Biomedical subjects

G Pacini

Publications and source records attributed to G Pacini.

At least 19 recordsLinked to original sources

PubMed2007

Impaired cardiac autonomic function in women with prior gestational diabetes mellitus.

BACKGROUND: Cardiac autonomic neuropathy is a common dysfunction in manifest diabetes mellitus and is associated with duration of diabetes and/or an inadequate glycaemic control. Heart rate variability (HRV) reflects autonomic heart function. The aim of the present study was to investigate whether in women with prior gestational diabetes (GD; pre-type 2 diabetes) alterations of cardiac autonomic function can be observed after delivery in relation to insulin sensitivity and glycaemic control. MATERIALS AND METHODS: Forty-eight healthy women with prior GD were consecutively admitted to the study. HRV was analysed by both time, as well as frequency, domain methods using 24-h Holter monitoring. In addition, 20 women with normal glucose tolerance during and after pregnancy were investigated as control subjects. All women underwent a frequently sampled intravenous glucose tolerance test (FSIGT) for measurement of insulin sensitivity. RESULTS: Time domain analysis (standard deviation of normal RR intervals; SDNN) showed a reduced HRV in 25 out of the 48 (52%) women with prior GD. Frequency domain analysis revealed that in these 25 subjects both low and high frequency components of power spectral density (reflecting mainly sympathetic respectively parasympathetic activity) were reduced, indicating that sympathetic as well as parasympathetic functional impairment may be assumed. However, a relative predominance of the sympathetic over parasympathetic cardiac function was observed. The impairment of cardiac autonomic function (reduced SDNN) was correlated with HbA1c values and the 2-h blood glucose concentration (oral glucose tolerance test) but not with insulin sensitivity. CONCLUSION: The present results demonstrate that in 52% of the women examined who had prior GD, an impairment of cardiac sympathetic as well as parasympathetic function was present, which related to glycaemic control, but not to insulin sensitivity. This infers that functional autonomic changes could be an early prognostic indicator in pre-type 2 diabetes.

Adult↗

PubMed2006

A novel approach to assess insulin sensitivity reveals no increased insulin sensitivity in mice with a dominant-negative mutant hepatocyte nuclear factor-1alpha.

In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (beta-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1alpha [RIP-DN HNF-1alpha (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that SI was the same in the two groups (0.78 +/- 0.21 x 10(-4) min.pmol(-1).l(-1) in WT vs. 0.60 +/- 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1alpha mice is not compensated with increased insulin sensitivity.

Animals↗

PubMed2006

Impaired beta-cell function in lean normotolerant former gestational diabetic women.

BACKGROUND: Former gestational diabetes (fGDM) constitutes a risk condition for the development of Type 2 diabetes. Former gestational diabetes is often characterized by obesity and hyperglycaemia, which may be concomitant and independent risk factors. MATERIALS AND METHODS: To assess insulin sensitivity and beta-cell function in fGDM uncomplicated by obesity and hyperglycaemia, we studied 24 lean fGDM women and 23 control women matched for age (30.7 +/- 0.7 years, whole cohort), body mass index (22.2 +/- 0.3 kg m(-2)), and indistinguishable for plasma glucose both at fasting and at 120 min. Several insulin sensitivity and beta-cell function indices were computed: homeostasis model assessment insulin resistance index (HOMA-R), insulin sensitivity index derived from an oral glucose tolerance test (OGIS), insulinogenic index, other empirical indices of insulin secretion and beta-cell function, and indices obtained using a beta-cell model. RESULTS: Though the majority of indices, and in particular insulin sensitivity (HOMA-R: 1.35 +/- 0.13 vs. 1.65 +/- 0.14; OGIS: 492.7 +/- 6.3 vs. 496.4 +/- 9.4 mL min(-1) m(-2)), were not significantly different in the two groups, the beta-cell glucose sensitivity obtained by modelling analysis was lower in fGDM (108 +/- 14 vs. 165 +/- 22 pmol min(-1) m(-2) mM(-1), P = 0.031). CONCLUSIONS: Impairment of beta-cell glucose sensitivity may be an intrinsic risk factor in fGDM independently of obesity and hyperglycaemia. Furthermore, we have shown that modelling analysis, in contrast to the empirical parameters, may be able to detect early beta-cell alterations in fGDM women.

