Glucose-dependent changes in SNARE protein levels in pancreatic β-cells

Prolonged exposure to high glucose concentration alters the expression of a set of proteins in pancreatic β-cells and impairs their capacity to secrete insulin. The cellular and molecular mechanisms that lie behind this effect are poorly understood. In this study, three either in vitro or in vivo models (cultured rat pancreatic islets incubated in high glucose media, partially pancreatectomized rats, and islets transplanted to streptozotozin-induced diabetic mice) were used to evaluate the dependence of the biological model and the treatment, together with the cell location (insulin granule or plasma membrane) of the affected proteins and the possible effect of sustained insulin secretion, on the glucose-induced changes in protein expression. In all three models, islets exposed to high glucose concentrations showed a reduced expression of secretory granule-associated vesicle-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins synaptobrevin/vesicle-associated membrane protein 2 and cellubrevin but minor or no significant changes in the expression of the membrane-associated target-SNARE proteins syntaxin1 and synaptosomal-associated protein-25 and a marked increase in the expression of synaptosomal-associated protein-23 protein. The inhibition of insulin secretion by the L-type voltage-dependent calcium channel nifedipine or the potassium channel activator diazoxide prevented the glucose-induced reduction in islet insulin content but not in vesicle-SNARE proteins, indicating that the granule depletion due to sustained exocytosis was not involved in the changes of protein expression induced by high glucose concentration. Altogether, the results suggest that high glucose has a direct toxic effect on the secretory pathway by decreasing the expression of insulin granule SNARE-associated proteins.     

Do 6-y changes in eating behaviors predict changes in body weight? Results from the Québec Family Study

OBJECTIVE: This study was performed to examine changes in eating behaviors as assessed by the three-factor eating questionnaire (TFEQ) and to quantify the potential associations between these eating behaviors and body weight changes in a 6-follow-up study. DESIGN AND SUBJECTS: Prospective study performed in men and women who were tested twice (Visit 1=1989-1995 and Visit 2=6 y later) in the Québec Family Study (QFS). RESULTS: Women were more restrained and less hungry than men. To reduce food intake, women relied more on strategic dieting behavior and avoided more fattening food. However, they had higher emotional and situational susceptibility to eat than men. Significant decreases in the disinhibition score were noted over time in women (P<0.01), which resulted from a decrease in habitual susceptibility behavior to increase food intake. In men, we observed an increase in the avoidance of fattening food (P<0.05). In both genders, we found that the 6-y change in restraint behavior was negatively correlated with body weight changes (P<0.05). In women, a high restraint behavior seems to promote weight gain, whereas in men, it is associated with the opposite trend. CONCLUSION: These results suggest that variables reflecting some eating behaviors are associated with body weight changes in a free-living context. However, these behaviors are expressed differently between men and women. These behaviors should be considered in clinical interventions for individuals seeking a better body weight control.     

Are changes in productive activities of older people associated with changes in their well-being? Results of a longitudinal European study

Using the first two waves from the Survey of Health, Ageing and Retirement in Europe (SHARE) we explore dynamics of participation in two different types of productive activities (voluntary work and care for a person) and test their association with changes in well-being across 11 European countries (N = 10,309) among people aged 50 and older. In order to measure changes in well-being, we use a standardized instrument of quality of life in early old age (CASP-12) and assess relevant decreases and increases between both waves, applying the Edwards–Nunnally method. Main findings demonstrate that older people who maintain or start their productive activity in terms of volunteering between both waves have a lower probability of experiencing a relevant decrease in well-being, while no association with a relevant increase in well-being is observed. In case of caring for a person changes in participation remain unrelated to changes in well-being. These results are maintained after adjusting for important confounders, such as functional limitation, socioeconomic position and living with a partner. These latter conditions were also strongly related to changes in well-being. Our results support a core assumption of the activity theory of ageing claiming that the initiation and maintenance of a productive activity is beneficial for older people’s well-being.     

