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Presents a response by M. Pinizzotto, E. Castillo, M. Fiaux, E. Temler, R. C. Gaillard, and J. Ruiz to a letter to the editor about their article "Paraoxonase2 Polymorphisms Are Associated With Neuropathy in Type II Diabetes," in the 2001 issue of "Diabetologia."

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.

Iodine deficiency disorders virtually disappeared in Switzerland after iodized salt was introduced in 1922 and the iodine content increased from 3.75 to 7.5 mg/kg in 1962 and to 15 mg/kg in 1980. However, a decreasing iodine intake has recently been reported again. The status of iodine nutrition in the Canton of Vaud was therefore assessed in 348 representative adolescents aged 11 to 17 years from the urban area of Lausanne in 1995. Thyroid size was estimated by inspection and palpation and thyroid volume measured by ultrasonography. Iodine concentration was determined in urine. Thyroid enlargement, as assessed by clinical examination, was found in 15% of the adolescents (stage 1a: 12.9%, 1b: 1.8%, 2: 0.3%), but its positive predictive value was low. The goitre prevalence determined by ultrasonography was only 1.4%. In addition, 4% of the adolescents had nodular or diffuse echo-structure abnormalities. Percentiles of thyroid volume as a function of sex, chronological age and body surface area were lower than WHO reference values. Median iodine concentration in urine was 92 micrograms/l (56.6% < 100 micrograms/l), slightly below WHO recommendations. Iodized cooking salt was consumed by 82% of the adolescents. In conclusion, the adolescents living in the Canton of Vaud had a low normal iodine intake with subclinical thyroid abnormalities. These findings support the recent decision to increase the salt iodine content to 20-30 mg/kg in order to prevent iodine deficiency during puberty and pregnancy. Percentiles of thyroid volume determined in the present study can be used as local reference.

Elevated free fatty acid concentrations are known to decrease insulin-mediated glucose uptake, glucose oxidation and glycogen synthesis. In order to determine whether free fatty acids inhibit glycogen synthesis at the level of liver cells, the effects of an infusion of lipids on carbohydrate metabolism were investigated in healthy subjects during a two-step (16.7 and 33.4 mumol/(kg.min) 13C-fructose infusion. Fructose infusion dose-dependently stimulated fructose (measured from 13CO2 production) and net carbohydrate oxidation (measured with indirect calorimetry). It also stimulated systemic 13C glucose appearance, indicating a dose-dependent stimulation of gluconeogenesis. Net glucose output (measured with 6,6 2H glucose) was however not altered. Lipid infusion significantly reduced fructose oxidation (measured from 13CO2 production) at both rates of fructose infusion, but did not alter plasma fructose or lactate concentrations, nor plasma 13C glucose appearance or net glucose production. Non oxidative fructose disposal was increased by 31% (p < 0.05) at the lowest, and by 18% (p < 0.01) at the highest infusion rate. Since nonoxidative fructose disposal corresponds mainly to liver glycogen deposition, these results suggest that lipid infusion increased hepatic glycogen synthesis, and hence that hepatic glycogen synthase is not inhibited by fatty acids.

Inhibition of pancreatic glucagon secretion has been reported to be mediated by glucose, insulin and somatostatin. As no human pancreatic alpha-cell lines are available to study in vitro the relative importance of insulin and glucose in the control of pancreatic glucagon release, we investigated a patient presenting with a malignant glucagonoma who underwent surgical resection of the tumour. Functional somatostatin receptors were present as octreotide administration decreased basal glucagon and insulin secretion by 52 and 74%, respectively. The removed tumour was immunohistochemically positive for glucagon, chromogranin A and pancreatic polypeptide but negative for insulin, gastrin and somatostatin. The glucagonoma cells were also isolated and cultured in vitro. Incubation experiments revealed that change from high (10 mM) to low (1 mM) glucose concentration was unable to stimulate glucagon secretion. A dose-dependent inhibition of glucagon release by insulin was however, observed at low glucose concentration. These findings demonstrate that insulin could inhibit glucagon secretion in vitro in the absence of elevated glucose concentrations. These data suggest, as observed in vivo and in vitro in several animal studies, that glucopenia-induced glucagon secretion in humans is not mediated by a direct effect of low glucose on alpha-cells but possibly by a reduction of insulin-mediated alpha-cell suppression and/or an indirect neuronal stimulation of glucagon release.

