Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations.

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro).

BACKGROUND AND PURPOSE: We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats. EXPERIMENTAL APPROACH: G-K rats aged 1.5-10 months and non-diabetic overweight or obese S-D rats aged 6-18 months were treated with 0-6 mg CHP plus 0-10 mg zinc L(-1) drinking water for 2-4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured. KEY RESULTS: The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg kg(-1) day(-1), in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats. CONCLUSIONS AND IMPLICATIONS: ZC treatment improved weight control and may be a possible treatment for overweight and obesity.

Caffeine restores regional brain activation in acute hypoglycaemia in healthy volunteers.

AIMS: Caffeine enhances counterregulatory responses to acute hypoglycaemia. Our aim was to explore its effects on cortical function, which are not known at present. METHODS: Regional brain activation during performance of the four-choice reaction time (4CRT) at different levels of complexity was measured using functional magnetic resonance imaging (fMRI) at euglycaemia (5 mmol/l) and hypoglycaemia (2.6 mmol/l) in the presence and absence of caffeine in six healthy right-handed men. RESULTS: During hypoglycaemia, caffeine enhanced adrenaline responses to hypoglycaemia (2.5 +/- 0.7 nmol/l to 4.0 +/- 1.0 nmol/l, P = 0.01) and restored the brain activation response to the non-cued 4CRT, the linear increases in regional brain activation associated with increased task complexity and the ability to respond to a cue that were lost in hypoglycaemia alone. CONCLUSIONS: Caffeine can sustain regional brain activation patterns lost in acute hypoglycaemia, with some restoration of cortical function and enhanced adrenaline responsiveness. A methodology has been established that may help in the development of therapies to protect against severe hypoglycaemia in insulin therapy for patients with diabetes and problematic hypoglycaemia.

Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid.

Previous studies have already shown that prostate extract (PE) has antidiabetic activity when given to animals and humans. In this study, we explore whether this antidiabetic activity is related to the high concentrations of zinc, cyclo (his-pro) (CHP), and the prostaglandin precursor, arachidonic acid (AA), in prostate tissue. When streptozotocin-induced diabetic rats were given drinking water containing 10 mg/L zinc and 100 mg/L PE for 3 weeks, fasting blood glucose levels and glucose clearance rates, but not plasma insulin levels, were significantly lower than at pretreatment. In subsequent experiments, blood glucose levels in rats given PE for 3 weeks were significantly lower than in rats given distilled water or 10 mg/L zinc alone. However, in rats given 100 mg/L CHP with zinc, blood glucose levels were also lower than in rats given PE alone. Time-course studies in diabetic rats given drinking water containing 20 mg/L Zn, 20 mg/L L-histidine, and 10 mg/L CHP showed that blood glucose levels dropped 209 +/- 53 mg/dL in 1 day and stayed low for 2 weeks. When CHP was replaced with 100 mg AA/L, blood glucose levels dropped 230 +/- 64 mg/dL in 5 days, but returned to the original values 11 days later. Growth rate improved and water consumption decreased significantly in CHP- and AA-treated diabetic rats. High intake of L-histidine and testosterone increased blood glucose concentrations in diabetic rats. To determine optimal dosages of CHP and AA, we gave rats drinking water containing 10 mg/L Zn and 0.5 mg/L L-histidine with various concentrations of CHP or AA. The most effective doses for reducing blood glucose levels were 0.32 mg CHP/kg/day and 11 mg AA/kg/day. These data suggest that the active antidiabetic ingredients in the PE are CHP, zinc, and AA or its precursors.

Effects of arachidonic acid and cyclo (his-pro) on zinc transport across small intestine and muscle tissues.

Previously we have shown that arachidonic acid (AA) plus zinc or cyclo (his-pro) (CHP) plus zinc improve clinical signs of diabetes in streptozotocin-induced diabetic rats. Since streptozotocin destroys pancreatic beta-cells, we hypothesize that the effect of either AA or CHP, plus zinc on glucose metabolism is via mobilization of intracellular zinc which in turn stimulates glucose uptake by peripheral tissues. We now report the relationship between zinc and AA and between zinc and CHP in controlling zinc influx and efflux across hindlimb muscle cells isolated from three-month old rats. Although CHP increased muscle zinc influx in a dose-dependent manner, AA was not effective. However, AA was more effective in stimulating zinc efflux than CHP. We have previously demonstrated that AA stimulates intestinal zinc uptake and absorption, and now present evidence that CHP also influences intestinal zinc transport. These results suggest that both AA and CHP affect glucose uptake in muscle cells via stimulating intestinal zinc absorption and muscle cell zinc flux.

