Effect Of Insulin Infusion Research Articles

C-Peptide Suppression During Insulin Infusion in the Extremely Preterm Infant Is Associated With Insulin Sensitivity.

Little is known about the individual response of glucose-regulating factors to administration of exogenous insulin infusion in extremely preterm infants. To evaluate longitudinal serum concentrations of insulin, C-peptide, and plasma glucose levels in a high-frequency sampling regimen in extremely preterm infants treated with insulin because of hyperglycemia. Prospective longitudinal cohort study. Two university hospitals in Sweden between December 2015 and September 2016. Serum samples were obtained from nine extremely preterm infants, gestational age between 22 (+3) and 26 (+5) weeks (+ days), with hyperglycemia (plasma-glucose >10 mmol/L) at the start of insulin infusion, at 12, 24, and every 24 hours thereafter during ongoing infusion, and 12, 24, and 72 hours after the end of insulin infusion. Longitudinal serum concentrations of insulin and C-peptide and plasma glucose levels. During insulin infusion, the serum C-peptide concentrations decreased compared with at start of infusion (P = 0.036), and then increased after ending the infusion. Individual insulin sensitivity based on the nonfasting plasma glucose/insulin ratio at the start of insulin infusion correlated with the initial decrease in serum ΔC-peptide[after 12h] (P = 0.007) and the degree of lasting decrease in serum ΔC-peptide[after end of infusion] (P = 0.015). Exogenous insulin infusion suppressed the C-peptide concentration to individually different degrees. In addition, the effect of insulin infusion on β cells may be linked to individual insulin sensitivity, where a low insulin sensitivity resulted in a more pronounced decrease in C-peptide during insulin infusion.

The effect of insulin infusion on heart rate and systemic blood pressure in horses with equine metabolic syndrome.

There is little evidence that horses with equine metabolic syndrome (EMS) have higher resting blood pressures than horses with normal insulin sensitivity. However, there are indications that EMS horses have an altered dynamic response to the cardiovascular effects of insulin. To examine heart rate and the systemic blood pressure response in EMS and control horses during insulin infusion. Cross-sectional study. Horses were examined with an oral sugar test (OST) and a euglycaemic hyperinsulinaemic clamp (EHC). Based on the results from the OST, the horses were classified as either EMS or control. Blood pressure was measured before the start of the EHC and at 60, 120 and 180min of the EHC. There were 16 EMS and 12 control horses. Mean resting heart rate was higher for EMS horses compared with control (35.6±5.1 vs. 30.3±3.5beats/min). Systolic, diastolic and mean arterial blood pressure did not differ between groups at the start of the EHC. Blood pressure decreased gradually during the EHC in the control group, whereas the EMS group showed no decline in systolic, diastolic or mean arterial pressure. Limited number of horses. Horses with EMS have cardiovascular changes that affect resting heart rate and systemic blood pressure during insulin infusion.

Serum irisin and its regulation by hyperinsulinemia in women with polycystic ovary syndrome.

Irisin is an adipokine/myokine which could be connected with insulin sensitivity. Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, hyperandrogenism and insulin resistance. The aim of the present study was to determine the relationship between serum irisin concentration and insulin sensitivity (Mffm) as well as the effect of insulin infusion on circulating irisin levels in PCOS women as compared with healthy controls. Seventy seven women were enrolled in the study - 57 with PCOS and 20 healthy controls matched for BMI and age. Hyperinsulinemic euglycemic clamps were performed in all of the study participants. The serum concentrations of irisin at baseline and after the clamp, as well as changes of serum irisin concentration in response to insulin supplied during the clamp (Δ irisin), were estimated. The mean serum concentrations of irisin at baseline and after hyperinsulinemia were higher in PCOS women in comparison to the control group (p=0.01; p=0.006, respectively). Insulin infusion resulted in a decrease of serum irisin concentration only in the PCOS group (p=0.007). In the control group, Δ irisin positively correlated with Mffm (r=0.56, p=0.009). In the entire group, multiple regression analysis showed that Δ irisin (β=0.70, p=0.0002), FFAs 60' during the clamp study (β=-0.22, p=0.01), SHBG (β=0.54, p<0.0001) and the interaction between Δ irisin and PCOS (β=-0.67, p=0.0004) were significantly associated with Mffm. The higher serum irisin concentrations at baseline and in response to insulin infusion might be secondary to insulin resistant conditions in PCOS women.

