Biomedical subjects

Claudio Cobelli

Publications and source records attributed to Claudio Cobelli.

At least 37 records · Page 2Linked to original sources

PubMed2005

Insulin sensitivity by oral glucose minimal models: validation against clamp.

Measuring insulin sensitivity in the presence of physiological changes in glucose and insulin concentrations, e.g., during a meal or OGTT, is important to better understand insulin resistance in a variety of metabolic conditions. Recently, two oral minimal models have been proposed to measure overall insulin sensitivity (S(I)) and its selective effect on glucose disposal (S(I)*) from oral tests. S(I) and S(I)* have been successfully validated against multiple tracer meal estimates, but validation against euglycemic hyperinsulinemic clamp estimates is lacking. Here, we do so in 21 subjects who underwent both a multiple-tracer OGTT and a labeled euglycemic hyperinsulinemic clamp. Correlation between minimal-model S(I), S(I) and corresponding clamp estimates S(I)(*clamp), S(I)(*clamp) was satisfactory, respectively r = 0.81, P < 0.001, and r = 0.71, P < 0.001. S(I) was significantly lower than S(I)(clamp) (8.08 +/- 0.89 vs. 13.66 +/- 1.69 10(-4) dl.kg(-1).min(-1) per microU/ml, P = 0.0002), whereas S(I) and S(I)(*clamp) were very similar (8.17 +/- 1.59 vs. 8.84 +/- 1.39 10(-4) dl.kg(-1).min(-1) per microU/ml, P = 0.52). These results add credibility to the oral minimal-model method as a simple and reliable physiological tool to estimate S(I) and S(I)*, also in large-scale clinical trials.

Adult↗

PubMed2005

Acute inhibition of lipolysis does not affect postprandial suppression of endogenous glucose production.

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and (1)H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 +/- 0.01 mmol/l at -10 min, P = 0) and throughout the postprandial period (0.03 +/- 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 +/- 0.4 vs. 10.1 +/- 0.5 mmol/l, P < 0.01), as was mean peak serum insulin (653.1 +/- 99.9 vs. 909 +/- 118 pmol/l, P < 0.01). Fasting EGP was similar (11.15 +/- 0.58 micromol.kg(-1).min(-1) placebo vs. 11.17 +/- 0.89 mg.kg(-1).min(-1) acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 +/- 1.52 vs. 3.69 +/- 1.21 micromol.kg(-1).min(-1) at 40 min). There was a significant negative correlation between the acipimox-induced decrease in peak plasma glucose and liver triglyceride content (r = -0.827, P = 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP.

Adult↗

PubMed2005

Measurement of selective effect of insulin on glucose disposal from labeled glucose oral test minimal model.

The oral glucose minimal model (OMM) measures insulin sensitivity (S(I)) and the glucose rate of appearance (R(a)) of ingested glucose in the presence of physiological changes of insulin and glucose concentrations. However, S(I) of OMM measures the overall effect of insulin on glucose utilization and glucose production. In this study we show that, by adding a tracer to the oral dose, e.g., of a meal, and by using the labeled version of OMM, OMM* to interpret the data, one can measure the selective effect of insulin on glucose disposal, S(I)*. Eighty-eight individuals underwent both a triple-tracer meal with the tracer-to-tracee clamp technique, providing a model-independent reference of the R(a) of ingested glucose (R(a meal)(ref)) and an insulin-modified labeled intravenous glucose tolerance test (IVGTT*). We show that OMM* provides not only a reliable means of tracing the R(a) of ingested glucose (R(a meal)) but also accurately measures S(I)*. We do so by comparing OMM* R(a meal) with the model-independent R(a meal)(ref) provided by the tracer-to-tracee clamp technique, while OMM* S(I)* is compared with both S(I)(* ref), obtained by using as known input R(a meal)(ref), and with S(I)* measured during IVGTT*.

Adult↗

PubMed2005

Obesity and type 2 diabetes do not alter splanchnic cortisol production in humans.

