difference in glycogen synthase mRNA concentration between the two groups. The glycogen synthase protein concentration correlated inversely with the rate of nonoxidative glucose metabolism (r = -0.63, P < 0.05). These findings indicate that the amount of glycogen synthase protein is increased in skeletal muscle of patients with NIDDM. The increase in the glycogen synthase protein may serve to compensate for a functional defect in the activation of the enzyme by insulin.

Athletes with IDDM exhibit impaired metabolic control and increased lipid utilization with no increase in insulin sensitivity.

Physical exercise is traditionally recommended to diabetic patients as part of their treatment. Although healthy athletes exhibit enhanced skeletal muscle insulin sensitivity, the metabolic effects of vigorous training in patients with insulin-dependent diabetes mellitus (IDDM) are not known. This study was designed to examine the effects of competitive sports on fuel homeostasis and insulin sensitivity in athletes with IDDM. We studied 11 athletes and 12 matched sedentary men with IDDM. In each subject, we measured glycemic control, insulin-stimulated glucose uptake in the whole body and forearm, rates of glucose and lipid oxidation, and muscle glycogen, glycogen synthase, and glucose transport protein (GLUT4) concentrations. The athletes had higher VO2max (52 +/- 1 vs. 42 +/- 1 ml.kg-1.min-1, P < 0.001) and HbA1c levels (8.4 +/- 0.4 vs. 7.2 +/- 0.2%, P < 0.05) than sedentary patients, but took smaller insulin doses (41 +/- 3 vs. 53 +/- 3 U/day, P < 0.05). The insulin-stimulated rates of whole-body and forearm glucose uptake and glucose oxidation were similar in the two groups, whereas both energy expenditure and lipid oxidation were increased in the athletes. Lipid oxidation correlated inversely with glycogen synthase activity. The mean glucose arterialized venous blood-deep venous blood (A-V) difference during the insulin infusion (60-240 min) correlated with the whole-body glucose disposal throughout the insulin infusion (after 60 min, r > 0.73, P < 0.001 for all 30-min periods). This association is accounted for by the relationship between glucose A-V difference and nonoxidative glucose disposal. Muscle glycogen and GLUT4 protein contents were not different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of menopause on carbohydrate metabolism]. / A klimaktérium hatása a szénhidrát-anyagcserére.

Endocrine alterations in menopause produce disadvantageous changes in the carbohydrate and lipid metabolism. The character and tendency of these alterations are very similar to those found in type II diabetes mellitus. The abdominal visceral fat content as well as the blood level of cholesterol, triglyceride, glucose and insulin increase in postmenopause. These changes can be advantageously influenced by hormone replacement therapy.

Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives.

We examined whether insulin resistance, i.e. impaired insulin stimulated glucose uptake in NIDDM patients and their first-degree relatives is associated with alterations in the effect of insulin on the expression of the GLUT-4 gene in skeletal muscle in vivo. Levels of GLUT-4 mRNA and protein were measured in muscle biopsies taken before and after a euglycaemic insulin clamp from 14 NIDDM patients, 13 of their first-degree relatives and 17 control subjects. Insulin stimulated glucose uptake was decreased in the diabetic subjects (19.8 +/- 3.0 mumol.kg LBM-1.min-1, both p < 0.001) compared with control subjects (44.1 +/- 2.5 mumol.kg LBM-1.min-1) and relatives (39.9 +/- 3.3 mumol.kg LBM-1.min-1). Basal GLUT-4 mRNA levels were significantly higher in diabetic subjects and relatives compared to control subjects (99 +/- 8 and 108 +/- 9 pg/micrograms RNA vs 68 +/- 5 pg/micrograms RNA; both p < 0.01). Insulin increased GLUT-4 mRNA levels in all control subjects (from 68 +/- 5 to 92 +/- 6 pg/micrograms RNA; p < 0.0001), but not in the diabetic patients (from 99 +/- 8 to 90 +/- 8 pg/micrograms RNA, NS), or their relatives (from 94 +/- 9 to 101 +/- 11 pg/micrograms RNA, NS). In the relatives, individual basal GLUT-4 mRNA concentrations varied between 55 and 137 pg/micrograms RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity.

UNLABELLED: We examined the mechanisms of enhanced insulin sensitivity in 9 male healthy athletes (age, 25 +/- 1 yr; maximal aerobic power [VO2max], 57.6 +/- 1.0 ml/kg per min) as compared with 10 sedentary control subjects (age, 28 +/- 2 yr; VO2max, 44.1 +/- 2.3 ml/kg per min). In the athletes, whole body glucose disposal (240-min insulin clamp) was 32% (P < 0.01) and nonoxidative glucose disposal (indirect calorimetry) was 62% higher (P < 0.01) than in the controls. Muscle glycogen content increased by 39% in the athletes (P < 0.05) but did not change in the controls during insulin clamp. VO2max correlated with whole body (r = 0.60, P < 0.01) and nonoxidative glucose disposal (r = 0.64, P < 0.001). In the athletes forearm blood flow was 64% greater (P < 0.05) than in the controls, whereas their muscle capillary density was normal. Basal blood flow was related to VO2max (r = 0.63, P < 0.05) and glucose disposal during insulin infusion (r = 0.65, P < 0.05). The forearm glucose uptake in the athletes was increased by 3.3-fold (P < 0.01) in the basal state and by 73% (P < 0.05) during insulin infusion. Muscle glucose transport protein (GLUT-4) concentration was 93% greater in the athletes than controls (P < 0.01) and it was related to VO2max (r = 0.61, P < 0.01) and to whole body glucose disposal (r = 0.60, P < 0.01). Muscle glycogen synthase activity was 33% greater in the athletes than in the controls (P < 0.05), and the basal glycogen synthase fractional activity was closely related to blood flow (r = 0.88, P < 0.001). IN CONCLUSION: (a) athletes are characterized by enhanced muscle blood flow and glucose uptake. (b) The cellular mechanisms of glucose uptake are increased GLUT-4 protein content, glycogen synthase activity, and glucose storage as glycogen. (c) A close correlation between glycogen synthase fractional activity and blood flow suggests that they are causally related in promoting glucose disposal.

Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance.

In order to test the hypothesis that maternal corticosterone influences hypothalamus-pituitary-adrenal (HPA) system activity in the adult rat and behaviors related to it, we induced a moderate increase in maternal plasma level of corticosterone by adding the hormone to the drinking water of the dams (200 micrograms/ml) from the day after delivery to weaning. Our previous experiments have shown that this procedure produces plasma levels of the hormone in the range of those following a mild psychic stress (from 4.3 +/- 0.5 to 9.5 +/- 1.8 micrograms/100 ml in the dams, and from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml in the pups at 10 days of lactation). Adrenal weights were slightly and temporarily decreased by treatment in both mothers and offspring. Only the male progeny was investigated in this study. Corticosterone-nursed rats had significantly less corticosterone and ACTH in basal conditions and after a 2 min restraint stress at 3 months of age, and showed better performances at weaning and at 1, 2 and 3 months of life in the Morris water maze. Our results demonstrate that a moderate increase in maternal corticosterone during lactation influences the activity of HPA axis and improves spatial learning ability of the adult offspring.