The Effect of Insulin Infusion on the Metabolites in Cerebral Tissues Assessed With Proton Magnetic Resonance Spectroscopy in Young Healthy Subjects With High and Low Insulin Sensitivity

OBJECTIVEInsulin may play important roles in brain metabolism. Proton magnetic resonance spectroscopy (1H-MRS) of the central nervous system gives information on neuronal viability, cellular energy, and membrane status. To elucidate the specific role of insulin action in the brain, we estimated neurometabolites with 1H-MRS and assessed their regulation by insulin infusion and their relationship with insulin sensitivity.RESEARCH DESIGN AND METHODSWe studied 16 healthy young men. 1H-MRS was performed at baseline and after 240 min of euglycemic-hyperinsulinemic clamp. Voxels were positioned in the left frontal lobe, left temporal lobe, and left thalamus. The ratios of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol, and glutamate/glutamine/γ-aminobutyric acid complex (Glx) to creatine (Cr) and nonsuppressed water signal were determined. The participants were divided into subgroups of high (high IS) and low (low IS) insulin sensitivity.RESULTSBaseline neurometabolic substrates were not different between the groups. Insulin infusion resulted in an increase in frontal NAA/Cr and NAA/H2O and frontal and temporal Glx/Cr and Glx/H2O and a decrease in frontal Cho/Cr and temporal Cho/H2O and myo-inositol/H2O (all P < 0.05, except temporal Glx/H2O, P = 0.054, NS) in the high-IS, but not in the low-IS, group. Insulin sensitivity correlated positively with frontal NAA/Cr and NAA/H2O and temporal Glx/H2O and negatively with temporal myo-inositol/Cr and myo-inositol/H2O assessed during the second 1H-MRS (all P < 0.05).CONCLUSIONSInsulin might influence cerebral metabolites, and this action is impaired in subjects with low whole-body insulin sensitivity. Thus, our results provide a potential link between insulin resistance and altered metabolism of the central nervous system.

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Introduction: Hyperglycemia has been associated with worse outcomes in critically ill patients. The effectiveness of insulin infusions in maintaining glycemic control is well established; however, little is known about glycemic control when insulin is transitioned from the intravenous (IV) to the subcutaneous (SC) route. Hypothesis: Transition from IV to SC insulin is associated with worsening of glycemic control. Methods: A cohort of ICU patients from 2006-2010 was defined as those requiring? 2 days of IV insulin, excluding patients with type I diabetes, parenteral nutrition, readmission within 28 days or oral intake. “IV phase” and “SC phase” were defined as the 48 hours before and after discontinuation of IV insulin. The following variables were collected: mean blood glucose (GlucIV and GlucSC), daily mean IV and SC insulin dose (InsulinIV and InsulinSC), daily mean carbohydrate intake (CHOIV and CHOSC), vasopressor use (VasoIV and VasoSC), steroid use (SteroidIV and SteroidSC), age, gender and BMI. Univariate and multivariate regression were used to test the association between GlucSC and the variables. Results: 462 patients met criteria. Median time on IV insulin was 7 (4-10) days; median age was 64 (51-74) years; mean BMI was 29.4 (±14.5). 29.8% of patients were diabetic. Mean InsulinIV was 41.0 (±24.6) units; mean InsulinSC was 5.0 (±14.2) units. Compared to the “SC phase”, more patients in the “IV phase” were on vasopressors (41.8% vs. 29.4%, p < 0.001) and steroids (24.2% vs. 18.4%, p < 0.001). Carbohydrate intake was higher in the “SC phase” (101.8 [±64.8] vs 109.4 [±62.9] grams, p < 0.01). Mean serum glucose in the SC phase was significantly higher than the IV phase (144.4 [±32.4] vs 120.8 [±19.8], p < 0.001). On multiple linear regression analysis, age, diabetes, InsulinIV, GlucIV, CHOSC and VasoSC were significantly associated with glycemic control in the subcutaneous phase. Conclusions: IV to SC insulin transitioning is associated with worsening in glycemic control. Our study identifies variables associated with this worsening. These findings hold the promise of identifying those who are poor candidates for transition and guidance in designing tailored insulin scales with optimal subcutaneous dosing.