CONTEXT: Cortisol is a potent regulator of carbohydrate, fat, and protein metabolism. OBJECTIVE: The objective of the study was to determine whether obesity alone or in combination with type 2 diabetes increases splanchnic and/or leg cortisol production. DESIGN: Splanchnic and leg cortisol production were measured using the hepatic and leg catheterization technique combined with infusion of D4-cortisol. SETTING: The study was conducted in a General Clinical Research Center. PARTICIPANTS: Nine lean nondiabetic, 10 obese nondiabetic, and 11 obese diabetic subjects were studied. INTERVENTIONS: Diabetic volunteers were withdrawn from their glucose-lowering medications before study. MAIN OUTCOME MEASURES: Rates of total body, splanchnic and leg cortisol, and D3-cortisol production were measured. RESULTS: Rates of splanchnic cortisol production equaled or exceeded those occurring in extrasplanchnic tissues (e.g. the adrenals) in all three groups. However, because concurrent splanchnic cortisol uptake also occurred, net splanchnic cortisol release was minimal. Splanchnic cortisol production and splanchnic D3-cortisol production (an index of splanchnic 11beta-hydroxysteroid dehydrogenase type 1 activity) did not differ among the three groups. In addition, splanchnic cortisol production did not correlate with either visceral fat or endogenous glucose production. On the other hand, splanchnic cortisol uptake was greater in the obese diabetic than lean nondiabetic subjects (25 +/- 2.9 vs. 15.3 +/- 2.5 microg/min; P < 0.05). Splanchnic, but not leg, D3-cortisol production was correlated with total body D3-cortisol production (r = 0.70; P < 0.001). CONCLUSIONS: Although large amounts of cortisol are produced within the splanchnic bed, implying high intrahepatic glucocorticoid concentrations, rates do not differ in lean and obese nondiabetic humans and are not influenced by the presence of type 2 diabetes mellitus. On the other hand, obesity but not diabetes increases splanchnic cortisol uptake.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2005

Surfactant disaturated phosphatidylcholine kinetics in infants with bronchopulmonary dysplasia measured with stable isotopes and a two-compartment model.

We previously found a shorter surfactant disaturated phosphatidylcholine palmitate (DSPC-PA) half-life in infants with bronchopulmonary dysplasia (BPD) by using a single stable isotope tracer and simple formulas based on a one-exponential fit of the final portion of the enrichment decay curve. The aim of this study was to apply noncompartmental and compartmental analysis on the entire enrichment decay curve of DSPC-PA and to compare the kinetic data with our previous results. We analyzed 10 preterm newborns with BPD (gestational age 26 +/- 0.6 wk, weight 777 +/- 199 g) and 6 controls (gestational age 26 +/- 1.4 wk, weight 787 +/- 259 g). All took part in our previous study. Endotracheal 13C-labeled dipalmitoyl phosphatidylcholine was administered, and the 13C-enrichment of surfactant DSPC-PA was measured from serial tracheal aspirates by gas chromatography-mass spectrometry. Noncompartmental and compartmental models were numerically identified from the tracer-to-tracee ratio and kinetic parameters related to the accessible (pool accessible to sampling, likely to be the lung alveolar pool) and to the nonaccessible pools (pools not accessible to samplings, likely to be the intracellular storage pool) were estimated in the two study groups. Comparison was performed by Mann-Whitney test. A two-compartment model provided the most reliable assessment of DSPC-PA kinetics. In BPD vs. controls, mean +/- SE residence time of DSPC-PA in the accessible was 17.5 +/- 2.6 vs. 32.2 +/- 6.4 h (P < 0.05), whereas it was 49.7 +/- 3.5 vs. 54.4 +/- 3.9 h (NS, not significant) in the nonaccessible pool; DSPC-PA recycling was 0.26 +/- 0.05 vs. 0.43 +/- 0.04% (NS), respectively. A two-compartment model of surfactant DSPC-PA kinetics allowed a thorough assessment of DSPC-PA kinetics, including masses, synthesis, and fluxes between pools. The most important findings of this study are that in BPD infants DSPC-PA loss from the alveolar pool was higher and recycling through the intracellular pool lower than in controls.

