Somatostatin infusion enhances hepatic glucose production during hyperglucagonemia

Somatostatin (SRIH) is widely employed in metabolic studies to permit quantitation of glucose production and disposal rates while the endocrine pancreas is suppressed and the hormonal milieu is under the investigator's control. In these studies it is assumed that if peripheral levels of insulin and glucagon are the same during SRIH infusion as during control studies, the effects of these hormones on glucose metabolism are equivalent. If the effect of glucagon is influenced by SRIH infusion, then these techniques may be unsuitable for the study of the regulation of hepatic glucose output. To assess the influence of SRIH on glucagon-stimulated hepatic glucose production (Ra), we determined Ra during paired studies in ten healthy (five younger and five older) subjects. In each study an insulin infusion designed to yield physiologic systemic insulin levels of 20 to 30 microU/mL was given from 0 to 210 minutes. In addition, from 60 to 210 minutes either glucagon alone (3.5 ng/kg/min) (I + IRG) or glucagon (3.5 ng/kg/min) and SRIH (250 micrograms/h) (I + IRG + SRIH) was infused. Since results for plasma levels of insulin, C-peptide, glucagon, and Ra were similar in young and old subjects, the two age groups were combined for analysis. Basal plasma insulin, glucagon, C-peptide, glucose, and Ra were similar in each arm of the study. Insulin values were nearly identical from 60 to 210 minutes (I + IRG, 23.8 +/- 1.1; I + IRG + SRIH, 24.0 +/- 1.0 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose and lactate interrelations during moderate-intensity exercise in humans

To evaluate circulating lactate and glucose kinetics during moderate-intensity exercise, we studied ten healthy endurance-trained men (aged 25 +/- 6 years) during 30 to 50 minutes of supine cycle ergometer exercise at 43% +/- 5% of maximal oxygen consumption (VO2 max) using isotopic tracer techniques. Seven subjects received [U-13C]-lactate and [6-14C]-glucose, and three received [1-14C]-lactate and [U-13C]-glucose. Arterial glucose and lactate concentrations were 94.0 +/- 4.1 and 5.66 +/- 0.87 mg/dL at rest, and 95.7 +/- 3.4 and 8.38 +/- 3.87 mg/dL, respectively, after 25 minutes of exercise. The rate of glucose disappearance (RdG) increased from 2.41 +/- 0.40 at rest to 3.38 +/- 0.77 mg x kg-1 x min-1 during exercise, compared with the much larger rise in the rate of lactate appearance (RaL), which increased from 1.25 +/- 0.20 to 3.47 +/- 0.79 mg x kg-1 x min-1. During exercise RaL was 103% of RdG, compared with only 52% at rest. The rate at which the blood was cleared of lactate increased from 22.7 +/- 2.2 at rest to 44.2 +/- 11.2 ml x kg-1 x min-1 after 25 minutes of exercise. From secondary labeling of lactate with glucose carbons, the rate of glucose conversion to lactate was estimated to be 0.65 +/- 0.16 mg x kg-1 x min-1 during exercise. Twenty percent of the glucose utilization went to lactate formation during exercise, and 20% of the blood lactate appearance came from blood glucose, with the balance presumably coming from muscle glycogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sepsis-induced increases in glucose uptake by macrophage-rich tissues persist during hypoglycemia.

