Instrumental assessment of dynamic postural stability in patients with unilateral vestibular hypofunction during straight, curved, and blindfolded gait.

PURPOSE: To characterise dynamic postural stability of gait in patients with vestibular hypofunction (PwVH) using a sensor-based assessment while performing dynamic tasks and to correlate the results of this evaluation with clinical scales. METHODS: This cross-sectional study involved 22 adults between 18 and 70 years old from a healthcare hospital centre. Eleven patients suffering from chronic vestibular hypofunction (PwVH) and eleven healthy controls (HC) were evaluated through a combined inertial sensor-based and clinical scale assessment. Participants were equipped with five synchronised inertial measurement units (IMUs) (128 Hz, Opal, APDM, Portland, OR, USA): three IMUs were located on the occipital cranium bone, near the lambdoid suture of the head, at the centre of the sternum, and at L4/L5 level, just above the pelvis, and were used to quantify gait quality parameters, while the other two were located slightly above lateral malleoli and used to perform stride and step segmentation. Three different motor tasks were performed in a randomized order: the 10-m Walk Test (10mWT), the Figure of Eight Walk Test (Fo8WT) and the Fukuda Stepping Test (FST). A set of gait quality parameters related to stability, symmetry and smoothness of gait were extracted from IMU data and correlated with the clinical scale scores. PwVH and HC results were compared to test for significant between-group differences. RESULTS: Significant differences were found for the three motor tasks (10mWT, Fo8WT and FST) when comparing PwVH and HC groups. For the 10mWT and the Fo8WT, significant differences between the PwVH and HC groups were found for the stability indexes. Considering the FST, significant differences between the PwVH and HC groups were also found in the stability and symmetry of gait. A significant correlation was found between the Dizziness Handicap Inventory and gait indices during the Fo8WT. CONCLUSIONS: In this study, we characterized the dynamic postural stability alterations during linear, curved, and blindfolded walking/stepping in PwVH combining an instrumental IMU-based with traditional clinical scales approach. Combining instrumental and clinical evaluation for dynamic stability of gait alterations in PwVH is useful in thoroughly evaluating the effects of unilateral vestibular hypofunction.

Magnetic-free Extended Kalman Filter for upper limb kinematic assessment in Yoga.

Human motion analysis is gaining increased importance in several fields, from movement assessment in rehabilitation to recreational applications such as virtual coaching. Among all the technologies involved in motion capture, Magneto-Inertial Measurements Units (MIMUs) is one of the most promising due to their small dimensions and low costs. Nevertheless, their usage is strongly limited by different error sources, among which magnetic disturbances, which are particularly problematic in indoor environments. Inertial Measurement Units (IMUs) could, thus, be considered as alternative solution. Indeed, relying exclusively on accelerometers and gyroscopes, they are insensitive to magnetic disturbances. Even if the literature has started to propose few algorithms that do not take into account magnetometer input, their application is limited to robotics and aviation. The aim of the present work is to introduce a magnetic-free quaternion based Extended Kalman filter for upper limb kinematic assessment in human motion (i.e., yoga). The algorithm was tested on five expert yoga trainers during the execution of the sun salutation sequence. Joint angle estimations were compared with the ones obtained from an optoelectronic reference system by evaluating the Mean Absolute Errors (MAEs) and Pearson's correlation coefficients. The achieved worst-case was 6.17°, while the best one was 2.65° for MAEs mean values. The accuracy of the algorithm was further confirmed by the high values of the Pearson's correlation coefficients (lowest mean value of 0.86).Clinical Relevance- The proposed work validated a magnetic free algorithm for kinematic reconstruction with inertial units. It could be used as a wearable solution to track human movements in indoor environments being insensitive to magnetic disturbances, and thus could be potentially used also for rehabilitation purposes.

Muscle synergies in archery: an explorative study on experienced athletes with and without physical disability.

