Reducing plasma free fatty acids by acipimox improves glucose tolerance in high‐fat fed mice

To study whether free fatty acids (FFAs) contribute to glucose intolerance in high‐fat fed mice, the derivative of nicotinic acid, acipimox, which inhibits lipolysis, was administered intraperitoneally (50 mg kg^?1) to C57BL/6J mice which had been on a high‐fat diet for 3 months. Four hours after administration of acipimox, plasma FFA levels were reduced to 0.46 ± 0.06 mmol L^?1 compared with 0.88 ± 0.10 mmol L^?1 in controls (P < 0.001). At this point, the glucose elimination rate after an intravenous glucose load (1 g kg^?1) was markedly improved. Thus, the elimination constant (K_G) for the glucose disposal between 1 and 50 min after the glucose challenge was increased from 0.54 ± 0.01% min^?1 in controls to 0.66 ± 0.01% min^?1 by acipimox (P < 0.001). In contrast, the acute insulin response to glucose (1–5 min) was not significantly different between the groups, although the area under the insulin for the entire 50‐min period after glucose administration was significantly reduced by acipimox from 32.1 ± 2.9 to 23.9 ± 1.2 nmol L^?1 × 50 min (P=0.036). This, however, was mainly because of lower insulin levels at 20 and 50 min because of the lowered glucose levels. In contrast, administration of acipimox to mice fed a normal diet did not affect plasma levels of FFA or the glucose elimination or insulin levels after the glucose load. It is concluded that reducing FFA levels by acipimox in glucose intolerant high‐fat fed mice improves glucose tolerance mainly by improving insulin sensitivity making the ambient islet function adequate, suggesting that increased FFA levels are of pathophysiological importance in this model of glucose intolerance.     

Conditional, tissue-specific expression of Q205L Gαi2 in vivo mimics insulin action

 Deficiency of the G protein subunit G_αi2 that is known to mediate the inhibitory control of adenylylcyclase impairs insulin action [11]. Using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional, tissue-specific expression of the constitutively active mutant form (Q205L) of G_αi2 was achieved in mice harboring the transgene. Expression of Q205L G_αi2 was detected in liver and adipose tissue of transgenic mice. Whereas the G_αi2 deficient mice displayed blunted glucose tolerance, the Q205L G_αi2 expressing mice displayed enhanced glucose tolerance. Hexose transport and the recruitment of GLUT4, but not GLUT1, transporters to the membrane were elevated in adipocytes from Q205L G_αi2 expressing mice in the absence of insulin. Additionally, hepatic glycogen synthase was found to be activated in Q205L G_αi2 expressing mice, in the absence of the administration of insulin. Serum insulin levels in transgenic mice fasted overnight were equivalent to those of their control littermates. These data demonstrate that much as G_αi2 deficiency leads to insulin resistance, expression of Q205L constitutively active G_αi2 mimics insulin action in vivo, reflecting a permissive role of G_αi2 in signaling via this growth factor receptor tyrosine kinase linked pathway. Received: 1 October 1996 / Accepted: 18 December 1996     

Ventilation during air breathing and in response to hypercapnia in 5 and 16 month-old <Emphasis Type="Italic">mdx</Emphasis> and C57 mice

Previous studies have shown a blunted ventilatory response to hypercapnia in mdx mice older than 7 months. We test the hypothesis that in the mdx mice ventilatory response changes with age, concomitantly with the increased functional impairment of the respiratory muscles. We thus studied the ventilatory response to CO₂ in 5 and 16 month-old mdx and C57BL10 mice (n = 8 for each group). Respiratory rate (RR), tidal volume (VT), and minute ventilation (VE) were measured, using whole-body plethysmography, during air breathing and in response to hypercapnia (3, 5 and 8% CO₂). The ventilatory protocol was completed by histological analysis of the diaphragm and intercostals muscles. During air breathing, the 16 month-old mdx mice showed higher RR and, during hypercapnia (at 8% CO₂ breathing), significantly lower RR (226 ± 26 vs. 270 ± 21 breaths/min) and VE (1.81 ± 0.35 vs. 3.96 ± 0.59 ml min⁻¹ g⁻¹) (P < 0.001) in comparison to C57BL10 controls. On the other hand, 5 month-old C57BL10 and mdx mice did not present any difference in their ventilatory response to air breathing and to hypercapnia. In conclusion, this study shows similar ventilation during air breathing and in response to hypercapnia in the 5 month-old mdx and control mice, in spite of significant pathological structural changes in the respiratory muscles of the mdx mice. However in the 16 month-old mdx mice we observed altered ventilation under air and blunted ventilation response to hypercapnia compared to age-matched control mice. Ventilatory response to hypercapnia thus changes with age in mdx mice, in line with the increased histological damage of their respiratory muscles. J. Gayraud and S. Matecki contributed equally to this work     

