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Biomedical subjects

S Del Prato

Publications and source records attributed to S Del Prato.

At least 19 recordsLinked to original sources
PubMed2000

Left ventricular mass in type 2 diabetes mellitus. A study employing a simple ECG index: the Cornell voltage.

Both type 2 diabetes mellitus (DM2) and left ventricular hypertrophy are associated with an increased risk of cardiovascular diseases (CVD). A strong association between hyperinsulinemia, which is the hallmark of DM2 and of insulin resistance syndrome (a cohort of metabolic abnormalities such as DM2, dyslipidemia, hyperuricemia, obesity, hypertension, hyperfibrinogenemia), and left ventricular (LV) hypertrophy was found in several studies. We studied 140 consecutive (both normo- and hypertensive) DM2 patients to determine a possible link between metabolic features and the degree of LV mass, calculated by the ECG method of Cornell voltage. The Cornell voltage value was 12.9+/-0.5 mm in the DM2 population as a whole, and 13.6+/-0.7 vs 11.7+/-0.9 mm (p=NS) in hypertensive and normotensive DM2 subgroups, respectively. Among all the metabolic parameters taken into account, the multivariate analysis shows that the fasting plasma insulin level is the strongest independent predictor of LV mass, both in the whole population (p=0.0005) and in the normo (p=0.0460) and hypertensive DM2 (p=0.0184) subgroups.

Adult↗
PubMed2000

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR).

BACKGROUND: Insulin resistance, dyslipidaemia and abnormal nonesterified fatty acid (NEFA) metabolism are features of the 'metabolic syndrome', but the mechanisms of these relationships are uncertain. MATERIALS AND METHODS: We studied associations between insulin resistance and lipoprotein concentrations by retrospective analysis of euglycaemic hyperinsulinaemic clamp data from 867 normoglycaemic subjects in 21 European centres. Data on NEFA concentrations were available in a subgroup of 541 subjects from 9 clinical centres. These subjects' characteristics do not vary significantly from those of the whole cohort. RESULTS: After adjustment for the effects of age, sex, obesity and intercentre variability, regression analysis showed relationships between triglycerides and markers of insulin sensitivity. There were significant correlations between triglycerides and fasting plasma glucose (P < 0.0001), fasting plasma insulin (P < 0.0001) and mean glucose infusion rate at steady state (M-value, P < 0.0001). Indices of insulin resistance were related to NEFA concentrations. Fasting NEFA were negatively correlated with the M-value (P < 0.0001). Non-esterified fatty acids at steady state were positively correlated with fasting markers of insulin resistance: fasting plasma glucose (P < 0.05), fasting plasma insulin (P < 0.005) and negatively correlated with the M-value (P < 0.0005). There were relationships between fasting concentrations of plasma lipids and of NEFAs. Non-esterified fatty acids at steady state correlated with fasting triglycerides (P < 0.0001), but not with any of the other plasma lipoprotein concentrations. The associations of fasting triglycerides with the M-value and with NEFAs at steady state were independent of each other. All these associations were independent of obesity and geographical location CONCLUSION: The results in this large cohort of healthy European subjects suggest that triglyceride concentrations depend upon both insulin's gluco-regulation (estimated by glucose uptake) and antilipolytic insulin action (measured by NEFA levels) during an euglycaemic clamp.

Adolescent↗
PubMed2000

Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition.

