Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome

OBJECTIVE The relationship between insulin resistance and hyperandrogenism led us to study insulin resistance in polycystic ovary syndrome (PCOS) in order to determine its prevalence and pathogenesis. DESIGN Blood samples were taken on the 8th day after menses commenced. PATIENTS Sixty-one women with PCOS, 30 with normal weight (BMK25 kg/m²) (group 1) and 31 with obesity (BMI<26 kg/m₂) (group 2) were studied. They were divided also according to LH level: group A, low or normal LH (n==23) and group B, high LH (n= 38). Twenty lean control women and 16 obese control women were studied. MEASUREMENTS Serum LH, testosterone, free testosterone, dehydroepiandrosterone, sex-hormone binding globulin, androstenedione, and fasting insulin were measured. Insulin sensitivity was explored by the insulin tolerance test (ITT). ITT was performed by bolus i.v. insulin of 0 1 IU/kg. Blood glucose was measured before (– 5, 0) and after injection (3, 5, 7, 10, 15 minutes). Insulin sensitivity was given by the ratio of glycaemic variation to initial blood glucose (AG/G index). RESULTS ΔG/G was correlated with other insulin resistance parameters, particularly fasting insulin r=–0.40, P<0.01. The PCOS groups had the following insulin resistances (mean ± SEM) compared to matched groups: ΔG/G lean PCOS vs lead controls: 0.45 ± 0.02 vs 0.61 ± 0.01, P< 0.001; ΔG/G obese PCOS vs obese controls: 0.32 ± 0.02 vs 0.40 ± 0.01, P<0.02. Insulin resistance was higher in group A than in group B: ΔG/G 0 29 ± 002 vs 0 45 ± 0 02, P < 0.001. The prevalence of insulin resistance was 63% in lean PCOS and 51% in obese PCOS. Positive correlations between AG/G index and LH were found in group 1 and 2, respectively r= 0.45, P<0.01 and r= 0.55, P<0.01. CONCLUSION PCOS was associated with a significant decrease of insulin sensitivity, independent of obesity. The correlation between LH and insulin sensitivity suggests a complementary action in PCOS.     

Skeletal muscle microvascular exchange capacity is associated with hyperglycaemia in subjects with central obesity

Aims Poor glycaemic control is associated with increased risk of microvascular disease in various organs including the eye and kidney, but the relationship between glycated haemoglobin (HbA_1c) and microvascular function in skeletal muscle has not been described. We tested the association between HbA_1c and a measure of microvascular exchange capacity (K_f) in skeletal muscle in people with central obesity at risk of developing Type 2 diabetes. Methods Microvascular function was measured in 28 women and 19 men [mean (± sd ) age 51 ± 9 years] with central obesity who did not have diabetes. We estimated insulin sensitivity by hyperinsulinaemic–euglycaemic clamp, visceral and total fatness by magnetic resonance imaging, fitness (VO₂ max by treadmill testing), physical activity energy expenditure [metabolic equivalents of tasks (METS) by use of the SenseWear Pro armband] and skeletal muscle microvascular exchange capacity (K_f) by venous occlusion plethysmography. Results In regression modelling, age, sex and fasting plasma glucose accounted for 30.5% of the variance in HbA_1c (r² = 0.31, P = 0.001). Adding K_f to this model explained an additional 26.5% of the variance in HbA_1c (r² = 0.57, P = 0.0001 and K_f was strongly and independently associated with HbA_1c (standardized B coefficient ?0.45 (95% confidence interval ?0.19, ?0.06), P = 0.001). Conclusions We found a strong negative independent association between a measure of skeletal muscle microvascular exchange capacity (K_f) and HbA_1c. K_f was associated with almost as much of the variance in HbA_1c as fasting plasma glucose.     

The effects of head-out-of-water immersion on arterial wave reflection in healthy adults

