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Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status.

Perhexiline is metabolized by CYP2D6 and has concentration-related hepatoxicity and peripheral neuropathy. The risk of toxicity is reduced using therapeutic drug monitoring. CYP2D6 genotyping before therapy may allow earlier appropriate dosing. This study aimed to determine whether assessment of CYP2D6 genotype in patients on perhexiline could predict accurately metabolizer status as determined by the perhexiline metabolic ratio (MR). Blood samples from patients stabilized on perhexiline were analysed for CYP2D6 genotype and for concentrations of perhexiline and its hydroxy metabolite. The MR was determined. Of 74 patients, five were poor metabolizers (PM) defined by a MR<0.4, and the remainder were extensive metabolizers (EM). The genotypes were: *1/*1 (n=21), *1/*4 (n=18), *1/*2 (n=12), *1/*3 (n=2), *1/*5 (n=1), *1/*9 (n=2), *1/*10 (n=2), *2/*4 (n=4), *2/*2 (n=3), *4/*41 (n=3), *2/*41 (n=1), *41/*41 (n=1), *4/*9 (n=1), *4/*5 (n=1), *5/*6 (n=1) and *4/*6 (n=1). Allele frequencies were consistent with those reported in population studies. The 3 PMs with the lowest MR were predicted by genotype (*4/*5, *5/*6, *4/*6). The other 2 PMs had intermediate metabolizer genotypes and were on CYP2D6 inhibiting drugs. Amongst the EMs, the highest MR was associated with *1 and *2 allele combinations and the MR was progressively lower with the presence of alleles with intermediate function (*9, *10, *41) followed by alleles with no functional product (*3, *4, *5, *6). Thus, a gene-dose effect was observed. Genotype predicted PM phenotype and also intermediate metabolizers. Determination of CYP2D6 genotype before therapy with perhexiline may help predict perhexiline dose requirements and reduce the risk of perhexiline concentration-related toxicity.

Adult↗

Dynamic and integrative aspects of the regulation of reproduction by metabolic status in male sheep.

Change in metabolic status, defined as a change in the availability of nutrients and energy to the tissues, is a powerful regulator of the reproductive function in small ruminants, especially in genotypes that are not strongly responsive to photoperiod such as the Merino sheep. In this paper, the dynamics of the response of the reproductive axis to changes in metabolic status are reviewed in the light of recent studies. The nature and the roles of the various components of the pathways linking metabolic status to reproduction are considered: nutrients and metabolites, the endocrine system, and the nervous system. We discuss the role of leptin and insulin in detail because of the central role of these two hormones in both the early gonadotrophin response to increase in nutrition and the long-term response of the testis to dietary stimulation. The possible roles of recently identified peptides, such as ghrelin and kisspeptin, are also considered as we develop a general hypothesis that encompasses the different levels of integration necessary to explain the complex interactions between reproductive function and metabolic status, and the possible existence of a "metabolic memory" in this interaction.

Animal Nutritional Physiological Phenomena↗

Reproductive endocrinology and postweaning performance in the multiparous sow. Part 1. Influence of metabolic status during lactation.

The metabolic status of the sow during lactation might influence reproductive endocrinology and the postweaning reproductive performance. With regard to the multiparous sow, previous studies addressing this topic are scarce and the results inconsistent. Blood samples were collected from 18 multiparous sows during lactation and after weaning for analysis of nonesterified fatty acids (NEFA), triglycerides, creatinine, urea progesterone, LH, and estradiol-17beta. Based on the average preweaning NEFA levels the sows were divided into a "high" and a "low" catabolism group. The NEFA values were higher in the "high" group during each of the last 3 weeks of lactation. The levels of urea, creatinine and progesterone were similar (P > 0.05) in the two groups throughout the study. Reproductive functions seemed equally inhibited during lactation in the two groups and there were no differences in postweaning reproductive performance. The results suggest that metabolic rate during lactation varies considerably between equally nourished multiparous sows but this has no influence on postweaning reproductive performance.