The purpose of the present study was to determine how hypoglycemia alters glucose uptake by individual tissues and whether this response is altered by gram-negative infection. A hypermetabolic septic state was produced in catheterized rats by subcutaneous injections of live Escherichia coli. The next morning, animals were infused with saline, somatostatin to produce a euglycemic insulinopenic state (6 mmol/L glucose, 5 microU/mL insulin), or 3-mercaptopicolinate (3-MP) to inhibit gluconeogenesis and produce a hypoglycemic insulinopenic (4.5 or 2 mmol/L glucose, 5 microU/mL insulin) condition. After 140 minutes, [14C]2-deoxyglucose was injected intravenously (IV) to determine in vivo glucose uptake by individual tissues. Sepsis increased whole body glucose disposal (Rd) by 53% under basal euglycemic conditions and this increase resulted from an enhanced rate of glucose removal by liver, spleen, lung, ileum, and skin. Under euglycemic insulinopenic conditions, total glucose Rd decreased in both septic and nonseptic rats as a result of a decreased rate of glucose uptake by muscle. However, because the absolute rate of glucose uptake was still elevated by sepsis, the rate of non-insulin-mediated glucose uptake (NIMGU) was 46% higher in septic rats than in nonseptic animals. Severe hypoglycemia (2 mmol/L) produced a relative insulin deficiency and decreased whole body Rd in both septic and nonseptic animals by 53% to 58%, compared with euglycemic insulinopenic animals. The decrease in blood glucose decreased glucose uptake by all tissues examined, except brain and heart. However, sepsis still increased glucose uptake by liver, spleen, lung, ileum, and skin (25% to 90%), compared with hypoglycemic nonseptic rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of phlorizin on hepatic bile production before and during glucose infusion

During intravenous infusion of glucose, bile secretion is reduced (cholestasis), indicating that hepatocellular metabolism of glucose could have harmful effects on the liver. Phlorizin has been identified as a compound capable of impeding glucose uptake of liver cells. To examine whether phlorizin had any effect on glucose-associated cholestasis, three groups of experiments were performed on anaesthetized pigs. In group I phlorizin (100 mg/kg body wt) during normoglycaemia stimulated bicarbonate-dependent bile secretion by 56 +/- 4%. After phlorizin, hyperglycaemia decreased both bile acid- and bicarbonate-dependent bile secretion by 37 +/- 4%. But after the glucose load normalization of plasma glucose concentration increased the bicarbonate-dependent fraction by 38 +/- 4%. In group II phlorizin (100 mg/kg body wt, infused intravenously) during hyperglycaemia stimulated bicarbonate-dependent bile secretion by 35 +/- 5%. In group III bile secretion was continuously stimulated by infusion of Na-taurocholate. Hyperglycaemia reduced bicarbonate-dependent bile secretion by 33 +/- 4%, but after phlorizin both bile acid- and bicarbonate-dependent bile secretion increased on average by 121 +/- 8%. The osmotic effect of hyperglycaemia cannot be blocked by phlorizin, but judged by the effect on bile secretion, phlorizin may decrease the cholestatic effect induced by metabolism of glucose. Phlorizin could be an interesting compound for use in solutions for organ preservation.     

Eight weeks of moderate-intensity exercise training increases heart rate variability in sedentary postmenopausal women

Background

Regular exercise is associated with increased heart rate variability (HRV). However, results from studies examining the effect of exercise training on HRV in postmenopausal women are inconclusive. In addition, the effect of hormone replacement therapy (HRT) on HRV remains a subject of speculation.

Methods

We examined 88 sedentary postmenopausal women in a randomized controlled trial who were assigned to exercise (n = 49) or control (n = 39) groups. The exercising women performed 8 weeks of aerobic exercise training at a heart rate equivalent to 50% of VO_2max, consisting on average of 44 minutes per session, 3 to 4 times per week. Resting HRV was measured in each participant at baseline and after 8 weeks of intervention. Ten minutes of resting R-R intervals were analyzed by time (standard deviation of mean R-R intervals, root of mean square successive differences) and frequency domain methods: low-frequency (LF) was defined as 0.04 to 0.15 Hz, high-frequency (HF) as 0.15 to 0.40 Hz, and total spectral power as 0.00 to 0.40 Hz. The LF and HF components in normalized units were also calculated.

Results

At baseline, there were no significant differences in HRV between control and exercise groups. Additionally, there were no differences in any HRV variables when women were grouped by HRT use (no HRT, estrogen-only HRT, and progestin-containing HRT). After 8 weeks, women randomly assigned to the exercise group increased all absolute time and frequency domain indexes (all P < .001) and reduced resting heart rate (P = .002) compared with women in the control group. The LF and HF components expressed as normalized units remained unchanged after exercise intervention. Additionally, HRT use did not modify the exercise-induced changes in HRV.