Cardiac and vascular changes in cirrhosis： Pathogenic mechanisms

Cardiovascular abnormalities accompany both portal hy-pertension and cirrhosis.These consist of hyperdynamiccirculation,defined as reduced mean arterial pressureand systemic vascular resistance,and increased cardiacoutput.Despite the baseline increased cardiac output,ventricular inotropic and chronotropic responses tostimuli are blunted,a condition known as cirrhotic car-diomyopathy.Both conditions may play an initiating oraggravating pathogenic role in many of the complicationsof liver failure or portal hypertension including ascites,variceal bleeding,hepatorenal syndrome and increasedpostoperative mortality after major surgery or livertransplantation.This review briefly examines the majormechanisms that may underlie these cardiovascular ab-normalities,concentrating on nitric oxide,endogenouscannabinoids,central neural activation and adrenergicreceptor changes.Future work should address the com-plex interrelationships between these systems.     

Metabolic syndrome induces changes in KATP-channels and calcium currents in pancreatic β-cells

Metabolic syndrome (MS) can be defined as a group of signs that increases the risk of developing type 2 diabetes mellitus (DM2). These signs include obesity, hyperinsulinemia and insulin resistance. We are interested in the mechanisms that trigger hyperinsulinemia as a step to understand how β cells fail in DM2. Pancreatic β cells secrete insulin in response to glucose variations in the extracellular medium. When they are chronically over-stimulated, hyperinsulinemia is observed; but then, with time, they become incapable of maintaining normal glucose levels, giving rise to DM2. A chronic high sucrose diet for two months induces MS in adult male Wistar rats. In the present article, we analyzed the effect of the internal environment of rats with MS, on the activity of ATP-sensitive potassium channels (K_ATP) and calcium currents of pancreatic β cells. After 24 weeks of treatment with 20% sucrose in their drinking water, rats showed central obesity, hyperinsulinemia and insulin resistance, and their systolic blood pressure and triglycerides plasma levels increased. These signs indicate the onset of MS. K_ATP channels in isolated patches of β cells from MS rats, had an increased sensitivity to ATP with respect to controls. Moreover, the macroscopic calcium currents, show increased variability compared with cells from control individuals. These results demonstrate that regardless of genetic background, a high sucrose diet leads to the development of MS. The observed changes in ionic channels can partially explain the increase in insulin secretion in MS rats. However, some β cells showed smaller calcium currents. These cells may represent a β cell subpopulation as it becomes exhausted by the long-term high sucrose diet.     

Metabolic syndrome induces changes in KATP-channels and calcium currents in pancreatic β-cells

Metabolic syndrome (MS) can be defined as a group of signs that increases the risk of developing type 2 diabetes mellitus (DM2). These signs include obesity, hyperinsulinemia and insulin resistance. We are interested in the mechanisms that trigger hyperinsulinemia as a step to understand how β cells fail in DM2. Pancreatic β cells secrete insulin in response to glucose variations in the extracellular medium. When they are chronically over-stimulated, hyperinsulinemia is observed; but then, with time, they become incapable of maintaining normal glucose levels, giving rise to DM2. A chronic high sucrose diet for two months induces MS in adult male Wistar rats. In the present article, we analyzed the effect of the internal environment of rats with MS, on the activity of ATP-sensitive potassium channels (K_ATP) and calcium currents of pancreatic β cells. After 24 weeks of treatment with 20% sucrose in their drinking water, rats showed central obesity, hyperinsulinemia and insulin resistance, and their systolic blood pressure and triglycerides plasma levels increased. These signs indicate the onset of MS. K_ATP channels in isolated patches of β cells from MS rats, had an increased sensitivity to ATP with respect to controls. Moreover, the macroscopic calcium currents, show increased variability compared with cells from control individuals. These results demonstrate that regardless of genetic background, a high sucrose diet leads to the development of MS. The observed changes in ionic channels can partially explain the increase in insulin secretion in MS rats. However, some β cells showed smaller calcium currents. These cells may represent a β cell subpopulation as it becomes exhausted by the long-term high sucrose diet.     