Animals↗

Refeeding in fasted rats: dietary self-selection according to metabolic status.

We investigated the influence of the metabolic status rats have reached during a fast on their selection of protein, fat and carbohydrate when allowed to refeed after fasting for different lengths of time. They were refed either while essentially relying on lipid fuels (group 1), or while in the further stage when there is a rise in protein breakdown (group 2). In contrast to previous studies in which rats could not select macronutrients, there was no transitory anorexia during refeeding. Macronutrient selection as well as food and energy intake on the first day of refeeding were the same for both groups, total food intake being significantly larger than prior to the fast. However, there was thereafter a distinct pattern of diet selection: while fat intake progressively decreased in group 1, it increased until the fifth day in rats of groups 2. These rats, moreover, exhibited a further rise in protein intake. The data are discussed in relation to the optimization of the restoration of body fuel reserves according to the metabolic status reached at the end of a long fast.

Animals↗

Prepartum intake, postpartum induction of ketosis, and periparturient disorders affect the metabolic status of dairy cows.

Nutritional management during the dry period may affect susceptibility of cows to metabolic and infectious diseases during the periparturient period. Thirty-five multiparous Holstein cows were used to determine the effect of prepartum intake, postpartum induction of ketosis, and periparturient disorders on metabolic status. Cows were fed a diet from dry-off to parturition at either ad libitum intake or restricted intake [RI; 80% of calculated net energy for lactation (NEL) requirement]. After parturition, all cows were fed a lactation diet. At 4 d in milk (DIM), cows underwent a physical examination and were classified as healthy or having at least one periparturient disorder (PD). Healthy cows were assigned to the control (n = 6) group or the ketosis induction (KI; n = 9) group. Cows with PD were assigned to the PD control (PDC; n = 17) group. Cows in the control and PDC groups were fed for ad libitum intake. Cows in the KI group were fed at 50% of their intake on 4 DIM from 5 to 14 DIM or until signs of clinical ketosis were observed; then, cows were returned to ad libitum intake. During the dry period, ad libitum cows ate more than RI cows; the difference in intake resulted in ad libitum cows that were in positive energy balance (142% of NEL requirement) and RI cows that were in negative energy balance (85% of NEL requirement). Prepartum intake resulted in changes in serum metabolites consistent with plane of nutrition and energy balance. Prepartum intake had no effect on postpartum intake, serum metabolites, or milk yield, but total lipid content of liver at 1 d postpartum was greater for ad libitum cows than for RI cows. The PD cows had lower intake and milk yield during the first 4 DIM than did healthy cows. During the ketosis induction period, KI cows had lower intake, milk yield, and serum glucose concentration but higher concentrations of nonesterified fatty acids and beta-hydroxybutyrate in serum as well as total lipid and triacylglycerol in liver than did control cows. Cows with PD had only modest alterations in metabolic variables in blood and liver compared with healthy cows. The negative effects of PD and KI on metabolic status and milk yield were negligible by 42 DIM, although cows with PD had lower body condition score and BW. Prepartum intake did not affect postpartum metabolic status or milk yield. Periparturient disorders and induction of ketosis negatively affected metabolic status and milk yield during the first 14 DIM.

3-Hydroxybutyric Acid↗

Challenge differentially affects cytokine production and metabolic status of growing and finishing swine.