Effect of Insulin Infusion on Spillover of Meal-Derived Fatty Acids

Spillover of chylomicron triglyceride fatty acids directly into the circulation as free fatty acids (FFAs) during lipoprotein lipase hydrolysis may contribute to the elevated total FFAs seen in insulin-resistant states. The objective of the study was to determine whether spillover is regulated by rates of intracellular lipolysis, we studied overweight and obese nondiabetic subjects (n = 7) on two occasions, during infusion of saline and insulin. During insulin infusion (20 mU · m(-2) · min(-1)), plasma glucose was clamped at the concentration achieved during saline infusion. On both study days, subjects sipped 1-2 oz of a liquid mixed meal every 15 min for 6.5 h to achieve steady-state chylomicron and FFA concentrations. Spillover was measured with infusions of [(3)H]triolein and [U-(13)C] oleate. Glucose concentrations were similar during saline compared with insulin (113 ± 2 vs. 113 ± 1 mg/dl, P = NS). Insulin levels during saline and insulin infusion were 18 ± 3 and 44 ± 5 μU/ml, respectively. Glucose infusion rate during insulin infusion was 5.5 ± 1.0 mg · kg fat-free mass(-1) · min(-1). Plasma FFA concentrations were lower during insulin compared with saline (75 ± 8 vs. 124 ± 13 μmol/liter, P = 0.002). Oleate rate of appearance was lower during insulin vs. saline (27 ± 3 vs. 36 ± 5 μmol/min, P = 0.004). Spillover was similar during saline and insulin (26 ± 2 vs. 25 ± 2%, P = 0.60). These results indicate that suppression of intracellular lipolysis with insulin does not reduce lipoprotein lipase-mediated spillover in humans during meal absorption. It is possible that spillover did not decrease because of an impaired or absent antilipolytic effect of increased insulin concentrations in visceral fat.

Effect of Insulin Infusion on Inflammatory Mediators in Patients Undergoing Cardiopulmonary Bypass

Effect of Insulin Infusion on Inflammatory Mediators in Patients Undergoing Cardiopulmonary Bypass

Prolonged Exercise-Induced Stimulation of Skeletal Muscle Glucose Uptake Is due to Sustained Increases in Tissue Perfusion and Fractional Glucose Extraction

The mechanisms behind the positive effects of physical activity on glucose metabolism in skeletal muscle and the time course of the effects need to be more elucidated. The aim was to examine the prolonged effects of an acute bout of one-legged exercise on local skeletal muscle glucose utilization and tissue perfusion. Interstitial glucose concentration, local tissue perfusion, glucose uptake, and effects of insulin infusion were studied 12 h after an acute bout of exercise and without prior exercise. Ten healthy subjects, five women and five men, participated in the study. Microdialysis measurements, (133)Xe clearance, and a 2-h hyperinsulinemic euglycemic clamp were performed on two occasions. We measured interstitial glucose concentration and tissue perfusion in the quadriceps femoris muscle of both legs. Tissue perfusion (3.3 ± 0.6 ml × 100 g(-1) × min(-1) vs. 1.4 ± 0.2 ml × 100 g(-1) × min(-1); P = 0.007) and basal glucose uptake (2.3 ± 0.5 μmol × 100 g(-1) × min(-1) vs. 0.9 ± 0.2 μmol × 100 g(-1) × min(-1); P = 0.006) were increased in the leg that had exercised compared to the resting leg; the findings in the resting leg were comparable to those in the control experiment without prior exercise. The relative effect of insulin on fractional skeletal muscle glucose uptake was the same in all experimental settings, and insulin did not affect tissue perfusion. The prolonged stimulatory effect of physical exercise on skeletal muscle glucose uptake was mediated via vascular effects combined with an increase in basal glucose transport independent of enhancement of insulin responses.