Archery technique requires a coordinated activation of shoulder girdle and upper extremity muscles to perform a successful shot. The analysis of muscle synergies can provide information about the motor strategy that underlies the shooting performance, also supporting the investigation of motor impairments in athletes with disability. For this purpose, electromyographic (EMG) data from five muscles were collected from a non-disabled and a W1 category Paralympic athlete, and muscle synergies were extracted from EMG envelopes using non-negative matrix factorization. Muscle synergies analysis revealed features of the motor strategy specific to the athletes' shooting technique, such as the contribution of the biceps muscle instead of the posterior deltoid during the arrow drawing and target aiming in the Paralympic athlete compared to the non-disabled athlete. It is concluded that the evaluation of the muscle synergies may be a valuable tool for exploring the motor strategies adopted by athletes with disability, providing useful information to improve athletic performance and possibly prevent the risk of injury.

Dynamic balance assessment during gait in children with Down and Prader-Willi syndromes using inertial sensors.

Down (DS) and Prader-Willi (PWS) syndromes are chromosomal disorders both characterized by obesity, ligament laxity, and hypotonia, the latter associated with gait instability. Although these shared features may justify a common rehabilitation approach, evidence exists that adults with DS and PWS adopt different postural and walking strategies. The development of an instrumented protocol able to describe these strategies and quantify patients' gait stability in the current clinical routine would be of great benefit for health professionals, allowing them to design personalized rehabilitation programs. This is particularly true for children with DS and PWS, where motor development is dramatically constrained by severe hypotonia and muscle weakness. The aim of this study was, thus, to propose an instrumented protocol, integrated with the clinical routine and based on the use of wearable inertial sensors, to assess gait stability in DS and PWS children. Fifteen children with DS, 11 children with PWS, and 12 typically developing children (CG) were involved in the study. Participants performed a 10-meter walking test while wearing four inertial sensors located at pelvis, sternum, and both distal tibiae levels. Spatiotemporal parameters (walking speed, stride frequency, and stride length) and a set of indices related to gait symmetry and upper-body stability (Root Mean Square, Attenuation Coefficient and Improved Harmonic Ratio) were estimated from pelvis and sternum accelerations. The Gross Motor Functional Measures (GMFM-88) and Intelligence Quotient (IQ Wechsler) were also assessed for each patient. A correlation analysis among the GMFM-88 and IQ scales and the estimated parameters was then performed. Children with DS and PWS exhibit reduced gait symmetry and higher accelerations at pelvis level than CG. While these accelerations are attenuated by about 40% at sternum level in CG and DS, PWS children display significant smaller attenuations, thus reporting reduced gait stability, most likely due to their typical "Trendelenburg gait". Significant correlations were found between the estimated parameters and the GMFM-88 scale when considering the whole PWS and DS group and the PWS group alone. These results promote the adoption of wearable technology in clinical routines to monitor gait patterns in children with DS and PWS: the proposed protocol allows to markedly characterize patient-specific motor limitations even when clinical assessment scores provide similar results in terms of pathology severity. This protocol could be adopted to support health professionals in designing personalized treatments that, in turn, could help improving patients' quality of life in terms of both physical and social perspectives.

Decreased stress responsivity of central and peripheral catecholaminergic systems in aged 344/N Fischer rats.

We investigated the effects of stress on central and peripheral sympatho-adrenal and sympatho-neural functions in healthy, intact young (3-4 mo) and aged (24 mo) male Fischer 344/N rats. Extracellular fluid (ECF) levels of the catecholamines norepinephrine (NE), dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and dihydroxyphenylacetic acid (DOPAC) were obtained by microdialysis in the paraventricular nucleus (PVN) of the hypothalamus at baseline and during immobilization (IMMO). The baseline levels of these substances were similar in both age groups, and their concentrations increased significantly in response to IMMO. The IMMO-induced increases of NE and MHPG, however, were significantly smaller in old than in young rats. Plasma levels of the catecholamines NE, DHPG, MHPG, DOPAC, dihydroxyphenylalanine (DOPA), epinephrine (EPI), dopamine (DA), and HVA were also determined in young and old rats during IMMO. Basal levels of these substances were significantly higher in old than in young rats. The magnitude of the IMMO-induced increases in the majority of these compounds however, was significantly smaller in old than in young rats. We conclude that, at the basal state, aging in the Fischer rat is associated with normal PVN ECF, but high plasma catecholamine levels; at stress state, however, old rats have substantially lesser activation of their central and peripheral catecholaminergic systems than young rats.