Conclusions

We conclude that moderate aerobic exercise increases HRV in sedentary postmenopausal women. This benefit is not influenced by the use of HRT.     

GnRH increases glucose transporter-1 expression and stimulates glucose uptake in the gonadotroph

GnRH is the main regulator of the hypothalamic-pituitary-gonadal (H-P-G) axis. GnRH stimulates the pituitary gonadotroph to synthesize and secrete gonadotrophins (LH and FSH), and this effect of GnRH is dependent on the availability of glucose and other nutrients. Little is known about whether GnRH regulates glucose metabolism in the gonadotroph. This study examined the regulation of glucose transporters (Gluts) by GnRH in the LβT2 gonadotroph cell line. Using real-time PCR analysis, the expression of Glut1, -2, -4, and -8 was detected, but Glut1 mRNA expression level was more abundant than the mRNA expression levels of Glut2, -4, and -8. After the treatment of LβT2 cells with GnRH, Glut1 mRNA expression was markedly induced, but there was no GnRH-induction of Glut2, -4, or -8 mRNA expression in LβT2 cells. The effect of GnRH on Glut1 mRNA expression is partly mediated by ERK activation. GnRH increased GLUT1 protein and stimulated GLUT1 translocation to the cell surface of LβT2 cells. Glucose uptake assays were performed in LβT2 cells and showed that GnRH stimulates glucose uptake in the gonadotroph. Finally, exogenous treatment of mice with GnRH increased the expression of Glut1 but not the expression of Glut2, -4, or -8 in the pituitary. Therefore, regulation of glucose metabolism by GnRH via changes in Gluts expression and subcellular location in the pituitary gonadotroph reveals a novel response of the gonadotroph to GnRH.     

Total cholesterol and HDL-cholesterol changes during acute, moderate-intensity exercise in men and women

Chronic endurance exercise training has been associated with decreased levels of total cholesterol and increased HDL-cholesterol. To our knowledge rapid changes in cholesterol and HDL-cholesterol during acute exercise have not been described under controlled conditions. We studied 28 subjects (14 males and 14 females) during bicycle exercise for 40 min at a work intensity of 55% of their maximal oxygen consumption. Total and HDL-cholesterol levels were measured (and LDL-cholesterol calculated) at rest, 10, 20, 30, and 40 min of exercise, and 15 min postexercise. There was a significant (p less than 0.001) increase in HDL-cholesterol levels at 10 min of exercise (58.8 +/- 13.9 mg/dl, mean +/- SD) above rest (53.1 +/- 13.4 mg/dl) for all subjects. This increase persisted (p less than 0.001) at all time points throughout the exercise session, but declined by 15 min postexercise. There was a small, insignificant decline in LDL-cholesterol. It is concluded that apparent favorable changes in lipoprotein patterns occur acutely, and are sustained during short-term, moderate intensity exercise. Analyses of these changes appears necessary if the biochemical mechanisms which underlie these metabolic alterations are to be elucidated.     

Increased tumour necrosis factor-alpha plasma levels during moderate-intensity exercise in COPD patients.

