Stimulus-secretion coupling of glucose-induced insulin release. Timing of early metabolic,ionic, and secretory events

The timing of the early metabolic, ionic, and secretory responses to glucose in rat pancreatic islets was monitored by measuring, at 12 sec intervals, the concentrations of glucose, lactic, and pyruvic acids, ³²P, ⁸⁶Rb, ⁴⁵Ca, and insulin in the effluent of perifused prelabeled islets. The increase in glucose concentration from zero to 16.7 mM was complete within 133 sec. The output of organic acids increased after 24 sec of exposure to glucose and, in the case of lactic acid, fell slightly after the initial elevation. The phosphate flush was initiated only after 96 sec of exposure to glucose, whereas the decreases in ⁸⁶Rb and ⁴⁵Ca outflow were both detectable within 72 sec of stimulation. The secondary rise in ⁴⁵Ca efflux was first seen after 157 sec of stimulation and its time course was not vastly different from that of insulin release. These data indicate that, in the secretory sequence, metabolic changes precede both the remodelling of ionic fluxes and the stimulation of insulin release. The results are compatible with the view that the secondary rise in ⁴⁵Ca outflow is attributable, in part at least, to the glucose-induced decrease in K conductance (but not to the increase in phosphate outflow), with resulting membrane depolarization and gating of voltage-dependent Ca channels.     

Glucokinase is not the pancreatic B-cell glucoreceptor

Summary A series of recent experimental findings are reviewed to indicate that glucokinase does not represent the pancreatic B-cell glucoreceptor. (1) Whether in liver, pancreatic islet or insulin-producing tumoral cell homogenates, glucokinase fails to yield a higher reaction velocity with -than -D-glucose. (2) At a high glucose concentration (40 mmol/l), when the phosphorylation of glucose by glucokinase is indeed higher with - than -D-glucose, no preference for -D-glucose is observed in intact islets, as judged from the utilization of D-[5-³H]glucose, production of lactic acid, oxidation of D-[U-¹⁴C] glucose, net uptake of ⁴⁵Ca or release of insulin. (3) The glucose 6-phosphate content of intact islets is higher in the presence of - than -D-glucose. (4) At a low glucose concentration (3.3 mmol/l), when the participation of glucokinase to hexose phosphorylation is minimal, -D-glucose is still better metabolized and stimulates both ⁴⁵Ca net uptake and insulin release more efficiently than -D-glucose, despite the fact that hexokinase yields a higher reaction velocity with - than -D-glucose. (5) In intact islets, -D-glucose is used preferentially to -D-glucose in the pentose cycle pathway as judged from the oxidation of - or -D-[1-¹⁴C]glucose relative to that of - or -D-[6-¹⁴C]glucose. (6) In islets removed from fasted rats, the rate of glycolysis is more severely decreased than expected from the repression of glucokinase. (7) The metabolism of glucose in tumoral insulin-producing cells differs, in several respects, from that in normal pancreatic islets, although the pattern of hexokinase and glucokinase activities is similar in these two types of cells. All these observations point to the participation of regulatory sites distal to glucose phosphorylation in the control of glucose metabolism in islet cells.     

No alteration in the PFA-100 in vitro bleeding time induced by the Ginkgo biloba special extract, EGb 761, in elderly patients with mild cognitive impairment.

EGb 761 is widely used in the management of mild cognitive impairment in the elderly population. Elucidation of the effects of EGb 761 on primary haemostasis via PFA-100 could represent an important step for better understanding of the haemostatic safety of EGb 761. The purpose of this prospective study is to assess the effects of Ginkgo biloba special extract, EGb 761, on PFA-100 in vitro bleeding time in elderly patients with mild cognitive impairment. A total of 40 elderly patients aged 65-79 years who were referred for geriatric assessment and who were diagnosed as having mild cognitive impairment were included. Patients were started on 80 mg EGb-761 three times daily. The complete set of PFA-100 in vitro bleeding time and coagulation parameters including prothrombin time, activated partial thromboplastin time and International Normalized Ratio were assessed before and on the seventh day of treatment with EGb 761. There was no statistically significant prolongation in PFA-100 in vitro bleeding time or coagulation parameters in patients receiving EGb 761 after 7 days. The data about the safety of EGb 761 from the point of primary haemostasis in our elderly patient population with mild cognitive impairment casts hope for the future management of this 'difficult-to-treat' population with the promising Ginkgo extracts.     

