Effects of glucagon-like peptide 1 (7–36 amide) on whole-body protein metabolism in healthy man

The incretin glucagon-like peptide 1 (GLP-1) shows glucose-dependent insulinotropic activity and may exert anabolic effects. Whole-body protein metabolism was assessed by measuring [1-¹³C]-leucine kinetics in 13 healthy volunteers during hyperglycaemic clamping with or without pancreatic clamping (somatostatin infusion) in order to differentiate between insulin-mediated and direct GLP-1 effects. During intact pancreatic secretion leucine flux and leucine oxidation rate as parameters of whole-body protein breakdown decreased markedly after 180 min of synthetic GLP-1 infusion (GLP-1 vs. placebo: P < 0.003). Indirect calorimetry showed an increase in energy expenditure and CO₂ production during GLP-1 administration (P < 0.0005). Plasma insulin increased after 3 h of GLP-1 infusion to 1486 ± 145 pmol L^?1 vs. 185 ± 12 pmol L^?1 for saline (P < 0.0001). When plasma insulin levels were kept constant (GLP-1 vs. saline, NS) during pancreatic clamping, GLP-1 effects on both protein metabolism and energy expenditure were abolished. Thus, GLP-1 infusion in man exerts protein anticatabolic and thermic effects, which are mediated by GLP-1-induced stimulation of insulin secretion.     

Inhibition of paracrine angiotensin-converting enzyme in vivo: effects on interstitial glucose and lactate concentrations in human skeletal muscle

Microdialysis was used to selectively assess the effect of the paracrine renin–angiotensin system (RAS) on interstitial glucose and lactate concentration profiles in skeletal muscle of healthy volunteers ( n  = 8) during basal and insulin-stimulated conditions. Paracrine RAS was selectively inhibited by local retrodialysis with enalaprilate. Under basal conditions, local administration of enalaprilate (2 μg mL⁻¹) increased interstitial dialysate glucose concentration from 0.71 ± 0.14 mmol L⁻¹ to 0.84 ± 0.14 mmol L⁻¹ and decreased the serum interstitial gradient (SIG_glu) compared with baseline ( P  < 0.02). Under clamp conditions, enalaprilate, even at the lowest concentration (0.02 μg mL⁻¹), increased interstitial dialysate glucose concentration from 0.77 ± 0.11 mmol L⁻¹ to 1.02 ± 0.09 mmol L⁻¹ and decreased SIG_glu compared with baseline ( P  < 0.01). Interstitial lactate concentrations slightly increased during basal as well as during clamp conditions ( P  < 0.05 vs. baseline). Selective inhibition of paracrine muscle angiotensin-converting enzyme (ACE) increases interstitial glucose and lactate concentrations and decreases SIG_glu in muscle by facilitating transcapillary glucose transport. This effect is more pronounced during hyperinsulinaemia and may be of clinical relevance in diabetic patients treated with therapeutic doses of enalapril.     

Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates

Summary.  Neonates have an excellent hemostasis despite, in comparison to adults, markedly decreased and delayed ability to generate thrombin. Only 30–50% of peak adult thrombin activity can be produced in neonatal plasma by means of conventional in vitro assays. We show that in contrast to conventional activation, activation with small amounts of lipidated tissue factor (<10 pmol L⁻¹) results in shorter clotting times and faster activated factor X- and thrombin generation in neonates compared with adults due to the concomitant action of low tissue factor pathway inhibitor and antithrombin. The concentrations of both inhibitors in cord plasma are approximately 50% of the respective adult values. After addition of 2.5 pmol L⁻¹ lipidated tissue factor, cord plasma clotted ∼90 s earlier than adult plasma and the amount of free thrombin generated was ∼90% of adult value (291 ± 14 vs. 329 ± 16 nmol L⁻¹ min⁻¹, P  < 0.01). Our results might help to explain the clinically observed excellent hemostasis of neonates despite low levels of procoagulant factors.     

