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Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min (Study I). The protocol was repeated on a separate day (Study II) except that plasma glucose was clamped at 8.3 mmol/1 between 60 and 180 min. [beta]-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-[sup.2][H.sub.2]]glucose and labeling of the 2 glucose loads with [1-[sup.2]H]glucose and [U-[sup.13]C]glucose). In both Studies I and H, the plasma glucose response to the second OGTT equaled 84 [+ or -] 2% (P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 [+ or -] 4.3 vs. 42.8 [+ or -] 5.1 nmol/[m.sup.2], P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 [+ or -] 0.02- vs. 0.92 [+ or -] 0.02-fold, P = 0.006), the increment being higher in Study II (+36 [+ or -] 5%) than Study I (+19 [+ or -] 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 [+ or -] 6 g for the first load and 52 [+ or -] 5 g for the second load (P = not significant). Fasting endogenous glucose production [ 13.3 [+ or -] 0.6 [micro]mol x [min.sup.-1] x kg fat-free mass [(FFM).sup.-1]] averaged 6.0 [+ or -] 3.8 [micro]mol x [min.sup.-1] x kg [FFM.sup.-1] between 0 and 180 min and 1.7 [+ or -] 2.6 between 180 and 360 min (P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect. glucose potentiation; glucose absorption; glucose tolerance

Pioglitazone has been shown to reduce fasting triglyceride levels. The mechanisms of this effect have not been fully elucidated, but decreased lipolysis may contribute to blunt the hypertriglyceridemic response to a meal. To test this hypothesis, we studied 27 type 2 diabetes mellitus (T2DM) patients and 7 sex-, age-, and body mass index-matched nondiabetic controls. Patients were randomized to pioglitazone (45 mg/day) or placebo for 16 wk. Whole body lipolysis was measured [as the [[sup.2][H.sub.5]]glycerol rate of appearance ([R.sub.a])] in the fasting state and for 6 h following a mixed meal. Compared with controls, T2DM had higher postprandial profiles of plasma triglycerides, free fatty acid (FFA), and [beta]-hydroxybutyrate, and a decreased suppression of glycerol [R.sub.a] (P < 0.04) despite higher insulin levels [268 (156) vs. 190 (123) pmol/1, median (interquartile range)]. Following pioglitazone, triglycerides and FFA were reduced (P = 0.05 and P < 0.04, respectively), and glycerol [R.sub.a] was more suppressed [-40 (137) vs. +7 (202) [micro]mol/min of placebo, P < 0.05] despite a greater fall in insulin [-85 (176) vs. -20 (58) pmol/l, P = 0.05]. We conclude that, in well-controlled T2DM patients, whole body lipolysis is insulin resistant, and pioglitazone improves the insulin sensitivity of lipolysis. insulin resistance; dyslipidemia; type 2 diabetes; thiazolidinediones

Apoptosis, a normal event in renal tissue homeostasis, has been considered as a major mechanism for either resolution of glomerular hypercellularity in glomerulonephritis or loss of cellularity and progression to glomerulosclerosis in chronic renal disease. This study was aimed at investigating the role of extracellular ATP (eATP) in mediating apoptosis in human mesangial cells (HMC) and identifying the subtype(s) of purinergic receptors involved, eATP, but not uridin-5'-triphosphate (UTP), caused dose-dependent modifications of cellular morphology, as assessed by contrast-phase microscopy, and late apoptosis, as measured by Annexin V/propidium iodide-based flow cytometry and caspase-3 activation. Both phenomena were prevented by the P2X antagonist oxidized-ATP. 2', 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) was less effective than ATP, whereas 1[N,O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl] -4-phenylpiperazine (KN62), a selective inhibitor of human P2[X.sub.7], prevented morphological changes but potentiated apoptosis induced by BzATP. P2[X.sub.7] was barely expressed in HMC and showed a relatively scarce functional activity, as assessed by monitoring nucleotide-induced intracellular calcium surge and plasma membrane depolarization by Fura-2/AM and bis[1,3-diethylthiobarbiturate]trimethineoxonal uptake, respectively. These data indicated a negligible role of P2[X.sub.7] in eATP-mediated apoptosis and pointed to the involvement of other P2X receptor(s). Molecular and inhibitor studies suggested a main role for P2[X.sub.4] receptor in nucleotide-induced apoptosis in HMC, indicating a relevant role for purinergic signaling in regulating death rate in these cells. extracellular ATP; purinergic receptors; mesangium doi:10.1152/ajprenal.00440.2006