Bronchopulmonary Dysplasia↗

PubMed2005

Effect of repaglinide and gliclazide on postprandial control of endogenous glucose production.

The effect of repaglinide and gliclazide on postmeal suppression of endogenous glucose production (EGP) has been studied using a variable-rate tracer methodology. Groups of age-, sex-, and weight-matched type 2 diabetic subjects randomized to gliclazide or repaglinide were studied after ingesting a standard mixed meal (550 kcal; 67% carbohydrate, 19% fat, 14% protein). Plasma glucose profiles were similar in each group and markedly different from that of a nondiabetic control group. Endogenous glucose production was similar basally (3.01 +/- 0.30 vs 3.06 +/- 0.19 mg/kg per minute, gliclazide and repaglinide, respectively). After glucose ingestion, EGP declined rapidly in both the groups until 30 minutes and the greatest suppression was reached earlier in the repaglinide group [0.88 mg/kg per minute at 120 minutes vs 0.77 mg/kg per minute at 210 minutes in gliclazide group (P < .05); median time, 85 vs 195 minutes, respectively (P < .05)]. The area under the curve (30-150) for EGP was significantly greater in the gliclazide group than in the nondiabetic control group (109 +/- 11 vs 198 +/- 22 mg/kg per min 2 ; P > .02) but not significantly different in the repaglinide group (153 +/- 25 mg/kg per min 2 ; P = .17). Repaglinide has minimal physiological advantage over gliclazide, but both therapies for type 2 diabetes fall far short of correcting the endocrine and metabolic abnormalities.

Adult↗

PubMed2005

Two-hour seven-sample oral glucose tolerance test and meal protocol: minimal model assessment of beta-cell responsivity and insulin sensitivity in nondiabetic individuals.

Highly informative yet simple protocols to assess insulin secretion and action would considerably enhance the quality of epidemiological and large-scale clinical trials. In an effort to develop such protocols, a 5-h, 11-sample oral glucose tolerance test (OGTT) was performed in 100 individuals and a 7-h, 21-sample meal in another 100. Plasma glucose, insulin, and C-peptide concentrations were measured. We show that virtually the same minimal model assessment of beta-cell responsivity (dynamic [Phi(d)] and static [Phi(s)]), insulin sensitivity (Si), and disposition index (DI) can be obtained with a reduced seven-sample 2-h protocol: Phi(d), reduced versus full: 871.50 vs. 873.32, r = 0.98 in OGTT and 494.88 vs. 477.99 10(-9), r = 0.91 in meal; Phi(s): 42.36 vs. 44.35, r = 0.88 in OGTT and 35.31 vs. 35.37 10(-9) min(-1), r = 0.90 in meal; Si: 24.33 vs. 22.77 10(-5) dl x kg(-1) x min(-1) per pmol/l, r = 0.89 in OGTT and 19.03 vs. 19.77 10(-5) dl x kg(-1) x min(-1) per pmol/l, r = 0.85 in meal; and DI: 1,282.26 vs. 1,273.23, r = 0.84 in OGTT and 726.92 vs. 776.97 10(-14) dl . kg(-1) x min(-2) per pmol/l, r = 0.84 in meal. This reduced protocol will facilitate the study of insulin secretion and action under physiological conditions in nondiabetic humans.

Adult↗

PubMed2004

Quantitative assessment of glucose transport in human skeletal muscle: dynamic positron emission tomography imaging of [O-methyl-11C]3-O-methyl-D-glucose.