Vasoactive substances in early dumping syndrome: effects of dumping provocation with and without octreotide

In patients after gastric surgery, early dumping symptoms can be provoked by oral glucose challenge. Octreotide effectively prevents the occurrence of dumping symptoms. We have studied plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP) concentrations in nine patients with early dumping, 10 surgical control subjects and nine healthy control subjects after an oral glucose challenge preceded by either placebo or 25 μg of octreotide subcutaneously (s.c.). In the dumping group, basal PRA was signifi-cantly ( P  < 0.01) higher (3.9 ± 0.6 μg L⁻¹ h⁻¹) than in either surgical or healthy control subjects (1.1 ± 0.3 μg L⁻¹ h⁻¹ and 1.1 ± 0.2 μg L⁻¹ h⁻¹ respectively) and showed a significant rise after glucose ingestion to 5.4 ± 0.9 μg L⁻¹ h⁻¹ that did not occur in control subjects. Aldosterone concentration showed a concomitant rise. In dumping patients, plasma ANP decreased after glucose ingestion from 31 ± 6 ng L⁻¹ to 21 ± 5 ng L⁻¹ ( P  < 0.05). This decrease did not occur in control subjects. Early dumping is associated with an activation of the renin–aldosterone axis and a decrease in plasma ANP, reflecting a hypovolaemic state. Octreotide prevents the occurrence of these changes.     

Stimulation of arginine vasopressin secretion by a small increase in blood ionized calcium in normal men

Evidence has been provided for an increase in baseline serum corticotrophin (ACTH) levels in response to a rise in circulating ionized calcium (Ca_i) levels within the physiological range. In order to establish whether small Ca_i increments are also able to modify the basal secretion of arginine vasopressin (AVP), we infused calcium gluconate through an intravenous infusion pump in eight healthy male subjects (25–31 years old). Serum Ca_i, ACTH and AVP concentrations were measured every 10 min over an infusion period lasting 90 min. A significant progressive rise in serum Ca_i (baseline: 42 ± 0.9 mg dL⁻¹; 90 min: 47.2 ± 0.9 mg dL⁻¹, P  < 0.001), ACTH (baseline: 30.7 ± 1.3 pg mL⁻¹; mean peak at 80 min: 37.4 ± 2.4 pg mL⁻¹, P  < 0.01) and AVP levels (baseline: 2.1 ± 0.6 pg mL⁻¹; mean peak at 80 min: 3.2 ± 0.5 pg mL⁻¹, P  < 0.01) was observed during calcium infusion. Furthermore, a significant positive correlation ( r  = 0.71; P  < 0.001) was observed between ACTH and AVP responses to calcium infusion at 60, 70, 80 and 90 min. These data demonstrate that AVP secretion is stimulated by a slight rapid increase in serum Ca_i levels even though absolute serum Ca_i levels remain within the normal range. In addition, the positive correlation between Ca_i-induced ACTH and AVP increments suggests that AVP plays a releasing role on ACTH secretion during calcium infusion.     

Cisplatin-induced renal effects and thromboxane A2 receptor blockade

The aim of this study was to evaluate the renal protective effect of linotroban, a thromboxane A₂ receptor antagonist, in 25 patients with malignant tumours scheduled for cisplatin therapy. Cisplatin was administered 1 h after the start of a 24-h continuous infusion of linotroban or placebo. Glomerular filtration rate and effective renal plasma flow were measured. Infusions of cisplatin decreased glomerular filtration rate by 17 ± 25 mL min⁻¹ ( P  = 0.049 vs. baseline) and effective renal plasma flow by 94 ± 150 mL min⁻¹ ( P  = 0.049 vs. baseline) in the placebo group. In the linotroban group a decrease in glomerular filtration rate by 11 ± 18 mL min⁻¹ ( P  = 0.050 vs. baseline) and in effective renal plasma flow by 26 ± 63 mL min⁻¹ ( P  = 0.2 vs. baseline) was noted. However, no difference was noted between groups in response to treatment. Our findings indicate that linotroban may not be useful for prevention of cisplatin's acute nephrotoxic effects.     

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 ± 11.3 vs. 427.5 ± 19.2 μmol L⁻¹; P  < 0.001). This was attributable to lower urate (209.4 ± 10.4 vs. 297.1 ± 16.7 μmol L⁻¹; P  < 0.001) and vitamin C levels (63.6 ± 6.0 vs. 87.5 ± 4.9 μmol L⁻¹; P  < 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 ± 25.4 vs. 473.9 ± 30.2 μmol L⁻¹; NS), reflecting lower urate (299.5 ± 19.4 vs. 324.8 ± 21.4 μmol L⁻¹; NS) and vitamin C levels (38.6 ± 5.7 vs. 58.5 ± 5.3 μmol L⁻¹; P  < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.     

Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus

Glucagon-like peptide-1 (7–36) amide (GLP-1) is released from the gut into the circulation after meals and is the most potent physiological insulinotropic hormone in man. In contrast to presently available therapeutic agents for non-insulin-dependent diabetes mellitus (NIDDM), GLP-1 has the advantages of both suppressing glucagon secretion and delaying gastric emptying. We report the first chronic study of subcutaneous (s/c) GLP-1 treatment in NIDDM. Five patients with poorly controlled NIDDM were entered into a six-week, double-blind crossover trial. Each received three weeks treatment with s/c GLP-1 40 nmol or saline, given three times a day immediately before meals. A standardized test meal was given at the beginning and end of each treatment period. GLP-1 reduced plasma glucose area under the curve (AUC) following the standard test meal by 25% (AUC, 0–180 mins, GLP-1 start of treatment 482.2 ± 38.2 vs. saline start of treatment 635.7 ± 45.4 mmol min L⁻¹, F  = 16.4, P  < 0.02). The beneficial effect of GLP-1 on plasma glucose concentration was fully maintained for the three-week treatment period. Plasma glucagon levels were significantly lower for 60 min postprandially after GLP-1 treatment. In this group of patients there was no significant increase in postprandial insulin levels with GLP–1. We have demonstrated a significant improvement in postprandial glycaemic control with s/c GLP-1 treatment that was fully maintained over a three-week treatment period. GLP-1 improves glycaemic control even in the absence of an insulinotropic effect and is a potential treatment for NIDDM.     

Low-density lipoprotein-induced formation of nitric oxide by cultured vascular smooth muscle cells of the rat

There is evidence that low-density lipoprotein (LDL) plays a crucial role in atherogenesis. On the cellular level, LDL has been shown to activate a number of mechanisms involved in atherogenesis and vasoconstriction. Local immoderate vasoconstriction is physiologically antagonized by nitric oxide, which is released from the endothelium. To find out whether LDL also influences the synthesis of nitric oxide in vascular smooth muscle cells, both the conversion of arginine to citrulline and the production of nitrite were determined as a measure of nitric oxide formation. After incubation of rat vascular smooth muscle cells with native LDL (25 μg mL⁻¹) for 24 h, the production of both l -[¹⁴C]-citrulline [39 600 (3600) cpm mg⁻¹ cell protein] and nitric oxide [2.95 (0.56) μmol L⁻¹] were about twice and 1.5-fold the amount of the corresonding values in untreated cells (mean ± SD, P  < 0.05, n  = 4). Oxidized LDL was less effective than the native form. The presence of the arginine analogue N ^G-methyl- l -arginine reduced citrulline production dose-dependently but augmented DNA synthesis, both induced by LDL. In addition, the lipoprotein caused a 1.6-fold increase in cyclic GMP production following a 24-h incubation [control = 10.9 (3.8) pmol mg⁻¹ cell protein, P  = 0.016]. The results suggest that native LDL might partly impair its atherogenic potential on the vasculature by stimulating the production by smooth muscle cells of both nitric oxide and cyclic GMP.     

The association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences

Summary.  Low birth weight is associated with an increased risk of atherothrombosis, which may be related in part to the association between low birth weight and high plasma fibrinogen. The association between birth weight and fibrinogen may be explained by intrauterine, socio-economic or genetic factors. We examined birth weight and fibrinogen in 52 dizygotic and 56 adolescent monozygotic (genetically identical) twin pairs. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a fibrinogen level that was higher compared with their co-twins with the highest birth weight [dizygotic twins: 2.62 ± 0.46 g L⁻¹ vs. 2.50 ± 0.41 g L⁻¹ ( P  = 0.04); monozygotic twins: 2.42 ± 0.45 g L⁻¹ vs. 2.49 ± 0.39 g L⁻¹ ( P  = 0.2)]. These findings suggest that the association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences and therefore that this association has genetic causes. Improvement of intrauterine nutrition may not lower fibrinogen levels in later life.     

