Differential effects of propofol and isoflurane on glucose utilization and insulin secretion

AimsVolatile anesthetics, such as isoflurane, reverse glucose-induced inhibition of pancreatic adenosine triphosphate-sensitive potassium (K_ATP) channel activity, resulting in reduced insulin secretion and impaired glucose tolerance. No previous studies have investigated the effects of intravenous anesthetics, such as propofol, on pancreatic K_ATP channels. We investigated the cellular mechanisms underlying the effects of isoflurane and propofol on pancreatic K_ATP channels and insulin secretion.Main methodsIntravenous glucose tolerance tests (IVGTT) were performed on male rabbits. Pancreatic islets were isolated from male rats and used for a perifusion study, measurement of intracellular ATP concentration ([ATP]_i), and patch clamp experiments.Key findingsGlucose stimulus significantly increased insulin secretion during propofol anesthesia, but not isoflurane anesthesia, in IVGTT study. In perifusion experiments, both islets exposed to propofol and control islets not exposed to anesthetic had a biphasic insulin secretory response to a high dose of glucose. However, isoflurane markedly inhibited glucose-induced insulin secretion. In a patch clamp study, the relationship between ATP concentration and channel activity could be fitted by the Hill equation with a half-maximal inhibition of 22.4, 15.8, and 218.8 μM in the absence of anesthetic, and with propofol, and isoflurane, respectively. [ATP]_i and single K_ATP channel conductance did not differ in islets exposed to isoflurane or propofol.SignificanceOur results indicate that isoflurane, but not propofol, decreases the ATP sensitivity of K_ATP channels and impairs glucose-stimulated insulin release. These differential actions of isoflurane and propofol on ATP sensitivity may explain the differential effects of isoflurane and propofol on insulin release.     

Effects of ketamine-xylazine and isoflurane on insulin sensitivity in dehydroepiandrosterone sulfate-treated minipigs (Sus scrofa domestica)

Isoflurane and ketamine-xylazine (KX) combinations are widely used veterinary anesthetics, KX being the particularly common agent for immobilizing swine. Results of previous studies indicate that KX and xylazine suppress insulin release. The steroid hormones, dehydroepiandrosterone (DHEA) and its sulfated form, dehydroepiandrosterone-sulfate (DHEAS), have variable effects on insulin sensitivity in animals. We evaluated the effect of DHEAS on plasma glucose and insulin concentrations in female Yucatan swine under KX and isoflurane anesthesia. A 2 x 2 factorial design was used. Twenty-four 17-week-old gilts were randomly assigned to receive vehicle (placebo) or DHEAS as part of an ongoing study. The KX was given intramuscularly to all animals prior to blood sample collection at weeks two and four. At week three, all animals received isoflurane by inhalation. During KX anesthesia, mean insulin concentration in DHEAS-treated and control groups approximated half the postisoflurane values (P < 0.001). While under isoflurane, the DHEAS group had significantly higher mean plasma insulin concentration and mean insulin-to-glucose ratio, compared with values for controls (P < 0.05). These findings are consistent with changes in insulin values following DHEAS treatment observed previously in nonanesthetized swine. The effect of DHEAS treatment was absent in animals under KX anesthesia. These results suggest that KX significantly decreases plasma insulin concentration and blunts DHEAS-associated insulin resistance in female minipigs.     