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic [beta]-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved [beta]-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53 [+ or -] 2 yr; BMI 29.4 [+ or -] 0.8 kg/[m.sup.2]; fasting plasma glucose (FPG) 10.3 [+ or -] 0.4 raM; Hb [A.sub.1c] 8.2 [+ or -] 0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU*[m.sup.-2]*[min.sup.-1]) clamp with [3-[sup.3]H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb [A.sub.1c], and insulin-mediated total body glucose disposal ([R.sub.d]) and decreased mean plasma FFA during OGTT (all P < 0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [[DELTA]ISR([DELTA]UC)/Aglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8 [+ or -] 0.7 (PIO + drug-naive diabetics), +0.7 [+ or -] 0.3 (PIO + sulfonylurea-treated diabetics), and 0.7 [+ or -] 0.2 (ROSI + sulfonylurea-withdrawn diabetics) vs. -0.2 [+ or -] 0.3 in the two placebo groups (P < 0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and [R.sub.d] and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved [beta]-cell function, which correlates strongly with improved glycemic control. type 2 diabetes; insulin secretion; insulin secretion/insulin resistance index

The mechanisms by which the enteroinsular axis influences [beta]-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate [beta]-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 [+ or -] 0.18, P = 0.004] amounted to 18 [+ or -] 2 nmol/[m.sup.2] (32 [+ or -] 4% of oral response), and its time course matched that of total insulin secretion. The [beta]-cell glucose sensitivity (OGTT/IV ratio = 1.52 [+ or -] 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 [+ or -] 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, [beta]-cell glucose sensitivity (75 [+ or -] 14 vs. 156 [+ or -] 28 pmol * [min.sup.1] * [m.sup-2] * [mM.sup.1] of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of [beta]-cell glucose sensitivity (OGTT/IV ratio = 1.73 [+ or -] 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of [beta]-cell function, particularly [beta]-cell glucose sensitivity. In IGT, [beta]-cell function is inherently impaired, whereas the incretin effect is only partially affected. glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; insulin secretion

We investigated [beta]-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The [beta]-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The [beta]-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 [+ or -] 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24- and 2-h MT and the OGTT yielded similar dose responses, and most [beta]-cell function parameters were intercorrelated (r = 0.50-0.86, P [less than or equal to] 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r = 0.49, P < 0.0001). Among [beta]-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r = -0.74, P < 0.001; 2-h MT: r = -0.52, P < 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ~20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on [beta]-cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous [beta]-cell function. insulin secretion; glucose-induced insulin release; potentiation of glucose-induced insulin release; insulin sensitivity

We investigated the effect of insulin on total and regional myocardial blood flow (MBF) and glucose uptake (MGU) in healthy subjects (50 [+ or -] 5 yr) by means of positron emission tomography (PET) with oxygen-15-labeled water ([H.sub.2][sup.15]O) and fluorine-18 labeled fluorodeoxyglucose ([sup.18]FDG) before and during physiological hyperinsulinemia (40 mU * [min.sup.-1] * [m.sup.-2]). Twelve male subjects were included in the study. During hyperinsulinemia, MBF increased from 0.91 [+ or -] 0.28 to 1.01 [+ or -] 0.31 ml * [min.sup.-1] * [g.sup.-1] (n = 7 patients, P = 0.05; n = 112 regions, P < 0.005). Intersubject variability ranged from -3.0 to + 41%. MGU increased from 0.11 [+ or -] 0.08 (n = 5) to 0.56 [+ or -] 0.08 [micro]mol * [min.sup.-1] * [g.sup.-1] (P < 0.0001, n = 7). MBF and insulin-mediated MGU were higher in the septum and anterior and lateral wall along short-axis regions of the heart. During hyperinsulinemia, MBF was also higher in the apex and midventricle compared with the base. MBF and MGU were positively correlated before (r = 0.66, P < 0.0001) and during hyperinsulinemia (r = 0.24, P < 0.05). These results provide evidence that insulin stimulates MBF in normal human hearts and appears to involve mainly those regions of the heart where insulin-mediated MGU is higher. Furthermore, regional distribution of insulin-stimulated MBF and MGU does not appear to be uniform across the left ventricular wall of healthy subjects. insulin; positron emission tomography; diabetes mellitus

Research was conducted to test whether acute alpha2-blockade influences insulin secretion, glucose and fat metabolism, hemodynamics and thermogenesis in humans. The glucose oxidase method was utilized to assay plasma glucose while plasma glucose specific activities were determined in arterialized blood samples. Results indicated that acute selective alpha2-blockade prevented epinephrine-mediated inhibition of insulin secretion but does not influence basal or glucose-induced insulin release.