Effects of glucose ingestion or glucose infusion on fuel substrate kinetics during prolonged exercise

To determine if bypassing both intestinal absorption and hepatic glucose uptake by intravenous glucose infusion might increase the rate of muscle glucose oxidation above 1 g · min^–1, ten endurance-trained subjects were studied during 125 min of cycling at 70% of peak oxygen uptake (VO_{2 peak}). During exercise the subjects ingested either a 15 g · 100 ml^–1 U-¹⁴C labelled glucose solution or H₂O labelled with a U-¹⁴C glucose tracer for the determination of the rates of plasma glucose oxidation (Rox) and exogenous carbohydrate (CHO) oxidation from plasma¹⁴C glucose and¹⁴CO₂ specific activities, and respiratory gas exchange. Simultaneously, 2-³H glucose was infused at a constant rate to measure glucose turnover, while unlabelled glucose (25% dextrose) was infused into those subjects not ingesting glucose to maintain plasma glucose concentration at 5 mmol · l^–1. Despite similar plasma glucose concentrations [ingestion 5.3 (SEM 0.13) mmol · l^–1; infusion 5.0 (0.09) mmol · l^–1], compared to glucose infusion, CHO ingestion significantly increased plasma insulin concentrations [12.9 (1.0) vs 4.8 (0.5) mU · l^–1;P<0.05], raised total Rox values [9.5 (1.2) vs 6.2 (0.7) mmol · 125 min^–1 kg fat free mass^–1 (FFM);P<0.05] and rates of CHO oxidation [37.2 (2.8)vs 24.1 (3.9) mmol · 125 min^–1 kg FFM^–1;P<0.05]. An increased reliance on CHO metabolism with CHO ingestion was associated with a decrease in fat oxidation. Whereas the contribution from fat oxidation to energy production increased to 51 (10)% with glucose infusion, it only reached 18 (4)% with glucose ingestion (P<0.05). Despite these differences in plasma insulin concentration and rates of fat oxidation, the rates of glucose oxidation by muscle were similar after 125 min of exercise for both trials [ingestion 93 (8); infusion 85 (5) mol · min^–1 kg FFM^–1], suggesting that peak rates of muscle glucose oxidation were primarily dependent on blood glucose concentration which, in turn, regulated the hepatic appearance of ingested CHO.     

Influence of muscle mass and work on post-exercise glucose and insulin responses in young untrained subjects

The 18 h post-exercise glucose and insulin responses of six male and six female subjects were measured following one- or two-leg cycling to determine the influence of muscle mass involvement and work. Each subject performed three exercise trials on a Cybex Met 100 cycle ergometer: (1) two-leg exercise for 30 min at 60% of the two-leg VO _{2 max}; (2) one-leg exercise for 30 min at 60% of one-leg VO _{2 max}; and (3) one-leg exercise (one-legTW) at 60% of the one-leg VO _{2 max} with the total work performed equal to that of the two-leg trial (duration ≈50 min). These trials were preceded by 2 days of inactivity and followed by an 18 h post-exercise 75 g oral glucose tolerance test (OGTT). The glucose response during the baseline OGTT demonstrated that the subjects had normal glucose tolerance with fasting serum glucose levels of 5.1 mM , and 1 and 2 h serum glucose less than 7.8 mM , respectively. The 18 h post-exercise glucose responses were significantly lower following the two-leg trial (P < 0.05), with the area under the curve values being 129.9 mM h^?1 less than the resting control level. The 18 h post-exercise insulin AUC response of the two-leg trial was significantly lower than either of the one-leg responses (14.7 pM below the one-leg and 5.0 pM below the one-leg TW) but was not associated with a change in C-peptide. The 18 h post-exercise insulin levels of the one-leg and one-legTW trials were above or near the resting control values, but were not accompanied by a significant change in C-peptide. In conclusion, the data presented here show that the amount of muscle tissue utilized during an exercise bout can influence both the glucose and insulin responses, whereas the amount of total work employed during the exercise had no effect on either of these parameters.     