Adult↗

PubMed2006

Fibrinolytic dysfunction in insulin-resistant women with previous gestational diabetes.

BACKGROUND: Women with a history of gestational diabetes (p-GDM) are at increased risk of developing type 2 diabetes mellitus (DM2) later in life, and therefore at increased risk for future cardiovascular disease. MATERIALS AND METHODS: Three months after delivery we investigated the plasma levels of plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen and von Willebrand factor (vWF) in 74 women with p-GDM and 20 healthy females with normal glucose tolerance during and after pregnancy, as well as the relation of fibrinolytic parameters to insulin resistance and glycaemic control. All women underwent an oral (OGTT) as well as an intravenous glucose tolerance test (FSIGT). Mathematical model analysis disclosed that 50% (n=37 each) of the p-GDM subjects had normal (NIS) or impaired (IIS) insulin sensitivity. Parameters of interest were determined using commercially available test systems. RESULTS: Women with p-GDM and IIS had significantly increased body fat mass (BFM) (P<or=0.001) compared with women with p-GDM and NIS and controls, whereas the waist to hip ratio (WHR) was similar in both p-GDM groups but was higher compared with the controls (P<or=0.001). Mean PAI-1 and t-PA as well as fasting and stimulated plasma concentrations of proinsulin, C-peptide and insulin were elevated, whereas the disposition index was lower in women with p-GDM and IIS compared with women with p-GDM and NIS and the controls (P<0.001). Plasma levels of fibrinogen and vWF did not differ between the groups. Obese women with IIS had higher PAI-1 levels than lean women with IIS (P<or=0.001). PAI-1 inversely correlated with the insulin sensitivity index (SI) but only in women with IIS (P<0.0001). On regression analysis, only fasting proinsulin and WHR remained significant independent predictors of PAI-1 elevation in IIS (P<or=0.0001 and P<or=0.001). The PAI-1/SI ratio was elevated in women with IIS independently of their glucose tolerance status (P<0.001 vs. NIS and controls). CONCLUSIONS: Plasminogen activator inhibitor type 1 is elevated in p-GDM women with IIS and depends on plasma proinsulin and abdominal obesity. An increase of the PAI-1/SI ratio further characterizes obese insulin-resistant p-GDM women who may be at risk for diabetes and angiopathy.

Adult↗

PubMed2006

Insulin sensitivity during oral glucose tolerance test and its relations to parameters of glucose metabolism and endothelial function in type 2 diabetic subjects under metformin and thiazolidinedione.

AIM: This study was designed to assess the usefulness of a model-based index of insulin sensitivity during an oral glucose tolerance test (OGTT) in the identification of possible changes in this metabolic parameter produced by pharmacological agents known to be potent insulin sensitizers, that is metformin (M) and thiazolidinedione (T). The association of these agents with several other factors related to glucose metabolism was also investigated, as well as the relation of insulin sensitivity and secretion with markers of endothelial function such as different adhesion molecules (cAMs), that is vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-Selectin. METHODS: Twenty type 2 diabetic patients treated with diet only underwent a 3-h OGTT for measurement of plasma glucose, insulin, proinsulin, C-peptide and cAMs before and after administration of randomly given M (n = 9; 1700 mg/day) or T (n = 11; 600 mg/day). After 16 weeks of treatment, a second OGTT was performed. Insulin sensitivity was calculated with homeostasis model assessment and with oral glucose insulin sensitivity (OGIS), which quantifies dynamic glucose clearance per unit change of insulin. Insulin secretion was assessed by modelling technique. Differences in these parameters before and after treatment, as well as possible relationships with cAMs, were assessed. RESULTS: Basal and stimulated plasma glucose decreased after therapy in both the groups by approximately 20%. Basal insulin resistance also decreased. Insulin sensitivity in dynamic conditions (OGIS: ml/min/m(2)) increased with M (289.3 +/- 18.8 vs. 234.7 +/- 18.1, p < 0.02) and tended to improve with T (323.5 +/- 18.1 vs. 286.8 +/- 22.1, p = 0.09). Total insulin secretion over the OGTT [TIS: nmol/l(3 h)] tended to decrease with M (17.1 +/- 2.5 vs. 27.3 +/- 0.3, p = 0.08) but not with T (23.6 +/- 3.5 vs. 22.5 +/- 2.7). Plasma concentrations of E-Selectin decreased in T (38.0 +/- 2.3 vs. 51.2 +/- 6.1 ng/ml, p < 0.05). No correlation was found between insulin sensitivity and cAMs. CONCLUSIONS: Model-based indices of insulin sensitivity and secretion during an OGTT can be able to detect changes observed in patients under treatment with pharmacological agents such as M or T. Both the drugs improved glucose control similarly. Decreased plasma E-Selectin concentrations were seen in patients on T therapy only.