Effects of insulin infusion on glucose homeostasis and glucose metabolism in rainbow trout fed a high-carbohydrate diet

The origin for the poor glucose utilization in carnivorous fish species fed high carbohydrate diets remains under debate. In the present study, we have fed rainbow trout a diet containing 30% carbohydrate for 1 or 5 days. In both cases, fish were implanted with mini-osmotic pumps releasing 0.7 i.u. kg(-1) day(-1) bovine insulin, and mRNA transcripts and the protein phosphorylation status of proteins controlling glycemia and glucose-related metabolism were studied in fish killed 6 h after the last meal. We demonstrate that when the exposure occurs over a short term (30 h), insulin exerts beneficial actions on trout glucose homeostasis, including a lowered glycemia and increased hepatic lipogenic and glycogenic potentials. However, when trout were fed for 5 days, these beneficial actions of insulin infusion were no longer observed. Thus, the increased lipogenic potential observed after one single meal was not present, and this together with the increased glycogenesis and the decreased glucose exported to the blood from the liver explains the lack of hypoglycemic action of insulin. The fact that insulin improved glucose homeostasis when administrated over a short time period implies that endogenous insulin secretion is inadequate in trout to deal with this amount of dietary carbohydrates. Moreover, the fact that a longer exposure to insulin resulted in a reduced response indicates that the rainbow trout is sensitive to insulin, re-enforcing the hypothesis that the hyperglycemia observed following a high carbohydrate meal is an insulin secretion issue rather an insulin action issue.

Acute hyperinsulinemia inhibits intramyocellular triglyceride synthesis in high-fat-fed obese rats

Hyperinsulinemia is common in obesity, but whether it plays a role in intramyocellular triglyceride (imcTG) buildup is unknown. In this study, hyperinsulinemic-euglycemic clamp experiments were performed in overnight-fasted lean and high-fat-fed obese rats, awake, to determine the effect of insulin on imcTG synthesis (incorporation of [(14)C]glycerol, [(14)C]glucose, and [(3)H]oleate). Insulin infusion at 25 (low insulin) and 100 (high insulin) pmol/kg/min increased plasma insulin by 5- and 16-fold, respectively, whereas plasma and intramyocellular glycerol, FFAs, triglycerides, and glucose levels were maintained at their basal levels by co-infusion of exogenous glycerol, FFAs, and triglycerides at fixed rates and glucose at varying rates. In obese rats, insulin suppressed incorporation of glycerol into the imcTG-glycerol moiety dose dependently (P < 0.01-P < 0.001) in gastrocnemius and tibialis anterior, but only the high insulin suppressed it in soleus (P < 0.05). The low insulin suppressed glucose incorporation into imcTG-glycerol in all three muscles (P = 0.01-P < 0.01). However, the low insulin did not affect (P > 0.05) and the high insulin suppressed (P < 0.05-P < 0.01) fatty acid incorporation into imcTG in all three muscles. Insulin also suppressed glycerol incorporation in lean rats (P < 0.01-P < 0.04). On the other hand, imcTG pool size was not affected by insulin (P > 0.05). These observations suggest that acute hyperinsulinemia inhibits imcTG synthesis and thus does not appear to promote imcTG accumulation via the synthetic pathway, at least in the short term.

Plasma semicarbazide‐sensitive amine oxidase is moderately decreased by pronounced exogenous hyperinsulinemia but is not associated with insulin sensitivity and body fat

Objective. Semicarbazide‐sensitive amine oxidase (SSAO) is widely expressed in adipose tissue, where it may contribute to stimulation of glucose transport via GLUT4 recruitment. We tested the relationships of soluble SSAO, as reflected by its plasma activity, with insulin sensitivity and indices of body fat, and determined whether insulin is involved in regulating plasma SSAO activity. Material and methods. In 24 non‐diabetic subjects, the relationships of plasma SSAO activity with insulin sensitivity (M‐value and free fatty acid (FFA) suppression during a 3‐h hyperinsulinemic (8.3 µU kg−1 s−1), euglycemic clamp), body mass index (BMI 25.5±3.1 kg m−2), waist‐hip ratio and fat mass were assessed. In 16 subjects, the effect of insulin infusion, administered at a rate of 8.3 µU kg−1 s−1 during 3 h, followed by 3‐h insulin infusion at a high rate of 41.7 µU kg−1 s−1 on plasma SSAO activity was determined. In the other 8 subjects, the response of plasma SSAO activity to 24‐h insulin infused at 8.3 µU kg−1 s−1 was assessed. Results. There were no relationships (all p >0.10) of plasma SSAO activity (215±60 mU L−1) with the M‐value or with any indices of body fat and FFA before and after insulin suppression. Plasma SSAO activity changed by −7.2 (95% CI, −14.5 to +0.2)% after 3 h (NS) and decreased by 10.1 (95% CI, 19.2 to 1)% after 6 h of insulin infusion (p <0.05). Plasma SSAO activity did not significantly change after 8 h (change 0.4 (95% CI, −15.3 to +16.2)%, NS) and after 24 h (change −8.8 (95% CI, −27.4 to +9.7)%, NS) of insulin infusion. Conclusions. It is unlikely that circulating SSAO is a clinically important marker of insulin sensitivity on glucose and fatty acid metabolism. The reduction in plasma SSAO activity in response to pronounced hyperinsulinemia suggests that insulin is involved in the regulation of the soluble form of this enzyme.