Oxidation of [13C]glucose ingested before and/or during prolonged exercise

Ingestion of glucose before exercise results in a transient increase in plasma insulin concentrations. We hypothesized that if glucose was also ingested during the exercise period the elevated plasma insulin concentration could increase exogenous glucose oxidation. The oxidation rate of glucose ingested 30 min before (50 g) and/or during (110 or 160 g in fractionated doses) exercise [120 min; 67.3 (1.2)% maximal O₂ uptake] was studied on six young male subjects, using ¹³C-labelling. Ingestion of glucose before exercise significantly increased plasma insulin concentration [from 196 (45) to 415 (57) pmol l^–1] but the value returned to pre-exercise level within the first 30 min of exercise in spite of a continuous increase in plasma glucose concentration. Ingestion of glucose 30 min before exercise did not increase the oxidation of exogenous glucose between minutes 30 and 60 during the exercise period [0.36 (0.03) vs 0.30 (0.02) g min^–1, when placebo or unlabelled glucose was ingested respectively]. Over the last 90 min of exercise, when glucose was ingested only during exercise, 49.2 (3.1) g [0.55 (0.04) g min^–1) was oxidized, while when it was ingested both before and during exercise, 65.7 (4.6) g [0.73 (0.05) g min^–1] was oxidized [26.7 (2.1) g of the 50 g ingested before exercise but only 39.0 (2.4) g of the 110 g ingested during the exercise period]. Thus, ingestion of glucose 30 min before the beginning of exercise did not enhance the oxidation rate of exogenous glucose ingested during the exercise period, although the total amount of exogenous glucose oxidized was larger than when ingested only during the exercise period.     

Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans

The effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose production and peripheral glucose utilization was investigated with or without infusion of somatostatin to inhibit insulin and glucagon secretion in 13 healthy, non-diabetic women aged 59 years. After 120 min 3-³H-glucose infusion, GLP-1 was added (4.5 pmol kg^?1 bolus + 1.5 pmol kg^?1 min^?1). Without somatostatin (n = 6), GLP-1 decreased plasma glucose (from 4.8 ± 0.2 to 4.2 ± 0.3 mmol L^?1, P = 0.007). Insulin levels were increased (48 ± 3 vs. 243 ± 67 pmol L^?1, P = 0.032), as was the insulin to glucagon ratio (P = 0.044). The rate of glucose appearance (R_a) was decreased (P = 0.003) and the metabolic clearance rate of glucose (MCR) was increased during the GLP-1 infusion (P = 0.024 vs. saline). Also, the rate of glucose disappearance (R_d) was reduced during the GLP-1 infusion (P = 0.004). Since R_a was reduced more than R_d, the net glucose flow was negative, which reduced plasma glucose. Somatostatin infusion (500 μg h^?1, n = 7) abolished the effects of GLP-1 on plasma glucose, serum insulin, insulin to glucagon ratio, R_a, R_d, MCR and net glucose flow. The results suggest that GLP-1 reduces plasma glucose levels mainly by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin to glucagon ratio in healthy subjects.     

Components of energy expenditure in themdx mouse model of Duchenne muscular dystrophy

Previous observations showing that basal heat production rates and glucose metabolism were reduced inmdx mouse skeletal muscles incubated in vitro led us to study the components of total energy expenditure by open-circuit indirect calorimetry in the intact, free-movingmdx mouse. Our purpose was to verify if themdx mouse exhibited whole-body alterations in energy metabolism. The results revealed that total and basal energy expenditure, as well as spontaneous activity, energetic cost of activity, and, therefore, energy expended in relation to activity were not significantly different in C57B1 / 10 (control) and in dystrophic (mdx) mice. In contrast, the thermic effect of food was 32% larger inmdx than in control mice and was accompanied by significant differences in postprandial glucose and lipid oxidation. The present in vivo study could not show a direct demonstration that impaired glucose metabolism by skeletal muscles participated in this phenomenon. However, since postprandial glucose metabolism by skeletal muscles contributes a significant part of the thermic effect of food, the present data are in line with previous studies in vitro that show thatmdx mouse skeletal muscles probably suffer an impaired control of their energy metabolism.     