Insulin inhibits tissue factor expression in monocytes

Summary.  Objectives:  Platelets from healthy subjects are inhibited by insulin but type 2 diabetes mellitus (T2DM) platelets have become insulin-resistant, which might explain their hyperactivity. In the present study we investigated whether monocytes are responsive to insulin. Methods and results:  LPS-induced tissue factor (TF) upregulation was measured in human monocytes and monocytic THP-1 cells in a factor Xa generation assay. Insulin (0.1–100 nmol L⁻¹) induced a dose-dependent inhibition in both cell types and in monocytes 100 nmol L⁻¹ insulin inhibited cytosolic, membrane-bound and microparticle TF by 32 ± 2, 27 ± 3 and 52 ± 4% ( n  = 3). Insulin induced Tyr phosphorylation of the insulin receptor (INS-R) and formation of an INS-R – G_iα₂ complex, suggesting interference with LPS-induced cAMP control. Indeed, insulin interfered with LPS-induced cAMP decrease and TF upregulation in a manner similar to an inhibitor of G_i (pertussis toxin) and agents that raise cAMP (iloprost, forskolin, IBMX) reduced TF upregulation. Although LPS failed to raise cytosolic Ca²⁺, quenching of Ca²⁺ increases (BAPTA-AM) reduced and induction of Ca²⁺ entry (ionophore, P2X7 activation) enhanced upregulation of TF mRNA and procoagulant activity. Insulin interfered with MCP-1-induced Ca²⁺ mobilization but not with ATP-induced Ca²⁺ rises. Conclusions:  Insulin inhibits TF expression in monocytes and monocyte-derived microparticles through interference with G_iα₂-mediated cAMP suppression, which attenuates Ca²⁺-mediated TF synthesis.     

Insulin resistance shows selective metabolic and hormonal targets in the elderly

Abstract. There has been no simultaneous evaluation of different aspects of insulin action in ageing. We studied 12 elderly (77 ± 2 years) and 12 young (26 ±1 years) subjects with normal glucose tolerance and matched for sex, body mass index, lean body mass (LBM), blood pressure and physical activity, using a euglycaemic-hyperinsulinaemic clamp at about 350 pmol L^-1 in combination with [³H]-glucose infusion. In the elderly group, hepatic glucose production was normal, fasting serum insulin and C-peptide were significantly increased ( P = 0.001) and glucose utilization (34.4 ±2.4 vs. 44.4± 3.2 μ mol kg^-1 LBM min^-1, P = 0.02) and the percentage maximal suppression of C-peptide (58 ± 6% vs. 79 ±5%, P = 0.02) during the clamp were reduced. Fasting plasma free fatty acid (FFA) and glycerol levels were similar in the two groups, but their percentage maximal suppression during the clamp was reduced in the elderly group (FFA 45± 5% vs. 77 ± 6%, P = 0.001; glycerol 43 ± 5% vs. 76± 3%, P = 0.001). Branched-chain amino acids (valine, leucine, isoleucine) and glucagon levels were similar in the two groups, both while fasting and during the clamp. Thus, insulin resistance in ageing appears selective on glucose utilization, inhibition of lipolysis and feedback inhibition of the B-cell secretion.     

Glycaemic control and in vivo non-oxidative Maillard reaction: urinary excretion of pyrraline in diabetes patients

The presence of pyrraline in human urine has recently been described. Using reversed-phase high-performance liquid chromatography, we measured urinary pyrraline in 45 insulin-treated diabetic patients with preserved renal function and in 30 age- and sex-matched healthy subjects. The relationship between urinary pyrraline and metabolic control parameters in the diabetic population (glycaemia, fructosamine, haemoglobin Al_c, and 1-year mean haemoglobin A1_c) was evaluated. The mean urinary level of pyrraline in diabetic patients with poor glycaemic control (HbA_1c > 9.5%) was higher than that in healthy subjects (1.12 ± 0.35 vs. 0.75 ± 0.2 μmol mmol⁻¹ creatinine, P  < 0.04), whereas in patients with good to moderate glycaemic control (HbA1_c < 9.5) it was slightly but not significantly higher than in healthy subjects (0.80 ± 0.3 μmol mmol⁻¹ creatinine vs. 0.75 ± 0.2 μmol mmol⁻¹ creatinine). There is a significant correlation between urinary pyrraline level and glycaemia ( P  < 0.008), haemoglobin A1_c ( P  < 0.01) and 1-year mean haemoglobin A1_c values ( P  < 0.007), but not with fructosamine. The results of the present work prove, for the first time, that glycaemic status influences circulating levels of advanced Maillard reaction products.     

