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.

Paraoxonase2 polymorphisms are associated with nephropathy in Type II diabetes.

AIMS/HYPOTHESIS: Paraoxonase is a member of a multigene family of three genes. Paraoxonase2 gene polymorphisms have been associated with coronary heart disease in non-diabetic patients and with an increased fasting glycaemia in patients with Type II (non-insulin-dependent) diabetes mellitus. We tested the hypothesis of whether paraoxonase1 and paraoxonase2 polymorphisms were associated with diabetic nephropathy. METHODS: Our case-control study of 299 Swiss patients with Type II diabetes included 147 patients with confirmed diabetic nephropathy. RESULTS: In univariate analyses the two paraoxonase2 polymorphisms were associated with diabetic nephropathy. When subjected to multivariate analyses, both paraoxonase2 polymorphisms remained statistically associated with diabetic nephropathy independent of traditional risk factors (paraoxonase2-148: OR = 2.53, p = 0.003; paraoxonase2-311: OR = 2.67, p = 0.002). In addition, BMI interacted with paraoxonase2 polymorphisms as a risk factor of nephropathy. CONCLUSIONS/INTERPRETATION: The paraoxonase2 gene polymorphisms were significantly associated with diabetic nephropathy independent of traditional risk factors in Type II diabetic patients. The susceptibility to diabetic nephropathy was intensified by the degree of obesity. Pathophysiological pathways should be investigated and could be involved in insulin resistance or lipids metabolism or both.

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.

[Iodine nutrition and prevalence of goiter in adolescents in the Canton of Vaud]. / Apport iodé et prévalence du goitre chez les adolescents dans le canton de Vaud.

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.

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.

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

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.

In vivo and in vitro effects of somatostatin and insulin on glucagon release in a human glucagonoma.

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.

Insulin secretion is regulated by the glucose-dependent production of islet beta cell macrophage migration inhibitory factor.

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.

Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion.

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.

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.

Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study.

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.

Normogonadotropic primary amenorrhea in a growth hormone-deficient woman with ectopic posterior pituitary: gonadotropin pulsatility and follicle-stimulating hormone bioactivity.

We studied the gonadotropic function in a 25-year-old woman suffering from congenital GH deficiency, complaining of primary amenorrhea and wishing to become pregnant. She disclosed a hypoplasic anterior pituitary within a small sella turcica and an ectopic posterior pituitary lobe located below the median eminence. Immunoreactive LH and FSH plasma levels were normal, basal and in response to a GnRH iv bolus but estradiol was low. LH pulse frequency was elevated and FSH bioactivity was low in a granulosa cell aromatase bioassay. Pulsatile administration of iv GnRH at a slower, normal pace, failed to induce ovulation or to increase FSH bioactivity, with or without concomitant GH replacement. However treatment with exogenous im gonadotropins, when preceeded by GH replacement, succeeded in inducing mature oocytes and pregnancy. We concluded that the hypogonadism observed in this patient was due to rapid GnRH pulsatility and poor biological activity of endogenous FSH.

Effects of infused sodium lactate on glucose and energy metabolism in healthy humans.

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.

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.

Effects of lactate on glucose metabolism in healthy subjects and in severely injured hyperglycemic patients.

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

Overnight glucose metabolism in obese non-insulin-dependent diabetic patients and in healthy lean individuals.

Increased fasting hepatic glucose production is present in NIDDM patients, and has been shown to be due to increased gluconeogenesis. In order to determine the contribution of the cycling between glucose and three-carbon compounds (Cori and glucose-alanine cycles) to the increased hepatic glucose production, glucose kinetics measured overnight in seven obese NIDDM patients and six lean healthy subjects with both 6.6 2H glucose and U-13C glucose were determined. At 0500 h obese NIDDM subjects showed a 40% increase in glucose appearance calculated from 6.6 2H glucose, whereas glucose appearance calculated from U-13C glucose was similar compared to lean subjects, indicating increased glucose cycling. Non-oxidative glucose disposal was also increased three-fold in NIDDM patients. Glucose cycling was increased by 111% in NIDDM patients (118 +/- 18 mumole min-1 vs. 56 +/- 11 in controls, P < 0.05) and was positively correlated with plasma glucose concentration (r = 0.831, P < 0.001) and with non-oxidative glucose disposal (r = 0.714, P < 0.01). Four NIDDM patients were studied again after 3 days of insulin therapy. Insulin restored near-normoglycaemia (7.4 +/- 0.8 mmole l-1) and normalized rates of glucose appearance and glucose cycling. It is concluded that increased glucose cycling in obese NIDDM patients accounts for a major part of the increased fasting hepatic glucose production and non-oxidative glucose disposal in obese NIDDM subjects.

Effects of infused amino acids and lipids on glucose metabolism in healthy lean humans.

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)

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.