Serum insulin concentration and arginine tolerance test in the cynomolgus monkey (Macaca fascicularis)

The standard value of serum insulin was determined to be less than 75 microU/ml with ninety-eight female adult cynomolgus monkeys of wild origin. Then, fifteen apparently healthy laboratory-bred female cynomolgus monkeys aged 6-8 years were studied to know the usefulness of the arginine tolerance test (ATT) by measuring blood glucose, insulin and glucagon. Prior to ATT, all animals had been diagnosed as non-diabetic by the intravenous glucose tolerance test (IVGTT). Arginine hydrochloride was infused intravenously at a dose of 0.5 g/kg. BW under anesthesia. According to the standard value of insulin, fifteen animals were divided into two groups, that is, the low (n = 7) and the high (n = 8) value groups. In the low value group, glucose and insulin value did not change significantly after arginine infusion and their responses were similar to those in the control group (saline infused, n = 4). But glucagon markedly increased from 10 to 45 minutes post infusion. In the high value group, glucagon response was similar to that in the low value group, while glucose and insulin values significantly decreased. It is concluded that the pancreatic alpha-cell function (glucagon secretion) can be judged by the ATT in the cynomolgus monkey but the beta-cell function (insulin secretion) can not be diagnosed.     

The effects of ketamine anesthesia on glucose clearance in African green monkeys

Ketamine hydrochloride's effect on glucose clearance-insulin secretion during intravenous glucose tolerance testing was studied in five African green monkeys. Animals were tested with ketamine anesthesia and then had indwelling cannulas implanted and were retested both in the presence and absence of ketamine anesthesia. Serum glucose and insulin concentrations were determined. There were no significant differences in the glucose clearance rate (K value), basal glucose and insulin concentrations, maximum insulin concentration, and area under the insulin response curve, among the three different conditions.     

Effects of ketamine sedation on glucose clearance,insulin secretion and counterregulatory hormone production in baboons (Papio hamadryas)

Since the effects of ketamine sedation seem to differ between subspecies of baboons, we assessed the endocrine response to an intravenous glucose tolerance test (IVGTT) in 12 hamadryas baboons. The first phase insulin secretion, basal insulin, and glucose levels, as well as the glucose clearance, were significantly lower in sedated baboons as compared to fully awake animals. Glucagon and Cortisol were significantly higher, while growth hormone was lower during ketamine sedation. Papio hamadryas appears to be a promising pre-clinical model for the study of endocrine replacement therapy in insulin-dependent diabetes. However, the data obtained must be interpreted with the knowledge that the anesthetic employed to allow for testing of the animals does have an effect on the parameters described in this report.     

Whole body insulin responsiveness is higher in beef steers selected for increased muscling

The aim of this experiment was to evaluate the impact of selection for greater muscling on whole body insulin responsiveness in cattle, as reflected by greater uptake of glucose in response to constant insulin infusion and greater glucose disappearance following an intravenous glucose tolerance test. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling over 15 years. Eleven high-muscled (High), 10 low-muscled (Low) and 3 high-muscled steers, which were heterozygous for a myostatin polymorphism (HighHet), were infused with insulin using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at two levels, 0.6 μIU/kg per min and 6.0 μIU/kg per min. Glucose was concurrently infused to maintain euglyceamia and the steady state glucose infusion rate (SSGIR) indicated insulin responsiveness. An intravenous glucose tolerance test was also administered at 200 mg/kg live weight. Sixteen blood samples were collected from each animal between -30 and 130 min relative to the administration of intravenous glucose, plasma glucose and insulin concentration was determined in order to analyse insulin secretion and glucose disappearance. Insulin-like growth factor-1 (IGF-1) was also measured in basal plasma samples. At the low insulin infusion rate of 0.6 mU/kg per min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low (P<0.05). At the high insulin infusion rate of 6.0 mU/kg per min, these differences were proportionately less with the High and the HighHet genotypes having only 27% and 34% higher SSGIR (P<0.05) than the Low-muscled genotype. The High-muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low-muscled cattle. There was no effect of muscling genotype on basal insulin or basal glucose concentrations, glucose disappearance or insulin secretion following an intravenous glucose tolerance test. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High-muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals.     