Swimming/hydrotherapy produces hemodynamic and physiological changes related to water immersion (WI). To evaluate the effects of head out (HO) WI on central hemodynamics, we prospectively studied 21 healthy subjects (62% male, age 37 ± 13 years). Central aortic blood pressures (CA-BPs) and reflected wave properties were evaluated using applanation tonometry at baseline and upon 2 minutes of waist (W) and mid-chest (C) HOWI. Heart rate (HR) decreased from 83 ± 15 to 73 ±10 beats/min (P < .001). Brachial artery pulse pressure (PP) was unchanged (45 ± 11 to 46 ± 7 mm Hg; P = .20), CA-PP increased stepwise (27 ± 7 to 32 ± 8 to 33 ± 6 mm Hg; P < .001). Reflected wave amplitude (P_s − P_i), and HR-corrected augmentation index (AI_a@75) increased stepwise from baseline-W-C level HOWI [(P_s − P_i): 2 ± 3 to 7 ± 4 mm Hg, P < .001; AI_a@75: 8 ± 11 to 19 ± 10%; P < .001]. HR-corrected ejection duration (ED_c) and reflected wave systolic duration (Δt_r) increased progressively (ED_c: 389 ± 23 to 408 ± 25 to 435 ± 13 milliseconds; P < .001; Δt_r: 106 ± 32 to 165 ± 21 ms; P < .001). Indices of left ventricular (LV) workload including wasted LV energy subendocardial viability and tension time index increased upon HOWI. HOWI increases the amplitude and the duration of the reflected aortic pressure wave, increases wasted LV pressure energy, workload, and oxygen demand.     

Secretory units of islets in transplantation index is a useful clinical marker to evaluate the efficacy of sitagliptin in treatment of type 2 diabetes mellitus

We carried out a retrospective analysis of 40 Japanese patients with type 2 diabetes mellitus who received sitagliptin. Glycated hemoglobin (HbA_1c) and fasting plasma glucose were significantly decreased from 7.53 ± 0.65% and 155.2 ± 29.4 mg/dL at baseline to 6.80 ± 0.60% (P < 0.01) and 131.2 ± 22.3 mg/dL (P < 0.01) at week 20, respectively. β‐Cell function was evaluated by the secretory units of islets in transplantation (SUIT) index, which was significantly increased from 28.5 ± 14.0 at baseline to 38.6 ± 17.0 at week 20 (P < 0.01). Multivariate analysis was carried out between ΔHbA_1c and several parameters (age, the duration of diabetes, body mass index, triglyceride [TG], C‐peptide [CPR], ΔCPR, HbA_1c [baseline] and ΔSUIT), which showed HbA_1c (baseline; β = 0.580, P < 0.001) and ΔSUIT (β = 0.308, P < 0.05) as significant independent determinants of ΔHbA_1c. These two variables explained 53% of the variance in HbA_1c response. These results suggest that SUIT index can be a clinical marker for the efficacy of sitagliptin in treatment of diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00109.x, 2011)     

Heart Failure–Specific Relationship Between Muscle Sympathetic Nerve Activity and Aortic Wave Reflection

BackgroundReflected arterial waves contribute to left ventricular (LV) afterload. Heart failure patients with reduced ejection fraction (HFrEF) are afterload sensitive and sympathetically activated. We tested the hypothesis that HFrEF patients exhibit a positive relationship between sympathetic vasoconstrictor discharge and aortic wave reflection.MethodsSixteen treated patients with HFrEF (61 ± 9 years of age, left ventricular ejection fraction 30 ± 7%, 3 women) and 16 similar-aged healthy control subjects (57 ± 7 years of age, 4 women) underwent noninvasive measurements of radial pulse waveforms (applanation tonometry) to calculate central blood pressures and aortic wave reflection characteristics: augmentation pressure (AP), augmentation index (AI_x), and AI_x corrected to a heart rate of 75 beats/min (AI_x@75). Muscle sympathetic nerve activity (MSNA) burst frequency was recorded from the fibular nerve (microneurography).ResultsHFrEF patients had higher AI_x (26 ± 9 vs 17 ± 15%; P < .05) and MSNA burst frequency (48 ± 7 vs 39 ± 11 bursts/min; P < .05) and lower central diastolic pressure than control subjects (64 ± 8 vs 70 ± 9 mm Hg; P = 0.05). There were no between-group differences in heart rate, other measures of blood pressure (brachial and central; P > .05), AP (11 ± 5 vs 7 ± 8 mm Hg; P = 0.11), or AI_x@75 (19 ± 9 vs 13 ± 11%,-P = 0.14). MSNA correlated positively with AP (r = 0.50; P < .05), AI_x (r = 0.51; P < .05), and AI_x@75 (r = 0.54; P < .05) in HFrEF patients but not in control subjects (r = 0.002–0.18; P > 0.49).ConclusionsIn patients with HFrEF, but not similarly aged healthy subjects, indices of aortic wave reflection correlate positively with MSNA. By increasing LV afterload, such neurovascular coupling could impair LV performance and worsen heart failure symptoms. Therapies that attenuate neurogenic vasoconstriction may benefit HFrEF patients by diminishing arterial wave reflection.     