Macrophage migration inhibitory factor (MIF), originally identified as a cytokine secreted by T lymphocytes, was found recently to be both a pituitary hormone and a mediator released by immune cells in response to glucocorticoid stimulation. We report here that the insulin-secreting beta cell of the islets of Langerhans expresses MIF and that its production is regulated by glucose in a time- and concentration-dependent manner. MIF and insulin colocalize by immunocytochemistry within the secretory granules of the pancreatic islet beta cells, and once released, MIF appears to regulate insulin release in an autocrine fashion. In perifusion studies performed with isolated rat islets, immunoneutralization of MIF reduced the first and second phase of the glucose-induced insulin secretion response by 39% and 31%, respectively. Conversely, exogenously added recombinant MIF was found to potentiate insulin release. Constitutive expression of MIF antisense RNA in the insulin-secreting INS-1 cell line inhibited MIF protein synthesis and decreased significantly glucose-induced insulin release. MIF is therefore a glucose-dependent, islet cell product that regulates insulin secretion in a positive manner and may play an important role in carbohydrate metabolism.

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low Km glucose transporter GLUT1 but no transcript for the high Km glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.

Objective: To evaluate the benefit of recombinant human growth hormone administration on muscle strength and duration of weaning in critically ill patients undergoing prolonged mechanical ventilation., Design: Prospective, randomized, controlled, single-blind study., Setting: Intensive care unit., Patients: Twenty patients requiring > or = 7 days of mechanical ventilation for acute respiratory failure., Intervention: Random assignment to receive either 0.43 IU (approximately 0.14 mg) recombinant growth hormone/kg body weight/day (treated group), or saline (nontreated group) for 12 days., Measurements and Main Results: Nutritional support was guided by indirect calorimetry. Cumulative nitrogen balance was positive throughout the study period in the treated group 17.3 (44.9 +/- 17.3[SEM] g/12 days) vs. the nontreated group (-65.8 +/- 11.8 g/12 days) (p<.0001). Despite similar initial plasma concentrations, recombinant growth hormone supplementation resulted in marked increases in growth hormone, insulin like growth factor-1, and insulin concentrations (p<.05, .02, and .0001, respectively, vs. nontreated group). Body impedance determined net fat-free mass increased in the treated group (0.8 +/- 0.6 kg) vs. the nontreated group (-1.1 +/- O.5 kg) (p<.03). Initial peripheral muscle function, assessed by computer-controlled electrical stimulation of the adductor pollicis, was similarly lower in treated and nontreated groups than sex and age-matched normal controls, and decreased further during the study period. Arterial blood gases, cumulative total mechanical ventilation time, and number of hrs/day of mechanical ventilation during weaning were similar in both patient groups. Only three of the ten patients in each group were weaned from mechanical ventilation by day 12., Conclusions: Daily administration of recombinant growth hormone in mechanically ventilated patients with acute respiratory failure promotes a marked nitrogen retention. However, this reaction is accompanied neither by an improvement in muscle strength nor by a shorter duration of ventilatory supports.

To assess the effects of lactate on glucose metabolism, sodium lactate (20 mumol.kg-1.min-1) was infused into healthy subjects in basal conditions and during application of a hyperinsulinaemic (6 pmol.kg-1.min-1) euglycaemic clamp. Glucose rate of appearance (GRa) and disappearance (GRd) were measured from plasma dilution of infused U- 13C glucose, and glucose oxidation (G(ox)) from breath 13CO2 and plasma 13C glucose. In basal conditions, lactate infusion did not alter G(ox) (8.8 +/- 0.9 vs 9.2 +/- 1.1 mumol.kg-1.min-1), while GRa slightly decreased from 15.2 +/- 0.8 basal to 13.9 +/- 0.9 mumol.kg-1.min-1 after lactate (p < 0.05). During a hyperinsulinaemic clamp, hepatic glucose production was completely suppressed with or without lactate. Lactate decreased G(ox) from 17.1 +/- 0.4 to 13.4 +/- 1.2 mumol.kg-1.min-1 (p < 0.05), whereas GRd was unchanged (39.7 +/- 3.6 vs 45.6 +/- 2.6 mumol.kg-1.min-1. It is concluded that infusion of lactate in basal conditions does not increase GRa or interfere with peripheral glucose oxidation, and that during hyperinsulinaemia lactate decreases glucose oxidation but does not alter hepatic or peripheral insulin sensitivity.