Isoflurane and Sevoflurane Induce Severe Hepatic Insulin Resistance in a Canine Model

IntroductionAnesthesia induces insulin resistance, which may contribute to elevated blood glucose and adverse post-operative outcomes in critically ill patients, and impair glycemic control in surgical patients with diabetes. However, little is known about the mechanisms by which anesthesia impairs insulin sensitivity. Here we investigate the effects of anesthesia on insulin sensitivity in metabolic tissues.MethodsHyperinsulinemic-euglycemic clamps were performed in 32 lean (control diet; n = 16 conscious versus n = 16 anesthetized) and 24 fat-fed (6 weeks fat-feeding; n = 16 conscious versus n = 8 anesthetized) adult male mongrel dogs in conjunction with tracer methodology to differentiate hepatic versus peripheral insulin sensitivity. Propofol was administered as an intravenous bolus (3mg/kg) to initiate anesthesia, which was then maintained with inhaled sevoflurane or isoflurane (2–3%) for the duration of the procedure.ResultsAnesthesia reduced peripheral insulin sensitivity by approximately 50% in both lean and fat-fed animals as compared to conscious animals, and insulin action at the liver was almost completely suppressed during anesthesia such that hepatic insulin sensitivity was decreased by 75.5% and; 116.2% in lean and fat-fed groups, respectively.ConclusionInhaled anesthesia induces severe hepatic insulin resistance in a canine model. Countermeasures that preserve hepatic insulin sensitivity may represent a therapeutic target that could improve surgical outcomes in both diabetic and healthy patients.     

Effects of physical and chemical restraint on intravenous glucose tolerance test in crested black macaques (Macaca nigra)

The effects of physical and chemical restraint on glucose clearance and insulin secretion were evaluated during intravenous glucose tolerance testing in Macaca nigra. Conscious monkeys placed in plexiglas cylindrical restraining devices (CRD) appeared relaxed, but glucose clearance and insulin secretion were impaired. A combination of midazolam with ketamine, compared to ketamine alone, did not cause detectable changes in the intravenous glucose tolerance tests; midazolam also reduced adverse reactions to ketamine and extended the duration of anesthesia. The cylindrical restraining device can be convenient for examining monkeys, but it is limited by its adverse affects on metabolic and hormonal measurements in intravenous glucose-tolerance tests. Chemical restraint using ketamine with midazolam was more effective than ketamine alone.     

Hormonal responses to intravenous glucose and arginine in patients with pancreatitis

19 subjects with an acute episode of pancreatitis, and 5 patients with chronic pancreatitis received intravenous glucose tolerance tests with measurement of glucose, insulin and glucagon. Patients recovering from acute pancreatitis demonstrated defects in their ability to dispose of a glucose load. 10 patients had overt glucose intolerance; of these, 4 were insulin-deficient, 3 had a loss of an acute insulin response to glucose, and 3 had marked hyperglucagonemia with normal to increased insulin levels. These abnormalities were seen in response both to intravenous glucose and intravenous arginine. Therefore, according to this study, at least three factors are clearly implicated in the production of glucose intolerance after an acute episode of pancreatitis: hypoinsulinemia, delayed insulin secretory response and hyperglucagonemia.     

Effects of truncal,selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Part II-Comparison of response to oral and intravenous glucose.

Paired oral and intravenous glucose tolerance tests were carried out in patients who had undergone truncal vagotomy and pyloroplasty, selective vagotomy and pyloroplasty, or highly selective vagotomy at least six months earlier. Intravenous glucose tolerance was similar in all three groups. Oral glucose elicited significantly higher concentrations of plasma insulin in patients who had undergone selective and highly selective vagotomy than in those treated by truncal vagotomy. When the same amount of glucose was given intravenously, however, plasma insulin concentrations were similar in all three groups of patients. The insulin secreted in response to intravenous glucose expressed as a percentage of that secreted in response to oral glucose was 112% for truncal vagotomy, 51% for selective vagotomy, and 52% for highly selective vagotomy. Truncal vagotomy thus led to a diminished insulin response to oral glucose, which was probably due to impaired release of small-bowel hormones.     

Hypoglycémie spontanée et insuffisance rénale chronique.