Blood Glucose↗

PubMed2005

Reduced insulin clearance contributes to the increased insulin levels after administration of glucagon-like peptide 1 in mice.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is known to be a potent stimulator of insulin secretion. However, whether GLP-1 also affects insulin clearance is not known. To explore this, we developed a technique to determine prehepatic insulin secretion in mice, based on deconvolution of plasma C-peptide concentrations. The estimated beta cell secretion was then related to plasma insulin levels to allow determination of clearance rate of endogenously produced insulin. MATERIALS AND METHODS: Kinetic parameters of C-peptide were estimated after i.v. injection of human C-peptide (0.8 or 3 nmol/kg) or glucose (1 g/kg), either alone or together with GLP-1 (10 nmol/kg), in anaesthetised NMRI mice. RESULTS: C-peptide was distributed in two compartments (distribution volume 11.4+/-0.4 ml, 42+/-2% of which was in the accessible compartment). Fractional C-peptide clearance was 8.2+/-0.6% of the total distribution volume per minute. GLP-1 markedly enhanced prehepatic insulin secretion; more than 80% of prehepatic secretion occurred during the first minute after injection. Fractional clearance of endogenously released insulin after glucose was 0.66+/-0.11 min(-1) and this was reduced to 0.36+/-0.10 min(-1) by GLP-1 (p=0.04). CONCLUSIONS/INTERPRETATION: It is possible to perform C-peptide deconvolution for estimating prehepatic insulin secretion in mice. GLP-1 reduces the clearance of endogenously released insulin; therefore, it may affect insulin levels by increasing prehepatic insulin secretion and by reducing insulin clearance.

Animals↗

PubMed2005

Preserved insulin sensitivity and {beta}-cell activity, but decreased glucose effectiveness in normal-weight women with the polycystic ovary syndrome.

Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8-5.1) vs. controls 4.5 (3.5-5.4) 10(-4) min(-1)/microU.ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3-4.2) vs. controls 3.7 (3.4-4.0) microU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1-3.0) vs. controls 3.8 (3.0-4.6) mg x 100 min(-1); P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.

Adult↗

PubMed2005

Comparative evaluation of simple insulin sensitivity methods based on the oral glucose tolerance test.

AIMS/HYPOTHESIS: We compared five surrogate insulin sensitivity (IS) methods against the euglycaemic-hyperinsulinaemic clamp. These methods were the homeostasis model assessment (HOMA) and four methods based on the OGTT (OGIS, MCRest, ISIcomp, SIORAL). METHODS: We compared these IS methods against the clamp (0.28 nmol.min(-1).m(-2) insulin infusion) M value in 147 women (58-61 years; BMI 19-38 kg/m2; 116 NGT, 25 IFG/IGT, six type 2 diabetic), by evaluating the correlation coefficient with M. We also tested the ability to reproduce the relationships between IS and typical IS correlates (BMI, fasting insulin, insulin to glucose OGTT area ratio and fasting, 2 h and mean glucose) by means of the "discrepancy index" D, in which (1) D=0 if the correlation between IS and the variable of interest is as with the clamp, (2) D is smaller than 0 if the correlation is overestimated, and (3) D is greater than 0 if underestimated. RESULTS: All IS methods correlated with M (r=0.57-0.83, p<0.0001); for MCRest the relationship was markedly curvilinear. All IS measures correlated with the considered variables (r=0.29-0.94, p<0.0005); however, no method had D approximately 0 for all variables. The best surrogates of M were OGIS (one D not =0) and MCRest (two D not =0); the other methods either under- or overestimated the degree of correlation (three or more D not =0), in particular with fasting insulin (HOMA: D=-57%; ISIcomp: D=-36%) and BMI (HOMA: D=-14%; ISIcomp: D=-14%; SiORAL: D=-11%). CONCLUSIONS/INTERPRETATION: All IS methods were correlated with M. OGIS and MCRest were preferable to the other methods and in particular to HOMA for reproducing relationships with the independent variables.