Growing (35 kg body weight) and finishing (85 kg body weight) swine challenged with endotoxin (Escherichia coli O55:B5) at a dose of either 2 or 20 microg/kg produced tumor necrosis factor (TNF)alpha in a dose-response relationship as measured by bioassay. Peak TNFalpha plasma levels were observed 1-2 hr post-challenge, returning to basal values 4 hr post-challenge. However, both an enzyme-linked immunosorbent assay specific for swine TNFalpha and total human TNFalpha demonstrated no dose-response relationship; peak plasma levels of immunoreactive TNFalpha were also observed 1-2 hr post-challenge. Maximal plasma interleukin-6 levels occurred 1-2 hr post-challenge and remained elevated through 8 hr post-challenge; there was no effect of lipopolysaccharide dose or metabolic status. Although the metabolic status of the animals also affected glucose levels, with growing animals exhibiting greater sensitivity compared with finishing animals, endotoxin-induced decreases in blood glucose levels were primarily dose-dependent. In contrast, changes in plasma urea nitrogen and free fatty acid (FFA) levels were strictly related to the metabolic status. Urea nitrogen levels were unchanged in growing swine, whereas they were increased in finishing swine and remained elevated 24 hr post-challenge. FFA levels in growing and finishing swine increased 3-6 hr post-challenge. FFA levels returned to basal values for finishing swine 24 hr post challenge, but in growing swine remained elevated 24 hr post-challenge. Plasma aspartate transaminase levels were increased through 24 hr post-challenge; animals given a dose of 20 microg/kg exhibited the greatest increase. Similarly, swine challenged with a dose of 20 microg/kg also exhibited the greatest increase in levels of conjugated bilirubin; there was no effect on unconjugated (free) bilirubin. These results demonstrate that endotoxin challenge of swine result in a pattern of changes that are dependent on both the dose of endotoxin used and the metabolic status of the animal examined.

Animals↗

Insulin resistance is associated with arterial stiffness in nondiabetic hypertensives independent of metabolic status.

We sought to determine whether insulin resistance (IR) is related to arterial stiffness in nondiabetic hypertensive patients, independent of metabolic status and gender. IR has been associated with increased arterial stiffness in patients with diabetes. In nondiabetic hypertensive patients, the correlation between IR and arterial stiffness has yet to be investigated. We enrolled 284 nondiabetic patients who were being treated for hypertension. At the time of enrollment, the patients underwent a baseline laboratory assessment including homeostatic model assessment (HOMA) IR index and pulse wave velocity (PWV). The HOMA IR index is used as a marker of IR, and brachial to ankle PWV (baPWV) was used as a marker of arterial stiffness. Of the 284 study subjects, 121 were classified as having metabolic syndrome. The patients with metabolic syndrome were older than the non-metabolic syndrome patients (55.4+/-10.7 vs. 52.1+/-11.6 years, p=0.013), but there was no gender difference between the two groups. The average baPWV was significantly higher in the patients with metabolic syndrome (1,506+/-235 vs. 1,435+/-211 cm/s, p=0.009). The HOMA index was independently associated with an increase in arterial stiffness (r=0.548, p<0.001) after controlling for age, systolic blood pressure (SBP), heart rate, medication and gender. The independent association of HOMA with arterial stiffness was demonstrated in subgroup analysis, regardless of the metabolic status and gender. In conclusion, increased IR was associated with arterial stiffness, independent of age, baseline SBP, gender and heart rate. This independent association of IR was demonstrated regardless of gender and metabolic status.

Adult↗

Relative androgen deficiency in relation to obesity and metabolic status in older men.