Post-training downregulation of muscle tumour necrosis factor (TNF)-alpha messenger ribonucleic acid (mRNA) expression and decrease in cellular TNF-alpha levels have been reported in the elderly. It is hypothesised that chronic obstructive pulmonary disease (COPD) patients may not show these adaptations due to their reduced ability to increase muscle antioxidant capacity with training. Eleven COPD patients (forced expiratory volume in one second 40 +/- 4.4% of the predicted value) and six age-matched controls were studied. Pre- and post-training levels of TNF-alpha, soluble TNF receptors (sTNFRs: sTNFR55 and sTNFR75) and interleukin (IL)-6 in plasma at rest and during exercise and vastus lateralis TNF-alpha mRNA were examined. Moderate-intensity constant-work-rate exercise (11 min at 40% of pretraining peak work-rate) increased pretraining plasma TNF-alpha levels in COPD patients (from 17 +/- 3.2 to 23 +/- 2.7 pg x mL(-1); p<0.005) but not in controls (from 19 +/- 4.6 to 19 +/- 3.2 pg x mL(-1)). No changes were observed in sTNFRs or IL-6 levels. After 8 weeks' endurance training, moderate-intensity exercise increased plasma TNF-alpha levels similarly to pretraining (from 16 +/- 3 to 21 +/- 4 pg x mL(-1); p<0.01). Pretraining muscle TNF-alpha mRNA expression was significantly higher in COPD patients than in controls (29.3 +/- 13.9 versus 5.0 +/- 1.5 TNF-alpha/18S ribonucleic acid, respectively), but no changes were observed after exercise or training. It is concluded that moderate-intensity exercise abnormally increases plasma tumour necrosis factor-alpha levels in chronic obstructive pulmonary disease patients without exercise-induced upregulation of the tumour necrosis factor-alpha gene in skeletal muscle.     

Nocturnal decrease in glucose tolerance during constant glucose infusion

Studies comparing glucose tolerance in the morning vs. that in the evening have suggested that time of day may influence glucose regulation. To examine the variation in glucose tolerance throughout the 24-h span, normal subjects were given an iv glucose infusion at a constant rate of either 5 or 8 g/kg.24 h during 30 h, and plasma levels of insulin and glucose were measured at 15-min intervals for the last 24 h of the infusion. The timing of initiation of the infusion was varied to differentiate effects of time of day from effects of duration of the infusion. A nocturnal elevation of glucose levels, culminating around midsleep and corresponding to an increase of about 15% above daytime levels, was observed in all subjects. The timing of this nocturnal maximum was not dependent on the rate of the infusion or on the time elapsed since the beginning of the infusion. Insulin levels did not show a consistent diurnal pattern. Both insulin and glucose exhibited large ultradian oscillations recurring at 100- to 150-min intervals. The amplitude of these oscillations increased with the rate of glucose infusion. These ultradian oscillations of glucose and insulin levels were temporally correlated, with a tendency for glucose pulses to lead insulin pulses by 15-30 min. These results demonstrate in normal subjects the existence of a diurnal variation in glucose tolerance distinct from the dawn phenomenon observed in diabetic subjects and indicate that spontaneous 100- to 150-min oscillations in peripheral glucose and insulin levels characterize stimulated pancreatic function, with the amplitude of the oscillations being dependent on the size of the stimulus.     

Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients

Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.     

Somatostatin infusion inhibits glucose production in burn patients

The acute response to a continuous infusion of somatostatin (0.1-0.15 micrograms/kg min) for between 30 to 180 min in five burn patients was investigated. In all patients the somatostatin reduced both insulin and glucagon levels, and the glucagon was reduced to a greater extent (on a molar basis) than the insulin. In all cases, the rate of production of glucose measured by the primed-constant infusion of 6,6-D2-glucose was suppressed during the infusion. Plasma glucose concentration, however, did not change in a predictable manner. Glucose clearance was consistently depressed, and the magnitude of change in glucose clearance was directly correlated to the magnitude of the reduction in insulin concentration induced by the somatostatin infusion (P less than 0.01). In one additional study, insulin was infused during the somatostatin infusion in order to maintain the basal level of insulin throughout the infusion, thus creating a selective drop in glucagon concentration. In this case, glucose clearance did not fall and the plasma glucose concentration declined owing to the lower rate of glucose production. These results suggested that in burn patients hyperglucagonemia stimulates glucose production and that insulin is effective in enhancing glucose clearance.     