Serum 7S domain of type IV collagen levels in essential hypertension and hypertensive type 2 diabetic patients

Metabolic alteration of Type IV collagen occurs in micro- or macrovascular basement membrane of diabetic patients. Hypertension, a risk factor for clinical progression of diabetic vascular disease, may influence this metabolic alteration. The object of this study was to evaluate the serum 7S domain of type IV collagen (7S-collagen) levels in patients with essential hypertension and in Type 2 diabetic patients with or without hypertension and to investigate the relationship between the type IV collagen metabolism and the arterial blood pressure. Serum 7S-collagen levels in 18 patients with essential hypertension were significantly higher than in 24 normal subjects (4.2 ± 0.5 vs 3.6 ± 0.4 ng ml⁻¹ p < 0.01). Serum 7S-collagen levels in 28 normotensive diabetic patients (4.2 ± 0.5 ng ml⁻¹) were significantly higher than in normal subjects (p < 0.01). The serum 7S-collagen levels were significantly higher in 22 diabetic patients with hypertension (4.8 ± 0.6 ng ml⁻¹) than in the other groups. There was a significant correlation between the serum 7S-collagen levels and the systolic blood pressure in cases with essential hypertension (r = 0.59, p < 0.001) and in all diabetic patients (r = 0.52, p < 0.001), suggesting that elevation of the systolic blood pressure may influence the type IV collagen metabolism of vascular basement membrane. We conclude that the metabolic alteration of basement membrane occurring in patients with diabetes mellitus may worsen in the presence of high systolic blood pressure. © 1997 by John Wiley & Sons, Ltd.     

Pharmacokinetics of intravenous recombinant human granulocyte colony-stimulating factor (rhG-CSF) in children receiving myelosuppressive cancer chemotherapy: Clearance increases in relation to absolute neutrophil count with repeated dosing

Limited evidence suggests increased efficacy of rhG-CSF by subcutaneous (SQ) compared with intravenous (IV) administration. To examine the possibility that rapid elimination of IV rhG-CSF could substantially shorten the duration of systemic exposure and could explain a difference in pharmacodynamics, we characterized the pharmacokinetic profile of IV rhG-CSF for comparison to that previously reported for SQ administration. Twelve children were randomly assigned to receive 10 or more days of IV rhG-CSF at dosages of 5 or 10 μg/kg a day beginning 24 hr after chemotherapy. Enzyme-linked immunosorbent assay (ELISA) was used to measure rhG-CSF concentrations in timed serum samples on days 1 and 10. Pharmacokinetic parameters were estimated by nonlinear, least squares regression. All serum concentration-time profiles were best described by a two-compartment model of elimination. Mean t_1/2β values ranged from 3.68 ± 0.86 to 22.4 ± 12.0 hr. ANC was correlated with log CL_T (r = 0.72, P < 0.05), and inversely with log dose-adjusted AUC (r = −0.75, P < 0.05) and log dose-adjusted C_max (r = −0.65, P < 0.05). Estimated duration of serum rhG-CSF concentrations above 1 ng/ml exceeded 24 hr for all but the 5 μg/kg cohort on day 1. Pharmacokinetic parameters of IV rhG-CSF are similar to those previously reported for SQ administration in children treated with myelosuppressive cancer chemotherapy. Daily IV administration should be suitable alternative route of administration in this patient population. Am. J. Hematol. 54:124–130, 1997 © 1997 Wiley-Liss, Inc.     

Tachycardia in adults with cystic fibrosis is associated with normal autonomic function

Background: Whether autonomic dysfunction contributes to tachycardia in cystic fibrosis (CF) is unknown. Methods: Heart rate variability (HRV) was assessed to determine high frequency power and the low/high frequency power ratio (HF, LF/HF) as markers of vagal and sympathovagal balance, respectively, under spontaneous and controlled breathing (15 breaths per minute (bpm)) conditions in 17 CF and 17 healthy control subjects. Results: Under spontaneously breathing conditions, the CF group was tachycardic (75.4 ±11.2 vs 60.2 ±9.0 br/min P < 0.001) and tachypnoeic (22.6 ±5.8 vs 13.6 ±4.1 br/min, P= 0.001) compared with controls. No significant difference in HRV was observed between groups during spontaneous or controlled breathing. Coexistent diabetes mellitus and β₂ agonist use were not associated with altered autonomic control. During controlled breathing, the CF group showed a negative correlation between forced expiratory volume in 1 s (FEV₁) % predicted and HF power (P= 0.013, r=?0.59) and a positive correlation between FEV₁ % predicted and LF/HF ratio (P= 0.002, r= 0.69) suggesting an exaggerated normal vagal response. Conclusion: CF patients have normal autonomic function.     