BACKGROUND: Although androgen deficiency in men has been linked with obesity and the metabolic syndrome, whether it predisposes to, or is a consequence of, type 2 diabetes mellitus (T2DM) is still unclear. OBJECTIVE: To determine the relationship between plasma androgen levels, obesity, metabolic status and T2DM in men of 70 years or older. DESIGN AND METHODS: A sample of 195 men from the Australian Longitudinal Study of Ageing with a mean age of 76.2 +/- 0.3 years were followed up for 8 years. Total testosterone (TT), fasting plasma glucose (FPG), urate, serum creatinine, total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG), blood pressure (BP), body mass index (BMI), waist circumference (WC) and diabetic status were assessed at baseline. Self-reported diabetic status was obtained after 8 years. Metabolic syndrome was diagnosed based on the Third National Cholesterol Education Program Adult Treatment Panel clinical criteria. RESULTS: TT levels were lower in diabetic men compared with non-diabetic men (12.1 +/- 0.7 vs. 14.2 +/- 0.4 nmol/l, p = 0.026). TT levels in healthy, non-diabetic men over 80 years of age were lower (11.9 +/- 0.8 vs. 15.0 +/- 0.5 nmol/l, p = 0.002) than TT levels in those aged 70-79 years, inversely related to BMI (r = -0.26, p = 0.001), WC (r = -0.30, p < 0.001) and TG (r = -0.22, p = 0.005) and positively related to LDL-C (r = 0.25, p = 0.002). Men with the metabolic syndrome had significantly lower levels of TT and HDL-C, and higher values of BP, FPG, TG, BMI and WC, compared with those without. However, no significant difference in plasma TT levels was noted between men with incident T2Dm and healthy men. Stepwise linear regression analysis revealed that only LDL-C and WC related significantly to the variance of TT. Multiple logistic regression revealed FPG to be the only independent predictor of incident diabetes (odds ratio = 60.2, p = 0.003). CONCLUSIONS: Testosterone levels continue to decline even in healthy men over the age of 80 years. Although TT levels were inversely related to visceral obesity and several components of the metabolic syndrome, our data do not support a predictive or causative role for decreasing TT levels in the development of incident T2Dm. Androgen deficiency is consequent upon, rather than a cause of, poor metabolic status.

Aged↗

Effects of pre- and postfresh transition diets varying in dietary energy density on metabolic status of periparturient dairy cows.

Effects of dietary energy density during late gestation and early lactation on metabolic status of periparturient cows were studied. Four weeks before expected calving, animals were fed a low (DL; 1.58 Mcal of NEL/kg) or high energy density diet (DH; 1.70 Mcal of NEL/kg). After calving, half of the cows from each prepartum treatment were assigned to a low (L; 1.57 Mcal of NEL/kg) or high energy density diet (H; 1.63 Mcal of NEL/kg) until d 20 postpartum. After d 20, all animals were fed H until d 70. Animals fed DH had a more positive energy balance during the prepartum period. Animals fed DH had higher plasma concentrations of glucose and insulin and lower concentrations of plasma nonesterified fatty acid (NEFA) on d -7 relative to calving compared with animals fed DL. No differences in blood concentrations of metabolites, insulin and liver triglycerides (TG) content were observed on d 1. Liver TG content at d 1 and 21 were more related to magnitude of change in energy intake prepartum than to energy intake in the last week of gestation. Cows fed H had higher concentrations of plasma glucose and insulin, but similar plasma NEFA during the postpartum period compared with cows fed L. Plasma concentrations of beta-hydroxybutyrate (BHBA) and liver TG content on d 21 were 46 and 30% lower, respectively, for cows fed H compared with cows fed L. Interactions between prepartum and postpartum treatments indicated that negative effects of delaying higher concentrate feeding until d 21 postpartum can be partially offset by increasing concentrate in the diet before calving. Cows fed L had a higher increase in white line hemorrhage scores between prepartum and 10 wk postpartum compared with cows fed H. Energy density of prepartum diets had a minor influence on metabolic status of cows postpartum. A more favorable metabolic profile occurs when increasing the concentrate content of the diet immediately postpartum compared with delaying the increase until d 21 postpartum.

3-Hydroxybutyric Acid↗

Salivary gland function and glucose metabolic status.

To study the relationship between glucose metabolic status and salivary gland function in different-aged persons, subjects with diabetes mellitus (DM = 11), impaired glucose tolerance (IGT = 26), and controls (n = 26), aged 24 to 93, were examined in the oral physiology component of the Baltimore Longitudinal Study of Aging. All were generally healthy (except DM) and nonmedicated. The controls and subjects with IGT were classified using World Health Organization criteria, and diabetic status was assessed using Hb1Ac levels. Unstimulated and 2% citrate-stimulated parotid and submandibular salivary flow rates were collected, and subjective responses to questions about salivary hypofunction were evaluated. No statistically significant differences were observed between the three groups, nor between young and old subjects with altered glucose metabolism. These findings suggest that among well-controlled individuals with altered glucose metabolism, salivary gland function is not significantly impaired.