Resveratrol Requires Red Wine Polyphenols for Optimum Antioxidant Activity.

OBJECTIVE: There is substantial evidence that a diet rich in fruit and vegetables may reduce the risk of aging and stress oxidative associated diseases. It has been suggested that benefits associated with fruit and red wine consumption could be due to pooled antioxidant microcomponents in diet. The aim of this study was to investigate the antioxidant activities of pure resveratrol (a well known phytoalexin, RSV) and red wine polyphenols (RWP), using UV-B radiated isolated rat hepatocytes as a model of oxidative stress. METHODS: Rat hepatocytes were isolated by the collagenase method. The cells were loaded with resveratrol and/or polyphenols at different concentrations. The production of thiobarbituric acid reactive substances (TBARS) released by UV-B radiated cells and the levels of lipid-soluble antioxidants (Dolichol, Vitamin E, Coenzyme Q9 and Q10) were measured. RESULTS: Resveratrol had pro-oxidant or antioxidant effects depending on (lower or higher) dosage. RWP protection from photolipoperoxidation was dose-dependent and increased with dosage. Combination of the two compounds exhibited synergistic antioxidant effect, and made resveratrol effective both at lower and higher dosages. CONCLUSIONS: These results suggest that resveratrol requires red wine polyphenols for optimum antioxidant activity.

A new method for the evaluation of the end-to-end distance of the knee ligaments and popliteal complex during passive knee flexion.

BACKGROUND: Accurate knowledge about the length variation of the knee ligaments (ACL, PCL, MCL and LCL) and the popliteal complex during knee flexion/extension is essential for modelling and clinical applications. The aim of the present study is to provide this information by using an original technique able to faithfully reproduce the continuous passive knee flexion-extension kinematics and to reliably identify each ligament/tendon attachment site. METHODS: Twelve lower limbs (femur, tibia, fibula, patella) were tested and set in motion (0-120°) using an ad hoc rig. Tibio-femoral kinematics was obtained using an optoelectronic system. A 3D digital model of each bone was obtained using low-dosage stereoradiography. Knee specimens were dissected and the insertion of each ligament and popliteal complex were marked with radio opaque paint. ACL, PCL and MCL were separated into two bundles. Bone epiphyses were CT-scanned to obtain a digital model of each ligament insertion. Bones and attachment site models were registered and the end-to-end distance variation of each ligament/tendon was computed over knee flexion. RESULTS: A tibial internal rotation of 18°±4° with respect to the femur was observed. The different bundles of the ACL, MCL and LCL shortened, whereas all bundles of the PCL lengthened. The popliteal complex was found to shorten until 30° of knee flexion and then to lengthen. CONCLUSION: The end-to-end distance variation of the knee ligaments and popliteal complex can be estimated during knee flexion using a robust and reliable method based on marking the ligaments/tendon insertions with radiopaque paint. LEVEL OF EVIDENCE: Level IV.

Effects of antilipolytic agents on rat liver peroxisomes and peroxisomal oxidative activities.

The mechanisms involved in the inhibitory effects of antilipolytic agents on rat liver peroxisomal fatty acid oxidative activity have been explored. Treatment of fasting rats with antilipolytic drugs (either 3,5-dimethylpyrazole (12 mg/kg body weight) or Acipimox (25 mg/kg body weight] resulted in a decrease in free fatty acid and glucose plasma levels within 5-10 and in a significant increase in the plasma glucagon to insulin ratio within 15. Changes in the fatty acid oxidative activity appeared with a 2.5-3 h delay and were then very rapid (a 30-40% decrease in the activity occurred in additional 2 h). Many peroxisomal enzyme activities (including non-beta-oxidative activities such as uricase and D-amino acid oxidase) exhibited similar changes with the same delay. Simultaneously with the enzyme changes, at the electron microscope level many autophagic vacuoles were detected in the liver cells, often containing peroxisomal structures. Glutamine, an inhibitor of proteolysis in vivo, prevented the decrease in enzyme activities. It was concluded that the decrease in peroxisomal enzyme activities may be the consequence of enhanced peroxisome degradation due to the stimulation of autophagic processes in liver cells.