Free fatty acids (FFA) are known to interfere with glucose metabolism. Moreover, it has been shown that they are able to impair the endothelium-dependent vasodilation. Therefore, we sought to determine whether their negative effect on endothelial function depends on their chain length or on their ability to modify PG production. Fourteen normal volunteers were studied under baseline conditions and then randomly allocated to two of the following four studies: 1) long chain triglyceride (LCT) emulsion and heparin infusion (n = 7), 2) infusion of an emulsion containing 56% medium chain triglycerides (MCT) and 44% LCT plus heparin (n = 7), 3) infusion of LCT and heparin preceded by an i.v. bolus of 900 mg lysine-salicylate (ASA; n = 7), and 4) after an i.v. bolus of ASA (n = 7). Basal forearm blood flow (FBF), endothelium-dependent vasodilation in response to intraarterial acetylcholine (Ach), and endothelium-independent vasodilation in response to intraarterial nitroprusside were assessed by venous occlusion plethysmography. Both LCT and MCT infusions significantly increased basal FBF from 1.58 +/- 0.35 to 2.60 +/- 0.76 and 2.28 +/- 0.56 mL/min 100 mL tissue, respectively (both P < 0.05). This increase was also observed for LCT plus heparin, but not after ASA alone. The percent increase in FBF during Ach was lowered during both LCT (252 +/- 34% of the ratio infused/control arm at maximal Ach dose) and MCT (255 +/- 41%) compared to the baseline conditions (436 +/- 44%; both P < 0.05). The response to Ach was also lower during LCT plus ASA, whereas it was similar to baseline with ASA alone. No differences were observed in the response to nitroprusside among the experimental conditions. In conclusion, 1) the effect of FFA on endothelium-dependent vasodilation is independent of their chain length; 2) both LCT and MCT increase baseline FBF, independently from cyclooxygenase inhibition; and 3) acute ASA administration does not affect endothelium-dependent vasodilation. The FFA effect on the endothelial response to Ach may contribute to altered endothelial function and, hence, to the development and progression of atherosclerotic cardiovascular disease.

Acetylcholine↗
PubMed2000

Effects of glucosamine infusion on insulin secretion and insulin action in humans.

Glucose toxicity (i.e., glucose-induced reduction in insulin secretion and action) may be mediated by an increased flux through the hexosamine-phosphate pathway. Glucosamine (GlcN) is widely used to accelerate the hexosamine pathway flux, independently of glucose. We tested the hypothesis that GlcN can affect insulin secretion and/or action in humans. In 10 healthy subjects, we sequentially performed an intravenous glucose (plus [2-3H]glucose) tolerance test (IVGTT) and a euglycemic insulin clamp during either a saline infusion or a low (1.6 micromol x min(-1) x kg(-1)) or high (5 micromol x min(-1) x kg(-1) [n = 5]) GlcN infusion. Beta-cell secretion, insulin (SI*-IVGTT), and glucose (SG*) action on glucose utilization during the IVGTT were measured according to minimal models of insulin secretion and action. Infusion of GlcN did not affect readily releasable insulin levels, glucose-stimulated insulin secretion (GSIS), or the time constant of secretion, but it increased both the glucose threshold of GSIS (delta approximately 0.5-0.8 mmol/l, P < 0.03-0.01) and plasma fasting glucose levels (delta approximately 0.3-0.5 mmol/l, P < 0.05-0.02). GlcN did not change glucose utilization or intracellular metabolism (glucose oxidation and glucose storage were measured by indirect calorimetry) during the clamp. However, high levels of GlcN caused a decrease in SI*-IVGTT (delta approximately 30%, P < 0.02) and in SG* (delta approximately 40%, P < 0.05). Thus, in humans, acute GlcN infusion recapitulates some metabolic features of human diabetes. It remains to be determined whether acceleration of the hexosamine pathway can cause insulin resistance at euglycemia in humans.

Adult↗
PubMed1999

Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man. EGIR (European Group for the Study of Insulin Resistance).

OBJECTIVE: To assess the impact of obesity and insulin sensitivity on resting (REE) and glucose-induced thermogenesis (GIT). DESIGN: Data from 322 studies carried out in non-diabetic subjects of either gender, covering a wide range of age (18-80y) and body mass index (BMI, 18-50 kg/m2). MEASUREMENTS: Insulin sensitivity and thermogenesis were measured by combining the euglycaemic insulin clamp technique with indirect calorimetry. RESULTS: REE was inversely related to age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001). In a multiple regression model, LBM-adjusted REE was estimated to decline by 9% between 18 and 80 y, independently of obesity and insulin sensitivity. In contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not with gender, age or BMI. By multiple regression analysis, GIT was linearly related to insulin sensitivity after controlling for gender, age, BMI and steady-state plasma insulin levels. Furthermore, both of the main components of insulin-mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated with GIT independently of one another. In the subset of subjects (n = 89) in whom waist-to-hip ratio (WHR) measurements were available, GIT was inversely associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin sensitivity and steady-state plasma insulin concentration). In this model, a significant interaction between WHR and gender indicated a stronger adverse effect on GIT of a high WHR in women than in men. CONCLUSIONS: In healthy humans, age, lean mass and respiratory quotient are the main independent determinants of resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent, abdominal obesity are the principal factors controlling glucose-induced thermogenesis.