Adult↗

Metabolic status of bacteria and fungi in the rhizosphere of ponderosa pine seedlings.

We determined the quantity and metabolic status of bacteria and fungi in rhizosphere and nonrhizosphere soil from microcosms containing ponderosa pine seedlings. Rhizosphere soil was sampled adjacent to coarse, fine, or young roots. The biovolume and metabolic status of bacterial and fungal cells was determined microscopically and converted to total and active biomass values. Cells were considered active if they possessed the ability to reduce the artificial electron acceptor 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride (INT) to visible intracellular deposits of INT formazan. A colorimetric assay of INT formazan production was also used to assess dehydrogenase activity. INT-active microorganisms made up 44 to 55% of the microbial biomass in the soils studied. The proportion of fungal biomass that exhibited INT-reducing activity (40 to 50%) was higher than previous estimates of the active proportion of soil fungi determined by using fluorescein diacetate. Comparison between soils from different root zones revealed that the highest total and INT-active fungal biomass was adjacent to fine mycorrhizal roots, whereas the highest total and active bacterial biomass was adjacent to the young growing root tips. These observations suggest that fungi are enhanced adjacent to the fine roots compared with the nonrhizosphere soil, whereas bacteria are more responsive than fungi to labile carbon inputs in the young root zone. Colorimetric dehydrogenase assays detected gross differences between bulk and rhizosphere soil activity but were unable to detect more subtle differences due to root types. Determination of total and INT-active biomass has increased our understanding of the role of spatial compartmentalization of bacteria and fungi in rhizosphere carbon flow.

Journal Article↗

Serum amyloid A: a marker of adiposity-induced low-grade inflammation but not of metabolic status.

OBJECTIVE: Adipocytes secrete a series of acute phase proteins including serum amyloid A (SAA); the link with metabolic status is unknown. We studied the variations of expression of the SAA gene in adipose and liver tissues and of SAA serum levels, as well as their relationships with metabolic features during weight loss. RESEARCH METHODS AND PROCEDURES: Plasmatic variations of SAA, inflammatory markers (high sensitivity C-reactive protein, interleukin-6, fibrinogen, and orosomucoid), and adipokines (adiponectin, leptin) were studied in 60 morbidly obese patients before and after gastric surgery. For 10 subjects, SAA mRNA expression was measured at baseline in subcutaneous white adipose tissue (scWAT) and visceral white adipose tissue (vWAT) and in the liver. The evolution of SAA mRNA expression was also studied after surgery in scWAT. RESULTS: SAA serum concentration displayed a significant reduction 3 months after surgery and remained stable beyond 6 months. mRNA expression of inducible SAA isoforms (SAA 1 and 2) in scWAT was higher than in vWAT (p = 0.01) and the liver (p < 0.01) and correlated significantly with BMI, SAA, and high sensitivity C-reactive protein serum concentrations but not with metabolic markers (glucose, insulin, lipid parameters, adiponectin). SAA serum level and its variation during weight loss significantly correlated with adiposity markers (BMI and adipocyte volume, p < 0.01) and inflammatory markers but not with variations of metabolic parameters. The variations of SAA expression in scWAT after surgery correlated with changes in BMI and SAA protein serum levels (p < 0.05). DISCUSSION: SAA can be considered as a marker of adiposity-induced low-grade inflammation but not of the metabolic status of obese subjects.

Adipose Tissue↗

The association of body fat location with haemodynamic and metabolic status in men and women aged 21-60 years.