Morphologic and biomechanical changes of rat oesophagus in experimental diabetes

AIM:To study morphologic and biomechanical changes ofoesophagus in diabetes rats.METHODS:Diabetes was induced by a single injection ofstreptozotocin(STZ).The type of diabetes mellitusinduced by parenteral STZ administration in rats wasinsulin-dependent(type I).The samples were excisedand studied in vitro using a self-developed biomaterialtest machine.RESULTS:The body mass was decreased after 4 d with STZtreatment.The length of esophagus shortened after 4,7,14 d.The opening angle increased after 14 d.The shear,longitudinal and circumferential stiffness were obviouslyraised after 28 d of STZ treatment.CONCLUSION:The changes of passive biomechanicalproperties reflect intra-structural alteration of tissue to acertain extent.This alteration will lead to some dysfunctionof movement.For example,tension of esophageal wallwill change due to some obstructive disease.     

Hormonal changes in aging men: a therapeutic indication?

The rise in male life expectancy is paralleled by increased age-related clinical signs and symptoms such as muscle weakness, osteoporosis, benign prostatic hyperplasia, changes in body composition, fatigue, decreased sexual interest and activity, and increased prevalence of erectile dysfunction, all of which limit the quality of life. Many of these symptoms are similar to those of clinically well-defined hormone deficiencies, e.g. Kallman syndrome, Prader--Labhart--Willi syndrome or deficiencies due to treatment of pituitary tumors. Three male endocrine axes are characterized by age-related changes in concentrations of circulating hormones: (i) the hypothalamic--pituitary--testicular axis with lower serum levels of testosterone (T) and higher serum levels of luteinizing and follicle-stimulating hormone, (ii) the hypothalamic--pituitary--adrenal axis with its gradual decline in dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), (iii) the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis showing decreased hormone production concomitant with symptoms similar to those of GH-deficient adults. The beneficial effects of hormone replacement in nonelderly hormone-deficient individuals and in postmenopausal women raised hope that hormone substitution might prevent or even reverse some of the symptoms of male aging. However, this approach is hampered by the lack of individual age-related hormone reference values and reliable clinical read-out parameters. The findings so far do not support the need for widespread hormone replacement in elderly men. Larger long-term prospective studies are needed to identify clinically useful read-out parameters, and then demonstrate that hormone replacement can translate into functional parameters, thereby providing the individual benefit of treatment for aging men.     

Skin changes in advanced age--biochemical findings corresponding to morphology?

The clinically relevant morphological changes of the skin during aging can be summarized by the term "senile atrophy". The changes are a diminished thickness of epidermis with a reduced mitosis rate of epidermal basal cells, shortened and attenuated rete ridges, reduction of epidermal appendages, and a decreased number of fibroblasts and capillaries in the dermis. Corresponding to these morphological findings regarding the cell number in the senile skin (cutis) we found a slight decrease in the DNA concentration of human and rat cutis. The specific DNA activity (3H-thymidine incorporation rate related to DNA concentration) decreased in presenile versus adult animals. The mesenchymal changes in the dermis have been morphologically described by the term "senile elastosis" or "elastoid collagen degeneration", but in fact they correspond to a progressive collagen denaturation with aging. The total collagen concentration, here determined as the hydroxyproline concentration in the human cutis, shows almost constant values from the 3rd until the 9th decade of life in both sexes. This is also true for the skin of two different rat strains. The insoluble collagen fraction shows a relative increase to the disadvantage of the soluble collagen fractions, which can be interpreted as an indicator of a decelerated collagen turnover. In spite of the decelerated turnover, i.e. a prolonged half-life of the collagen metabolism in the skin, the indicators of the collagen neosynthesis (14C-proline incorporation rate, specific hydroxyproline activity, prolyl-hydroxylase activity) are significantly elevated in the cutis of presenile versus adult rats. Any connection of these findings with a possible change in the distribution of collagen types in the senile skin (e.g. pericapillar fibrosis with increase of collagen type I as well as changes in the distribution of type I, III, IV and V) can only be discussed at present. The glycosaminoglycans in the cutis show a minimal increase of the total content of hexosamines and uronic acids with a significant shift in the ratio of the glycosaminoglycan components in favour of dermatan sulfate and keratan sulfate and to the disadvantage of hyaluronic acid and partly also of chondroitin-4-sulfate and -6-sulfate. The neosynthesis of sulfated glycosaminoglycans (indicator method: 35S-sulfate incorporation rate) is only slightly increased whereas the enzyme activities being specific for the glycosaminoglycan catabolism (beta-glucuronidase, beta-N-acetyl-glucosaminidase) are significantly decreased with aging of the skin.(ABSTRACT TRUNCATED AT 400 WORDS)     

The day-night changes in ambulatory blood pressure: another risk indicator in hypertension?]