Indinavir increases glucose production in healthy HIV-negative men

In the absence of HIV infection, changes in adipose tissue and lipid levels, HIV protease inhibitor therapy increases fasting glucose levels,suggestive of hepatic insulin resistance. After 4 weeks of indinavir treatment in nine HIV-negative healthy men, fasting glucose production and glycogenolysis were significantly increased. During the euglycemic hyperinsulinemic clamp, indinavir blunted the ability of insulin to suppress glucose production. Therefore, indinavir worsens hepatic insulin sensitivity, increasing endogenous glucose production.     

Exogenous nitric oxide increases basal leg glucose uptake in humans

This study addressed the role of blood flow and nitric oxide in leg glucose uptake. Seven subjects (5 men, 2 women) were studied during conditions of resting blood flow and increased blood flow, achieved by infusion of the nitric oxide (NO) donor sodium nitroprusside (SNP) into the femoral artery. Femoral arterial and venous blood samples were obtained and blood flow was determined by infusion of indocyanine green dye. SNP infusion significantly increased leg blood flow (769 +/- 103 v 450 +/- 65 mL. min(-1). leg(-1), P <.001), but did not affect arterial (4.68 +/- 0.13 mmol/L control, 4.63 +/- 0.09 mmol/L SNP) or venous (4.60 +/- 0.14 mmol/L control, 4.54 +/- 0.10 mmol/L SNP) glucose concentrations. Glucose uptake was significantly (P <.01) higher during SNP infusion (65 +/- 6 micromol. min(-1). leg(-1)) than during the basal period (34 +/- 6 micromol. min(-1). leg(-1)), whereas lactate release was unaffected (rest, 45 +/- 11 micromol. min(-1). leg(-1); SNP, 42 +/- 14 micromol. min(-1). leg(-1)). We conclude that blood flow and/or NO increase basal leg glucose uptake.     

Chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport.

Leptin, the product of the ob gene, has been shown to reduce fat mass, food intake, hyperglycemia, and hyperinsulinemia and to increase whole-body glucose disposal. However, it is unknown if leptin improves insulin action in skeletal muscle. Therefore, the purpose of this investigation was to determine if chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport. Sixty-nine female Sprague-Dawley rats (240 to 250 g) were randomly assigned to one of three groups: (1) control, (2) pair-fed, and (3) leptin. All animals were subcutaneously implanted with miniosmotic pumps that delivered 0.5 mg leptin/kg/d to the leptin animals and vehicle to the control and pair-fed animals for 14 days. Following this 14-day period, all animals were subjected to hindlimb perfusion to determine the rates of skeletal muscle glucose uptake and 3-O-methyl-D-glucose (3-MG) transport under basal, submaximal (500 microU/mL), and maximal (10,000 microU/mL) insulin concentrations. Chronic leptin treatment significantly increased (P < .05) the rate of glucose uptake across the hindlimb by 27%, 32%, and 47% under basal, submaximal, and maximal insulin, respectively, compared with the control and pair-fed condition. However, when the submaximal rate of glucose uptake was expressed as a percentage of maximal insulin-stimulated glucose uptake, no differences existed among the groups, indicating that leptin treatment does not increase insulin sensitivity. Rates of 3-MG transport in the soleus, plantaris, and white and red portions of the gastrocnemius (WG and RG) were significantly increased (P < .05) in leptin animals under all perfusion conditions. 3-MG transport was not different between control and pair-fed animals. Collectively, these findings suggest that improvements in insulin-stimulated skeletal muscle glucose uptake and transport following chronic leptin treatment result from increased insulin responsiveness.     