The effects of infusion of a triglyceride emulsion (which induces peripheral insulin resistance) and amino acids (which stimulate gluconeogenesis) on glucose metabolism were investigated in healthy lean humans during exogenous infusion of glucose. One group of subjects (n = 5) was infused for 7.5 h with 11.1 mumol/kg/min glucose; during the last 4 h, amino acids were also infused at a rate of 3.33 mg/kg/min. A second group of subjects (n = 5) was infused with glucose+lipids (Lipovenös, 10% 10 ml/min) for 7.5 h and amino acids were added during the last 4 h. Infusion of lipids suppressed the increase in glucose oxidation observed during infusion of glucose alone (delta glucose oxidation: -2.1 +/- 1.1 vs. + 4.5 +/- 1.4 mumol/kg/min; P < 0.05) and during infusion of glucose+amino acids (delta glucose oxidation: + 1.6 +/- 1.4 vs. + 10.6 +/- 1.2 mumol/kg/min; P < 0.05). Gluconeogenesis (determined from 13C glucose synthesis during infusion of 13C bicarbonate) increased from 1.1 +/- 0.2 mumol/kg/min during infusion of glucose and 1.6 +/- 0.3 during infusion of glucose+lipids to 3.2 +/- 0.4 and 3.1 +/- 0.4, respectively, when amino acid infusion was superimposed (P < 0.05 in both instances). Plasma glucose concentrations were identical during infusion of glucose alone or glucose+amino acids, with or without lipids. Insulin concentrations were significantly increased by lipids both during infusion of glucose alone and of glucose+amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Obese patients have markedly increased plasma insulin concentrations indicating insulin resistance. In contrast, plasma IGF-1 concentrations are little affected. Since the biological effects of IGF-1, including several insulin-like actions, appear to be modulated by serum carrier proteins, alterations of IGF-1 binding proteins were investigated in the serum of lean healthy individuals, and of obese patients with normal glucose tolerance. Obese patients had increased fasting plasma insulin and decreased plasma h-GH concentrations, compared to lean controls. IGF-1 concentrations were similar in both groups. Serum IGF-1 binding proteins were separated by polyacrylamide gel electrophoresis under non-reducing conditions, electroblotted onto a nitrocellulose sheet, and quantified by ligand blot with 125I IGF-1 and autoradiography. IGF-1 binding proteins of apparent molecular weight 42 kDa, 39 kDa, 35 kDa, 30 kDa and 24 kDa were observed. Obese patients had a level of IGF-1 binding proteins of 35 kDa which was decreased to 40 +/- 25% (s.d.) of control values. This 35 kDa protein corresponds to IGF-BP2, which may be involved in glucose homeostasis. It is concluded that alterations of IGF-1 binding proteins are present in obesity and may have consequences for glucose metabolism.

The purpose of this study was to verify in man the relationships of muscle glycogen synthase and phosphorylase activities with glycogen concentration that were reported in animal studies. The upper level of glycogen concentration in muscle is known to be tightly controlled, and glycogen concentration was reported to have an inhibitory effect on synthase activity and a stimulatory effect on phosphorylase activity. Glycogen synthase and phosphorylase activity and glycogen concentration were measured in muscle biopsies in a group of nine normal subjects after stimulating an increase of their muscle glycogen concentration through either an intravenous glucose-insulin infusion to stimulate glycogen synthesis, or an Intralipid (Vitrum, Stockholm, Sweden) infusion in the basal state to inhibit glycogen mobilization by favoring lipid oxidation at the expense of glucose oxidation. Phosphorylase activity increased from 71.3 +/- 21.0 to 152.8 +/- 20.0 nmol/min/mg protein (P < .005) after the glucose-insulin infusion. Phosphorylase activity was positively correlated with glycogen concentration (P = .005 and P = .0001) after the glucose-insulin and Intralipid infusions, respectively. Insulin-stimulated glycogen synthase activity was significantly negatively correlated with glycogen concentration at the end of the Intralipid infusion (P < .005). In conclusion, by demonstrating a negative correlation of glycogen concentration with glycogen synthase and a positive correlation with phosphorylase, this study might confirm in man the double-feedback mechanism by which changes in glycogen concentration regulate glycogen synthase and phosphorylase activities. It suggests that this mechanism might play an important role in the regulation of glucose storage.