Insulin-stimulated glucose transport in skeletal muscle is regarded as a key determinant of insulin sensitivity, yet isolation of this step for quantification in human studies is a methodological challenge. One notable approach is physiological modeling of dynamic positron emission tomography (PET) imaging using 2-[18-fluoro]2-deoxyglucose ([(18)F]FDG); however, this has a potential limitation in that deoxyglucose undergoes phosphorylation subsequent to transport, complicating separate estimations of these steps. In the current study we explored the use of dynamic PET imaging of [(11)C]3-O-methylglucose ([(11)C]3-OMG), a glucose analog that is limited to bidirectional glucose transport. Seventeen lean healthy volunteers with normal insulin sensitivity participated; eight had imaging during basal conditions, and nine had imaging during euglycemic insulin infusion at 30 mU/min.m(2). Dynamic PET imaging of calf muscles was conducted for 90 min after the injection of [(11)C]3-OMG. Spectral analysis of tissue activity indicated that a model configuration of two reversible compartments gave the strongest statistical fit to the kinetic pattern. Accordingly, and consistent with the structure of a model previously used for [(18)F]FDG, a two-compartment model was applied. Consistent with prior [(18)F]FDG findings, insulin was found to have minimal effect on the rate constant for movement of [(11)C]3-OMG from plasma to tissue interstitium. However, during insulin infusion, a robust and highly significant increase was observed in the kinetics of inward glucose transport; this and the estimated tissue distribution volume for [(11)C]3-OMG increased 6-fold compared with basal conditions. We conclude that dynamic PET imaging of [(11)C]3-OMG offers a novel quantitative approach that is both chemically specific and tissue specific for in vivo assessment of glucose transport in human skeletal muscle.

Adult↗

PubMed2004

Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method.

Measuring insulin sensitivity during the physiological milieu of oral glucose perturbation, e.g., a meal or an oral glucose tolerance test, would be extremely valuable but difficult since the rate of appearance of absorbed glucose is unknown. The reference method is a tracer two-step one: first, the rate of appearance of glucose (R(a meal)(ref)) is reconstructed by employing the tracer-to-tracee ratio clamp technique with two tracers and a model of non-steady-state glucose kinetics; next, this R(a meal)(ref) is used as the known input of a model describing insulin action on glucose kinetics to estimate insulin sensitivity (SI(ref)). Recently, a nontracer method based on the oral minimal model (OMM) has been proposed to estimate simultaneously the above quantities, denoted R(a meal) and SI, respectively, from plasma glucose and insulin concentrations measured after an oral glucose perturbation. This last method has obvious advantages over the tracer method, but its domain of validity has never been assessed against a reference method. It is thus important to establish whether or not the "nontracer" R(a meal) and SI compare well with the "tracer" R(a meal)(ref) and SI(ref). We do this comparison on a database of 88 subjects, and it is very satisfactory: R(a meal) profiles agree well with the R(a meal)(ref) and correlation of SI(ref) with SI is r = 0.86 (P < 0.0001). We conclude that OMM candidates as a reliable tool to measure both the rate of glucose absorption and insulin sensitivity from oral glucose tests without employing tracers.

Absorption↗

PubMed2004

Insulin minimal model indexes and secretion: proper handling of uncertainty by a Bayesian approach.

The identification of the insulin minimal model (MM) for the estimation of insulin secretion rate (ISR) and physiological indexes (e.g. beta-cell sensitivity) requires the knowledge of C-peptide (CP) kinetics. The four parameters of the two-compartment model of CP kinetics in a given individual can be derived either from an additional bolus experiment or, more frequently, from a population model. However, in both situations, the CP kinetics is uncertain and, in MM identification, it should be treated as such. This paper shows how to handle CP kinetics uncertainty by using a Bayesian methodology. In seven subjects, MM indexes and ISR were estimated together with their confidence intervals, using either the bolus data or the population model to assess CP kinetics. The two main results that arise from the application of the new methodology are: (i) the use of the population model in place of the bolus data to determine CP kinetics does not affect, on average, the point estimates of ISR profile and MM parameters but only the confidence intervals which becomes wider (less than 50%); (ii) in both the bolus and population situation neglecting the uncertainty of CP kinetics, as done in MM literature so far, introduces no bias, on average, on point estimates of MM indexes but only an underestimation of confidence intervals.