Gender differences in the insulin-like growth factor axis response to a glucose load

Aims: The insulin‐like growth factors (IGFs) are thought to contribute to glucose homeostasis. The aim of our study was to examine the response of the IGFs and their binding proteins to an intravenous load of glucose in a cohort of young men and women with normal glucose tolerance. Methods: The intravenous glucose tolerance test (IVGTT) was used to quantify insulin sensitivity and insulin secretion in 160 adults aged 20–21 years in Adelaide, Australia. Serum IGF‐I, IGF‐II, IGF‐binding protein (IGFBP)‐1 and IGFBP‐3 were measured during the IVGTT. Results: Women were less insulin sensitive than men with higher fasting insulin (women 55.6 ± 4.4, men 44.1 ± 3.6 pmol L^?1, P = 0.001) and first phase insulin secretion (women 3490 ± 286, men 3038 ± 271 pmol L^?1 min, P = 0.042). Women showed lower fasting free IGF‐I (women 0.29 ± 0.02, men 0.36 ± 0.02 μg L^?1, P = 0.004) but higher IGFBP‐3 (women 46.3 ± 0.53, men 43.3 ± 0.58 mg dL^?1, P = 0.001) and higher IGFBP‐1 concentrations (women 37.0 ± 2.9, men 24.8 ± 2.3 μg L^?1, P = 0.012). IGFBP‐1 fell by 5 min and remained suppressed. IGFBP‐3 and total IGF‐I fell until 60 min rising again by 2 h. IGF and IGFBP values were all higher in women. IGFBP‐1 showed a negative association with fasting and stimulated insulin concentrations in both genders. First phase insulin secretion however showed positive correlations with IGFBP‐3 (r = 0.321, P = 0.004) and IGF‐I (r = 0.339 P = 0.002) in men but not women. Conclusion: Our data show that IGFBP‐1, IGFBP‐3 and IGF‐I show acute changes following a glucose load and there are marked gender differences in these responses.     

Glucose kinetics during prolonged exercise in euglycaemic and hyperglycaemic subjects

To determine the limits to oxidation of exogenous glucose by skeletal muscle, the effects of euglycaemia (plasma glucose 5 mM, ET) and hyperglycaemia (plasma glucose 10 mM, HT) on fuel substrate kinetics were evaluated in 12 trained subjects cycling at 70% of maximal oxygen uptake (VO_{2, max}) for 2 h. During exercise, subjects ingested water labelled with traces of U-¹⁴C-glucose so that the rates of plasma glucose oxidation (R _ox) could be determined from plasma ¹⁴C-glucose and expired ¹⁴CO₂ radioactivities, and respiratory gas exchange. Simultaneously, 2-³H-glucose was infused at a constant rate to estimate rates of endogenous glucose turnover (R _a), while unlabelled glucose (25% dextrose) was infused to maintain plasma glucose concentration at either 5 or 10 mM. During ET, endogenous liver glucose R _a (total R _a minus the rate of infusion) declined from 22.4±4.9 to 6.5±1.4 mol/min per kg fat-free mass [FFM] (P<0.05) and during HT it was completely suppressed. In contrast, R _ox increased to 152±21 and 61±10 mol/min per kg FFM at the end of HT and ET respectively (P<0.05). HT (i. e., plasma glucose 10 mM) and hyperinsulinaemia (24.5±0.9 U/ml) also increased total carbohydrate oxidation from 203±7 (ET) to 310±3 mol/min per kg FFM (P<0.0001) and suppressed fat oxidation from 51±3 (ET) to 18±2 mol/min per kg FFM (P<0.0001). As the rates of oxidation at more physiological euglycaemic concentrations of glucose were limited to 92±9 mol/ min per kg FFM, and were similar to those reported when carbohydrate is ingested, the results of the current study suggest that the concentrations of glucose and insulin normally present during prolonged, intense exercise may limit the rate of muscle glucose uptake and oxidation.     

Lack of dystrophin but normal calcium homeostasis in smooth muscle from dystrophic mdx mice

Summary The free cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in the dystrophin-lacking smooth muscle from mdx mice was studied to gain new insights into the relation between dystrophin and cytoplasmic Ca²⁺ hoemostasis, which was reported to be impaired in the mdx skeletal muscle. We observed that [Ca²⁺]_i, as measured with the fluorescent Ca²⁺ indicator fura-2, was not elevated in resting smooth muscle of the vas deferens from mdx mice, in comparison with control C57 mice. Changes of the external Ca²⁺ concentration evoked similar changes of [Ca²⁺]_i in mdx and control vas deferens. During contraction, cytosolic Ca²⁺ transients were identical, both in amplitude and in kinetics, whether or not dystrophin was present. Stretches evoked similar Ca²⁺ increases in muscles from both strains. Intracellular Ca²⁺ homeostasis appears to be unimpaired in mdx smooth muscle. Thus, the lack of dystrophin per se does not automatically induce a perturbation of Ca metabolism in muscle cells.     