Changes in Subcutaneous Interstitial Fluid Pressure,Tissue Oxygenation,and Skin Red Cell Flux during Venous Congestion Plethysmography in Men

Objective : Venous congestion plethysmography enables noninvasive assessment of microvascular filtration capacity (K_f) in limbs. However, increases in fluid filtration might alter the balance of Starling forces; for example, progressive increases in interstitial fluid pressure (P_i) would reduce net fluid flux, thus underestimating K_f. Furthermore, elevation of cuff pressure to values close to diastolic blood pressure, as used in the protocol, may by itself impair tissue perfusion with unknown effects on the microvascular parameters investigated. Methods : P_i was measured in healthy volunteers (n = 14) with a modified “Wick in needle” technique during small (8 mm Hg) cumulative increases in venous pressure (0–95 mm Hg). Changes in the hemoglobin (Hb) concentration, oxygenated hemoglobin (HbO₂) concentration, and oxidized cytochrome aa3 concentration were assessed in the calf using noninvasive near-infrared spectroscopy. Skin red blood cell flux close to the strain gauge was evaluated by laser Doppler fluxmetry. Results : P_i at control was ?0.89 ± 0.8 mm Hg and during elevation of venous pressure remained constant until a cuff pressure of 30 mm Hg was reached. It rose thereafter to 1.57 ± 1.3 mm Hg (mean SD). Skin red cell flux was significantly reduced when cuff pressure exceeded 30 mm Hg and, following cuff deflation, evidence of reactive hyperemia was obtained. Hb concentration increased significandy as a result of venous pressure elevation. No change in either HbO₂ or cytochrome aa3 concentration was observed as long as cuff pressure remained under diastolic blood pressure. Conclusions : The small increase in P_i together with an absence of impaired tissue oxygenation during the venous congestion plethysmography protocol described by Gamble et al. supports the contention mat this protocol enables accurate assessment of filtration capacity.     

Noninvasive evaluation of kinetics of gallbladder emptying and filling in the dog

Patterns of gallbladder contraction induced by a meal or cerulein were examined by means of real-time ultrasonography in conscious dogs. The postprandial gallbladder emptying was characterized by two parameters of the power-exponential function: the gallbladder half emptying timeT1/2=47.3 ± 4.7 min and the curve shape paremeterS=0.866 ± 0.036. Cerulein infused at stepwise increasing rates of 0.7, 2.2, 7.4, 22.2, and 66.5 pmol/kg/hr, administered each for 10 min, evoked a gallbladder contraction to 87.4 ± 3.8%, 66.7 ± 2.4%, 44.5 ± 1.5%, 25.9 ± 2.1%, and 11.9 ± 2.0% of the basal volume, respectively. The dependence of the gallbladder emptying on the dose of cerulein was described by the equation of linear regressiony –21.33 [ln(dose + 1)] + 95.81 (r=–0.963,P<0.001). Accordingly, the cerulein dose required to evoke a 50% reduction of the gallbladder volume amounted to 7.6 pmol/kg/hr (95% confidence interval: 6.8–8.6 pmol/kg/hr). A plateau at the level of about 44% of the basal gallbladder volume characterized the time-course of the gallbladder emptying between 20 and 60 min of the infusion at a constant rate of 7.4 pmol/kg/hr. On the other hand, the 1-hr infusion of 22.2 pmol/kg/hr evoked a continuous decrease in the gallbladder volume with a nadir of 10.2 ± 0.7% achieved at 60 min. Refilling of the gallbladder, contracted after a 1-hr infusion of cerulein, was complete within 30 and 60 min after the end of infusion for rates of 7.4 pmol/kg/hr and 22.2 pmol/kg/hr, respectively. The time course of the gallbladder filling after cessation of 1-hr infusion of cerulein at 7.4 pmol/kg/hr was described by the equation of linear regression of relative gallbladder volumes vs time:y=1.732x + 48.61 (r=0.739,P < 0.001). Refilling of the gallbladder was faster during the first 30 min (y=2.191x+7.13,r=0.885,P<0.001) and slower between 30 and 60 min (y=1.218x + 74.97,r=0.533,P < 0.001) after the end of a 1-hr infusion of cerulein at a rate of 22.2 pmol/kg/hr.     