Amlodipine increases nitric oxide production in exhaled air during exercise in patients with essential hypertension

BACKGROUND: Endothelial production of nitric oxide (NO) is attenuated in patients with essential hypertension. We investigated whether treatment with amlodipine increased exhaled NO output (VNO) at rest and during exercise in patients with essential hypertension. METHODS: We studied the effect of amlodipine in seven untreated hypertensive patients. Cardiopulmonary exercise testing and NO measurement of exhaled air were performed on these patients before and after 2 months of amlodipine treatment. RESULTS: Amlodipine decreased blood pressure (BP) both at rest and during exercise (at rest: 147.1 +/- 6.4 [SEM]/89.9 +/- 4.4 v 133.6 +/- 5.4/82.7 +/- 3.9 mm Hg, P <.05; at peak exercise: 224.9 +/- 8.0/113.1 +/- 5.3 v 207.0 +/- 6.0/100.7 +/- 5.0 mm Hg, P <.05) without affecting heart rate (at rest: 67.6 +/- 3.9 v 70.4 +/- 4.5 beats/min, P =.33; peak exercise: 146.4 +/- 7.4 v 144.0 +/- 7.2 beats/min, P =.49). Amlodipine did not affect minute ventilation (VE) at rest or during exercise. It did not alter anaerobic threshold, peak oxygen uptake (peak VO(2)), or peak workload. However, after amlodipine treatment, VNO was significantly greater both at rest (130.8 +/- 19.4 v 180.4 +/- 24.8 nL/min, P <.05) and at peak exercise (380.0 +/- 47.5 v 582.6 +/- 74.3 nL/min, P <.05). CONCLUSIONS: Amlodipine increased NO production, at least in the pulmonary circulation, in patients with essential hypertension. In addition to its antihypertensive effect, the enhancement of NO production by amlodipine in the vasculature of other organs may contribute to its beneficial effects on the cardiovascular system.     

Vascular compliance during insulin infusion and oral glucose challenge

BackgroundVascular stiffness predicts cardiovascular disease (CVD). Pulse wave velocity (PWV), reflecting vascular stiffness, though determined largely by mean arterial pressure; is also sensitive to insulin and glucose. Capacitance in small (C2) and large vessels (C1), reflecting vascular responsiveness to hemodynamic challenges, may also be influenced by insulin and glucose. The purpose of this study was to test the effects of insulin and glucose on arterial function in healthy individuals.MethodsExcluding people with BMI >27.5 kg/m², diabetes, impaired glucose tolerance, hypotension or hypertension, 14 adults were enrolled. Subjects underwent randomly either a 2 h euglycemic clamping, or a 2-h OGTT first, with the other procedure performed up to one month later. Pulse wave velocity (PWV) and vascular compliance were measured by tonometry.ResultsThe sample (n = 14) included 10 Caucasians, 8 males, mean age = 28 ± 8 years, BMI = 24 ± 2 kg/m², SBP = 113 ± 9 mmHg, DBP = 70 ± 6 mmHg, and glucose = 73 ± 11 mg/dl. There was a significant increase in mean PWV between 30 and 120 min (p = 0.049), during the euglycemic clamp. PWV change during OGTT was not significant.ConclusionPWV increased during euglycemic clamp conditions without significant changes in C1 or C2. Oral glucose had less effect on PWV and changes in C1 and C2 were minimal. These data support mechanisms that link insulin and arterial stiffness in vascular physiology and suggest that part of the mechanism of CVD in insulin resistance may relate to insulin's effects on arterial stiffness.     

Effect of difference in glucose infusion rate on quantification of hepatic glucose production

This study was carried out to determine whether hepatic glucose production (HGP) could be suppressed in normal subjects by infusing different amounts of glucose, in the absence of significant changes in steady state plasma glucose (SSPG) or insulin (SSPI) concentrations. Consequently, subjects were infused with somatostatin (215 nmol/h), insulin (28.7 pmol/m2.min), and amounts of glucose varying from 0-200 mumol/m2.min in the absence or presence of glucagon (5.2 pmol/m2.min). SSPI concentrations were constant (60-70 pmol/L) during these studies, and values for the total glucose appearance rate (glucose infusion rate plus HGP) and SSPG did not vary significantly as a function of the rate of exogenous glucose infusion. However, values for HGP fell in response to increases in glucose infusion rate and could be suppressed to approximately 50% of the original value despite the fact that SSPG, SSPI, and glucose appearance rate did not change significantly. These data indicate that HGP can be regulated by varying the rate of exogenous glucose infusion during glucose clamp studies.     