Adolescent↗
PubMed1999

Measurement of insulin resistance in vivo.

Insulin sensitivity, which can be impaired in both glucose-intolerant and non-glucose-intolerant individuals, is a valuable parameter because of its potential as a marker for the future development of diabetes and increased cardiovascular risk. Techniques available for the determination of insulin sensitivity include the glucose clamp, insulin tolerance test, insulin suppression test, the frequently sampled intravenous glucose tolerance test and the regional artero-venous balance. Model assessment methods are also available for the measurement of insulin sensitivity at steady-state plasma glucose and insulin levels or after a standardised glucose infusion. Methods vary in their complexity, and the choice between them depends on the nature of the information required. There is also evidence for a strong genetic contribution to insulin sensitivity; although identification of the relevant gene(s) has not yet been successful, accurate phenotyping should still be carried out as part of the assessment of a patient's clinical status.

Diabetes Mellitus, Type 2↗
PubMed1999

Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.

The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.

Blood Glucose↗
PubMed1999

Effect of acute ketosis on the endothelial function of type 1 diabetic patients: the role of nitric oxide.

In type 1 diabetic patients, acute loss of metabolic control is associated with increased blood flow, which is believed to favor the development of long-term complications. The mechanisms for inappropriate vasodilation are partially understood, but a role of endothelium-derived nitric oxide (NO) production can be postulated. We assessed, in type 1 diabetic patients, the effect of the acute loss of metabolic control and its restoration on forearm endothelial function in 13 type 1 diabetic patients who were studied under conditions of mild ketosis on two different occasions. In study 1, after basal determination, a rapid amelioration of the metabolic picture was obtained by insulin infusion. In study 2, seven type 1 diabetic patients underwent the same experimental procedure, except that fasting plasma glucose was maintained constant throughout. Basal plasma venous concentrations of nitrites/nitrates (NO2- + NO3-) were determined both before and after intravenous insulin infusion. Endothelium-dependent and -independent vasodilation of the brachial artery was assessed by an intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA) and sodium nitroprusside (SNP), respectively. The same parameters were determined in 13 control subjects at baseline conditions and during a hyperinsulinemic-euglycemic glucose clamp. Baseline forearm blood flow (4.89 +/- 0.86 vs. 3.65 +/- 0.59 ml x (100 ml tissue)(-1) x min(-1)) and NO2- + NO3- concentration (30 +/- 8 vs. 24 +/- 3 micromol/l) were higher in type 1 diabetic patients than in control subjects (P < 0.05). Insulin infusion was associated with lower forearm blood flow and plasma (NO2- + NO3-) concentration (P < 0.05), irrespective of the prevailing glucose levels, as compared with patients under ketotic conditions. The responses to L-NMMA were significantly lower in type 1 diabetic patients during euglycemia and hyperglycemic hyperinsulinemia (-11 +/- 5 and -10 +/- 4%, respectively, of the ratio of the infused arm to the control arm) than in control subjects at baseline (-18 +/- 6%, P < 0.05) and during hyperinsulinemia (-32 +/- 11%, P < 0.01). We conclude that the acute loss of metabolic control is associated with a functional disturbance of the endothelial function characterized by hyperemia and increased NO release during ketosis and blunted NO-mediated vasodilatory response during restoration of metabolic control by intravenous insulin. This functional alteration is unlikely to be explained by hyperglycemia itself.