Hospitalization and mortality of diabetes in older adults. A 3-year prospective study.

OBJECTIVE: In light of increased fatality from acute events and the increased frequency of chronic complications, life expectancy might well be shortened in older patients with diabetes. The current studies investigated factors affecting the likelihood of dying or being hospitalized in older patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 135 older patients with diabetes were followed for 3 years after predictive factors were evaluated and compared with a cohort of patients without diabetes. RESULTS: Mortality was only 3,250 per 100,000 patient-years, similar to that for patients without diabetes, but the frequency of hospitalizations was more than twice as high in patients with diabetes. Five factors predicted hospitalization and death. Of these, the geriatric depression score was the best predictor of these poor outcomes. CONCLUSIONS: Older patients with diabetes were hospitalized more often than those without diabetes, but mortality was similar. Dysphoria is a major predictor of poor outcomes in older patients with diabetes.

Effects of bovine prostate powder on zinc, glucose, and insulin metabolism in old patients with non-insulin-dependent diabetes mellitus.

Since rabbit prostate extract strongly stimulated intestinal zinc absorption and improved the diabetic condition of streptozotocin-induced diabetic rats, we examined the effects of 200 mg bovine prostate powder supplemented with 20 mg zinc (Pro-Z) on the clinical manifestations of older male patients with type II diabetes. Twenty-two male patients who received Pro-Z capsules two to four times per day for 3 months showed reduced mean fasting blood glucose levels from 202 to 169 mg/dL, hemoglobin A1C-(HbA1C) concentrations from 12.2% to 9.5%, and mean values for the 3-hour area response above the fasting glucose concentration (TAFGC) from 141 to 102 mg glucose/dL/h. In eighteen patients who received placebo, mean values for fasting blood glucose decreased from 167 to 165 mg/dL and HbA1C from 10.4% to 10.2%, and for TAFGC increased from 121 to 126 mg glucose/dL/h. No detrimental changes occurred in the liver and kidney function of patients receiving either Pro-Z or placebo. However, blood cholesterol and low-density lipoprotein in patients receiving Pro-Z decreased slightly, whereas values in the placebo group tended to increase. The mean fasting plasma insulin decreased 15.5 to 13.8 microU/mL in subjects given Pro-Z, while the zinc concentration increased from 1.21 to 1.39 microg/mL. In contrast, the mean value for plasma insulin in the placebo group changed from 14.4 to 15.4 microU/mL (worsened), and for zinc, from 1.24 to 1.30 microg/ml. Interestingly, fasting urinary glucose concentrations in subjects given Pro-Z decreased from 1,249 to 378 mg/dL, whereas in those given placebo the values changed from 877 to 778 mg/dL. Since plasma zinc concentrations in both the placebo and the Pro-Z group were normal, these results suggest that biochemical constituents in the prostate including zinc may be involved in controlling glucose metabolism in patients with non-insulin-dependent diabetes mellitus.

Effects of relaxation training on glucose tolerance and diabetic control in type II diabetes.

The present study examined the effects of progressive relaxation training and EMG biofeedback on acute glucose disposal in diabetic subjects, as measured by glucose tolerance and three other measures of diabetic metabolic control. Twenty subjects with non-insulin-using Type II diabetes took part in progressive relaxation training and EMG biofeedback in a pre-post treatment versus wait-list experimental design. Treatment effects were assessed on glucose tolerance along with three measures of diabetic control: fasting blood glucose, two-hour postprandial blood glucose, and fructosamine. Stress reduction and relaxation was assessed with two physiological measures and two subjective questionnaires. The training program produced significant reductions in stress, as measured by State Anxiety, and significant changes in physiological measures of muscle activity and skin conductance compared to the control condition. However, no changes were found in glucose tolerance (while practicing relaxation) nor in any of the three measures of general diabetic metabolic control. The major implication of this study is that relaxation training does not appear to directly improve diabetic control in mildly stressed non-insulin-using Type II diabetic patients.

