Glucose utilization and production in patients with maturity-onset diabetes of the young caused by a mutation of the hepatocyte nuclear factor-1alpha gene.

Mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause impaired insulin secretion and hyperglycemia in patients with maturity-onset diabetes of the young (MODY)3. Whether these mutations also affect glucose metabolism in tissues other than the beta-cell has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidative glucose disposal, and glucose production during a two-step hyperglycemic clamp and a euglycemic hyperinsulinemic (0.4 mU x kg(-1) x min(-1)) clamp. Compared with healthy control subjects, MODY3 patients had higher fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin secretion were virtually abolished during the hyperglycemic clamp, and glucose production was suppressed by only 43% in MODY3 patients vs. 100% in healthy control subjects. The rate of glucose infusion required to produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen deposition) was inhibited by 39%, and net carbohydrate oxidation during hyperglycemia was 25% lower in MODY3 patients compared with control subjects. Insulin-stimulated glucose utilization and oxidation measured during the hyperinsulinemic clamp (at approximately 200 pmol/l insulin) were identical in MODY3 patients and in healthy control subjects, indicating that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization, oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essentially secondary to insulinopenia, whereas insulin sensitivity remains intact.

Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients.

We reviewed the clinical features, essential laboratory data, pituitary imaging findings (computerized tomography and magnetic resonance imaging), management, and outcome of 353 consecutive patients with the presumptive diagnosis of pituitary tumor investigated from January 1984 through December 1997 at University Hospital, Lausanne, Switzerland. In 18 cases primary empty sella turcica was diagnosed, and in 13 cases of pseudacromegaly there were no endocrine abnormalities. The remaining 322 patients disclosed abnormal pituitary masses, including 275 pituitary adenomas, 18 craniopharyngiomas, 6 cases of primary pituitary hyperplasia, 6 intrasellar meningiomas, 6 cases of distant metastases, 4 intrasellar cysts, 2 chordomas, 1 primary lymphoma, and 1 astrocytoma. Biologic data and immunohistochemical analysis of the excised tissues demonstrated that prolactinomas and nonsecreting adenomas (NSAs) were the most frequent pituitary tumors (40% and 39%, respectively), followed by somatotropic adenomas with acromegaly (11%) and Cushing disease (6%). In contrast with the vast majority of NSAs, which significantly expressed glycoprotein hormones in tissue without secreting them, there was a small group of glycoprotein hormone-secreting adenomas (2%), which had a more severe clinical course after surgery. Thirty-eight pituitary masses were incidentally discovered, most of them NSAs. The expansion of pituitary adenomas into the right cavernous sinus was twice as frequent as to the left cavernous sinus. For the differential diagnosis of hyperprolactinemia, basal prolactin (PRL) levels above 85 micrograms/L, in the absence of renal failure and PRL-enhancing drugs, and a PRL increment of less than 30% after thyrotropin-releasing hormone (TRH) accurately ruled out functional hyperprolactinemia due to NSA, and were typical of prolactinomas. For screening and follow-up of acromegaly, basal growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, as well as the paradoxical GH response to TRH (present in 2/3 acromegalic patients), could be used as convenient tools, but the most accurate test for diagnosis and prediction of outcome after therapy was GH (lack of) suppression during oral glucose tolerance test. In Cushing disease, single evening plasma cortisol was as good as the overnight dexamethasone suppression test for screening, and a combined dexamethasoneovine corticotropin-releasing hormone (oCRH) test was as accurate as the long dexamethasone suppression test to confirm the diagnosis. Bilateral inferior petrosal sinus catheterization coupled with oCRH test confirmed the pituitary origin of excess adrenocorticotropic hormone (ACTH) in all patients, including those with normal pituitary on magnetic resonance imaging (50% of the cases). However, this procedure failed to predict tumor localization correctly within the pituitary in 21% of patients. Pituitary cysts, meningiomas, and craniopharyngiomas with an intrasellar component were correctly diagnosed based on pituitary imaging in 75%, 67%, and 44% of cases, respectively. The remainder, as well as the cases of pituitary hyperplasia, metastases, and other less frequent pathologies, were initially diagnosed as NSAs or as masses of unknown nature. When surgery was indicated, pituitary adenomas and other intrasellar masses were operated on by the transsphenoidal route, with the exception of 100% of meningiomas, 83% of craniopharyngiomas, and 10% of NSAs, which were operated on by the transcranial route. Favorable late surgical outcome of prolactinomas could be predicted by a restored PRL response to TRH. However, dopamine agonist (DA) therapy, usually resulting in satisfactory control of PRL levels and in tumor shrinkage, progressively displaced surgery as primary treatment for prolactinomas throughout the study period. After full-term pregnancy, the size of prolactinoma decreased in 7 of 9 patients, and PRL was normal in 2. Surgery was the first treatment for NSAs, with a tumor rela