Blood Glucose↗

PubMed2005

Islet adaptation to insulin resistance: mechanisms and implications for intervention.

Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The relation between insulin sensitivity and secretion is curvilinear and mathematically best described as a hyperbolic relation. Several potential mediators have been suggested to be signals for the beta cells to respond to insulin resistance such as glucose, free fatty acids, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1). Failure of these signals or of the pancreatic beta cells to adequately adapt insulin secretion in relation to insulin sensitivity results in inappropriate insulin levels, impaired glucose intolerance (IGT) and type 2 diabetes. Therefore, treatment of IGT and type 2 diabetes should aim at restoring the normal relation between insulin sensitivity and secretion. Such treatment includes stimulation of insulin secretion (sulphonylureas, repaglinide and nateglinide) and insulin sensitivity (metformin and thiazolidinediones), as well as treatment aimed at supporting the signals mediating the islet adaptation (cholinergic agonists and GLP-1). Both, for correct understanding of diabetes pathophysiology and for development of novel treatment modalities, therefore, the non-linear inverse relation between insulin sensitivity and secretion needs to be acknowledged.

Adaptation, Physiological↗

PubMed2004

Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance.

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.

Administration, Oral↗

PubMed2003

Acylation stimulating protein stimulates insulin secretion.

Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal.

Animals↗

PubMed2003

Inverse relation between amylin and glucagon secretion in healthy and diabetic human subjects.

BACKGROUND: The role of amylin, which is cosecreted together with insulin by the pancreatic B-cells, in the pathogenesis of type-2 diabetes is still unclear. To elucidate a possible relation between amylin and glucagon we directly evaluated the respective prehepatic secretions following administration of a 75-g oral glucose load (OGL) in humans. MATERIALS AND METHODS: We studied six healthy controls (C), six obese, insulin resistant subjects (O) and six patients with type 2 diabetes (D). Catheters were placed in the femoral artery and hepatic vein according to the hepatic vein catheterization technique. Splanchnic blood flow was assessed by infusion of indocyanine-green dye. The measured variables were analyzed by a general circulatory model for calculation of prehepatic secretion. RESULTS: The total amount of released glucagon was not different between the respective groups (20.5 +/- 2.3 in C, 27.7 +/- 5.1 in O and 27.9 +/- 5.4 micro g/4 h in D). When considered as the difference from the fasting profile, however, glucagon secretion was reduced by 3.5 +/- 14% in C, 25 +/- 12% in O and increased by 36 +/- 21% in D (P = 0.051, D vs. C). Amylin secretion was increased in O (1.10 +/- 0.15) vs. C (0.63 +/- 0.05, P < 0.05) and D (0.24 +/- 0.10 nmol, P < 0.01). Following glucose administration, glucagon secretion significantly inversely correlated with secretion of amylin (r = -0.6, P < 0.01), but not with that of insulin (r =-0.23, P = 0.36). CONCLUSIONS: The inverse correlation between amylin and glucagon secretion suggests that amylin modulates glucagon secretion following oral glucose administration. This study proves for the first time a role of endogenous amylin in the regulation of glucose homeostasis.

Adult↗

PubMed2002

Circulating concentrations of asymmetrical dimethyl-L-arginine are increased in women with previous gestational diabetes.