Proliferative,structural and molecular features of the Mdx mouse prostate

The prostate is fundamental to the male reproductive process, and the stroma–epithelium interaction has an important role in prostate maintenance. Studies suggest that dystroglycan (DG) plays a role in cancer development in various organs. Thus, the aims of this work were to characterize morphological and proliferative features of the prostatic stroma and epithelium of mdx mice; to verify the immunolocalization of the α and β DG, IGF‐1 and laminin α3 receptors; and to relate those structural and molecular events to prostate pathogenesis and to verify the viability of this experimental model in prostate studies. Thirty male mice (mdx and C57BL10/Uni) were divided into control and mdx groups. Samples from the ventral prostate were collected for immunological, Western Blotting, transmission electron microscopy and morphometric analyses. Oestradiol and testosterone measurements were verified. The results showed diminished testosterone and increased oestradiol levels in the mdx group. Atrophied cells and hypertrophied stroma were seen in the mdx mice. Weak α and β DG and laminin α3 immunolocalization was demonstrated in the mdx group. Intense insulin‐like growth factor receptor α‐1 (IGFRα‐1) localization was identified in the mdx animals. Thus, mdx animals showed changes in molecular and structural integrity and proliferation signals, leading to glandular homoeostasis imbalance, and compromise of prostate function. Also, the steroid hormone imbalance and the increased IGF‐1 receptor level detected in mdx mice could be considered as a crucial factor in the pathogenesis of prostatic disorders.     

Effects of high glucose plus high insulin on proliferation and apoptosis of mouse endothelial progenitor cells

Objective:  To study the effects of high glucose plus high insulin (GI) on proliferation, apoptosis, morphology and differentiation of endothelial progenitor cells (EPC). Methods:  EPC were isolated and identified by magnetic cell sorting and flow cytometry. EPC proliferation and apoptosis were measured by MTT assay and Annexin-V/PI double labeling, respectively. Cell proliferation- and apoptosis-related factors were examined by Western blotting. Results:  Seven days after GI treatment, EPC were arrested at the G₀/G₁ phase. Treatment with high glucose alone (HG) or GI but not HI (high insulin alone) decreased EPC proliferation and their expression of cyclin E, cdk2 and PCNA compared to control. The inhibitory effects of HG on EPC proliferation and growth-related proteins were more significant than those of GI. HG, GI and HI promoted EPC apoptosis along with caspase-3 overexpression. Conclusion:  The result indicated that GI-induced apoptosis and growth inhibition might be one of mechanisms of EPC reduction and dysfunction in diabetes. Received 17 June 2008; accepted by I. Ahnfeld-R?nne 10 July 2008 W. Zhang, X. Wang: These authors contributed equally.     

Effect of a 2-h hyperglycemic-hyperinsulinemic glucose clamp to promote glucose storage on endurance exercise performance

Carbohydrate stores within muscle are considered essential as a fuel for prolonged endurance exercise, and regimes for enhancing such stores have proved successful in aiding performance. This study explored the effects of a hyperglycaemic–hyperinsulinemic clamp performed 18 h previously on subsequent prolonged endurance performance in cycling. Seven male subjects, accustomed to prolonged endurance cycling, performed 90 min of cycling at ~65% VO_2max followed by a 16-km time trial 18 h after a 2-h hyperglycemic–hyperinsulinemic clamp (HCC). Hyperglycemia (10 mM) with insulin infused at 300 mU/m²/min over a 2-h period resulted in a total glucose uptake of 275 g (assessed by the area under the curve) of which glucose storage accounted for about 73% (i.e. 198 g). Patterns of substrate oxidation during 90-min exercise at 65% VO_2max were not altered by HCC. Blood glucose and plasma insulin concentrations were higher during exercise after HCC compared with control (p < 0.05) while plasma NEFA was similar. Exercise performance was improved by 49 s and power output was 10–11% higher during the time trial (p < 0.05) after HCC. These data suggest that carbohydrate loading 18 h previously by means of a 2-h HCC improves cycling performance by 3.3% without any change in pattern of substrate oxidation.     