Effect of trestatin, an amylase inhibitor, incorporated into bread, on glycemic responses in normal and diabetic patients.

The effect of incorporating the pancreatic alpha-amylase inhibitor trestatin into bread on postprandial plasma glucose and insulin excursions was tested in healthy volunteers and non-insulin-dependent diabetic patients. At both dose levels of trestatin (3 and 6 mg/75 g starch) the peak values of plasma glucose and insulin were reduced markedly (compared with placebo) after the ingestion of 75 g starch in the form of bread. In healthy control subjects as well as in diabetic patients, trestatin produced significantly lower insulin excretions but also significant reductions in incremental plasma glucose areas in a dose-dependent fashion. It is concluded that it is technologically feasible to incorporate trestatin into starchy foods without loss of activity or impairment of taste. Furthermore, the positive effect of trestatin on glycemic and insulinemic responses in diabetics and the lack of serious side effects offer a great potential in the dietary treatment of diabetic patients.

Clinical relevance of L-carnitine-supplemented total parenteral nutrition in postoperative trauma. Metabolic effects of continuous or acute carnitine administration with special reference to fat oxidation and nitrogen utilization.

Carnitine-free total parenteral nutrition (TPN) is claimed to result in a carnitine deficiency with subsequent impairment of fat oxidation. The present study was designed to evaluate the possible benefit of carnitine supplementation on postoperative fat and nitrogen utilization. Sixteen patients undergoing total esophagectomy were evenly randomized and received TPN without or with L-carnitine supplementation (74 mumol.kg-1.d-1) during 11 postoperative days. On day 11, a 4-h infusion of L-carnitine (125 mumol/kg) was performed in both groups. The effect of supplementation was evaluated by indirect calorimetry, N balance, and repeated measurements of plasma lipids and ketone bodies. Irrespective of continuous or acute supplementation, respiratory quotient and fat oxidation were similarly maintained throughout the study in both groups whereas N balance appeared to be more favorable without carnitine. We conclude that carnitine-supplemented TPN does not improve fat oxidation or promote N utilization in the postoperative phase.

Counterregulatory responses to hypoglycemia in patients with maturity-onset diabetes of the young caused by HNF-1alpha gene mutations (MODY3).

Mutations of HNF-1alpha lead to severe beta cell dysfunction, resulting in decreased glucose-induced insulin secretion. HNF-1alpha is also expressed in liver, kidney and pancreatic alpha cells, but the functional consequences of HNF-1alpha mutations in these organs remain unknown. We therefore assessed the counterregulatory responses to hypoglycemia in six patients with HNF-1alpha mutations (MODY3), five patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine healthy controls. Plasma glucagon concentrations and endogenous glucose production were measured every 15 min during a hyperinsulinemic clamp with progressive hypoglycemia. Plasma glucagon concentrations were similar at basal glycemia (73+/-6, 69+/-5 and 69+/-7 ng/l) and reached peak values of 88+/-9, 88+/-11 and 89+/-7 ng/l at a glycemia of 3.6 mmol/l in MODY3 patients, patients with NIDDM and controls respectively (NS). Suppression of endogenous glucose production by insulin was blunted in MODY3 patients (3.3+/-1.2 micromol/kg per min) and in patients with NIDDM (4.4+/-0.6 micromol/kg per min) compared with controls (1.7+/-0.5 micromol/kg per min, P<0.05 compared with both MODY3 patients and patients with NIDDM). During hypoglycemia, endogenous glucose production increased to 8.6+/-2.1, 8.8+/-0.7 and 7.0+/-1.0 micromol/kg per min in MODY3 patients, patients with NIDDM and controls respectively (all NS). These data indicate that mutations of HNF-1alpha in MODY3 do not result in a decreased glucagon secretion or alterations of glucose production during hypoglycemia.

Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown.

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.

Metabolic factors in the insulin resistance in human obesity.

Insulin resistance is frequently observed in obese subjects. The present work was initiated to study its relationship with the increased lipid metabolism generally observed in obesity. A first group of five obese subjects (146 +/- 10% of their ideal body weight [IBW] with normal glucose tolerance was submitted to a 75-g oral glucose tolerance test (OGTT) as a control and during an intralipid infusion (20% fat emulsion, 1 mL/min, started 90 minutes prior to the glucose load). Lipid and glucose oxidation were measured by continuous indirect calorimetry. The significant rise over control conditions in both plasma FFA and lipid oxidation rate during the lipid infusion was accompanied by a marked decrease in glucose tolerance (two hours venous plasma glucose: 151 +/- 12 during intralipid infusion v 110 +/- 3 mg/dL, P less than .01) together with a rise of the plasma insulin curve. Glucose oxidation was significantly decreased. A second group of five obese subjects (146 +/- 7% of their IBW) with impaired glucose tolerance was submitted to a similar OGTT, as a control, and during an infusion of beta-pyridyl-carbinol, a nicotinic acid derivative, to lower FFA. Both plasma FFA and lipid oxidation rates were decreased already prior to the OGTT. The previously impaired glucose tolerance was normalized (two hours venous plasma glucose: 129 +/- 13 during the beta-pyridyl-carbinol infusion v 172 +/- 7 mg/dL, P less than .01), and the insulin curve lowered. Glucose oxidation was increased during the early phase of the OGTT.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of substrate competition in the mechanism of insulin resistance in man.

Carbohydrate (CHO) oxidation induced by a glucose or fructose (0.5 g/kg X h) infusion over two hours was compared for 160 minutes by means of continuous indirect calorimetry in seven normal subjects without or with a concomitant infusion of Intralipid, a neutral fat emulsion. The glucose infusion was accompanied by a rise over basal values in both glucose (99 +/- 10 mg/dL) and insulin (36 +/- 7 microU/mL) plasma levels, with a further rise of both curves during the Intralipid infusion (140 +/- 7 mg/dL and 53 +/- 12 microU/mL). By contrast, plasma glucose and insulin rose only minimally during the fructose infusion (3.5 +/- 2.9 mg/dL and 5.3 +/- 1.4 microU/mL, respectively, without Intralipid, and 10.6 +/- 2.1 mg/dL and 9.6 +/- 2.0 microU/mL with Intralipid). During the two-hour sugar infusion, a mean quantity of 68.7 g glucose or fructose was infused. The total CHO oxidation was 15.6 +/- 1.2 g for glucose and 21.6 +/- 2.6 for fructose infusion for the 160 minutes of the test. During the Intralipid infusion, CHO oxidation was inhibited with values of 5.9 +/- 1.3 g for glucose (P less than .005) and 13.8 +/- 1.8 g (P less than .05) for fructose infusion. Lipid oxidation was increased in both cases during the Intralipid infusion. These results show that the lipid-induced inhibition of CHO oxidation observed with glucose infusion also occurs to some extent with fructose, suggesting that insulin might not be primarily involved. They suggest a metabolic origin for insulin resistance during elevated fat metabolism.

Effect of alpha-glycohydrolase inhibitors (Bay m1099 and Bay o1248) on sucrose metabolism in normal men.

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.

Non oxidative fructose disposal is not inhibited by lipids in humans.

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.

Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations.

The glucokinase gene is expressed not only in pancreatic B cells and in the liver, but also in pancreatic alpha cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(- 2) H glucose) were monitored during an hyperinsulinemic clamp at about 2.4 pmol.kg(- 1).min(- 1) insulin with progressive hypoglycemia in 7 maturity onset diabetes of the young (MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subjects. Basal glucose concentrations were significantly higher in MODY2 patients (7.6 +/- 0.4 mmol.l(- 1) ) and type 2 diabetic patients (12.4 +/- 2.3 mmol.l(- 1) ) than in healthy subjects (5.3 +/- 0.1 mmol.l(- 1), p<0.01) but counterregulatory hormones concentrations were identical. Insulin-mediated glucose disposal and suppression of endogenous glucose production at euglycemia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. During progressive hypoglycemia, the glycemic thresholds of MODY2 patients for increasing glucose production (5.0 +/- 0.4 mmol.l(- 1) ) and for glucagon stimulation (4.5 +/- 0.4 mmol. l(- 1) ) were higher than those of healthy subjects and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(- 1) respectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(- 1) for glucagon stimulation, p <0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may be secondary to decreased glucokinase activity in hypothalamic neuronal cells, or to alterations of glucose sensing in pancreatic alpha cells and liver cells.