A wheelchair cushion designed to redistribute sites of sitting pressure.

OBJECTIVES: Despite the diversity of wheelchair cushions currently in clinical use, pressure on bony prominences continues to be a major problem for wheelchair-bound patients, and the incidence of pressure ulcers remains high. No static surface has been reported to reduce resting pressure under the ischial tuberosities to below that of capillary pressure, which may well be the threshold for inducing tissue damage. An entirely new form of seating was designed to decrease absolute pressure using a prosthetic fitting technique analogous to a below-the-knee prosthesis. DESIGN: A repeated measures randomized design was used to test differences between the experimental (TCS) and three other standard cushions. SETTING: A Veterans Medical Center outpatient service. PATIENTS: Wheelchair-bound volunteer subjects, n = 47, were selected who weighed more than 60kg. MAIN OUTCOME MEASURES: Pressures were measured by a standard air pressure pad and also by a computer-linked array of pressure transducers. The grid was standardized and used to generate topographic maps for each site over time. These data were used to measure the seating interface pressures. RESULTS: There was a significant main effect of cushion over site, F = 131 for left ischial tuberosity. Pressure were lowest while patients sat on the experimental seat and differences were significant at all time points. Using 1psi as presumed capillary pressure, frequency of success at achieving this pressure threshold was greatest for the experimental seat, p < .001. This difference persisted throughout the 30 minutes of testing. CONCLUSIONS: A computerized pressure grid was developed that allowed evaluation of anatomically localized pressures. The prosthetically designed TCS displays lower seating pressures than any other cushion tested. Consistent and sustained pressures were below the postulated threshold for tissue damage.

Alterations of adenylyl cyclase-linked G proteins in rat liver during aging.

beta-Adrenergic stimulation of adenylyl cyclase in rat liver increases during aging. We examined whether this increase is related to alterations in the stimulatory and inhibitory G proteins (Gs and Gi) linked to adenylyl cyclase. Levels of immunoreactive alpha- and beta-subunits of Ga and Gi in liver plasma membranes from 6-, 12-, 18-, and 24-mo-old rats were unchanged with age, as was pertussis toxin-catalyzed [32P]ADP ribosylation of Gi alpha. Cholera toxin-catalyzed [32P]ADP ribosylation of Ga alpha and Gs bioactivity, assessed as reconstitution of adenylyl cyclase activity in S49 cyc- cell membranes, increased two- to threefold between 6 and 12-18 mo, and declined by 24 mo. Recombinant ADP ribosylation factor (ARF) enhanced cholera toxin labeling of Gs alpha at all ages, yet abolished the increase in toxin labeling at 12-18 mo. Auto-ADP ribosylation of the cholera toxin A1 peptide also increased transiently with age. Alteration of Gs alpha, as reflected by increased cholera toxin labeling and Gs bioactivity, may be involved in the regulation of beta-adrenergic-responsive adenylyl cyclase in rat liver during aging. Moreover, changes in endogenous ARF levels could contribute to age differences in cholera toxin labeling of Gs alpha.

Serum glucose, glucose tolerance, corticosterone and free fatty acids during aging in energy restricted mice.

Energy restriction, the only method known to increase maximum life span in laboratory animals, was used as a tool to test hypotheses regarding possible mechanisms of aging. Serum glucose and corticosterone (CS) concentrations in mice of a long-lived hybrid mouse strain, aged 7, 17, and 29 months, and on 50%, 80%, and 100% of ad libitum intake, were measured. Serum glucose and CS concentrations were also measured in response to intraperitoneal (i.p.) glucose challenge in mice at ages 7 and 29 months. Serum glucose and CS concentrations were also measured at several time points over 36 h, to assess their diurnal variation. There were no differences in single fasting glucose concentrations in 7- and 29-month-old mice at the same degree of energy restriction, but energy restriction decreased glucose concentrations. Serum CS concentrations were generally increased restricted animals with respect to fully fed ones. Average serum glucose concentrations were found to be significantly decreased by dietary restriction. Glucose tolerance curves were unchanged by age in ad libitum fed or 50% restricted animals, but in 80% ad libitum groups, older animals showed evidence of decreased glucose tolerance with respect to young animals. For each age, peak serum glucose concentrations after i.p. glucose loading varied with degree of energy restriction, with more severely restricted animals showing less glucose tolerance. Average serum CS concentrations were elevated at 7 months by restriction, especially at night and long after feeding, but we found no differences with age or diet in average CS concentrations. Our serum glucose results support the hypothesis that nonenzymatic glycation is mechanistically involved in normal aging. Our serum CS results do not support the hypothesis that CS contributes significantly to the pathophysiology of normal aging in mice.