Use of knee height for the estimation of stature in elderly Turkish people and their relationship with cardiometabolic risk factors

The determination of the approximately truest value in height measurement is important in many fields, but it is difficult to perform true measurements, especially in the elderly individuals. We planned to investigate the following items in geriatric Turkish population: to calculate the decrease in height with advancing age by using the standing height measurement and estimated height derived from the knee height; to evaluate the significance of difference between the two measurement methods in the calculation of body mass index (BMI) and waist/height ratio (WHtR); to determine the cut-off value of WHtR according to estimated height in elderly individuals. We studied 551 cases aged between 19 and 97 years. Knee height was measured using a sliding caliper in a sitting position. Linear regression analysis was carried out to derive predictive equations for the estimation of stature with adults (≤50 years of age) according to the gender. This equation was then used to estimate height among elderly subjects. Of the cases, 60.3% were <60 years (mean: 48.75 ± 7.50); 39.7% of the cases were >60 years (mean: 69.51 ± 7.12). Estimated BMI (EBMI) measurements in the females and males >60 years were in average 1.23 kg/m² and 0.92 kg/m² higher than their real BMIs, respectively. EBMI measurements in the females <60 years were 0.32 kg/m² higher than their real BMIs (p < 0.01). There is a statistically significant difference between WHtR in the females of both age groups, and in the males >60 years, as compared to our estimated WHtR (EWHtR) measurements (p < 0.01). The cut-off point of WHtR was 0.61 and 0.58 in the female and male cases of >60 years in our study, respectively. WHtR seemed to be a better anthropometric index that could predict most cardiometabolic risk factors in our study. EWHtR emerged to be a better cardiometabolic risk index especially in the elderly group.     

nNOS expression in the brain of rats after burn and the effect of the ACE inhibitor captopril

Objective

To investigate the role of endogenous neuronal nitric oxide synthase (nNOS) on brain injury after burn and the effects of the captopril.

Methods

Wistar albino rats (200–250 g) were exposed on the dorsal surface to 90 °C (burn) or 25 °C (sham) water for 10 s. The ACE group was treated with intraperitoneal 10 mg/kg captopril immediately after burn and this treatment was repeated twice daily. At the end of the 24 h brain samples were taken. nNOS was studied in brain areas by immunohistochemistry.

Results

There was no difference between the cerebellar and hypothalamic areas the nNOS expression of all groups. nNOS expression increased in the frontal cortex, striatum and midbrain in the burn group compared to the control group. In the frontal cortex, nNOS expression significantly decreased after ACE inhibitor treatment (p < 0.05). The striatal nNOS of the ACE group significantly increased when compared to the control group (p = 0.001). In the midbrain of the animals, nNOS decreased in the ACE group. Hippocampal nNOS expression did not change after burn and significantly increased after ACE inhibitor therapy (p < 0.05).

Conclusions

Our data showed that the pathophysiological events following burn appear to be related to an acute inflammatory reaction which is associated with nNOS in the frontal cortex, striatum and midbrain, and captopril treatment abrogates the nNOS response in the frontal cortex and midbrain.     

Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression

A review of the literature indicated that sirtuin-1 expression, a regulator of nitric oxide bioavailability in erectile dysfunction (ED) after melatonin therapy, has not yet been investigated. The objective of this study was to evaluate the protective effects of melatonin for erectile function with sirtuin-1 protein expression in type 1 diabetic rat models. Fifty male Sprague Dawley rats were placed into five groups. Except for those in the control group (C), each animal received a single dose (60 mg/kg) of streptozotocin to induce diabetes. The animals were placed into the diabetes (D) group, insulin (I) group (6 U/kg/day), melatonin (Mel) group (10 mg kg⁻¹ day⁻¹) and combined treatment (I + Mel) group. Ten weeks later, the serum testosterone levels, intracavernosal pressure (ICP), mean arterial pressure (MAP), malondialdehyde (MDA), cyclic guanosine monophosphate (c-GMP), 8-hydroxydeoxyguanosine (8-OHdG), nitric oxide synthase (NOS), caspase-3 activity, sirtuin-1 and endothelial nitric oxide synthase (eNOS) protein expression and histological findings were assessed. The mean ICP/MAP ratio for the D group was lower than the mean ratios for the other groups. The treatment groups, particularly the I + Mel group, exhibited lower 8-OHdG and MDA levels and caspase-3 activity than the D group. The sirtuin-1 and eNOS expression and cavernosal tissue (CT) histology seemed to have been preserved by the melatonin and/or insulin therapy. These results were indicative of a profound protective effect of melatonin by the activation of sirtuin-1 protein expression against hyperglycemia-induced oxidative CT injury.