Adult↗

PubMed2004

"Population" approach improves parameter estimation of kinetic models from dynamic PET data.

Kinetic modeling is used to indirectly measure physiological parameters from dynamic positron emission tomography (PET) data. Usually, the unknown parameters of the model are estimated, in any given region of interest (ROI), by least squares (LS). However, when the signal-to-noise ratio (SNR) of PET data is too low, LS does not allow reliable parameter estimation. To overcome this problem, we study in this paper the applicability of approaches originally developed in the pharmacokinetic/pharmacodynamic literature and referred to as "population approaches." In particular, we consider the iterative two stage (ITS) method, which, given a set of M ROIs drawn on PET images of a given individual, estimates the unknown model parameters of each ROI by exploiting the information contained in all the M ROIs. After having revised the theory behind ITS, we assess its performance versus LS by using Monte Carlo simulations which allow us to evaluate the bias of the two methods in a variety of situations. Then, we compare the performance of LS and ITS in two case studies on [18F]FDG kinetics in human skeletal muscle. Both simulated and real case studies results show that a population approach is of potential in modeling PET images since it allows to reliably estimate model parameters also in those ROIs where either a bad SNR or a poor sampling (e.g., infrequent scanning and/or short experiment duration) make the use of LS unsuccessful.

Algorithms↗

PubMed2004

Pubertal changes in HOMA and QUICKI: relationship to hepatic and peripheral insulin sensitivity.

BACKGROUND: Homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) are measures of insulin resistance and insulin sensitivity derived from fasting glucose (FG) and insulin levels. They thus should reflect, in principle, insulin action on both the liver and the periphery. METHODS: Twenty-three prepubertal and early pubertal adolescents were studied at baseline and after 6 months, using the frequently sampled intravenous glucose tolerance test (IVGTT) with labeled glucose. Total body insulin sensitivity (SI) was calculated using the minimal model and total glucose concentrations. Peripheral insulin sensitivity (SI*) was calculated from labeled glucose concentrations. Hepatic insulin resistance (HIR) was calculated by multiplying glucose production over the last hour by the average insulin level. HOMA and QUICKI were calculated from the fasting glucose and insulin values. RESULTS: HOMA, QUICKI fasting insulin, and glucose to insulin ratio were all significantly related to SI (p <0.05) but were not independently related to SI* or HIR. Multiple linear regression analysis revealed that both SI* and HIR independently predicted HOMA and fasting glucose (p <0.1). QUICKI, fasting insulin, and glucose to insulin ratio were not independently related to SI, SI*, or HIR. CONCLUSIONS: HOMA and fasting insulin reflect total body insulin sensitivity and HIR but not peripheral insulin sensitivity in prepubertal and early pubertal adolescents.

Blood Glucose↗

PubMed2004

Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes.

Decreased skeletal muscle glucose disposal and increased endogenous glucose production (EGP) contribute to postprandial hyperglycemia in type 2 diabetes, but the contribution of hepatic glycogen metabolism remains uncertain. Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular lipid (HCL) content was quantified by 1H NMRS. Before dinner, hepatic glycogen was lower in type 2 diabetic patients (227 +/- 6 vs. CON: 275 +/- 10 mmol/l liver, P < 0.001). After meal ingestion, net synthetic rates were 0.76 +/- 0.16 (type 2 diabetic patients) and 1.36 +/- 0.15 mg x kg(-1) x min(-1) (CON, P < 0.02), resulting in peak concentrations of 283 +/- 15 and 360 +/- 11 mmol/l liver. Postprandial rates of EGP were approximately 0.3 mg x kg(-1) x min(-1) (30-170 min; P < 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured approximately 54% lower (P < 0.03) net hepatic glycogen synthesis and approximately 0.5 mg x kg(-1) x min(-1) higher (P < 0.02) EGP. Hepatic glucose storage negatively correlated with HCL content (R = -0.602, P < 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic hyperinsulinemia. Thus, impaired insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered insulin-to-glucagon ratio or increased free fatty acids accounts for defective hepatic glycogen metabolism in type 2 diabetic patients.