Acute autonomic responses to postural change, Valsalva maneuver, and paced breathing in older type II diabetic men.

PURPOSE: To examine the effects of advanced age and diabetes on the response to standard tests of cardiovascular reflexes. DESIGN: Group comparison. SETTING: Psychophysiology laboratory, Department of Veterans Affairs Medical Center. PATIENTS: Sixteen elderly male (67-81 years old) non-insulin dependent diabetic subjects without hypertension and nine elderly male (63-77 years old) controls. MAIN OUTCOME MEASURES: Continuous (beat-by-beat) measures of heart rate, systolic blood pressure, diastolic blood pressure, and skin conductance were studied during tests of Valsalva maneuver, deep breathing, and postural change from sitting to standing. RESULTS: In comparison with elderly controls, the diabetic patients showed altered cardiovascular responses in measures of heart rate variability during Valsalva and standing. None of the subjects evidenced frank postural hypotension, but there was a greater fall in diastolic blood pressure immediately after standing for the diabetic patients compared with the controls. There was also a significant relationship between this response and decreased heart rate variability during Valsalva. CONCLUSIONS: Older type II diabetic patients compared with healthy controls had mild cardiovascular abnormalities. These results parallel those of studies comparing younger diabetics and controls.

Role of hypothalamic paraventricular nucleus alpha- and beta-adrenergic receptors in regulation of blood glucose, free fatty acids and corticosterone.

The potential roles of adrenergic and noradrenergic terminals in the hypothalamic paraventricular nucleus in the regulation of blood glucose and free fatty acids, the two major metabolic fuels, were examined. Corticosterone was also measured, both to assess the specificity of any effects for metabolic fuels, and because endogenous catecholamines in this site have previously been implicated in corticosterone regulation. In the first experiment adult male albino rats having chronically implanted guide cannulae aimed at the hypothalamic paraventricular nucleus or the caudate nucleus received microinjections of the agonists methoxamine (alpha 1), clonidine (alpha 2), and isoproterenol (beta) (0, 10, 30, 100 nmol/500 nl), and blood samples were taken from the tail tip. In the second experiment a different set of rats received 30 nmol clonidine or vehicle subcutaneously instead of brain microinjections. Intracranial clonidine and isoproterenol produced marked and moderate hyperglycemia, respectively; methoxamine did not alter glucose. For neither clonidine nor isoproterenol was there any difference in hyperglycemia as a function of microinjection site; also, subcutaneous clonidine injections produced the same peak glucose response as was found after both paraventricular and caudate nucleus microinjections of the same dose. Free fatty acid levels were increased by clonidine and isoproterenol, but slightly suppressed by methoxamine; the alpha agonist effects, but not the beta agonist effect, were greater after paraventricular microinjections than after caudate microinjections. Corticosterone was increased by both alpha agonists after paraventricular but not after caudate nucleus microinjections; beta agonist microinjections into the paraventricular and caudate nuclei produced equivalent corticosterone elevations. These results suggest that most, if not all, of the hyperglycemic effects of alpha and beta adrenergic agonist microinjection into the paraventricular nucleus can be ascribed to leakage of the material into the vasculature, with subsequent action at a distant site. In contrast, all 3 agonists seem capable of acting within the brain to alter free fatty acid levels. The effects on corticosterone of both the alpha 1 and alpha 2 agonists, but not the beta agonist, also appear due, at least in part, to actions within the brain. Previous suggestions that catecholamine terminals in the hypothalamic paraventricular nucleus are directly and strongly involved in metabolic fuel regulation may require reconsideration.

Bombesin-induced hypothermia and hypophagia are associated with plasma metabolic fuel alterations in the rat.