The Effect of Insulin Infusion Upon Protein Metabolism in Neonates on Extracorporeal Life Support

Critically ill neonates on extracorporeal life support (ECLS) demonstrate elevated rates of protein breakdown that, in turn, are associated with increased morbidity and mortality. This study sought to determine if the administration of the anabolic hormone insulin improved net protein balance in neonates on ECLS. Twelve parenterally fed neonates, on ECLS, were enrolled in a randomized, prospective, crossover trial. Subjects were administered a hyperinsulinemic euglycemic clamp and a control saline infusion. Protein metabolism was quantified using ring-D5-phenylyalanine and ring-D2-tyrosine stable isotopic infusions. Statistical comparisons were made by paired sample t tests (significance at P < 0.05). Serum insulin concentration increased 20-fold during insulin infusion compared with saline infusion control (P < 0.0001). Protein breakdown was significantly decreased during insulin infusion compared with controls (7.98 +/- 1.82 vs. 6.89 +/- 1.03 g/kg per day; P < 0.05). Serum amino acid concentrations were significantly decreased by insulin infusion (28,450 +/- 9270 vs. 20,830 +/- 8110 micromol/L; P < 0.02). Insulin administration tended to decrease protein synthesis (9.58 +/- 2.10 g/kg per day vs. 8.60 +/- 1.20; P = 0.05). For the whole cohort, insulin only slightly improved net protein balance (protein synthesis minus protein breakdown) (1.60 +/- 0.80 vs. 1.71 +/- 0.89 g/kg per day; P = 0.08). In neonates receiving > or =2 g/kg per day of dietary amino acids insulin significantly improved net protein balance (2.17 +/- 0.34 vs. 2.40 +/- 0.26 g/kg per day; P < 0.01). Insulin effectively decreases protein breakdown in critically ill neonates on ECLS. However, this is associated with a significant reduction in plasma amino acids and a trend toward decreased protein synthesis. Insulin administration significantly improves net protein balance only in those ECLS neonates in whom adequate dietary protein is provided.

Intensive Insulin Therapy In The Critically-Ill Patients: Does Benefit Extend Beyond Normoglycemia?

Objective: To review studies on intensive insulin therapy in critically ill patients and understand possible mechanisms of benefit beyond glycemic control. The Ovid, Pub Med and Medline databases were searched for articles using the keywords insulin, glycemic control and critically ill. Data Synthesis: Beyond normoglycemia, insulin therapy seems to offer additional benefit by its direct effects on the lipid metabolism, the skeletal muscles and cardiac function. The effect of insulin infusion on nitric oxide pathway is investigational. Continuous infusion of insulin improves white cell functions .The lowering of acute phase reactant C-reactive protein levels by insulin infusion in critically ill patients also suggests that it may have anti-inflammatory properties. Conclusion: Emerging evidence shows that insulin therapy may have additional beneficial metabolic effects on lipids, vascular tone, skeletal muscles, cardiac, hematological or the immune system in critically ill patients beyond glycemic control.