Rapid improvement of static compliance after surfactant treatment in preterm infants with respiratory distress syndrome

Respiratory mechanics were measured in 20 preterm infants before and in the 24-hr period after treatment with surfactant. All infants were enrolled in the rescue clinical trial with Curosurf® carried out in the Neonatal Intensive Care Unit. They received a dose of 200 mg/kg lipid surfactant intratracheally after birth. Static compliance of the respiratory system (C_rs) was measured by the single breath occlusion technique during both spontaneous and mechanical ventilation. Resistance of the respiratory system (R_rs) and expiratory time constant (T_rs) were also measured. As early as 3 hr after surfactant administration a significant improvement of 45% in Crs measured during mechanical ventilation (C_rsV) was noted (0.40 ± 0.14 vs 0.58 ± 0.17 mL/cm H₂O/kg, P < 0.001), together with a significant improvement of the arterial/alveolar O₂ tension ratio (Pa/Ao₂) (0.12 ± 0.03 vs 0.30 ± 0.16. P < 0.01). The improvement of C_rsV and Pa/Ao₂ was confirmed 24 hr later (0.55 ± 0.15 mL/cm H₂O/kg and 0.33 ± 0.18, respectively). A significant correlation was found between C_rs and P_a/Ao₂ ratio (r = 0.56, P < 0.001). Time constant values were significantly higher after surfactant treatment (0.15 ± 0.07 vs 0.09 ± 0.03 sec; P < 0.01). R_rs remained unchanged. These data indicate that Curosuf® given intratracheally after birth determines a rapid improvement of respiratory mechanics as soon as 3 hr after dosing, together with the improvement of oxygenation. From the findings obtained with the present study we show evidence that respiratory system mechanics may be a useful physiological measure to guide ventilatory strategy following surfactant therapy. © 1993 Wiley-Liss, Inc.     

Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance

Aims/hypothesis. We hypothesized that beta-cell responses to changes in glucose would not be normal in subjects with impaired glucose tolerance (IGT). Methods. Three groups of 6 subjects were studied: normal weight with normal glucose tolerance (control subjects); obese with normal glucose tolerance (Obese-NGT); and obese with IGT (Obese-IGT). All subjects had a graded glucose infusion protocol to increase (step-up) and then decrease (step-down) plasma glucose. We obtained average insulin-secretion rates (ISR) over the glucose range common to all three groups during step-up and step-down phases, minimal model indices of beta-cell function (f_b, f_d, f_s, T_up, T_down ), and insulin sensitivity (Si). Results. ISR differed significantly between step-up and -down phases only in Obese-IGT individuals. Basal (f_b) and stimulated (f_d, f_s) beta-cell sensitivity to glucose were similar in the three groups. Delays between glucose stimulus and beta-cell response during both step-up (T_up) and -down (T_down) phases were higher in Obese-IGT compared to Controls and Obese-NGT individuals. The product ISR × Si (10^–5·min^–2× l) was lower in Obese-IGT compared to Controls, both during step-up (919 ± 851 vs 3192 ± 1185, p < 0.05) and step-down (1455 ± 1203 vs 3625 ± 691, p < 0.05) phases. Consistently, the product f_s× Si (10^–14·min^–2· pmol^–1× l) was lower in Obese-IGT than in control subjects (27.6 ± 25.4 vs 103.1 ± 20.2, p < 0.05). Conclusion/interpretation. Subjects with IGT are not able to secrete insulin to compensate adequately for insulin resistance. They also show delays in the timing of the beta-cell response to glucose when glucose levels are either rising or falling. [Diabetologia (2002) 45: ▪–▪] Received: 30 July 2001 and in revised form: 21 November 2001     

Poor correlations between measurements of bone quality by quantitative ultrasound sonography and dual energy X-ray absorptiometry in patients with beta-thalassaemia major