Acute Disease↗
PubMed1999

Protein kinase C activity is acutely regulated by plasma glucose concentration in human monocytes in vivo.

Activation of protein kinase C (PKC) by hyperglycemia is implicated in the pathogenesis of long-term diabetic complications. Monocyte activation and transformation into macrophages is a key step in the atherosclerotic process. Therefore, in this study, we sought to determine 1) the effect of hyperglycemia on monocyte PKC activity and on the distribution of Ca2+-dependent and diacylglycerol-sensitive PKC isoforms; and 2) whether the effects on these parameters are determined by hyperglycemia per se, independent of the diabetic state. The studies were performed in 19 type 2 diabetic patients and 14 control subjects. Plasma glucose concentration was higher and insulin sensitivity lower (both P < 0.01) in diabetic patients than in control subjects. Monocytes from diabetic patients showed similar cytosol PKC activity to those from control subjects but higher membrane PKC activity (78+/-6 vs. 50+/-5 pmol x min(-1) x mg(-1) protein; P < 0.01). A direct correlation was observed between fasting plasma glucose and membrane PKC activity (r2 = 0.4008, P = 0.0001). In contrast, a reciprocal correlation was observed between membrane PKC activity and insulin sensitivity index (r2 = 0.28, P < 0.05). Using immunoblotting analysis, we found that membrane beta2, but not alpha, isoform of PKC was more abundant in monocytes from diabetic patients. In diabetic patients, when euglycemia was acutely induced, membrane PKC activity decreased by approximately 42% and beta2 isoform by approximately 15%. In two normal subjects in whom hyperglycemia was induced, membrane PKC increased from 63 and 57 to 92 and 128.6 pmol x min(-1) x mg(-1) protein, respectively. This increase was associated with an increase in the membrane isoform beta2; alpha isoform was unchanged. We conclude that 1) monocytes express the glucose-sensitive beta2 isoform of PKC; 2) the prevailing plasma glucose acutely regulates the activity of the membrane PKC and the content of membrane PKC beta2 isoform; and 3) this effect appears to be a direct effect of glucose per se, since the phenomenon was observed in normal control subjects when hyperglycemia was induced. Monocyte PKC activation may account for the accelerated atherosclerosis of patients with type 2 diabetes.

Blood Glucose↗
PubMed1998

Role of tissue-specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle.

BACKGROUND: Conflicting evidence exists concerning whether insulin-induced vasodilation plays a mechanistic role in the regulation of limb glucose uptake. It can be predicted that if insulin augments blood flow by causing tissue recruitment, this mechanism would enhance limb glucose uptake. METHODS AND RESULTS: Twenty healthy subjects were studied with the forearm perfusion technique in combination with the euglycemic insulin clamp technique. Ten subjects were studied at physiological insulin concentrations (approximately 400 pmol/L) and the other 10 at supraphysiological insulin concentrations (approximately 5600 pmol/L). Four additional subjects underwent a saline control study. Pulse injections of a nonmetabolizable extracellular marker (1-[3H]-L-glucose) were administered into the brachial artery, and its washout curves were measured in one ipsilateral deep forearm vein and used to estimate the extracellular volume of distribution and hence the amount of muscle tissue drained by the deep forearm vein. Both during saline infusion and at physiological levels of hyperinsulinemia we observed no changes in blood flow and/or muscle tissue drained by the deep forearm vein. However, supraphysiological hyperinsulinemia accelerated total forearm blood flow (45.0+/-1.8 versus 36.5+/-1.3 mL x min(-1) x kg(-1), P<0.01) and increased the amount of muscle tissue drained by the deep forearm vein (305+/-46 versus 229+/-32 g, P<0.05). The amount of tissue newly recruited by insulin was strongly correlated to the concomitant increase in tissue glucose uptake (r=0.789, P<0.01). CONCLUSIONS: Acceleration of forearm blood flow mediated by supraphysiological hyperinsulinemia is accompanied by tissue recruitment, which may be a relevant determinant of forearm (muscle) glucose uptake.