Dietary restriction counteracts age-related changes in cholesterol metabolism in the rat.

The effects of ageing on the metabolism of cholesterol were examined in three different organs (liver, aorta and brain) of 6-, 12- and 24-month-old male Sprague-Dawley rats. Ageing was associated with a significant increase in intracellular cholesterol esters in all three organs. Steady state mRNA levels of multidrug resistance protein (MDR) and acylCoA:cholesterol acyl transferase (ACAT), enzymes involved in cholesterol import and esterification, were also increased. By contrast, expression of mRNA for neutral cholesterol ester hydrolase (nCEH) and caveolin-1, proteins involved in cholesterol ester hydrolysis and export, were significantly reduced. Dietary restriction is the only intervention shown to extend lifespan and retard age-related declines in function in mammals. To further explore the possible correlation between changes in cholesterol esterification and ageing, we analysed cholesterol metabolism in liver, aorta, and brain of aged rats exposed to two dietary restriction regimens: intermittent (alternate-day) fasting (IF) and food intake restriction (60% of ad libitum feeding). Both dietary regimens attenuated the age-related changes in cholesterol esters and in the expression of genes involved in cholesterol metabolism. These results provide evidence that distinctive age-associated changes in intracellular cholesterol metabolism occur in rats. Furthermore, these modifications can be partially reversed by dietary restriction, a condition known to affect the ageing process. Age-related changes in cholesterol metabolism may play a role in triggering and/or aggravating senescence-related disorders characterized by altered cholesterol homeostasis.

Factors associated with climacteric symptoms in women around menopause attending menopause clinics in Italy.

OBJECTIVE: To obtain data on correlates of climacteric symptoms in women around menopause attending menopause clinics in Italy. METHODS: Since 1997 a large cross sectional study has been conducted on the characteristics of women around menopause attending a network of first level menopause outpatient's clinics in Italy. A total of 66,501 (mean age 54.4 years) women are considered in the present paper. RESULTS: The odds ratios of moderate and severe hot flashes/night sweats were lower in more educated women and (for severe symptoms only) in women reporting regular physical activity. Depression, difficulty to sleep, forgetfulness and irritability tended to be less frequent in more educated women and (depression only) in women reporting regular physical activity. Parous women reported more frequently these symptoms. CONCLUSIONS: This large study confirms in Southern European population that low education, body mass index and low physical activity are associated with climacteric symptoms. Parous women are at greater risk of psychological symptoms.

The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases.

Macroautophagy is a degradation/recycling system ubiquitous in eukariotic cells, which generates nutrients during fasting under the control of amino acids and hormones, and contributes to the turnover and rejuvenation of cellular components (long-lived proteins, cytomembranes and organelles). Tight coupling between these two functions may be the weak point in cell housekeeping. Ageing denotes a post-maturational deterioration of tissues and organs with the passage of time, due to the progressive accumulation of the misfunctioning cell components because of oxidative damage and an age-dependent decline of turnover rate and housekeeping. Caloric restriction (CR) and lower insulin levels may slow down many age-dependent processes and extend lifespan. Recent evidence is reviewed showing that autophagy is involved in ageing and in the anti-ageing action of anti-ageing calorie restriction: function of autophagy declines during adulthood and is almost negligible at older age; CR prevents the age-dependent decline of autophagic proteolysis and improves the sensitivity of liver cells to stimulation of lysosomal degradation; protection of autophagic proteolysis from the age-related decline co-varies with the duration and level of anti-ageing food restriction like the effects of CR extending lifespan; the pharmacological stimulation of macroautophagy has anti-ageing effects. Besides the involvement in ageing, macroautophagy may have an essential role in the pathogenesis of many age-associated diseases. Higher protein turnover may not fully account for the anti-ageing effects of macroautophagy, and effects of macroautophagy on housekeeping of the cell organelles, antioxidant machinery of cell membranes and transmembrane cell signaling should also be considered.