Objectives: Osteopenia/osteoporosis is a major component of morbidity even in young patients with β‐thalassaemia major. Dual energy X‐ray absorptiometry (DXA) is the reference method for determining bone mineral density (BMD). Quantitative ultrasound sonography (QUS) for bone measurement is a relatively new, inexpensive and radiation‐free method that could serve as an alternative to DXA. Our aim was to assess bone status in thalassaemic patients both with QUS and DXA and, consequently, to investigate the degree of correlation between the two methods. Methods: Thirty‐three patients (15 male and 18 female) with β‐thalassaemia major, regularly transfused and systematically iron‐chelated, participated in the study. Mean age was 22.0 ± 8.0 yr (range: 6.5–41.0 yr). All patients were evaluated with QUS at radius and tibia and had DXA scan at lumbar spine vertebrae (L2–L4), whereas 20 patients were additionally assessed with DXA at the left hip (femoral neck, trochanter region and Ward’s triangle). Results: Results were expressed as Z‐scores compared with sex‐ and age‐matched population. Lowest mean Z‐scores measured with DXA were recorded at lumbar spine and Ward’s triangle (?1.1 ± 1.13 and ?0.95 ± 1.07, respectively). Lowest mean QUS‐derived Z‐scores were measured at radius, statistically significant compared with Z‐scores measured at tibia (?0.6 ± 1.1 vs. 0.4 ± 1.1, P < 0.001). QUS measurements at radius were significantly correlated to QUS measurements at tibia (r = 0.51, P = 0.002). The latter were correlated to BMD measured at lumbar spine (r = 0.516, P = 0.002) and at trochanter region (r = 0.646, P = 0.003). All BMD measurements at hip were significantly correlated to each other. Lumbar spine BMD was correlated to BMD at femoral neck (r = 0.607, P = 0.003) and to BMD at Ward’s triangle (r = 0.438, P = 0.027). Finally, no agreement was recorded between the two methods in identifying thalassaemic patients at risk for osteoporosis (κ = 0.203, P = 0.04). Conclusion: Quantitative ultrasound sonography could not serve as an alternate to DXA.     

Creatinine: an inadequate filtration marker in glomerular diseases

The exaggerated clearance (C) of creatinine relative to inulin in patients with renal disease has been attributed to (1) increased tubular creatinine secretion (TS_creatinine) and (2) reduced inulin filtration due to restricted transglomerular inulin transport. In an attempt to gain further insight into the disparate clearances of these commonly employed markers of glomerular filtration, we performed simultaneous clearance studies of creatinine (Einstein-Stokes radius (ESR) = 3 Å, inulin ESR = 14 Å and dextran fractions with ESR = 16 ? 24 Å) in seven normal subjects, 10 patients with cardiac failure and 38 subjects with the nephrotic syndrome. Notwithstanding equivalent depression of mean C_inulin to 47 ± 6 and 42 ± 5 ml/min/1.73 m² in cardiac and nephrotic subjects, respectively, C_creatinine: C_inulin was more increased in the latter (1.70 ± 0.11 versus 1.22 ± 0.14, p < 0.01). In contrast, for dextran molecules with ESR = 16 and 18 Å, C_dextran: C_inulin was not significantly different from unity in all three experimental groups. This suggests that uncharged polysaccharides with ESR < 20Å, including inulin, are freely filtered by normal and pathologic glomeruli and that intrinsic glomerular damage is associated with relatively increased TS_creatinine, thus accounting for the increase of C_creatinine above C_inulin in patients with the nephrotic syndrome.     

Measuring Gastric Emptying: Comparison of 13C-Octanoic Acid Breath Test and Scintigraphy

The aim of this study was to compare scintigraphy, the standard method, and the ¹³C-octanoic acid breath test (OBT) for measuring gastric emptying. Patients with functional dyspepsia (N = 21, 8 men and 13 women; ages, 40–75) underwent standardized dynamic scintigraphy and OBT. Scintigraphic images were obtained for 90 min and breath samples for 4 hr. The gastric half-emptying time for solids (T_1/2) was calculated by two previously described mathematical models for the OBT samples: the nonlinear least-squares method and the geometrical method. T_1/2 was significantly longer measured by OBT than by scintigraphy (167 ± 50 min for the nonlinear least-squares method (P < 0.05) and 185± 52 min for the geometrical method (P < 0.005) vs. 109 ± 74 min for scintigraphy). No correlation appeared between T_1/2 measured by scintigraphy and T_1/2 measured by OBT (r = 0.26) for nonlinear least-squares method and (r = −0.13) for geometrical method). Furthermore, the correlation between the two mathematical models appeared to be low (r = 0.15). Although OBT is simple and safe, its correlation with scintigraphy appears to be weak. The usefulness of this test for measuring gastric emptying thus requires further validation.     