Glucagon and hepatic glucose production: modulation by low-dose bradykinin infusion

The effect of a low-dose bradykinin (BK) infusion (30 ng/kg min) on glucagon-induced hepatic glucose production and glucose cycling was studied in five normal volunteers. Studies were performed during constant insulin concentration as achieved by simultaneous somatostatin infusion and insulin replacement. In the basal period glucagon was infused at a rate of 0.5 ng/kg min. Then, glucagon infusion rate was increased to 3 ng/kg min to test the response to hyperglucagonemia. In a second set of experiments BK was infused concomitantly with the high dose glucagon. Each subject served as his own control. BK infusion did not prevent the glucagon-induced rise in hepatic glucose production and glucose cycling. However, at a later stage BK accelerated the negative feedback mechanisms activated by glucagon (decrease in hepatic glucose production) significantly. These findings suggest that intravenous BK may interact with mechanisms involved in the down-regulation of hepatic glucagon effects.     

Liver-selective glucocorticoid receptor antagonism decreases glucose production and increases glucose disposal, ameliorating insulin resistance

It is unclear how hepatic glucocorticoid receptor (GR) function and hypothalamic-pituitary-adrenal axis tone contribute to the diabetic state and in particular whole-body glucose fluxes. We have previously demonstrated that long-term exposure to hepatic GR inhibition lowers glucose levels in ob/ob mice (J Pharmacol Exp Ther 2005;314:191). The purpose of this study was to determine the effects of a novel GR antagonist (A-348441) on whole-body glucose fluxes in a model of insulin resistance, the Zucker fatty (fa/fa) rat. After an overnight fast, euglycemic-hyperinsulinemic clamp studies were performed 2 hours after single oral dosing as follows: (1) A-348441 at 100 mg/kg or (2) vehicle. Furthermore, effects of 1 week of treatment with either vehicle or A-348441 (3, 10, 30, or 100 mg/kg PO, once per day) were investigated in separate groups of rats fasted overnight and given a final dose of their respective compound, followed 2 hours later by a euglycemic-hyperinsulinemic clamp. One week after catheter implantation, body weight returned to presurgery levels, with no difference between groups. A single, 100-mg/kg dose of A-348441 significantly increased glucose infusion rate 4-fold (P < .05) and reduced endogenous glucose production by 37% (P < .05) but did not change glucose disposal. After 1 week of sub-long-term dosing, fasting glucose levels were reduced dose-dependently with A-348441 vs vehicle (-8%, not significant; -14%, -20%, and -25%, P < .05, at 3, 10, 30, and 100 mg/kg, respectively) with no observed hypoglycemia or change in fasting insulin levels. A-348441 increased the glucose infusion rates after 1-week treatment by 1.3-, 5.7-, 7.3-, and 6.4-fold (P < .05). Endogenous glucose production was decreased (-25%, -44%, -50%, and -61%, P < .05), whereas glucose disposal was increased (29% and 13%, not significant; 23% and 34%, P < .05), with A-348441. In summary, single-dose treatment with the liver-selective GR antagonist A-348441 decreases glucose production with no effect on glucose disposal or fasting glucose levels. After 1 week of treatment with A-348441, (1) there was no effect on body weight, (2) fasting glucose levels decreased, (3) both glucose disposal and glucose infusion rate increased during clamping, and (4) endogenous glucose production was greatly reduced. In addition, hepatic glucose production was highly correlated with fasting glucose levels (r = 0.97). In conclusion, these results indicate that A-348441 increases insulin sensitivity at both the liver and peripheral tissues, leading toward a normalization of the insulin resistant state. Furthermore, with 1-week vs single-dose liver-selective glucocorticoid antagonism, we have determined that the peripheral effect is secondary to the primary event of reduced hepatic glucose production. The approach of inhibiting the hepatic GR may be an advantageous treatment paradigm for individuals with type 2 diabetes mellitus.