Adult↗
PubMed1998

Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria.

We assessed blood pressure (BP), body weight, renal hemodynamics, and insulin sensitivity (by euglycemic-hyperinsulinemic clamp) in nine normoalbuminuric and seven microalbuminuric IDDM patients after 6 days on a low-sodium diet (20 mEq) and after 6 days on a high-sodium diet (250 mEq). In microalbuminuric but not in normoalbuminuric IDDM patients, switching from a low to a high-sodium diet was associated with a significant increase in mean BP (from 92 +/- 3 to 101 +/- 4 mmHg; P < 0.001) and in body weight (2.91 +/- 0.63 vs. 1.47 +/- 0.26 kg; P < 0.05). Moreover, under high-sodium conditions, angiotensin II infusion (3 ng x kg(-1) x min(-1)) caused a greater increase in mean BP (14 +/- 2 vs. 7.4 +/- 1 mmHg; P < 0.05) and a smaller reduction in renal plasma flow (-122 +/- 29 vs. -274 +/- 41 ml x min(-1) x 1.73 m2; P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Under low sodium conditions, aldosterone increments after angiotensin II infusion were lower (P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Insulin-mediated glucose disposal was not affected by sodium dietary content, but it was lower in microalbuminuric (P < 0.05) than in normoalbuminuric IDDM patients. The salt-induced changes in mean BP were related to insulin sensitivity (r = -0.78; P < 0.001). In conclusion, in IDDM patients, microalbuminuria is associated with 1) an increased responsiveness of BP to salt intake and angiotensin II, 2) impaired modulation of renal blood flow, and 3) insulin resistance. Therefore, salt sensitivity in IDDM patients clusters with other factors that are likely to play an important role in the pathogenesis of diabetic nephropathy and its cardiovascular complications.

Adrenal Glands↗
PubMed1997

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance.

UNLABELLED: The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-3H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 +/- 0.6, 15.7 +/- 0.7, and 26.3 +/- 1.1 mumol/kg.min). In NIDDM (10.5 +/- 0.2, 12.1 +/- 1.0, and 17.5 +/- 1.1 mumol/kg.min), and IDDM (11.2 +/- 0.8, 12.9 +/- 1.0, and 15.6 +/- 1.1 mumol/kg.min) glucose disposal was lower during all three steps (p < 0.05-0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+4.4 +/- 0.7 mumol/kg.min) only at +11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+3.1 +/- 0.7; +3.5 +/- 0.9, and +10.8 +/- 1.7 mumol/kg.min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = +0.5 +/- 1.5; NIDDM = +0.2 +/- 0.6 mumol/kg.min) and non-oxidative glucose metabolism was hampered (IDDM = +1.8 +/- 1.5, +3.1 +/- 1.7, and +4.3 +/- 1.8; NIDDM = +0.7 +/- 0.6, 2.1 +/- 0.9, and +7.0 +/- 0.8 mumol/kg.min; p < 0.05-0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. IN CONCLUSION: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients.

Adult↗
PubMed1997

Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients.