AIMS/HYPOTHESIS: The concentration of asymmetrical dimethyl- L-arginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, is increased in patients at risk or with cardiovascular disease. We have investigated ADMA concentrations in women with a history of gestational diabetes (GDM), who could develop endothelial dysfunction and Type II (non-insulin-dependent) diabetes mellitus after delivery, and in healthy control subjects. METHODS: Previous GDM patients were grouped according to their BMI as obese (> or =25 kg/m(2), n=46) or non-adipose (<25 kg/m(2), n=31). Serum samples were taken 14 to 16 weeks after delivery and after 1 year. The control group comprised 17 healthy women (BMI<25 kg/m(2)). ADMA concentrations were analysed by high performance liquid chromatography. RESULTS: ADMA concentrations were comparable between obese and non-adipose GDM patients (0.58+/-0.02 and 0.57+/-0.02 micro mol/l, respectively), and higher than in the control group (0.47+/-0.03 micro mol/l; p<0.006). Insulin resistance as estimated by the insulin sensitivity index was more frequent among the obese than the non-adipose GDM women (p<0.05) and control subjects (p<0.05, both). No change in ADMA concentrations was found after 1 year in women with GDM. There was only a slight correlation between ADMA and BMI (r=0.26, p<0.02), triglycerides (r=0.29, p<0.004), or fasting plasma glucose (r=0.21, p<0.05), and not with the insulin sensitivity index or other parameters. In a multiple regression analysis ADMA serum concentrations were only associated with triglycerides. CONCLUSION/INTERPRETATION: Circulating ADMA concentrations are increased in normoglycaemic women with previous GDM. This increase is independent from other risk factors or surrogate markers for diabetes or cardiovascular events.

Adult↗

PubMed2002

Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents.

Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5 micro-units/ml and is activated at 50 micro-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. The aims of the present study were to determine whether a substantial enhancement of blood insulin levels restores the PDH activity in CL from obese adolescents and abolishes the in vitro alterations, and whether PDH activity and indices of insulin resistance are correlated. Six obese adolescents and six normal-weight controls underwent a 4 h frequently sampled intravenous glucose test with minimal model analysis, to bring about a sharp rise in blood insulin and provide a reliable index of insulin sensitivity (S(I)). PDH activity was evaluated in CL obtained from blood samples at set times before and after their exposure to insulin in vitro. Insulin levels rose in all subjects in the first 10 min, although to a much greater extent in the obese group, and then decreased until the end of the test (240 min; t(240)). PDH activity in CL paralleled the insulin pattern in the control subjects, whereas in the obese subjects it was below normal 3 min before the start of the test (t(-3)), but rose significantly throughout the test. PDH responses in vitro to insulin in CL taken from the control subjects at t(-3) and t(240) and in CL taken from the obese subjects at t(-3) were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t(240). Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with S(I). These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.

Adolescent↗

PubMed2001

Increased plasma leptin in gestational diabetes.

AIMS/HYPOTHESIS: Insulin resistance as well as marked changes in body weight and energy metabolism are associated with pregnancy. Its impact on plasma leptin is not known and was determined in this longitudinal study in both diabetic and normal pregnancy. METHODS: At 28 gestational weeks plasma concentrations of leptin and B-cell hormones were measured at fasting and after an oral glucose load (OGTT:75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant (C). RESULTS: Plasma leptin (ng/ml) was higher (p < 0.001) in women with gestational diabetes (24.9 +/- 1.6) than in women with normal glucose tolerance (18.2 +/- 1.5) and increased in both groups when compared with the non-pregnant women (8.2 +/- 1.3; p < 0.0005). No change in plasma leptin concentrations was induced by OGTT in any group. Basal insulin release was higher (p < 0.05) in women with gestational diabetes compared with the pregnant women with normal glucose tolerance. Marked insulin resistance was confirmed by a 20 % lower (p < 0.05) insulin sensitivity in subgroup analysis and a decrease of almost 40% in fasting glucose/insulin ratio (p < 0.005) in women with gestational diabetes. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose (p < 0.02), insulin (p < 0.004) and proinsulin (p < 0.01) as well as with BMI (p < 0.001) and overall pregnancy induced maternal weight gain (p < 0.009). With normalisation of blood glucose 8 weeks after delivery in women with gestational diabetes their plasma leptin decreased (p < 0.0005) to 17.3 +/- 1.9 ng/ml but did not completely normalize (p < 0.05 vs non-pregnant women). CONCLUSION/INTERPRETATION: Our data show that women with gestational diabetes without any change in plasma leptin upon oral glucose loading have increased plasma leptin concentrations during and after pregnancy, a clear association of plasma leptin with the respective concentration of glucose and insulin resistance as well as with changes in body weight, and a failure to normalize spontaneously BMI to the same extent as pregnant women with normal glucose tolerance when compared with matched control subjects.

Adult↗

PubMed2001

Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients.