Blood Glucose↗

PubMed2004

Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway.

Glucocorticoids are potent regulators of protein, fat, and carbohydrate metabolism. To determine if cortisol production occurs within the splanchnic bed in humans, 11 nondiabetic subjects were studied using the hepatic/leg catheterization method along with an infusion of [9,11,12,12-2H4] cortisol (D4-cortisol) as proposed by Andrews et al. In the fasting state, there was net release (P < 0.05) of cortisol from the splanchnic bed (6.1 +/- 2.6 microg/min) and net uptake (P < 0.05) by the leg (1.7 +/- 0.7 microg/min). This, along with cortisol production by other tissues (e.g., the adrenals), resulted in a total-body cortisol appearance rate of 18.1 +/- 1.9 microg/min. Fractional splanchnic D4-cortisol extraction averaged 12.9 +/- 1.3% (P < 0.001), splanchnic cortisol uptake 14.8 +/- 2.0 microg/min (P < 0.001), and splanchnic cortisol production 22.2 +/- 3.3 microg/min (P < 0.001). On the other hand, fractional leg D4-cortisol extraction averaged 5.6 +/- 1.8% (P < 0.02), leg cortisol uptake 2.3 +/- 0.7 microg/min (P < 0.01), and leg cortisol production 0.4 +/- 0.4 microg/min, which did not differ from zero. Because D4-cortisol loses a deuterium during conversion to [9,12,12-2H3] cortisone (D3-cortisone), which in turn generates [9,12,12(2)H3] cortisol (D3-cortisol) via 11-beta hydroxysteroid dehydrogenase (11beta-HSD) type 1, D3-cortisol production can be used as an index of 11beta-HSD type 1 activity. Net splanchnic D3-cortisol release (3.9 +/- 0.4 microg/min) and splanchnic D3-cortisol production (7.1 +/- 0.7 microg/min) occurred (P < 0.01) in all subjects. In contrast, there was minimal leg D3-cortisol production (0.04 +/- 0.01 microg/min), resulting in a strong correlation between splanchnic D3-cortisol production and total-body 3D-cortisol production in both the fasting state (r = 0.84; P < 0.02) and during an infusion of insulin (r = 0.97; P < 0.01). Thus, splanchnic production of cortisol occurs in nondiabetic humans at rates approximating that which occurs in the remainder of the body. These data support the possibility that alterations in splanchnic cortisol production contribute to visceral fat accumulation and the hepatic insulin resistance of obesity or type 2 diabetes.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2003

Impaired beta-cell compensation to dexamethasone-induced hyperglycemia in women with polycystic ovary syndrome.

Deterioration in glucose tolerance occurs rapidly in women with polycystic ovary syndrone (PCOS), suggesting that pancreatic beta-cell dysfunction may supervene early. To determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by the glucocorticoid dexamethasone differs in women with PCOS and control subjects, we studied 10 PCOS and 6 control subjects with normal glucose tolerance. An oral glucose tolerance test (OGTT) and a graded glucose infusion protocol were performed at baseline and after subjects took 2.0 mg of dexamethasone orally. Basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and global (Phi) indexes of beta-cell sensitivity to glucose were derived. Insulin sensitivity (S(i)) was calculated using the minimal model; a disposition index (DI) was calculated as the product of S(i) and Phi. PCOS and control subjects had nearly identical fasting and 2-h glucose levels at baseline. Phi(b) was higher, although not significantly so, in the PCOS subjects. The Phi(d), Phi(s), and Phi indexes were 28, 19, and 20% higher, respectively, in PCOS subjects. The DI was significantly lower in PCOS (30.01 +/- 5.33 vs. 59.24 +/- 7.59) at baseline. After dexamethasone, control subjects averaged a 9% increase (to 131 +/- 12 mg/dl) in 2-h glucose levels; women with PCOS had a significantly greater 26% increase to 155 +/- 6 mg/dl. The C-peptide-to-glucose ratios on OGTT increased by 44% in control subjects and by only 15% in PCOS subjects. The accelerated deterioration in glucose tolerance in PCOS may result, in part, from a relative attenuation in the response of the beta-cell to the demand placed on it by factors exacerbating insulin resistance.