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.     

Increased glucose disappearance rate after short-term clofibrate administration in normal subjects and in patients with chemical diabetes

Following seven days clofibrate administration, the glucose disappearance rate during an intravenous glucose tolerance test was significantly increased in 6 normal subjects and in 11 patients with chemical diabetes. Both the acute and the total insulin secretory response were unchanged. Though fasting serum levels of free fatty acids, triglycerides, and cholesterol were significantly lowered by treatment, no correlation was found between the decrease in serum lipids and the increase in glucose disappearance rate. It is suggested and clofibrate improves glucose utilization by reducing insulin resistance irrespective of its effects on serum lipids concentration.     

Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus

The effect of 1 week clofibrate administration on glucose and insulin responses to oral glucose and to intravenous tolbutamide was evaluated in 21 patients with mild maturity-onset diabetes (fasting plasma glucose 108-152 mg/100 ml). After treatment, oral glucose tolerance and hypoglycaemic effect of tolbutamide were significantly improved; plasma insulin response was reduced after glucose and unmodified after tolbutamide; fasting plasma glucose was also significantly reduced. These findings did not correlate with the observed fall in serum lipids. Short-term clofibrate improves glucose metabolism in mild diabetes irrespective of its effects on lipid metabolism. It is suggested that the drug's action may be mediated by reduced insulin resistance.     

Intensive exercise training does not improve intravenous glucose tolerance in severely diabetic rats

Several studies have recently demonstrated that exercise training improves glucose tolerance in mildly diabetic rats. To test whether some minimal levels of circulating insulin are required to observe the beneficial effects of exercise training, severe diabetes was induced by injecting female Wistar rats with streptozotocin. Half of diabetic and control rats were submitted to a strenuous program of swimming exercise. After 4 wks of training, intravenous glucose tolerance tests (IVGTT) were performed in precannulated, unrestrained and unanesthetized animals. In non-diabetic rats, exercise training significantly reduced both basal and glucose-stimulated levels of insulin (P less than 0.01) without altering glucose tolerance. On the other hand, the same training program applied to severely diabetic animals (basal plasma insulin levels less than 8 microU/ml) failed to reduce the marked hyperglycemia in the resting state (400 mg% range) as well as during the entire IVGTT (400-500 mg%). The results indicate that exercise training effectively increased the sensitivity of peripheral tissues to insulin in non-diabetic but not in diabetic animals. The data also suggest that a minimal amount of circulating insulin is required in order to observe the beneficial effects of exercise training.     

Hyperglycemia-induced insulin resistance in diabetic dyslipidemic Yucatan swine

Hyperglycemia, dyslipidemia, and associated insulin resistance are hallmarks of diabetes mellitus. Purposes of the study reported here were to develop practical methods for assessment of in vivo insulin sensitivity and determine contributions of hyperglycemia and dyslipidemia to insulin resistance in the porcine model of alloxan-induced diabetes mellitus and dyslipidemia. Male Yucatan swine groups were treated for 20 weeks: control (C), high fat-fed (2% cholesterol) hyperlipidemic (H), alloxan-induced diabetic normolipidemic (D), diabetic high fat-fed (diabetic dyslipidemic, DD), and diabetic dyslipidemic treated with the lipid-lowering agent atorvastatin (DDA). Plasma cholesterol concentration increased sixfold in animals of groups H, DD, and DDA, whereas triglyceride concentration increased threefold in animals of group DD only. Diabetics had decreases in glucose tolerance and pancreatic immunostaining for insulin. Use of the gold standard hyperinsulinemic euglycemic clamp procedure indicated that maximal insulin-stimulated glucose uptake was similar to that in humans, but this method was not practical for use in pigs. Instead, a more convenient and valid insulin sensitivity test involving suppression of insulin secretion with somatostatin and a single insulin injection was used. Insulin sensitivity was greatly impaired by anesthesia with isoflurane, but was not affected by use of the anxiolytic agent diazepam. Insulin sensitivity decreased by 75% in diabetics (groups D, DD, DDA), compared with animals of groups C and H, and was inversely related to fasting blood glucose concentration (r = -0.72). Insulin treatment to restore blood glucose values of diabetics (> 250 mg/dl) to near control values (< 100 mg/dl) promptly restored insulin sensitivity to control values. We conclude that hyperglycemia is a major cause of insulin resistance in the porcine model of alloxan-induced diabetes mellitus and dyslipidemia.     