Immunosuppressive effects of endotoxins and bile acids in vivo in the rat

Cell-mediated immunity is impaired during cholestasis. The aim of this study was to evaluate in vivo the effects on this immune defect of high serum levels of endotoxin and bile acids. Heterotopic cardiac allotransplantations were performed in the DA/Lewis rat combination. Cholestasis, induced by ligation/section of the common bile duct, was responsible for a significant delay in the rejection time (16 ± 0.5 vs. 7.1 ± 0.4 days in controls, P <0.01). Elimination of Gram-negative intestinal bacteria from cholestatic rats by a vancocin/colimycin/tobramycin (VCT) mixture induced a significant reduction in endotoxin levels and a reduction in rejection times (9.5 ± 1.0 days, P <0.01) that remained, however, significantly longer than those of controls ( P <0.05). Oral administration of chenodeoxycholic acid in non-cholestatic rats significantly enhanced the serum concentration of total bile acids (60.6 ± 15.3 μmol L⁻¹ vs. 17.4 ± 1.9 μmol L⁻¹ in controls, P <0.01) and postponed allograft rejection (10.7 ± 0.6 days, P <0.01 vs. controls). These data suggest that increased endotoxin level and serum bile acid concentration may play a role in the immunosuppressive effect of cholestasis.     

Increased serum concentrations of the carboxy-terminal cross-linked telopeptide of collagen type I in patients with Gram-negative septicaemia

The authors determined serum levels of the carboxy-terminal cross-linked telopeptide and the carboxy-terminal propeptide of type 1 collagen (ICTP and PICP) in 18 patients with Gramnegative septicaemia before (day 0) and 28 days after therapy and in 18 age- and sex-matched controls by radioimmunoassay. Elevated levels of ICTP were observed in septicaemic patients [median (range): 15 (7–49) μg L⁻¹ before therapy and 14 (6–45) μg L⁻¹ 28 days after therapy vs. 2.1 (1.4–4.3) μg L⁻¹ in normal subjects; P  < 0.01 for both], whereas PICP levels were not different between patients and controls [median (range): 119 (52–275) μg L⁻¹ (day 0) and 133 (79–288) μg L⁻¹ (day 28) vs. 91 (54–213) μg L⁻¹ in normal subjects, P  > 0.05 for all]. The findings suggest an increased production or release of ICTP in Gram-negative septicaemia, presumably owing to an alteration of extracellular matrix during septicaemia-related vascular inflammation.     

Assay of human erythrocyte sodium-dependent lithium efflux: the importance of timing of blood sampling

The activity of the human erythrocyte sodium–lithium countertransport (SLC) is stable over long periods in individuals. However, it is becoming increasingly evident that the transport system is susceptible to modulation, both acutely and chronically, by various factors. In this study, the authors observed temporal variation in SLC over a period of 10 h (08.00–18.00 hours) in healthy volunteers. SLC V _max was maximum (0.354 ± 0.051 mmol L⁻¹ cell⁻¹ h⁻¹; mean ± SE) at 'mid-day' and significantly higher than in the morning (0.291 ± 0.035 mmol L⁻¹ cell, h; P  < 0.010). Its value in the evening (0.316 ± 0.042 mmol L⁻¹ cell⁻¹ h⁻¹) was lower than at 'mid-day' ( P  < 0.045) but higher than in the morning ( P  < 0.037). These changes were not accompanied by any significant change in the affinity of the transporter for external sodium, K _m. Changes in SLC V _max did not correlate with the corresponding ones in either plasma cortisol or aldosterone. However, they correlated well with those in plasma renin activity, the correlation between mid-day and a.m. sets of values ( r  = 0.718; P  = 0.019) being better than that between mid-day and p.m. ( r  = 0.688; P  = 0.028). The authors conclude that changes in SLC occur during the day, and this need be taken into account in the planning and execution of studies involving determination of the activity of this transport system.     