Intravenous fat tolerance tests (IVFTT) were performed in 13 healthy men volunteers once a day during three consecutive days in order to compare three different fat emulsions randomly administered (Intralipid 20%, Hausmann Lipid 20%, Lipovenös 20%). The amount of fat was 0.1 g/kg of body weight injected within 32 +/- 4 sec and the lipid clearance was determined over 40 min. The fractional removal rates k for the three different emulsions of fat were 5.38 +/- 1.67, 4.95 +/- 2.15, 3.92 +/- 1.31 %/min, respectively (mean +/- SD), and the half-life time of clearance T1/2 were 14.5 +/- 5.8, 16.9 +/- 7.4, 19.2 +/- 5.2 min, respectively. The highest fat particles values were observed 5 min after the bolus and all concentrations remained within the normal range (0-3 g/liter) during the study. In addition, no adverse effects were observed throughout the IVFTT. The nonparametric analysis of variance (Friedman's test) showed no significant differences between groups, even if Lipovenös 20% tended to be cleared more slowly than Intralipid 20%. These results suggest that the three fat emulsions are similarly eliminated from the blood stream and do not result in acute intolerance. Further studies based on prolonged infusion should be carried out to determine whether the two new emulsions might be alternatively used for intravenous nutritional support.

The oxidative and nonoxidative glucose metabolism represent the two major mechanisms of the utilization of a glucose load. Eight normal subjects were administered oral loads of 50, 100 and 150 g glucose and gas exchange measurements were performed for eight hours by means of computerized continuous indirect calorimetry. The glycemic peaks were almost identical with all three doses with a rise to between 141 and 147 mg/dl at 60 min. The fall back to basal level was reached later with the high than with the low glucose doses. The glucose oxidation rate rose to values between 223 and 253 mg/min after the three glucose doses, but while falling immediately after the peak at 120 min following the 50 g load, the glucose oxidation rate remained at its maximum rate until 210 min for the 100 g glucose load and plateaued up to 270 min for the 150 g glucose dose. The oxidation rates then fell gradually to reach basal levels at 270, 330 and 420 min according to the increasing size of the load. Altogether 55 +/- 3 g glucose were oxidized during the 8 hours following the 50 g glucose load, 75 +/- 3 g after the 100 g load and 80 +/- 5 g after the 150 g load. The nonoxidative glucose disposal, which corresponds essentially to glucose storage, varied according to the size of the glucose load, with uptakes of 20 +/- 1, 60 +/- 1 and 110 +/- 1 g glucose 180 min after the 50, 100 and 150 g glucose loads respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Sixty-seven subjects with moderate obesity (50 +/- 3 percent above ideal body weight) were given an oral glucose tolerance test with the simultaneous measurement of rates of glucose and lipid oxidation by continuous indirect calorimetry. When the subjects were stratified into nine 5-year classes of duration of obesity, the prevalence of impaired glucose tolerance (IGT) and overt diabetes both increased with increasing duration of obesity. Both basal and post-OGTT lipid oxidation rates were, however, similar in all classes. To assess the independent influence of IGT, diabetes, age, and duration of obesity on glucose metabolism, the data were subjected to analysis of variance using a factorial design with metric covariates. Age by itself was found to be associated (P less than 0.05) with a decline in total post-OGTT glucose oxidation. Both IGT and diabetes, on the other hand, were associated with increased plasma insulin and free fatty acid (FFA) levels, both in the fasting state and following glucose ingestion (P = 0.05-P less than 0.002). Only diabetes, however, was associated with a drastic reduction in nonoxidative glucose disposal, which marked the appearance of, and strongly correlated with (r = -0.81, P less than 0.001), fasting hyperglycemia. Duration of obesity had significant metabolic consequences in its own right: a fall in the insulin response to glucose (P = 0.05) and in the rate of total glucose oxidation (P = 0.03), and a rise in post-OGTT glucose levels (P = 0.04). We conclude that: (a) increased lipid oxidation is common in obesity, but is not sufficient to explain the deterioration of glucose tolerance in long-term obesity; (b) very-long-term obesity may be associated with partial exhaustion of the beta cell, and the resultant insulinopenia may cause depressed glucose oxidation and impaired glucose tolerance, and (c) a defect in nonoxidative glucose disposal is a characteristic feature of frank diabetes at any stage of obesity.

The inhibitory effect of N- beta-(4-ethoxycarbonylphenoxy-ethyl-1-desoxynojirimycin (BAY o1248) and of N-hydroxyethyl-1-desoxynojirimycin (BAY o1099) was studied in normal men. Nine healthy volunteers (weight range of 82% to 117% of their ideal body weight) ingested a 50 g sucrose load together with placebo, 50 mg BAY m1099, or 10 mg BAY of o1248. Their substrate oxidation rate was measured by continuous indirect calorimetry during four hours. The plasma glucose and plasma insulin peaks were both significantly blunted and the late fall of glycemia reduced. Mean plasma glucose, fructose, and insulin were reduced by both drugs during the first two hours following the sucrose load and led to a decrease of the suprabasal glucose oxidation (oxidation above baseline) during the first two hours of the test. However, the total suprabasal glucose oxidation during the four hours of the test was not significantly different from that of the control. Breath hydrogen, as an index of malabsorption, was shown to increase with both 50 mg BAY m1099 and 10 mg BAY o1248, starting from the third hour. These findings are consistent with a significant delay of sucrose absorption induced by these new alpha-glycohydrolase inhibitors.