Androgens and insulin resistance in type 1 diabetic men

OBJECTIVE In healthy men, both high and low serum testosterone concentrations are associated with insulin resistance, whereas low concentration of sex hormone binding globulin (SHBG) is related to reduced insulin sensitivity. The aim of our study was to examine the association of sex hormones, SHBG, dehydroeplandrosterone (DHEAS) and insulin-like growth factor binding protein-1 (IGFBP-1) on Insulin sensitivity in type 1 diabetic patients. PATIENTS We examined 23 male patients with the mean age of 29 ± 1 years, body mass index 22.9 ± 0.4 kg/m², Insulin dose 47 ± 3 units/day, glycosylated haemoglobin (HbA_1c) 7.8 ± 0.3% and duration of diabetes 13 ± 1 years. DESIGN Each patient was studied With a 4-hour euglycaemic (5.5 ± 0.1 mmol/l), hyperinsulinaemic (612 ± 26 pmol/l) clamp with indirect calorimetry. Muscle biopsies (quadriceps femoris) for the determination of glycogen synthase were performed In 15 patients before and at the end of the clamp. RESULTS insulin infusion reduced the concentrations of IGFBP-1 by 90% (P < 0.001), DHEAS by 11% (P < 0.001), and SHBG by 4% (P < 0.01), whereas free or bound testosterone levels remained unchanged. The fall in IGFBP-1 level was closely related to the basal concentration (r= 099, P < 0.001). Basal SHBG concentration Correlated directly with total (r= 0.51, P <0.05) and non-oxidative glucose disposal (r= 0.41, P < 0.05), and with the decrease in lipld oxidation (r= 0.47, P <0.05) during Insulin Infusion. The fall in SHBG was inversely related to the mean (30–240 min) FFA concentration durlng hyperinsulinaemia (r=-0.64, P < 0.001). The fractional activity of glycogen synthase at the end of insulin infusion correlated directly with fasting SHBG (r= 0.71, P <0.01) and DHEAS concentrations (r= 0.67, P <0.01). CONCLUSIONS In male type 1 diabetic patients: (1) acute hyperinsulinaemia decreases IGFBP-1, DHEAS and SHBG concentrations with the greatest decline in IGFBP-1, (2) SHBG concentration is positively associated with factors Indicating good insulin sensitivity, (3) association between fuel homeostasis and SHBG, DHEAS and insulin antagonists suggests a network of these factors In the regulation of insulin action in type 1 diabetic patients.     

ORIGINAL ARTICLE: Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican‐American patients with Type 2 diabetes: a double tracer OGTT study

Objectives By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes. Methods In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4‐h) double tracer oral glucose tolerance test (OGTT) (1‐¹⁴C‐glucose orally and 3‐³H‐glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. β‐cell function was assessed as the incremental ratio of insulin to glucose (ΔI/ΔG) during the OGTT. Results Pioglitazone decreased fasting plasma glucose concentration (10·5 ± 0·7 to 7·8 ± 0·6 mm , P < 0·0003) and HbA1c (9·7 ± 0·7 to 7·5 ± 0·5%, P < 0·003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20·0 ± 1·1 to 17·3 ± 0·8 μmol/kg_ffm min, P < 0·005) and HepIR (from 8194 declined by 49% to 3989, P < 0·002). During the OGTT, total glucose Ra during the 0‐ to 120‐min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0‐ to 240‐min time period, pioglitazone caused only a modest increase in MCR (P < 0·07) but markedly increased ΔI/ΔG (P = 0·003). The decrease in 2h‐postprandial hyperglycaemia correlated closely with the increase in ΔI/ΔG (r = ?0·76, P = 0·004) and tissue clearance (r = ?0·74, P = 0·006) and with the decrease in HepIR (r = 0·62, P = 0·006). Conclusions In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving β‐cell function.     

Comparison of the effects of acetazolamide and aminophylline on apnea incidence and on ventilatory response to CO2, in preterm infants