Analysis of the influence of insulin on uric acid (UA) excretion in humans reveals the presence of a positive relationship between body weight, blood pressure and fasting plasma insulin and fasting plasma UA concentrations. Hyperinsulinemia does not change serum UA levels but reduces urinary UA excretion and urine Na excretion in a coupled manner. Fractional UA excretion and Na fractional excretion are interrelated under basal conditions.

Comparative studies of in control and transgenic hypertensive TGR (mREN-2)27 rats reveal that individual tissue and whole body insulin sensitivity do not vary due to single-gene hypertension. Fasting concentrations of insulin, plasma glucose, triglycerides and free fatty acids and fasting rates of glucose generation in the liver are normal in the transgenic rats. Both control and transgenic rats exhibit similar levels of activated whole body glucose utilization during euglycemic hyperinsulinemic clamp. Brown and white adipose tissues and various skeletal muscles of control and transgenic rats exhibit similar glucose utilization indices.

Lactate performs a major role in intermediary metabolism, and this function may be used to include competition with free fatty acids and glucose to perform the function of an oxidative substrate. Metabolic and thermogenic effect of small sodium lactate infusion levels between 2.0-2.4 millimols was evaluated. These readings were derived from physiological or pathological mechanisms influencing the entire body or forearm glucose metabolism during stages of fasting and regulated physiological hyperinsulinemia.

Cardiac vein and arterial catheterization coupled with a clamp and thermodilution methods were utilized in the investigation of the effect of insulin on human hearts. Results show that the absorption of glucose,lactate and pyruvate was increased and that for fatty acids and ketones abolished upon induction of hyperinsulinemia. The cardiac musculature also shifted its substrate dependence from fatty acids to carbohydrates because of insulin inhibition of lipolysis. Moreover, insulin has no effect on blood dynamics or cardiac output.

Gastaldelli, Amalia, Michele Emdin, Fabrizio Conforti, Stefania Camastra, and Ele Ferrannini. Insulin prolongs the QTc interval in humans. Am J Physiol Regulatory Integrative Comp Physiol 279: R2022-R2025, 2000.--Insulin hyperpolarizes plasma membranes; we tested whether insulin affects ventricular repolarization. In 35 healthy volunteers, we measured the Q-T interval during electrocardiographic monitoring in the resting state and in response to hyperinsulinemia (euglycemic 1-mU [multiplied by] [min.sup.-1] [multiplied by] [kg.sup.-1] insulin clamp). A computerized algorithm was used to identify T waves; Bazett's formula was employed to correct Q-T (QTc) by heart rate (HR). In the resting state, QTc was inversely related to indexes of body size (e.g., body surface area, r = -0.53, P = 0.001) but not to indexes of body fatness. During the clamp, HR (67 [+ or -] 1 to 71 [+ or -] 1 beats/min, P [+ or -] 0.0001) and plasma norepinephrine levels (161 [+ or -] 12 to 184 [+ or -] 10 pg/ml, P [is less than] 0.001) increased. QTc rose promptly and consistently, averaging 428 [+ or -] 6 ms between 30 and 100 min (P = 0.014 vs. the resting value of 420 [+ or -] 5 ms). Fasting serum potassium (3.76 [+ or -] 0.03 mM) declined to 3.44 [+ or -] 0.03 mM during insulin. After adjustment for body size, resting QTc was directly related to fasting plasma insulin (partial r = 0.43, P = 0.01); furthermore, QTc was inversely related to serum potassium levels both in the fasting state (partial r = -0.16, P [is less than] 0.04) and during insulin stimulation (partial r = -0.47, P = 0.003). Neither resting nor clamp-induced QTc was related to insulin sensitivity. Physiological hyperinsulinemia acutely prolongs ventricular repolarization independent of insulin sensitivity. Both insulin-induced hypokalemia and adrenergic activation contribute to this effect. insulin action; heart rate; Q-T interval; ventricular repolarization; hypokalemia; sympathetic activation

Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach. Am J Physiol Endocrinol Metab 278: E794-E801, 2000.--The traditional methods for the assessment of insulin sensitivity yield only a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clearance ([Cl.sub.max]) and an insulin concentration at halfmaximal response ([EC.sub.50]). We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous insulin administration (two steps of 20 and 200 mU [multiplied by] [min.sup.-1] [multiplied by] [m.sup.-2], 100 min each). The effect of insulin on plasma glucose clearance was calculated from non-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Michaelis-Menten function of insulin concentration with a delay ([t.sub.1/2]). In seven nondiabetic subjects, the model predicted adequately the tracer concentration: the model residuals were unbiased, and their coefficient of variation was similar to the expected measurement error (~3%), indicating that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects had similar half-times for insulin action ([t.sub.1/2]= 25 [+ or -] 9 vs. 25 [+ or -] 8 min) and maximal responses ([Cl.sub.max] = 705 [+ or -] 46 vs. 668 [+ or -] 259 ml [multiplied by] [min.sup.-1] [multiplied by] [m.sup.-2], respectively), whereas [EC.sub.50] was 240 [+ or -] 84 [micro]U/ml in the lean vs. 364 [+ or -] 229 [micro]U/ml in the obese (P [is less than] 0.04). [EC.sub.50] and the insulin sensitivity index (ISI, initial slope of the dose-response curve), but not [Cl.sub.max], were related to body adiposity and fat distribution with r of 0.6-0.8 (P [is less than] 0.05). Thus, despite the small number of study subjects, we were able to reproduce information consistent with the literature. In addition, among the lean individuals, [t.sub.1/2] was positively related to the ISI (r = 0.72, P [is less than] 0.02). We conclude that the test here presented, based on a more elaborate representation of glucose kinetics and insulin action, allows a reliable quantitation of the insulin doseresponse curve for whole body glucose utilization in a single session of relatively short duration. insulin sensitivity

Apoptosis, a normal event in renal tissue homeostasis, has been considered as a major mechanism for either resolution of glomerular hypercellularity in glomerulonephritis or loss of cellularity and progression to glomeruloscierosis in chronic renal disease. This study was aimed at investigating the role of extracellular ATP (eATP) in mediating apoptosis in human mesangial cells (HMC) and identifying the subtype(s) of purinergic receptors involved. eATP, but not uridin-5′-triphosphate (UTP), caused dose-dependent modifications of cellular morphology, as assessed by contrast-phase microscopy, and late apoptosis, as measured by Annexin V/propidium iodide-based flow cytometry and caspase-3 activation. Both phenomena were prevented by the P2X antagonist oxidized-ATP. 2′, 3′-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) was less effective than ATP, whereas I[N,O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN62), a selective inhibitor of human P2X7, prevented morphological changes but potentiated apoptosis induced by BzATP. P2X7 was barely expressed in HMC and showed a relatively scarce functional activity, as assessed by monitoring nucleotide-induced intracellular calcium surge and plasma membrane depolarization by Fura-2/AM and bis[1,3-diethylthiobarbiturate]trimethineoxonal uptake, respectively. These data indicated a negligible role of P2X7 in eATP-mediated apoptosis and pointed to the involvement of other P2X receptor(s). Molecular and inhibitor studies suggested a main role for P2X4 receptor in nucleotide-induced apoptosis in HMC, indicating a relevant role for purinergic signaling in regulating death rate in these cells. [ABSTRACT FROM AUTHOR]

To investigate early secretory defects in prediabetes, we evaluated β-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. β-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 ± 6 vs. 87 ± 6 pmol· min-1·m-2, P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, ρ = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 · M1.23), compensation for insulin resistance was impaired in FDR (10.8 ± 1.0 vs. 13.4 ± 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 ± 0.08 vs. 1.62 ± 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). β-Cell function parameters were also related to mean 24-h glucose levels (r² = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, β-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a β-cell defect in the amplifying pathway of insulin secretion. [ABSTRACT FROM AUTHOR]

Tests the effects of acute alpha2-blockade on insulin action and secretion in human beings. Rise in plasma insulin and C-peptide levels; Consequence of hyperglycemia; Increments of resting energy expenditures and external cardiac work; Values of gas exchange and indirect calorimetry.