Endothelium-dependent and -independent vascular responses were assessed in 10 NIDDM patients and 6 normal subjects with no evidence of atherosclerotic disease. Changes in forearm blood flow and arteriovenous (AV) serum nitrite/nitrate (NO2-/NO3-) concentrations were measured in response to intra-arterial infusion of acetylcholine (ACh) (7.5, 15, 30 microg/min, endothelium-dependent response) and sodium nitroprusside (SNP) (0.3, 3, 10 microg/min, endothelium-independent response). Insulin sensitivity (determined by minimal model intravenous glucose tolerance test) was lower in NIDDM patients (0.82 +/- 0.20 vs. 2.97 +/- 0.29 10(4) min x microU(-1) x ml(-1); P < 0.01). Baseline forearm blood flow (4.8 +/- 0.3 vs. 4.4 +/- 0.3 ml x 100 ml(-1) tissue x min(-1); NS), mean blood pressure (100 +/- 4 vs. 92 +/- 4 mmHg; NS), and vascular resistance (21 +/- 1 vs. 21 +/- 1 units; NS), as well as their increments during ACh and SNP, infusion were similar in both groups. No difference existed in baseline NO2-/NO3- concentrations (4.09 +/- 0.33 [NIDDM patients] vs. 5.00 +/- 0.48 micromol/l [control subjects]; NS), their forearm net balance (0.31 +/- 0.08 [NIDDM patients] vs. 0.26 +/- 0.08 micromol/l x 100 ml(-1) tissue x min(-1); NS), and baseline forearm glucose uptake. During ACh infusion, both NO2- and NO3- concentrations and net balance significantly increased in both groups, whereas glucose uptake increased only in control subjects. When data from NIDDM and control groups were pooled together, a correlation was found between the forearm AV NO2- and NO3- differences and blood flow (r = 0.494, P = 0.024). On the contrary, no correlation was evident between NO2- and NO3- concentrations or net balance and insulin sensitivity. In summary, 1) no difference existed in basal and ACh-stimulated NO generation and endothelium-dependent relaxation between uncomplicated NIDDM patients and control subjects; 2) in both NIDDM and control groups, forearm NO2- and NO3- net balance following ACh stimulation was related to changes in the forearm blood flow; and 3) ACh-induced increase in forearm blood flow was associated with an increase in glucose uptake only in control subjects but not in NIDDM patients. In conclusion, our results argue against a role of impaired NO generation and blood flow regulation in determining the insulin resistance of uncomplicated NIDDM patients; rather, it supports an independent insulin regulation of hemodynamic and metabolic effects.

Acetylcholine↗
PubMed1997

Fasting hyperglycaemia following trans-catheter arterial chemo-embolization for hepatocellular carcinoma in cirrhosis.

BACKGROUND AND AIMS: Following a hyperosmolar diabetic coma in a cirrhotic patient with hepatocellular carcinoma undergoing transcatheter arterial chemo-embolization, we assessed the prevalence, severity, causes and prognostic impact of impaired glucose metabolism following transcatheter arterial chemo-embolization. METHODS: Plasma glucose, pancreatic and thyroid hormones, cortisol, growth hormone, ACTH and TSH concentrations were determined before and after transcatheter arterial chemo-embolization in 98 patients (70 with a normal fasting glucose, 7 with mild fasting hyperglycaemia and 21 diabetics) undergoing 226 transcatheter arterial chemo-embolization procedures. Child status, body temperature, serum ALT and amylase levels, tumour size, gelfoam embolization and disease aetiology were recorded. Liver function was assessed before and after transcatheter arterial chemo-embolization by measuring monoethylglycinexylidide formation after i.v. lidocaine. RESULTS: A significant rise in glucose levels (p < 0.0001) was observed in 30/98 patients. Hyperglycaemia was more frequent in diabetics (67%) and patients with mild fasting hyperglycaemia (71%). Glucose concentrations doubled in 12 patients; 4 required long-term insulin. Fever, a previously altered carbohydrate metabolism and raised ALT levels were prognostic factors for hyperglycaemia (p < 0.01). Plasma C-peptide, glucose/insulin and glucose/C-peptide ratios, were increased after transcatheter arterial chemo-embolization (p < 0.05). Transcatheter arterial chemo-embolization was followed by a reduction in the monoethylglycinexylidide formation capacity (p < 0.05), particularly in hyperglycaemia patients (p < 0.02). CONCLUSIONS: Transcatheter arterial chemo-embolization is frequently followed by a derangement in glucose metabolism which is potentially severe, associated with preceding glucose imbalance, fever and a transient deterioration in liver function.

Adult↗
PubMed1996

Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals.