Plasma adiponectin is modestly decreased during 24‐hour insulin infusion but not after inhibition of lipolysis by Acipimox

Objective. Plasma adiponectin is associated with insulin resistance and atherosclerosis. Adiponectin expression in adipose tissue is up‐regulated by peroxisome proliferator‐activated receptor (PPAR)‐γ agonist treatment and its plasma level may be affected by insulin. We tested the hypothesis that prolonged exogenous insulin infusion decreases plasma adiponectin, and examined whether a possible effect of insulin on plasma adiponectin is attributable to inhibition of lipolysis. Material and methods. The effect of insulin infusion on plasma adiponectin (Linco enzyme‐linked immunosorbent assay) was evaluated during a 24‐h moderately hyperinsulinemic clamp (8.3 µU kg−1 s−1) in 8 male type 2 diabetic patients and in 8 healthy men. On a separate day, acipimox (250 mg/4 h for 24 h) was administered to inhibit lipolysis. Insulin and acipimox were administered in random order with 1 week between study days. Results. In type 2 diabetic patients, insulin infusion decreased plasma adiponectin from 7.74±2.53 mg/l to 6.76±2.41 mg/l after 24 h (p<0.05). In healthy subjects, the change in plasma adiponectin after 24 h of insulin was not significant (8.10±2.76 and 7.55±2.41 mg/l at baseline and after 24 h of insulin, respectively). The change in plasma adiponectin after 24 h insulin in healthy subjects was not different from the change in diabetic patients. Plasma adiponectin did not decrease after 24 h acipimox administration in either group (type 2 diabetic patients: 6.84±2.19 and 6.54±2.93 mg/l at baseline and after 24 h, respectively (NS); healthy subjects; 7.35±2.52 and 8.31±3.37 mg/l, at baseline and after 24 h, respectively (NS)). When the results from diabetic and healthy subjects were combined, the decrease in plasma adiponectin after 24 h of insulin infusion (−0.76±1.08 mg/l, equivalent to a −9% change from baseline, p<0.05) was different (p = 0.05) from the change after 24 h acipimox (+0.33±1.74 mg/l, equivalent to a +4% change from baseline). Plasma free fatty acids decreased during insulin infusion (p<0.01 for both groups after 24 h) as well as in response to acipimox (p<0.05 for healthy subjects; p<0.01 type 2 diabetic patients after 24 h). After administration of acipimox, plasma insulin did not change in either group. Conclusions. Plasma adiponectin is modestly decreased during 24 h of insulin infusion. It is unlikely that this response to exogenous insulin is attributable to inhibition of lipolysis, since plasma adiponectin did not decrease after acipimox.

Effects of insulin on the cardiac autonomic nervous system in insulin-resistant states

The effects of insulin infusion on cardiac autonomic nervous system (ANS) activity were investigated in healthy subjects (n=15) and in patients with various types of insulin-resistance, such as obese subjects (n=20) and those with hypertension (n=15) or type II (non-insulin-dependent) diabetes (n=22). Healthy subjects and patients underwent euglycaemic hyperinsulinaemic glucose clamp, and cardiac ANS and haemodynamic changes were investigated by continuous recording of heart rate variability by the Holter technique and by venous occlusion plethysmography respectively. At baseline, healthy subjects had the highest values for total spectral power and the low-frequency (LF) component, and the lowest value for the high-frequency (HF) component. In the pooled data (n=72), the fasting plasma insulin concentration was correlated with baseline total spectral power (r=-0.37; P<0.001) and the LF/HF ratio (r=-0. 35; P<0.003). Such correlations were still significant (P<0.01 for both) after adjustment for body fat and mean arterial blood pressure. In a multivariate linear stepwise analysis (n=72), a model including body fat, waist/hip ratio, fasting plasma glucose concentration and insulin-mediated glucose uptake explained 47% of the variability of the change in the LF/HF ratio, with body fat (t=-3.11; P<0.01) and insulin-mediated glucose uptake (t=-3.48; P<0. 008) being significantly and independently associated with insulin-mediated changes in the LF/HF ratio. Insulin infusion reduced the total spectral power and increased the LF/HF ratio in healthy subjects, but not in insulin-resistant patients. In conclusion, our study demonstrates that insulin fails to stimulate cardiac ANS activity in insulin-resistant patients, independently of the causes of insulin resistance.