Different mechanisms in testosterone action on glycogen metabolism in rat perineal and skeletal muscles.

Testosterone affects glycogen levels in perineal and skeletal muscles by two distinct mechanisms. Both of them show similar sensitivity to androgens (0.1 mg/rat/day of testosterone being effective) and to antiandrogen administration. However, they differ because of the pattern of glycogen increase (early after the androgen injection in the perineal muscles; slowly and with a linear function of time in the skeletal muscles), and because of the different sensitivities to adrenolectomy, diabetes and hypophysectomy. Also, the biochemical changes induced by testosterone in muscles differ. The rate of sugar uptake and phosphorylation is increased in the perineal muscle only; the rate of glucose incorporation into glycogen is increased in the perineal but depressed in the skeletal muscles. Therefore, in the former case glycogen accumulation depends mainly on increased synthesis; in the latter, it is probably the result of a glycogen sparing effect.

Age-dependent changes in the sensitivity of the rat to a diabetogenic agent (streptozotocin).

Changes of plasma glucose levels have been investigated in rats of 50, 70, 90, 110 and 150 g BW after the intravenous injection of 0, 40, 60, 80 or 100 mg/kg BW of streptozotocin. The effect of streptozotocin was dependent on the dose used and on the size of the animals. With all animal sizes studied, a transient acute hyperglycemic response to streptozotocin was observed at doses lower than those required to produce persistent hyperglycemia. Smaller animals required higher doses of streptozotocin in order to produce changes comparable to those observed in larger animals.

Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis with advancing age.

We investigated the effects of aging on the regulation of hypothalamic-pituitary-adrenal function and hippocampal steroid receptors in a series of in vivo and in vitro studies conducted in healthy intact 2-, 8-, 18-, and 24-month-old male Fischer 344/N rats. Basal plasma ACTH levels were similar among age groups, and basal plasma corticosterone levels showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. In contrast, the i.v. injection of a muscarinic agonist, arecoline, elicited similar ACTH and corticosterone responses in all age groups. An i.v. injection of ACTH-(1-24) evoked lower corticosterone responses in the older (18- and 24-month-old) than in the younger (2- and 8-month-old) groups of rats, consistent with an impairment of hypothalamic-pituitary-adrenal axis function in older animals. Steady state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational, rather than senescent, changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, CRF content, and in vitro secretion by whole explanted hypothalami were progressively and significantly reduced with age, whereas the steady state levels of arginine vasopressin mRNA were significantly increased with age. Steady state levels of POMC mRNA were decreased, and ACTH content and in vitro secretion by corticotrophs were increased with age in the anterior pituitary. We conclude that male Fischer 344/N rats show a progressive hypothalamic CRH deficiency with advancing age, which appears to be associated with elevated production of arginine vasopressin in the hypothalamus.

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats.

This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0.13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18- and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18- and 26-month-old rats from basal values of 4.3+/-0.8, 4.7+/-0.5 and 5.6+/-1.0 ng/ml (means+/-s.e.m.) respectively, rose to 11.9+/-1.7, 29.1+/-5.5 and 27.9+/-2.7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-month-old animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3- and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values. Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups. In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance.

Ageing and oxidative stress: a role for dolichol in the antioxidant machinery of cell membranes?

Dolichol is a polyprenol compound broadly distributed in membranes, biosynthetized by the general isoprenoid pathway from acetate via mevalonate and farnesyl pyrophosphate. Dolichol lays inside the membrane between the two leaflets of the lipid bilayer very close to the tail of phospholipid fatty acids. No definite catabolic pathways for this molecule have yet been identified. Evidence is produced that dolichol levels increase dramatically with increasing age; that anti-ageing caloric restriction retards this age-associated change; that dolichol may act as a radical scavenger of peroxidized lipids belonging to the cell membranes. In view of the polyunsaturated fatty acids (PUFA), dolichol and Vitamin E location and stechiometry, it is proposed that molecules might interact each-other to form a highly matched free-radical-transfer chain, whose malfunctioning might be involved in statin toxicity and neurodegenerative diseases.