Insulin resistance: the link between metabolic disorders and cystic ovarian disease in high yielding dairy cows?

A preliminary investigation was performed to examine whether insulin resistance is a factor in the pathogenesis of cystic ovarian disease (COD) in high-yielding dairy cows. In total 30 cows, of which 15 were diagnosed as suffering from COD based on the anamnesis and clinical examination, and the other 15 served as matched controls, were subjected to an intravenous glucose tolerance test (IVGTT). The aim of the study was to investigate whether insulin activity was altered in COD cows. Differences in glucose clearance between the COD cows and their controls were analyzed comparing the fractional turnover rate (k), the glucose half-time (T1/2), and the area under the curve (AUC) 60 and 120 min after infusion. Differences in insulin response were analyzed comparing the insulin increment, the insulin peak concentration, and the AUC 60 and 120 min after glucose infusion. Although insulin resistance, attended by a secondary hyperinsulinemia, is stated to directly contribute to the ovarian abnormalities that characterize the polycystic ovary syndrome (PCOS) in human medicine, this was not observed in COD cows. On the contrary, COD cows appeared to have a low insulin response following an intravenous glucose load as compared with their matched controls. This was illustrated by significantly lower insulin increments (P = 0.04) and lower insulin peak concentrations (P = 0.04). As COD cows had a significantly lower insulin response to a standard glucose load, it was concluded that insulin could be a factor in the pathogenesis of COD in dairy cows.     

Leptin responses to glucose infusions in obesity-prone rats

The secretion of leptin is dually regulated. In fasting animals, plasma leptin concentrations reflect body fat stores, whereas the incremental leptin response to fasting or refeeding most likely reflects insulin-mediated energy flux and metabolism within adipocytes. Impaired secretion of leptin in either pathway could result in obesity. We therefore measured plasma leptin concentrations in fasted animals and plasma leptin concentrations after an intravenous glucose infusion in a rat model of obesity. Young Sprague-Dawley (S-D) and Fischer 344 (F344) rats had similar percent body fat and fasting glucose and fasting leptin concentrations. However, F344 animals had higher insulin concentrations and leptin responses to intravenous glucose than did the S-D animals. The animals were then fed a control or high-fat diet for 6 wk. High-fat fed animals gained more weight and body fat than did the control fed animals. Control and high-fat fed F344 animals gained approximately 40% (P < 0.0001) more weight and >100% (P < 0.01) more body fat than did the S-D animals. Fasting leptin concentrations and leptin concentrations after intravenous glucose infusions and feeding were more than double (P < 0.05) in F344 animals compared with S-D animals. Whether an animal is fed a control or high-fat diet had little effect on the leptin response to intravenous glucose. In conclusion, young, lean F344 animals, before the onset of obesity, demonstrated a greater acute leptin response to intravenous glucose than similarly lean S-D animals. After a 6-wk diet, F344 animals had a greater percent increase in body weight and insulin resistance and exhibited higher fasting leptin concentrations and a greater absolute leptin response to intravenous glucose compared with the S-D animals. The chronic diet (control or high fat) had little impact on the acute leptin response to intravenous glucose. F344 animals exhibit leptin resistance in young, lean animals and after aging and fat accumulation.     

Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice

Because biotin treatment may lower blood glucose in insulin-dependent diabetes, we chose to study such an effect in non-insulin dependent diabetes. Twenty-six diabetic KK mice, moderately hyperglycemic and insulin resistant, were treated for 10 weeks: 9 animals with 2 mg of biotin/Kg, 8 with 4 mg of biotin/Kg, and 9 with saline (controls). Blood glucose levels, oral glucose tolerance, insulin response to oral glucose, and blood glucose decrease in response to insulin were quantitated. Compared to controls, biotin treatment lowered post-prandial glucose levels, and improved tolerance to glucose and insulin resistance. Serum immunoreactive insulin levels in biotin-treated mice were like the controls.     

Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats

Increasing evidence supports a negative role of glycogen synthase kinase-3 (GSK-3) in regulation of skeletal muscle glucose transport. We assessed the effects of chronic treatment of insulin-resistant, prediabetic obese Zucker (fa/fa) rats with a highly selective GSK-3 inhibitor (CT118637) on glucose tolerance, whole body insulin sensitivity, plasma lipids, skeletal muscle insulin signaling, and in vitro skeletal muscle glucose transport activity. Obese Zucker rats were treated with either vehicle or CT118637 (30 mg/kg body wt) twice per day for 10 days. Fasting plasma insulin and free fatty acid levels were reduced by 14 and 23% (P < 0.05), respectively, in GSK-3 inhibitor-treated animals compared with vehicle-treated controls. The glucose response during an oral glucose tolerance test was reduced by 18% (P < 0.05), and whole body insulin sensitivity was increased by 28% (P < 0.05). In vivo insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (50%) and IRS-1-associated phosphatidylinositol-3' kinase (79%) relative to fasting plasma insulin levels were significantly elevated (P < 0.05) in plantaris muscles of GSK-3 inhibitor-treated animals. Whereas basal glucose transport in isolated soleus and epitrochlearis muscles was unaffected by chronic GSK-3 treatments, insulin stimulation of glucose transport above basal was significantly enhanced (32-60%, P < 0.05). In summary, chronic treatment of insulin-resistant, prediabetic obese Zucker rats with a specific GSK-3 inhibitor enhances oral glucose tolerance and whole body insulin sensitivity and is associated with an amelioration of dyslipidemia and an improvement in IRS-1-dependent insulin signaling in skeletal muscle. These results provide further evidence that selective targeting of GSK-3 in muscle may be an effective intervention for the treatment of obesity-associated insulin resistance.     

Short-Term Estrogen Replacement Effects on Insulin Sensitivity and Glucose Tolerance in At-Risk Cats for Feline Diabetes Mellitus

Male domestic cats that are neutered and overweight are at an increased risk for developing a type-2-like diabetes mellitus. Beneficial effects of 17β-estradiol (E2) on glucose homeostasis may be lost with neutering and thereby account for increased diabetes risk. To evaluate this, adult male neutered overweight cats (n=6) were given daily E2 (1.0 μg/kg) or vehicle (Vh; ethanol, 1.0μL/kg) in a single crossover trial of 14-day periods with a 7-day washout. The E2 and Vh were voluntarily ingested on food. The E2 dosage was determined in a pre-trial to significantly and transiently reduce food intake with no measurable change in plasma E2 concentration. During treatments, physical activity was assessed with collar-mounted accelerometers on days 9-11, and tests of intravenous insulin tolerance and intravenous glucose tolerance were conducted on days 13 and 14, respectively. Over the 14 days, E2 compared to Vh treatment reduced (p=0.03) food intake (- 22%) but not enough to significantly reduce body weight; activity counts were not significantly changed. With E2 compared to Vh treatment, the late-phase plasma insulin response of the glucose tolerance test was less (p=0.03) by 31%, while glucose tolerance and insulin sensitivity indexes were not significantly changed. The results indicate that oral E2 at a dosage that moderately affects food intake may reduce insulin requirement for achieving glucose homeostasis in neutered male cats. Further investigation is needed to identify the mechanism underlying the E2 effect.