To address whether a renal tubular dysfunction is encountered in a particular patient subgroup with urolithiasis, the following parameters of tubular function were measured in urine taken in the morning from 214 stone formers after fasting: pH, excretion of lysozyme and gamma-glutamyl transferase (gamma-GT); fractional excretion (FE) of glucose, insulin, Mg, K, and HCO3 after an alkali loading; and the renal threshold for phosphate (TmP/GFR). The following diagnoses were made in the patient group: primary hyperparathyroidism (N = 8), medullary sponge kidneys (N = 21), hyperuricemia (N = 10), cystinuria (N = 2), struvite stone disease (N = 6), idiopathic hypercalciuria of the absorptive (N = 25), dietary (N = 69) or renal (N = 7) type, and normocalciuric idiopathic urolithiasis (N = 66). In 31% of the patients TmP/GFR was below 0.80 mmole/liter and in 13% of the patients, FE HCO3 after alkali loading was above normal. Urinary excretion of lysozyme and that of gamma-GT both were elevated in 17% of the patients. FE glucose, FE insulin, FE Mg, and FE K were elevated in 8, 9, 3, and 7% of the patients, respectively. This study demonstrates that a significant number of stone formers present with signs of renal tubular dysfunction, primarily involving the proximal tubule since apparent leaks of phosphate and of bicarbonate were most frequently encountered. The defects were not specific for a given etiologic group of patients; on the other hand, occurrence was related to the presence of large stones in the pyelocaliceal system at the time data were gathered. Taken together these data suggest that the tubulopathy in nephrolithiasis is the consequence rather than the cause of the stone.

An increased incidence of diabetes mellitus and glucose intolerance has been reported in thalassaemia major treated with a high transfusion programme (HTP). To investigate beta-cell function, serum immunoreactive insulin (IRI), C-peptide (CP) and glucose were measured fasting and at 3, 6 and 10 min after i.v. administration of 1 mg glucagon in 20 thalassaemia patients treated by many transfusions and in nine healthy control subjects. Fasting C-peptide concentrations (mean +/- SEM) were higher in the thalassaemic group (2.15 +/- 0.17 ng/ml) than in the controls (1.41 +/- 0.13 ng/ml). After stimulation with glucagon, C-peptide concentrations were consistently higher (P less than 0.01) by approximately 50% in the thalassaemic than in the control group (5.29 +/- 0.31 vs 3.36 +/- 0.21 ng/ml, at 3 min; 5.22 +/- 0.30 vs 3.53 +/- 0.21 ng/ml at 6 min and 4.69 +/- 0.27 vs 3.30 +/- 0.17 ng/ml after 10 min). Plasma IRI concentrations increased in both groups after glucagon stimulation but were not significantly different. The glucose values were approximately 15% higher at each sampling time in the thalassaemic group than those of the normal subjects. It is concluded that disturbances in carbohydrate metabolism in thalassaemia major treated with HTP are the consequence of hepatic cirrhosis which accompanies secondary haemosiderosis, and possibly iron deposition in the beta-cells of the pancreas.

Anterior pituitary hypersecretion can be due to abnormal hypothalamic regulation, decreased peripheral hormone feedback or pituitary tumor. In some cases hypersecretion gives rise to a typical clinical syndrome involving acromegaly, hyperprolactinemia, and excess corticotropin (ACTH). The etiology of acromegaly is a growth hormone (GH)-secreting pituitary tumor in the vast majority of cases. Hyperprolactinemia and excess cortisol, however, may be due to many causes among which prolactin (PRL)- and ACTH-secreting pituitary tumors are not frequent. Glycoprotein-secreting pituitary tumors, especially gonadotropin (LH and FSH) and free subunits usually do not cause a typical excess hormone syndrome. Perhaps for this reason they are seldom recognized clinically, although histopathological studies are increasingly disclosing the gonadotrope nature of many pituitary tumors. Mixed hormonal secretions are common. When pituitary hormone secretion can be selectively suppressed by medical therapy, a significant reduction of tumor size is by no means rare. In other cases, pituitary irradiation or surgery, or even treatment aimed at a peripheral target gland, may be necessary.