Effects of branched-chain-enriched amino acids and insulin on forearm leucine kinetics

Although amino acid mixtures enriched in branched-chain amino acids (BCAA) and deficient in aromatic amino acids (AAA) are often used together with insulin and glucose in clinical nutrition, their physiological effects on muscle protein anabolism are not known. To this aim, we studied forearm leucine kinetics in post-absorptive volunteers, before and after the systemic infusion of BCAA-enriched, AAA-deficient amino acids along with insulin and the euglycaemic clamp. The results were compared with the effects of insulin infusion alone. A compartmental leucine forearm model was employed at steady state. Hyperaminoacidaemia with hyperinsulinaemia (to approximately 80-100 micro-units/ml) increased the leucine plasma concentration (+70%; P<0.001), inflow into the forearm cell (+150%; P<0.01), disposal into protein synthesis (+100%; P<0.01), net intracellular retention (P<0.01), net forearm balance (by approximately 6-fold; P<0.01) and net deamination to alpha-ketoisocaproate (4-methyl-2-oxopentanoate) (+9%; P<0.05). Leucine release from forearm proteolysis and outflow from the forearm cell were unchanged. In contrast, hyperinsulinaemia alone decreased plasma leucine concentrations (-35%; P<0.001) and leucine inflow (-20%; P<0.05) and outflow (-30%; P<0.01) into and out of forearm cell(s), it increased net intracellular leucine retention (P<0.03), and it did not change leucine release from forearm proteolysis (-20%; P=0.138), net leucine deamination to alpha-ketoisocaproate, leucine disposal into protein synthesis or net forearm protein balance. By considering all data together, leucine disposal into protein synthesis was directly correlated with leucine inflow into the cell (r=0.71; P<0.0001). These data indicate that the infusion of BCAA-enriched, AAA-deficient amino acids along with insulin is capable of stimulating forearm (i.e. muscle) protein anabolism in normal volunteers by enhancing intracellular leucine transport and protein synthesis. These effects are probably due to hyperaminoacidaemia and/or its interaction with hyperinsulinaemia, since they were not observed under conditions of hyperinsulinaemia alone.

Effect of hyperinsulinemia on plasma leptin concentrations and food intake in rats.

We investigated the dose- and time-dependent effect of insulin infusion on peripheral and portal plasma leptin concentrations in normal rats. Three groups were studied: group I: euglycemic (6 mmol/l) insulin (6 mU . kg-1 . min-1) clamps for 0, 2, 4, 12, and 24 h; group II: euglycemic insulin (18 mU . kg-1 . min-1) clamp for 2 h; and group III: euglycemic insulin (3 mU . kg-1 . min-1) clamp for 7 days. In group III, food intake was quantified during days 1-7. After an overnight fast, peripheral and portal plasma leptin levels were identical (1.5 +/- 0.2 and 1.6 +/- 0.2 ng/ml). Insulin infusion (6 mU . kg-1 . min-1) for 2 h had no effect on plasma leptin levels (1.5 +/- 0.2 ng/ml). After 4 h (2.0 +/- 0.2 ng/ml), 12 h (2.2 +/- 0. 4 ng/ml), and 24 h (2.7 +/- 0.6 ng/ml; all P < 0.05) of insulin infusion, a progressive time-related increase in plasma leptin concentration was observed; portal vein leptin levels rose in parallel and were similar to peripheral levels. When insulin (18 mU . kg-1 . min-1) was infused for 2 h, plasma leptin levels increased to 3.0 +/- 0.3 ng/ml (P < 0.01). Seven days of constant insulin infusion (3 mU . kg-1 . min-1) resulted in a progressive increase in fasting plasma leptin and a parallel decrease in food intake. A mean increase in plasma leptin concentration of 1 ng/ml during the 7-day insulin infusion period was associated with a mean decrease in food intake of 2.5 g/day (multivariate ANOVA, P < 0.05). We conclude that the insulin-induced rise in peripheral and portal vein leptin levels is similar and both dose and time dependent. The inverse relationship between plasma leptin concentration and food intake during prolonged hyperinsulinemia, but not during short-term hyperinsulinemia, supports the role of leptin in long-term food consumption.