The contribution of muscle tissues of non-insulin-dependent diabetes mellitus (NIDDM) patients to blood lactate appearance remains undefined. To gain insight on intracellular pyruvate/lactate metabolism, the postabsorptive forearm metabolism of glucose, lactate, FFA, and ketone bodies (KB) was assessed in seven obese non-insulin-dependent diabetic patients (BMI = 28.0 +/- 0.5 kg/m2) and seven control individuals (BMI = 24.8 +/- 0.5 kg/m2) by using arteriovenous balance across forearm tissues along with continuous infusion of [3-13C1]-lactate and indirect calorimetry. Fasting plasma concentrations of glucose (10.0 +/- 0.3 vs. 4.7 +/- 0.2 mmol/liter), insulin (68 +/- 5 vs. 43 +/- 6 pmol/liter), FFA (0.57 +/- 0.02 vs. 0.51 +/- 0.02 mmol/liter), and blood levels of lactate (1.05 +/- 0.04 vs. 0.60 +/- 0.06 mmol/liter), and KB (0.48 +/- 0.04 vs. 0.29 +/- 0.02 mmol/liter) were higher in NIDDM patients (P < 0.01). Forearm glucose uptake was similar in the two groups (10.3 +/- 1.4 vs. 9.6 +/ 1.1 micromol/min/liter of forearm tissue), while KB uptake was twice as much in NIDDM patients as compared to control subjects. Lactate balance was only slightly increased in NIDDM patients (5.6 +/- 1.4 vs. 3.3 +/- 1.0 micromol/min/liter; P = NS). A two-compartment model of lactate and pyruvate kinetics in the forearm tissue was used to dissect out the rates of lactate to pyruvate and pyruvate to lactate interconversions. In spite of minor differences in the lactate balance, a fourfold increase in both lactate- (44.8 +/- 9.0 vs. 12.6 +/- 4.6 micromol/min/liter) and pyruvate-(50.4 +/- 9.8 vs. 16.0 +/- 5.0 micromol/min/liter) interconversion rates (both P < 0.01) were found. Whole body lactate turnover, assessed by using the classic isotope dilution principle, was higher in NIDDM individuals (46 +/- 9 vs. 21 +/- 3 micromol/min/kg; P < 0.01). Insights into the physiological meaning of this parameter were obtained by using a whole body noncompartmental model of lactate/pyruvate kinetics which provides a lower and upper bound for total lactate and pyruvate turnover (NIDDM = 46 +/- 9 vs. 108 +/- 31; controls = 21 +/- 3 - 50 +/-13 micromol/min/kg). In conclusion, in the postabsorptive state, despite a trivial lactate release by muscle, lactate- and pyruvate-interconversion rates are greatly enhanced in NIDDM patients, possibly due to concomitant impairment in the oxidative pathway of glucose metabolism. This finding strongly suggest a major disturbance in intracellular lactate/pyruvate metabolism in NIDDM.

Adult↗
PubMed1996

Unresectable hepatocellular carcinoma in cirrhosis: survival, prognostic factors, and unexpected side effects after transcatheter arterial chemoembolization.

To evaluate the efficacy of transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma, the prognostic factors, and the side effects, 72 patients undergoing 170 chemoembolizations with lipiodol-mediated injection of adriamycin were investigated. The 1-, 2-, and 3-year survivals are 83, 61, and 56%, respectively. Significant prognostic factors for survival (by Mantael-Haenszel) are Child-Pugh and Okuda status (p = 0.00001 and p = 0.01 respectively), number of TACE courses (p = 0.002) and of courses completed with embolization (p = 0.05), stabilization or reduction of alpha-fetoprotein (p = 0.003), and concurrent tamoxifen treatment (p = 0.04). Side effects included fever, pain, increased serum amylase and transaminase levels, and one liver abscess with death of liver failure. In addition, mild hyperglycemia was observed in 19% of patients and severe in 8% (with one hyperosmolar diabetic coma), in the absence of pancreatic damage. In conclusion, transcatheter arterial chemoembolization is useful in patients with unresectable hepatocellular carcinoma. Prognostic factors are Child-Pugh and Okuda status, number of TACE courses and of embolizations, changes of alpha-fetoprotein levels, and association with tamoxifen treatment. The development of mild to severe changes of glucose metabolism suggests that glucose tolerance should be evaluated before and glycemia strictly monitored after each TACE course.

Abdominal Pain↗