Microinfusion of bombesin into the preoptic area (POA) has previously been shown to reduce core body temperature and feeding in rats that are food-deprived or made hypoglycemic with insulin. The present study determined the metabolic fuel state of rats under these experimental conditions. In addition, changes in plasma metabolic fuels following the microinfusion of bombesin (50 ng/0.25 microliters) into the POA were evaluated. Rats (n = 8) were tested under conditions of food satiation, food deprivation (20 h), and insulin pretreatment (10 U/kg). Prior to peptide infusion, food-deprived rats exhibited the expected elevation in free fatty acids coupled with a small decline in plasma glucose. Insulin treatment resulted in hypoglycemia which persisted for at least 120 min. Following bombesin infusion, free fatty acids and corticosterone levels were elevated in food-sated rats. Food-deprived rats exhibited elevation in plasma glucose, free fatty acids, and corticosterone following peptide infusion. In insulin-treated rats, bombesin attenuated the hypoglycemia observed in controls and increased corticosterone levels. These findings suggest that bombesin-like peptides localized within the POA may participate in the regulation of metabolic fuels.

mu-receptor mediates elevated glucose and corticosterone after third ventricle injection of opioid peptides.

Four experiments were done to determine which receptor type(s) mediates the effects of third ventricular microinjections of four opioid peptide agonists on blood levels of glucose, free fatty acids, and corticosterone. Tests were performed in unanesthetized adult male albino rats having chronic intraventricular cannulas; blood samples were taken from the tail tip at 0, 15, 30, 60, 90, and 120 min postmicroinjection. In experiment 1, the agonists DAGO (Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol), beta-endorphin, DSLET (d-Ser2-Leu-enkephalin-Thr), and dynorphin A-(1-17) (0, 0.3, 1, 3, and 10 nmol/rat) produced three distinct patterns of changes in serum glucose, free fatty acid, and corticosterone values. Experiment 2 showed that the effects of DAGO and beta-endorphin were inhibited by prior injection with the opiate-receptor blocker naloxone (1 mg/kg sc) and that the effects of dynorphin were not diminished. Experiment 3 determined that dynorphin effects were also not diminished by naloxone given intraventricularly. Experiment 4 found that blockade of the mu-receptor by intraventricular pretreatment with the specific antagonist beta-funaltrexamine (20 micrograms/rat, 24 h before) completely abolished the effects of DAGO and beta-endorphin on glucose and corticosterone. The mu-receptor is critical to the mediation of the hyperglycemia and hypercorticosteronemia induced by the central administration of opiate agonists. These results imply that mu-opioid binding sites previously identified in central autonomic regions may be involved in the regulation of circulating glucose and corticosterone.

Geriatrics: an updated bibliography.

This is the author's fifth revision of a geriatrics bibliography. Approximately one-third of the previous references have been replaced by more current or more delimited articles. Because the literature pertinent to geriatrics has continued to grow ever more rapidly, it has been necessary to omit many informative articles from the bibliography. Preference is given to recent publications; almost all of the reference data from the past four years. Some articles were selected to highlight current controversies or changes in viewpoint. Most of the references deal specifically with an elderly patient population, though few use a multidisciplinary approach. Studies of the elderly are confounded by concomitants of aging frequent but not universal in our society: inactivity, obesity, malnutrition, and psychosocial trauma. The articles cited are primarily concerned with medical ailments of the elderly; legal, ethical, and sociological topics receive more limited coverage. The references are divided into categories. The first set (I) deals with some possible causes of aging; the second (II) with physiologic decline accompanying aging; the third (III) with the atypical and nonspecific characteristics of illness among geriatric patients; the fourth (IV) with the elderly and society; and the fifth (V) with care options. The remainder of the references are cited by pertinent medical specialty. Within each category, references are divided by disease process. Articles are further subgrouped by aspects of those diseases such as evaluation or therapy.

Towards selective and improved performance of the mental status examination.

Performance of mental status examinations (MSE) is often useful but is not warranted for all new patients, except for training, research, special request, or policy. Reasons for doing MSE must be weighed against possible detrimental effects on patients or on patient-clinician relationships. Both sides are reviewed. Methods for ameliorating or preventing adverse effects are described. Validity of findings using MSE are frequently doubtful and examiners often misinterpret their significance. A decision tree is presented to help decide whether to use the MSE in particular instances.