Regional Hyperinsulinemia Induces Vasodilation But Does Not Modulate Adrenergic Responsiveness in Humans

The relation between insulin resistance/ hyperinsulinemia and cardiovascular disease may be related to one of the cardiovascular effects of insulin. In acute experiments in humans, systemic euglycemic hyperinsulinemia induced vasodilation in skeletal muscle. Furthermore, the sympathetic nervous system is activated, although this does not lead to increase in blood pressure (BP). We hypothesized that insulin could induce vasodilation either by reduction of alpha- or by augmentation of beta-adrenergic responsiveness. The effect of insulin infusion into the brachial artery (regional forearm hyperinsulinemia; venous insulin concentration approximately 500 pM) on forearm blood flow (FBF: plethysmography) was studied. Responses to the alpha-adrenoceptor-mediated vasoconstrictor norepinephrine (NE: once with and once without the beta-adrenoceptor antagonist propranolol, 2 x n = 12; 9 participated in both), and to the beta-adrenoceptor-mediated vasodilator isoproterenol (n = 12) were measured before and during local hyperinsulinemia. Time/control studies (n = 6) were performed. Insulin alone induced vasodilation, as indicated by an increase in FBF-ratio (infused/ control arm) from 1.2 +/- 0.1 to 1.6 +/- 0.2, p = 0.009. Increasing dosages of NE (1.25 to 240 ng.dl-1.ml-1) induced vasoconstriction that was more pronounced during concomitant propranolol infusion (p < 0.001), indicating a dose-dependent vasodilatory component in the effect of NE. Isoproterenol (ISO 0.03 to 10 ng.dl-1.ml-1), a pure beta-adrenoceptor agonist, induced vasodilation. The percentage changes of FBF-ratio during NE+propranolol were similar and not significantly different before and during hyperinsulinemia. The same was true of the response to NE alone and the response to ISO. Neither was the intrinsic beta-agonist component of NE influenced by insulin. Repeated NE infusion showed no time- or vehicle effect. We conclude that regional hyperinsulinemia in the physiological range induces local vasodilation in the skeletal muscle vascular bed, but this vasodilation is not mediated through modulation of alpha- or beta-adrenergic responsiveness.

Differential Expression of ob mRNA in Rat Adipose Tissues in Response to Insulin

The recently cloned obese (ob) gene encodes a fat-specific mRNA and a protein which is believed to regulate satiety and metabolic rate so as to control fat storage. In the present study we investigated rat ob mRNA levels in different fat depots and the effects of insulin infusion on ob mRNA expression. Northern blot analysis showed the abdominal fat (epididymal and perirenal fat pads) had higher ob mRNA levels than subcutaneous fat. After a 2.5-hr infusion of insulin into fasted rats, ob mRNA levels were increased by 3.0 and 1.9-fold in epididymal and perirenal fat pads, respectively. However, no change of ob mRNA level was observed in the subcutaneous fat depot. These data demonstrate adipose depot site-specific expression of ob mRNA and support the hypothesis that insulin plays an important role in the expression of ob mRNA.

Insulin-mediated increase in calf blood flow is not related to blood pressure levels in patients with type 2 diabetes mellitus.

An association between insulin resistance and blood pressure levels has been found both in non-diabetic subjects and in type 2 diabetic patients. In non-diabetic subjects, infusion of insulin increases skeletal muscle blood flow, and it has been suggested that an attenuated flow-response to insulin may cause insulin resistance and may also serve as a mechanism relating insulin resistance to elevated blood pressure. We wanted to explore whether these findings could be extended to patients with type 2 diabetes. The effect of insulin infusion during a hyperinsulinaemic euglycaemic glucose clamp investigation on calf blood flow and its relationship to average diastolic blood pressure (DBPAVG), insulin sensitivity (GFRIlbm), body fat and total exercise capacity (TEC) was examined in 11 patients with type 2 diabetes. We found that insulin infusion increased median calf blood flow from 2.3 to 2.7 ml/min.100 g (p = 0.01). The change in blood flow (delta flow) did not correlate to the subjects' average blood pressure levels or their insulin sensitivity. Significant correlations between delta flow and leg fat %, fasting and clamp-insulin levels and total exercise capacity were observed. In conclusion, we found that insulin infusion increased calf blood flow significantly in patients with type 2 diabetes. However, our hypothesis that a negative correlation exists between blood pressure levels and insulin stimulated blood flow, was invalidated. Leg fat was identified as an important predictor of delta flow, GDRILBM and TEC in these patients.