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls.

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.

Comparative clearance of two new fat emulsions--Hausmann Lipid 20% and Lipovenös 20%--versus intralipid 20%.

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.

Metabolic and respiratory effects of sodium lactate during short i.v. nutrition in critically ill patients.

BACKGROUND: Hyperglycemia and an increased ventilatory demand secondary to an increased CO2 production are frequent undesirable effects of total parenteral nutrition (TPN) in critically ill patients. This study was performed to assess whether sodium lactate as a metabolic substrate may affect these variables. METHODS: Five male patients with multiple trauma during the flow phase were studied during two consecutive 3-hour periods of isocaloric (1.1 x resting energy expenditure) TPN. Sixty-five percent of total calories was provided as carbohydrate, 15% as lipids, and 20% as amino acids during the first period (TPN-glucose), whereas 35% carbohydrate, 30% lactate, 20% lipids, and 15% amino acids (TPN-lactate) were substituted during the second period. Respiratory gas exchanges and net substrate oxidation were assessed by means of indirect calorimetry. Glucose kinetics was determined by primed-constant infusion of U-13C glucose. RESULTS: Compared with TPN-glucose, TPN-lactate decreased glycemia by 20%, insulinemia by 43%, net carbohydrate oxidation (assessed from indirect calorimetry) by 34%, and plasma glucose oxidation (assessed from 13CO2) by 54%. Respiratory oxygen exchange were increased by 3.7% due to a 20% thermic effect of lactate, but respiratory CO2 exchanges did not change. Pao2 decreased by 11.3 mm Hg, indicating that the increased O2 consumption was not matched by an appropriate increase in spontaneous ventilation. Arterial pH increased from 7.41 +/- 0.04 to 7.46 +/- 0.05. CONCLUSION: Sodium lactate as a metabolic substrate limits hyperglycemia but induces metabolic alkalosis and does not spare the ventilatory demand.

Effects of L-carnitine supplemented total parenteral nutrition on lipid and energy metabolism in postoperative stress.

During episodes of trauma carnitine-free total parenteral nutrition (TPN) may result in a reduction of the total body carnitine pool, leading to a diminished rate of fat oxidation. Sixteen patients undergoing esophagectomy were divided randomly in two equal isonitrogenous groups (0.2 g/kg.day). Both received TPN (35 kcal/kg.day; equally provided as long-chain triglycerides and glucose) over 11 days without (group A) and with (group B) L-carnitine supplementation (12 mg/kg.day = 75 mumol/kg.day). Compared with healthy controls, the total body carnitine pool prior to the operation was significantly reduced in both groups, suggesting a state of semistarvation and muscle wasting. In group A the plasma levels of total carnitine and its subfractions (free carnitine, short- and long-chain acylcarnitine) remained stable during the study whereas in group B the total plasma carnitine concentration rose mainly due to an increase in free carnitine. In group A the cumulative urinary carnitine losses were 11.5 +/- 2.6 mmol (= 15.5 +/- 3.1% of the estimated total body carnitine pool). In group B 3.1 +/- 1.9 mmol (= 11.1 +/- 7.6%) of the infused carnitine was retained in the immediate postoperative phase until day 6, but this amount was completely lost at completion of the study period. No significant differences in the respiratory quotient or in the plasma levels of triglycerides, free fatty acids, and ketone bodies were observed, between or within the groups, before the operation and after 11 days of treatment. It is concluded that the usefulness of carnitine supplementation during postoperative TPN was not apparent in the present patient material.

Plasma IGF-1 binding proteins in lean and obese non-diabetic subjects.

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.

Effects of muscarinic blockade on insulin secretion and on glucose-induced thermogenesis in lean and obese human subjects.