Adult↗

PubMed2003

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects.

Excess cortisol has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P < 0.05), hypercortisolemia resulted in higher glucose (P < 0.05) and free fatty acid concentrations (P < 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P < 0.01), indicating the presence of steroid-induced insulin resistance. Postabsorptive glucose production (P = 0.64) and the fractional contribution of gluconeogenesis to EGR (P = 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P < 0.05), implying a decrease in net glucose effectiveness (4.42 +/- 0.52 vs. 6.65 +/- 0.83 ml.kg-1.min-1; P < 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 +/- 0.24 vs. 3.82 +/- 0.51 ml.kg-1.min-1; P < 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P < 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-3H]glucose during hydrocortisone than during saline infusion (P < 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal beta-cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess impairs glucose tolerance by decreasing both insulin action and glucose effectiveness.

Adult↗

PubMed2003

Numerical non-identifiability regions of the minimal model of glucose kinetics: superiority of Bayesian estimation.

The so-called minimal model (MM) of glucose kinetics is widely employed to estimate insulin sensitivity (S(I)) both in clinical and epidemiological studies. Usually, MM is numerically identified by resorting to Fisherian parameter estimation techniques, such as maximum likelihood (ML). However, unsatisfactory parameter estimates are sometimes obtained, e.g. S(I) estimates virtually zero or unrealistically high and affected by very large uncertainty, making the practical use of MM difficult. The first result of this paper concerns the mathematical demonstration that these estimation difficulties are inherent to MM structure which can expose S(I) estimation to the risk of numerical non-identifiability. The second result is based on simulation studies and shows that Bayesian parameter estimation techniques are less sensitive, in terms of both accuracy and precision, than the Fisherian ones with respect to these difficulties. In conclusion, Bayesian parameter estimation can successfully deal with difficulties of MM identification inherently due to its structure.

Bayes Theorem↗

PubMed2003

Design, methods, and evaluation directions of a multi-access service for the management of diabetes mellitus patients.

Recent advances in information and communication technology allow the design and testing of new models of diabetes management, which are able to provide assistance to patients regardless of their distance from the health care providers. The M2DM project, funded by the European Commission, has the specific aim to investigate the potential of novel telemedicine services in diabetes management. A multi-access system based on the integration of Web access, telephone access through interactive voice response systems, and the use of palmtops and smart modems for data downloading has been implemented. The system is based on a technological platform that allows a tight integration between the access modalities through a middle layer called the multi-access organizer. Particular attention has been devoted to the design of the evaluation scheme for the system: A randomized controlled study has been defined, with clinical, organizational, economic, usability, and users' satisfaction outcomes. The evaluation of the system started in January 2002. The system is currently used by 67 patients and seven health care providers in five medical centers across Europe. After 6 months of usage of the system no major technical problems have been encountered, and the majority of patients are using the Web and data downloading modalities with a satisfactory frequency. From a clinical viewpoint, the hemoglobin A1c (HbA1c) of both active patients and controls decreased, and the variance of HbA1c in active patients is significantly lower than the control ones. The M2DM system allows for the implementation of an easy-to-use, user-tailored telemedicine system for diabetes management. The first clinical results are encouraging and seem to substantiate the hypothesis of its clinical effectiveness.

Diabetes Mellitus↗