The importance of body fat location as a predictor of metabolic aberrations was evaluated in 214 males and 244 females [aged 21-60] randomly selected from the patients of one general practice of Castel D'Azzano (Italy). The metabolic pattern, indexed by blood pressure, blood glucose, uric acid, serum triglycerides, HDL- and LDL-cholesterol was summarized in a haemodynamic-metabolic score (HMS). Association of HMS with age, anthropometric variables (skinfold thicknesses, girth lengths) and degree of overweight (body mass index, BMI) was evaluated in males and females using multiple regression analysis. Body fat location was associated with metabolic status independent of age in both sexes. This association was also independent of the degree of overweight. BMI, in general, was associated with HMS to a greater extent than anthropometric variables, except for waist girth; when its effect was taken into account BMI did not significantly improve the prediction power of HMS values in males. Among skinfolds, epimesogastric showed in both sexes the highest association with HMS. These results support the abdominal adiposity hypothesis and suggest that waist circumference could be a good index for assessing metabolic status. The abdominal location of adipose tissue, more than just the degree of overweight, could play a role in obesity related disorders.

Adipose Tissue↗

Influence of body condition score on relationships between metabolic status and oxidative stress in periparturient dairy cows.

Twenty-four dairy cows were monitored during the transition period. We observed changes of oxidative status and relationships between oxidative and metabolic status. Body condition score (BCS) of the 24 animals at the beginning of the trial (30.4 +/- 2 d before expected calving) was between 2.0 and 3.6. The BCS was recorded and blood samples were collected weekly during the last 30 d of pregnancy and the first 30 DIM. Plasma samples were analyzed to determine indices of oxidative status: reactive oxygen metabolites (ROM); thiobarbituric acid-reactive substances (TBARS); thiol groups (SH); glutathione peroxidase (GSH-Px), and indices of energy metabolism: glucose, beta-hydroxybutyrate, and nonesterified fatty acids. In erythrocytes we determined indices of oxidative status: GSH-Px, superoxide dismutase (SOD), and intracellular SH. Before calving, cows showed an increase of plasma SH, SOD, and GSH-Px, a decrease of erythrocyte GSH-Px and plasma ROM, and no changes in erythrocyte SH. After calving, cows showed a decrease of plasma and erythrocyte SH and SOD, and an increase of ROM, TBARS, and plasma GSH-Px. Cows with higher BCS at the beginning of the trial and greater loss of BCS after calving, had higher plasma ROM, TBARS, and SH, and lower SOD and erythrocyte SH in the postpartum period. Oxidative status of dairy cows was related to energy status. Cows with higher BHBA and NEFA showed higher ROM and TBARS and lower levels of antioxidants. Results of the present study demonstrated that cows can experience oxidative stress during the peripartum period, and cows with higher BCS and greater BCS losses are more sensitive to oxidative stress.

3-Hydroxybutyric Acid↗

Serum carnitine levels, lipid profile, and metabolic status of patients on continuous ambulatory peritoneal dialysis.

The purpose of our study was to evaluate the influence of serum carnitine levels on the metabolic status and lipid profile of patients on continuous ambulatory peritoneal dialysis (CAPD). We studied the lipid profile, the metabolic status (triceps, skinfold thickness, midarm muscle circumference, relative body weight, serum total protein, albumin), and serum carnitine levels in 22 patients (11 male, 11 female) on CAPD. The results are summarized as follows: mean serum total carnitine (TC) was normal, free carnitine (FC) was reduced, while acylcarnitine (AC) was elevated in our patients (p < 0.001). A positive correlation was found between TC (p < 0.02), FC (p < 0.05), and serum total protein. A positive correlation was also found between TC (p < 0.05), AC (p < 0.02), AC/FC (p < 0.02), and relative body weight, and TC (p < 0.001), FC (p < 0.02), AC (p < 0.01), AC/FC (p < 0.02), and triglycerides. No correlation was found between carnitine and mid-arm muscle circumference, triceps skinfold thickness, albumin, total cholesterol, and HDL- or LDL-cholesterol. Further studies are needed to confirm our results.

Adult↗

[Glucose metabolism status and angiographic features of coronary artery in patients undergoing their first coronary angiography: study of 553 cases].