In many different clinical situations, including some cases of secondary hypertension, nighttime blood pressure (BP) is abnormally increased in the majority of patients, with consequent flattening of the 24-hour BP profile, but the clinical importance of this finding in such conditions is unknown. In patients with essential hypertension, ambulatory BP has been shown to decrease by 10-20% from day to night, but in severe or malignant hypertension this diurnal BP rhythm may be blunted or even abolished. One of the reasons why the noninvasive monitoring of BP may be a reliable tool in assessing the day-night BP changes is the demonstration that frequent cuff inflations do not interfere to a significant extent with the haemodynamic effects of sleep. Part of the differences between the studies in the reported day-night BP drop may be artifactual, owing to the very different time intervals defining the daytime and nighttime subperiods in the single studies. In unselected patients with essential hypertension, a sizable proportion of subjects (17 to 40%) shows abnormally high nighttime BP, with consequent flattening of the 24-hour BP profile (the so called "non dippers", as opposed to the "dippers" who show a maintained diurnal BP rhythm). Several clinical studies carried out in independent laboratories show that the target organ damage induced by hypertension (left ventricular hypertrophy, cerebrovascular lesions) is more severe in hypertensive "non dippers" than in "dippers", possibly because of the different duration of exposure to high BP levels over the 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is there a need for changes in renal biopsy criteria in proteinuria in type 2 diabetes?

Criteria for renal biopsy in proteinuric type 2 diabetes mellitus (T2DM) patients have been not defined. Usually criteria for renal biopsy in type 1 diabetes mellitus (T1DM) are used (microhaematuria, absence of diabetic retinopathy (DR), uncharacteristic change in renal function or immunological abnormalities). The aim of this study was to reconsider the indications for renal biopsy in T2DM using T1DM criteria, to determine whether they are useful in identifying patients with potentially treatable lesions. We studied 127 proteinuric patients with T2DM. Renal biopsy was performed in 35 who met the criteria for biopsy. Biopsy revealed diabetic glomerulopathy (DG) in 29 (83%) (in three associated with nondiabetic renal disease), immunoglobulin A (IgA) glomerulonephritis in three, focal glomerulosclerosis in one and normal glomeruli in two. DG was diagnosed in 17 (74%) of the patients without DR, in 18 (78%) of the patients with microhaematuria and in 10 (67%) of the patients with microhaematuria and without DR. All patients with DR had DG alone, except three with sudden unexpected changes in renal function. We conclude that DG is the most commonly found renal lesion in T2DM patients with proteinuria biopsied according to T1DM criteria, even in patients with microhaematuria or without retinopathy. Thus, these biopsy criteria are not useful in identifying patients with potentially treatable other renal diseases.     

Are there changes in gastric emptying during the menstrual cycle?

BACKGROUND: The questions of whether gastric emptying of solids and liquids differs in men and women and whether emptying is influenced by the action of sex hormones on gastric smooth muscle remain unresolved. METHODS: We analysed the gastric emptying of digestible solids (GES), liquids (GEL), and radiopaque indigestible solids (GER) in three groups of healthy volunteers: 50 women in the follicular phase of the menstrual cycle, 50 women in the luteal phase, and 100 men. [99mTc]-labelled diethylenetriamine pentaacetic acid (DTPA) was used as the radioactive marker for digestible solids, and [111In]DTPA was used as the marker for liquids, to time gastric motility after a solid and a liquid meal. GER was evaluated on a different day in abdominal roentgenograms. RESULTS: GES and GEL were slower in women than in men (P < 0.05), but GER was similar in the two sexes. However, there were no significant differences in GES, GEL, or GER between women in the follicular and those in the luteal phase, between plasma concentrations of oestradiol and progesterone and the variables used to characterize gastric emptying. CONCLUSIONS: Evidence of postprandial 'physiologic gastroparesis' was found in women, although no differences were found between men and women in gastric motility during fasting. The rate of emptying was not related to changes in plasma concentrations of sex hormones during the menstrual cycle.