Metabolic response to prolonged cycling with 13C-glucose ingestion following downhill running

The purpose of this study was to describe the effect of muscle damage and delayed-onset muscle soreness (DOMS) on the metabolic response during a subsequent period of prolonged concentric exercise (120 min, ~61% O_2max, on a cycle ergometer), with ingestion of 3 g of ¹³C-glucose/kg body mass. We hypothesized that the oxidation of plasma and exogenous glucose would be reduced, while the oxidation of glucose arising from muscle glycogen would be increased. Six male subjects were studied during exercise in a control situation and 2 days following downhill running, at a time when plasma creatine kinase (CK) activity was increased, and DOMS was present. Carbohydrate and lipid oxidation were computed from indirect respiratory calorimetry corrected for protein oxidation, while the oxidation of plasma glucose and muscle glycogen were computed from ¹³CO₂ and the ratio of ¹³C/¹²C in the plasma glucose. All data were presented as the mean and the standard error of the mean. The oxidation of protein (~6% energy yield, in the control and the experimental trial), lipid (~15 and ~18%), and carbohydrate (~79 and ~76%), as well as that of plasma glucose (~41 and ~46%), glucose from the liver (~12 and ~14%), and glucose from muscle glycogen (~38 and ~31%) were not significantly different between the control and experimental (DOMS) trials. The response of the plasma glucose, insulin, lactate, and free fatty acid concentrations was not modified by the previous eccentric exercise. These results indicate that the metabolic response to prolonged concentric exercise is not modified by muscle damage and DOMS resulting from a bout of eccentric exercise performed 2 days before.     

Gender difference in the metabolic response to prolonged exercise with [13C]glucose ingestion

The metabolic response to a 120-min cycling exercise with ingestion of [¹³C]glucose (3 g kg^–1) was compared in women in the follicular phase of the cycle [n=6; maximum rate of oxygen uptake (O_2max) 44.7 (2.6) ml kg^–1 min^–1] and in men [n=6; O_2max 54.2 (4.3) ml kg^–1 min^–1] working at the same relative workload (~65% O_2max: 107 and 179 W in women and men, respectively). We hypothesized that the contribution of endogenous substrate oxidations (indirect respiratory calorimetry corrected for protein oxidation) to the energy yield will be similar in men and women, but that women will rely more than men on exogenous glucose oxidation. Over the exercise period, the respective contributions of protein, lipid and carbohydrate oxidation to the energy yield, were similar in men [3.7 (0.9), 21.7 (2.9) and 74.6 (3.5)%] and women [3.4 (0.8), 21.5 (2.2), 75.1 (2.5)%]. The rate of exogenous glucose oxidation was ~45% lower in women than men (0.5 and 0.6 g min^–1 vs 0.7 and 0.9 g min^–1, between min 40 and 80, and min 80 and 120, respectively). However, when the ~39% difference in absolute workload and energy expenditure was taken into account, the contribution of exogenous glucose oxidation to the energy yield was similar in men and women: 22.5 vs 24.2% between min 40 and 80, and 25.7 and 28.5% between min 80 and 120, respectively. These data indicate that when fed glucose, the respective contributions of the oxidation of the various substrates to the energy yield during prolonged exercise at the same %O_2max are similar in men and in women in the follicular phase of the cycle.     

Dynamics of insulin action in hypertension: assessment from minimal model interpretation of intravenous glucose tolerance test data

Based on glucose kinetics minimal model (GKMM) interpretation of frequently sampled intravenous glucose tolerance test (FSIGTT), the aim was to broaden the characterization of insulin-mediated glucose disposal in hypertension by aid of a dynamic insulin sensitivity index, S_\textI^\textD S_{\text{I}}^{\text{D}} , and the related efficiency, h = S_\textI^\textD /S_\textI , \eta = S_{\text{I}}^{\text{D}} /S_{\text{I}} , of the metabolic system to convert the maximal individual response capacity, measured by S _I, into an effective insulin control on glucose. The C-peptide minimal model (CPMM) was used to interpret the role of β-cell function. Plasma glucose, insulin, and C-peptide concentrations were measured, during a 5-h FSIGTT, in eighteen normoglycemic individuals: ten hypertensive patients (H-group) and eight normotensive subjects (N-group) with no metabolic syndrome. Compared to our N-group, the H-group showed a significant (P < 0.05) reduction of both S _I (56%) and S_\textI^\textD S_{\text{I}}^{\text{D}} (50%), no significant change of η, a significant increase of both the first-phase β-cell responsiveness to glucose (105%) and total insulin secretion (55%), and no significant change in disposition indexes, defined as the product of insulin sensitivity (either S _I and S_\textI^\textD S_{\text{I}}^{\text{D}} ) and β-cell responsiveness. These findings suggest that, in spite of no change of efficiency, insulin resistance in normoglycemic hypertensive patients is primarily compensated by an increase in first-phase insulin secretion to preserve glucose tolerance to intravenous glucose load.     