Nonalcoholic steatohepatitis (NASH) is a syndrome frequently associated with obesity, diabetes mellitus, and dyslipidemia. Increased fasting insulinemia and blood glucose levels may trigger a reduced catabolism of lipoproteins rich in triglycerides by lipoprotein lipase (LPL) and an increase in their fasting and postprandial levels. An association between postprandial lipemia and coronary heart disease has been observed, and many studies now support this concept. The most important result of our study is the increase in triglyceride-rich lipoproteins response after a fat load in NASH patients, the increase of incremental area under the postprandial curve, and the duration of the hypertriglyceridemic peaks. The persisting postprandial plasma triglyceride elevation in NASH patients was mostly due to the elevated plasma level of large triglyceride-rich particles. These data are coupled with lower plasma HDL2-cholesterol levels. As for lipoprotein analyses, the number of apolipoprotein B100 (ApoB100) particles is not significantly different between the two groups, and the higher content of triglycerides in NASH very low density lipoproteins (VLDL) increases the triglyceride-to-ApoB ratio and the particle size. A decreased enzymatic activity of LPL or a defective assembly and secretion of VLDL from hepatocytes due to a moderate reduction in microsomal triglyceride transfer protein could be involved in the overloading of VLDL. Moreover, the undetectable levels of ApoB48 in triglyceride-rich lipoproteins fraction A could be related to the synthesis of smaller and denser chylomicrons. NASH patients not only are insulin resistant but also tend to present alterations in fatty meal delivery, suggesting that an increase in fasting plasma insulin and glucose, with insulin resistance, joins with depressed metabolism of triglyceride-rich lipoproteins. An increase in postprandial triglyceride levels with production of large VLDL suggests an atherogenic behavior of lipid metabolism, in accordance with the high prevalence of the metabolic syndrome in NASH patients. This paper suggests that a fat load may be useful in early detection of atherogenic risk in the presence of otherwise normal fasting plasma lipids.

Adult↗

PubMed2001

Gemfibrozil improves insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients.

BACKGROUND: Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated. MATERIALS AND METHODS: This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow-mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low-density lipoprotein (LDL) distribution and flotation properties, insulin action and flow-mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed. RESULTS: GF decreased serum triglyceride (TG) concentration with an absolute difference of 1.79 +/- 1.28 mmol L-1 (P < 0.0016) between active treatment and placebo, and significantly increased serum high-density lipoprotein (HDL) cholesterol (P = 0.0233). No differences were observed in total, intermediate-density lipoproteins (IDL), LDL cholesterol concentration and LDL peak buoyancy between treatments. GF also improved SI, an index of insulin action (P = 0.005). The FMD was 7 +/- 3% in the baseline condition, 7 +/- 2% during placebo and 14 +/- 3% after GF (P < 0.006). CONCLUSIONS: GF treatment improves both insulin action and flow-mediated vasodilatation in type 2 diabetic patients. The reduction of TG concentration allows the simultaneous correction of two important components of the metabolic syndrome.

Aged↗

PubMed2001

Myocardial infarction before the age of 40 years is associated with insulin resistance.

Insulin resistance is associated with atherosclerosis, and hyperinsulinemia is predictive of coronary heart disease. However, a quantitative estimation of in vivo insulin sensitivity in juvenile myocardial infarction is still lacking and the mechanism of hyperinsulinemia is unknown. We estimated insulin sensitivity, beta-cell secretion, and hepatic insulin extraction using the minimal model analysis of a frequently sampled intravenous glucose tolerance test (FSIGT) in 25 normal-weight subjects without glucose intolerance and hypertension who had an acute myocardial infarction before the age of 40 years, and 10 control subjects comparable for age, sex, body mass index, and blood pressure. All patients underwent a coronary angiography. Insulin sensitivity was significantly lower in patients than in control subjects (mean +/- SEM, 4.6 +/- 0.6 v8.5 +/- 1.2 10(-4). min(-1)(microU/mL), P = .002). The basal C-peptide secretion rate (P = .02), total C-peptide secretion (P = .005), area under the curve (AUC) of insulin (P = .04) and C-peptide (P = .01), and hepatic insulin extraction (P = .04) were higher in patients versus control subjects. In conclusion, insulin resistance is evident in subjects with early myocardial infarction accurately selected to avoid the influence of other factors known to reduce insulin sensitivity, and hyperinsulinemia is due to an increase in beta-cell secretion rather than a decrease in hepatic insulin extraction.

Adult↗