Changes in 5'-nucleotidase and adenosine deaminase distribution across the rat left ventricle wall during growth and aging.

The concentrations of the adenosine-generating enzyme 5'-nucleotidase (5'-N) and of the adenosine-degrading enzyme adenosine deaminase (ADA) in the rat left ventricle change as a function of the age of the animal. The enzyme distribution across the left ventricle wall is non-uniform in adult or old rats (in the case of 5'-N) or in all age-groups (in the case of ADA). In the oldest rats, 5'-N activity exhibited a significant increase in the mid-myocardium and in the inner myocardial layers as compared with the young adult controls.

The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction.

Restricting caloric intake (CR) well below that of ad libitum (AL) fed animals retards and/or delays many characteristics of ageing and the occurrence and progression of age-associated diseases, efficacy depending on duration. The hypothesis that the anti-ageing effect of CR might involve stimulation of the cell-repair mechanism autophagy was tested. The effects of ageing and duration of anti-ageing CR on liver autophagic proteolysis (AP) were explored in male AL Sprague-Dawley rats aged 2-, 6-, 12- and 24-months; and 24-month-old rats on a CR diet initiated at 2-, 6- and 12-month of age or initiated at age 2-months and interrupted at age 18 months. The age-related changes in the regulation of AP were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells by an HPLC procedure. Results show that the maximum attainable rate and the regulation of AP decline with increasing age; that changes are prevented by anti-ageing CR initiated at young age, that the protective effects of CR change with the duration of diet. It is concluded that the data are compatible with the hypothesis that AP and improved membrane maintenance might be involved in the antiageing mechanism of CR.

Age-related changes in the urinary excretion of aldehydes in ad libitum fed and food-restricted rats.

Age-related changes in the urinary excretion of aldehydes arising from lipid peroxidation have been investigated in male Sprague-Dawley rats aged 2, 4, 6, 12, 18, 24 and 27 months, fed ad libitum or subjected to two different regimens of calorie restriction (namely every-other-day ad libitum feeding--EOD--and 40% calorie restriction--40%DR). For only some age groups, results were compared with those obtained in ad libitum fed male Fisher 344 and Lewis rats. Results show that the urinary excretion of malondialdehyde (MDA) and formaldehyde (FA) significantly decreases, whereas that of propionaldehyde (PROP) progressively increases with age, and that urinary excretion of acetaldehyde (ACT) does not show any significant age-related variations. Dietary restriction significantly increases the urinary levels of MDA, FA and PROP without affecting their age-related modifications, and does not affect ACT urinary excretion. In conclusion, results indicate that the quantitative pattern of aldehyde production and urinary excretion may be altered by the process of aging.

Age-dependent reduction in GLUT-2 levels is correlated with the impairment of the insulin secretory response in isolated islets of Sprague-Dawley rats.

In this study we have investigated the insulin secretory response to glucose and other secretagogues (2-ketoisocaproate, 3-isobutyl-1-methyl-xanthine and arginine) of pancreatic islets isolated from Sprague-Dawley rats of various ages (from 2 to 28 months). Our results showed a significant decline in the glucose-stimulated insulin secretion, starting at 12 months of age. On the other hand, the response to non-glucose secretagogues (and mainly to 2-ketoisocaproate) was less impaired with advancing age than that to glucose. We also observed a progressive age-related decline of protein levels of the glucose transporter GLUT-2 in pancreatic islets, which was temporally concomitant and quantitatively comparable with the beta-cell alteration in glucose responsiveness (-40/50%). Finally, we observed a significant increase of the islets insulin content in older rats with respect to younger animals. We conclude that in the islet of older rats the impaired capability to respond to glucose could be dependent, at least in part, on the age-dependent reduction in GLUT-2 and could be compensated by mechanisms including a preserved responsiveness to non-glucose secretagogues and/or the development of islet hypertrophy.