Acetazolamide (ACTZ) reduces sleep apnea in adults exposed to high altitude and augments the ventilatory response to CO₂. In order to determine the effect of ACTZ on the ventilatory response to CO₂ and the incidence of apnea in preterm infants, 7 infants (BW, 1070 ± 191 g; postnatal age, 9 ± 7 days) were randomized to receive ACTZ (5 mg/kg/dose 06h for 36 hr) and 7 infants (BW, 1092 ± 292 g; post-natal age, 5 ± 2 days) received aminophylline (AMINO; 8 mg/kg bolus then 2.5 mg/kg Q12h for 36 hr). Minute ventilation (V_E), end-tidal CO₂, (P), ventilatory response to CO₂ number of apneic episodes (≥15 sec duration), and arterial blood gases were measured before and 24–36 hr after starting therapy. In the AMINO group there was a significant decrease in apnea frequency from 6 ± 1 to 2 ± 2 episodes over an 8 hr epoch (P < 0.05), while no significant change was observed in the ACTZ group. The end-tidal CO₂, decreased significantly from 44 ± 7 to 38 ± 6 mmHg in the AMINO group and from 47 ± 5 to 36 ± 5 mmHg in the ACTZ (P < 0.05), which lead to a shift to the left of the CO₂,-response curve in both groups. The slope of the CO₂, response curve did not change Significantly in the AMINO group and decreased in the ACTZ group. There was a significant decrease of pH from 7.43 to 7.26 in the ACTZ group, whereas in the AMINO group pH increased from 7.38 to 7.44. No significant changes in V_E, tidal volume, respiratory rate, lung compliance, or resistance were observed with treatment in any of the two groups. These findings demonstrate that both AMINO and ACTZ decreased end-tidal CO₂ and caused a shift of the CO₂ response curve to the left. Despite these similar effects, ACTZ did not have an effect on apnea incidence. Pediatr Pulmonol. 1994; 17:291–295. © 1994 Wiley-Liss, Inc.     

Effects of aging and sex on progression of carotid intima‐media thickness: A retrospective 6‐year follow‐up study

Aim: We retrospectively examined the relationship of aging, sex and risk factors to increased carotid intima‐media thickness (IMT) over a follow‐up period of 6 years in patients with multiple risk factors. Methods: Subjects were comprised of 463 patients (287 men, 176 women) with a mean age of 64 ± 0.4 years who had undergone carotid ultrasonography twice or more at intervals of 5 years or older. The mean follow‐up period was 6.0 ± 0.1 years. Results: Mean baseline IMT for all subjects was 1.40 ± 0.02 mm, and no significant difference was seen between sexes. Mean IMT after 6 years for all subjects was 1.84 ± 0.03 mm, and was significantly greater in men than in women. Mean annual increase in IMT (ΔIMT) for all subjects was 0.073 ± 0.005 mm/year, with a significant positive correlation between baseline age and ΔIMT (r = 0.11, P < 0.05), and ΔIMT was significantly greater in men than in women (0.087 ± 0.007 mm vs 0.050 ± 0.007 mm, P < 0.001). IMT increased with age in both men and women, but ΔIMT increased with age only in men. Multivariate analysis showed baseline age and diabetes mellitus as significant risk factors with baseline IMT as the objective variable. Age and sex represented significant risk factors with ΔIMT as the objective variable. Conclusion: Sex differences exist in the relationship between increases in IMT and age. Age, sex and diabetes mellitus represented the main risk factors.     

Total, free and bound leptin and thyroid function in elderly women with different body weights

Objective The present study was aimed at evaluating the relationship of total leptin, and its free leptin (FL) and bound leptin (BL) fractions with adipose mass in very old euthyroid women, in relationship to thyroid function. Subjects and methods Twenty‐five older women (age: 73–95 years) were studied. Subjects representing underweight, normal weight and overweight/obese conditions were included. Plasma leptin, TSH, free T₄ (FT₄) and free T₃, (FT₃) total and HDL cholesterol were measured. FL and BL were evaluated by Fast Protein Liquid Chromatography (FPLC) analysis. Results Plasma leptin concentration was positively correlated with body mass index (BMI) (r = 0·64, P = 0·0005) and tricipital skin‐fold thickness (TF) (r = 0·46, P = 0·0187). Leptin was positively correlated with TSH (r = 0·50, P = 0·0116) and inversely with FT₃ (r = –0·40, P = 0·0477). TSH correlated with the adiposity indexes BMI (r = 0·40, P = 0·05) and TF (r = 0·42, P = 0·0336). Plasma FT₃ was positively correlated with FT₄ (r = 0·49, P = 0·012). FL and BL were evaluated in 8 out of 25 subjects. FL positively correlated with BMI (r = 0·81, P = 0·0218) and leptin (r = 0·83, P = 0·0004), whereas BL did not correlate with these parameters. Conclusions The present results indicate that in very old women, plasma leptin concentrations reflect the extent of adipose mass and suggest that a complex regulatory interaction exists between leptin and thyroid function, possibly taking place at central (hypothalamus–pituitary) and peripheral (deiodinase activity) levels.