To determine whether hyperinsulinaemia of human obesity is dependent on the activity of the parasympathetic nervous system, and whether activation of the parasympathetic nervous system plays a role in glucose-induced thermogenesis, the metabolic effect of a continuous intravenous glucose infusion [44.4 mumol kg-1 body weight (bw) min-1] with or without atropine infusion was assessed in 11 obese patients and 10 lean controls. Compared with lean controls, obese patients had increased basal and glucose-stimulated plasma insulin and C-peptide concentrations and increased plasma glucose concentrations during glucose infusion. Glucose oxidation during i.v. glucose was lower in obese patients than in lean controls. Glucose-induced thermogenesis was similar in obese patients and in lean controls. Atropine infusion did not affect basal plasma glucose, insulin or free fatty acid concentrations nor glucose-stimulated plasma glucose, insulin, C-peptide, glucagon or free fatty acid concentrations in both groups of subjects. Glucose and lipid oxidation rates and glucose-induced thermogenesis were also unaffected by atropine administration. It is concluded that (1) glucose-stimulated hyperinsulinaemia in human obesity is not dependent on a hyperactivity of the parasympathetic nervous system, which indicates that human obesity is different from most animal models of obesity; (2) glucose-induced thermogenesis is similar in obese and lean subjects when a similar load of glucose is administered; (3) inhibition of the parasympathetic nervous system does not affect the thermic effect of i.v. glucose.

[Anterior pituitary hypersecretion syndromes]. / Les syndromes d'hypersécrétion antéhypophysaire.

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.

Dissociated recovery of cortisol and dehydroepiandrosterone sulphate after treatment for Cushing's syndrome.

We have studied the variation of ACTH, cortisol and DHEA-S plasma levels in 6 patients before and up to 15 months after surgical remission of Cushing's syndrome in order to compare the relative dependency of cortisol and adrenal androgens towards ACTH. Three patients with adrenal adenoma were treated by unilateral adrenalectomy. Three other patients with Cushing's disease underwent transsphenoidal pituitary tumorectomy. Preoperative ACTH was undetectable in patients with adrenal adenoma and high-normal or elevated in patients with Cushing's disease. All patients became rapidly hypocortisolemic after surgery and ACTH and cortisol levels eventually recovered at different intervals. Patients with adrenal adenoma had an initially low DHEA-S which failed to normalize for the entire follow-up period. Patients with Cushing's disease had normal or high-normal DHEA-S which became low immediately after surgery, following ACTH decrease, and it remained low during the entire follow-up period. In conclusion, after removal of corticotropic inhibition secondary to excess cortisol, DHEA-S remains suppressed for a longer period of time than cortisol. Moreover it only takes a short period of relatively low ACTH (after pituitary tumor excision) to induce a long lasting DHEA-S inhibition. Therefore the DHEA-S secreting adrenal cells seem to be more sensitive to the lack of corticotropic stimulation than cortisol secreting cells.

Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis.

Endogenous glucose production rate (EGPR) remains constant when lactate is infused in healthy humans. A decrease of glycogenolysis or of gluconeogenesis from endogenous precursors or a stimulation of glycogen synthesis, may all be involved; This autoregulation does not depend on changes in glucoregulatory hormones. It may be speculated that alterations in basal sympathetic tone may be involved. To gain insights into the mechanisms responsible for autoregulation of EGPR, glycogenolysis and gluconeogenesis were measured, with a novel method (based on the prelabelling of endogenous glycogen with 13C glucose, and determination of hepatic 13C glycogen enrichment from breath 13CO2 and respiratory gas exchanges) in healthy humans infused with lactate or saline. These measurements were performed with or without beta-adrenergic receptor blockade (propranolol). Infusion of lactate increased energy expenditure, but did not increase EGPR; the relative contributions of gluconeogenesis and glycogenolysis to EGPR were also unaltered. This indicates that autoregulation is attained, at least in part, by inhibition of gluconeogenesis from endogenous precursors. beta-adrenergic receptor blockade alone (with propranolol) did not alter EGPR, glycogenolysis or gluconeogenesis. During infusion of lactate, propranolol decreased the thermic effect of lactate but EGPR remained constant. This indicates that alterations of beta-adrenergic activity is not required for autoregulation of EGPR.