Control oriented model of insulin and glucose dynamics in type 1 diabetics

The aim of the study was to realize a mathematical model of insulin–glucose relationship in type I diabetes and test its effectiveness for the design of control algorithms in external artificial pancreas. A new mathematical model, divided into glucose and insulin sub-models, was developed from the so-called “minimal model”. The key feature is the representation of insulin sensitivity so as to permit the personalisation of the parameters. Real-time applications are based on an insulin standardised model. Clinical data were used to estimate model parameters. Root mean square error between simulated and real blood glucose profiles (G_rms) was used to evaluate system efficacy. Results from parameter estimation and insulin standardisation showed a good capability of the model to identify individual characteristics. Simulation results with a G_rms 1.30 mmol/l in the worst case testified the capacity of the model to accurately represent glucose–insulin relationship in type 1 diabetes allowing self tuning in real time.     

Involvement of phosphatidylinositol 5-phosphate in insulin-stimulated glucose uptake in the L6 myotube model of skeletal muscle

The phosphoinositide phospholipid PtdIns5P has previously been implicated in insulin-stimulated translocation of the glucose transporter GLUT4 into the plasma membrane of adipocytes, but its potential role in glucose transport in muscle has not been explored. The involvement of PtdIns5P in insulin-stimulated glucose uptake was therefore investigated in myotubes of the skeletal muscle cell line L6. Stimulation with insulin produced a transient increase in PtdIns5P, which was abolished by the over-expression of the highly active PtdIns5P 4-kinase PIP4Kα. PIP4Kα over-expression also abolished both the enhanced glucose uptake and the robust peak of PtdIns(3,4,5)P ₃ production stimulated by insulin in myotubes. Delivery of exogenous PtdIns5P into unstimulated myotubes increased Akt phosphorylation, promoted GLUT4 relocalisation from internal membrane to plasma membrane fractions and its association with plasma membrane lawns and also stimulated glucose uptake in a tyrosine kinase and phosphoinositide 3-kinase (PI 3-kinase)-dependent fashion. Our results are consistent with a role for insulin-stimulated PtdIns5P production in regulating glucose transport by promoting PI 3-kinase signalling.     

Insulin production by pancreatic islets of obese-hyperglycemic mice cultured for one week in different glucose concentrations

Anderson , A., K. Asplund and R. Larkins , Insulin production by pancreuric islets of obese-hyperglycemic mice cultured for one week in different glucose concentrations. Acta physiol. scand. 1978. 104. 377–385. Culture of pancreatic islets isolated from obese-hyperglycemic mice (gene symbol oh) for one week in media containing widely different concentrations of glucose (3.3, 5.6 or 16.7 mM) was found to markedly influence the functional behaviour of the islet B-cells. Thus, the insulin content of islets cultured at 3.3 or 16.7 mM glucose (subphysiological or supraphysiological glucoce concentrations respectively) was markedly reduced. Islets cultured in 5.6 or 16.7 mM glucose displayed a normal insulin secretory response when stimulated with glucose, whereas islets cultured in a subnormal glucose concentration (3.3 mM) showed a reduced insulin response to glucose stimulation in batch type incubations and also lacked a second phase of insulin secretion in islet perifusion experiments. The rate of insulin biosynthesis of non-cultured ob/ob islets was higher than that of islets from Lheir lean siblings but cuiture for one week in 3.3 mM glucose induced a pronounced impairment of the insulin biosynthesis in islets of obese as well as lean mice. The present data indicate that the hyperfunction of the islets of the ob/ob mouse at least in part is a reversible phenomenon, suggesting that inherent properties of islet B-cells do not act as “primary” factors in the development of the obese-hyperglycemic syndrome.