OBJECTIVE: To investigate the correlation between glucose metabolism status and coronary artery lesion in the patients undergoing their first coronary angiography (CAG). METHODS: Oral glucose tolerance test (OGTT) and CAG were performed in 553 patients with suspected or confirmed coronary artery disease (CAD), aged 60.1 +/- 9.7. The anthroposomatologic parameters, blood pressure, HbA1c, and lipid profile of these patients were collected. Their glucose metabolism status was assessed based on the WHO diagnostic criteria of diabetes mellitus 1999 and American Heart Association's grading standards for evaluating coronary artery stenosis and Gensini score were applied to analyze the coronary artery lesion. According to the CAG results the patients were divided into CAD group and non-CAD group and then the glucose metabolic characteristics in both groups were analyzed by comparison based on the glycometabolic status. The patients were also grouped into diabetic and non-diabetic groups and the coronary artery angiographic features in both groups were compared. RESULTS: Among the 533 patients 277 (50.1%) had normal OGTT, 127 (23.0%) were diagnosed as with impaired glucose regulation, 61 (11%) were newly diagnosed as with type 2 diabetes mellitus, and the other 88 patients (15.9%) were already known diabetics. The prevalence of abnormal glycometabolism in the CAD group was 56.4%, significantly higher than that in the non-CAD group (34.5%, P < 0.05). The prevalence of multiple branches involvement in the diabetic group was 63.8%, significantly higher than that of the non-diabetic group (44.1%, P < 0.05), and the Gensini score in the diabetic group was 15 (30.5), significantly higher than that of the [20 (27), P < 0.05]. CONCLUSION: Abnormal glycometabolism is common in the population undergoing coronary angiography. Both the prevalence of multiple branches involvement and the degree of stenosis of coronary in the diabetics are higher than that in those without diabetes.

Aged↗

Vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide: effects on insulin release in isolated mouse islets in relation to metabolic status and age.

Obesity and development of the metabolic syndrome is related to an increased parasympathetic tone and hyperinsulinemia. We have now studied the effects of age and metabolic status on glucose-induced insulin release stimulated by the neuropeptides vasoactive intestinal polypeptide (VIP; 10 nM) and pituitary adenylate cyclase activating polypeptide (PACAP; 10 nM), that are constituents of the parasympathetic nerves in the islets, and the cholinergic agonists acetylcholine (ACh; 10 microM) and carbachol (10 microM), in isolated islets from female obese ob/ob mice and lean mice. Both VIP and PACAP enhanced insulin secretion in islets from 4-week-old hyperglycemic ob/ob mice. VIP did not increase 11.1 mM glucose-induced insulin release in islets from 4-week-old lean normoglycemic mice and neither did PACAP in the absence of bicarbonate. The neuropeptides increased insulin release in islets from 9 to 10-month-old mice but VIP and PACAP had no effect in islets from very old mice. ACh had no effect in islets from 9 to 10-months and older ob/ob mice in the absence of bicarbonate. The combination of VIP and cholinergic agonists had an additive effect in islets from ob/ob mice, and PACAP combined with carbachol potentiated insulin release in islets from 4-week-old lean mice. VIP increased early phase insulin release in perifused islets from young mice. A higher concentration of theophylline was needed to potentiate glucose-induced insulin release in islets from young lean mice than in islets from old lean mice and ob/ob mice. The present results demonstrate age-related dynamics in the effects of neuropeptides affecting cAMP in pancreatic islets. We suggest that VIP and PACAP contribute to the developing metabolic syndrome in ob/ob mice by aggravating hyperinsulinemia.

Aging↗

[Radiation response of mitochondria in dependence on their metabolic status (author's transl)].

The influence of the metabolic status of mitochondria upon their radiation response was studied. It turned out that the reduction of pyridine nucleotides by addition of beta-hydroxybutyrate (BOH) and the decrease through respiration were distinctly impaired in mitochondria with a substrate deficit by an irradiation with 2.7 krd already. The evolution of the lesion depends on the incubation conditions following irradiation, a presence of BOH having protective effects. The general redox level seems to be essential for radiation response of mitochondria. An exit of NAD from mitochondria has proved to be the main cause for inhibition of the respiratory BOH-consumption.

Animals↗