Effect of jejunal infusion of different caloric loads on pancreatic enzyme secretion and gastro-intestinal hormone response in man

Abstract. It has recently been demonstrated that the infusion of a high caloric load (3.3 kcal min^-1≙ 14.0 kJ min ^-1) into human upper jejunum inhibited pancreatic enzyme and bile salt secretion. The aim of the present study was to investigate whether this phenomenon was mediated by gastrointestinal hormones which interfere with pancreatic secretion. In six healthy volunteers, jejunal infusion of 1.3 kcal min^-1 (5.5 kJ min^-1) did not modify secretion of lipase and chymotrypsin to any significant extent compared with saline infusion, but the rate of 3^.3 kcal min^-1 (14.0 kJ min^-1) resulted in an inhibition. Somatostatin and pancreatic polypeptide, which are known to inhibit exocrine pancreatic secretion, remained unchanged during jejunal nutrient infusion. The inhibition of pancreatic enzyme secretion was observed in temporal relationship with an increase of the stimulators of pancreatic exocrine secretion such as secretin, neurotensin, and CCK. The existence of an hitherto undetined inhibitor and a feedback mechanism is postulated.     

Identification of functional GRP-preferring bombesin receptors on human melanoma cells

Bombesin was originally isolated from amphibian skin, wherease its mammalian counterpart, gastrin-releasing peptide (GRP), was first identified in the nervous system of the gastrointestinal tract. Whether GRP is present in the human skin is not known. Bombesin-like peptides are also known to modulate growth. We therefore investigated whether human melanoma cell lines express functional GRP-preferring bombesin receptors and whether they alter growth or other specific cellular functions of these tumour cells. GRP receptor mRNA was found in HBL, D-10, Me-28 and A375-6 cell lines, but only A375-6 cells express a large number of high-affinity binding sites for [¹²⁵I]-[Tyr⁴] bombesin ( K _d 0.31 ± 0.04 nmol L⁻¹, 3880 ± 429 binding sites per cell). Bombesin dose-dependently increased cytosolic calcium, but did not alter interleukin (IL) 1β-induced reduction of cell viability or IL-6 secretion, both A375-6-specific cell functions. Growth of A375-6 cells was not altered by bombesin or the specific GRP receptor antagonist BIM26226 as measured by [³H]-thymidine incorporation or methylene blue assay, whereas insulin alone or in combination with other potential growth factors dose-dependently stimulated growth of these cells. The newly characterized GRP-preferring bombesin receptors on highly malignant human melanoma cells could initiate studies of growth effects on solid tumours or in vivo scanning using radiolabelled tracers.     

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 ± 6.4 vs. 13.1 ± 0.3 mg kg^–1 day^–1; P  < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 ± 0.04 vs. 0.33 ± 0.008 pools day^–1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate ( R  = –0.82; P  < 0.05). Plasma lipoprotien (a) [Lp(a)] levels were significantly ( P  < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate ( R  = 0.90; P  < 0.01), VLDL-cholesterol ( R  = 0.95; P  < 0.001) and VLDL-triglycerides ( R  = 0.80; P  < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.     

Effects of low-dose l-arginine on insulin-mediated vasodilatation and insulin sensitivity

The present study was carried out to evaluate the effect of a low-dose intravenous supplementation of l -arginine on insulin-mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects ( n  = 7) and patients with obesity ( n  = 9) and non-insulin-dependent diabetes mellitus (NIDDM) ( n  = 9). Insulin-mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of l -arginine (0.52 mg kg⁻¹ min⁻¹). l -Arginine restored the impaired insulin-mediated vasodilatation observed in obesity (22.4 ± 4.1%, P  < 0.01 vs. without l -arginine) and NIDDM (20.3 ± 3.2%, P  < 0.01 vs. without l -arginine). In healthy subjects, no effect on insulin mediated-vasodilatation was observed (24.8 ± 3.1% vs. 21.4 ± 3.1%). Insulin sensitivity was improved significantly ( P  < 0.001) in all three groups by infusion of l -arginine. No effect of l -arginine was observed on insulin, insulin-like growth factor I (IGF-I), free fatty acids (FFAs) or C-peptide levels during the insulin suppression test. Our data indicate that defective insulin-mediated vasodilatation in obesity and NIDDM can be normalized by intravenous l -arginine. Furthermore, l -arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin-mediated vasodilatation.