Insulin Concentration Curve Research Articles

Effects of electrical stimulation of the lower extremities on postprandial hyperglycemia and arterial stiffness.

To compare the acute effects of electrical stimulation (ES) of the lower extremities on postprandial hyperglycemia and arterial stiffness during oral glucose tolerance testing (OGTT). In a randomized crossover study, eight healthy young men completed three experimental trials in which they underwent ES for 30 min, starting 60 min before (Before) or 30 min after (After) ingesting 75 g of glucose; ES was not performed in the control trial (Control). The subjects' blood glucose levels and brachial-ankle pulse wave velocity (baPWV) were measured as an index of arterial stiffness at baseline and 30, 60, and 120 min after glucose ingestion. Serum insulin levels were measured at baseline and 60 min after glucose ingestion. The subjects' glucose intake led to an increase in their blood glucose concentration in all trials, however, in the After trial, ES resulted in significantly lower blood glucose concentrations at 60 min post glucose ingestion compared to the Control and Before trials. The area under the curve (AUC) of serum insulin concentrations during the OGTT in the After trial was significantly lower than that in the other two trials. Moreover, glucose ingestion did not increase the baPWV, however, 30 min of ES during the postprandial state acutely reduced the baPWV. These results suggest that ES is most effective in reducing postprandial hyperglycemia when administered after a meal. Thus, lower extremity ES may be an alternative exercise method to activate postprandial glucose metabolism in healthy individuals.

278-LB: The Effect of Combining Very-Low-Calorie Diet with Semaglutide on Beta-Cell Function in Individuals with Type 2 Diabetes

Type 2 diabetes (T2D) is characterised by the loss of the first phase response of insulin-producing pancreatic beta cells. Recently, Very-low calorie diets (VLCD - defined as less than 800 kilocalories per day) have been shown to restore this first phase response to induce remission of T2D, while Glucagon-like peptide-1 agonists also improve the first phase response by enhancing postprandial insulin secretion. Here, we present interim results of an investigation exploring the effect of combining these two interventions on beta cell function, in individuals with T2D. Eighteen individuals with T2D and body mass index >27kg.m-2 were randomly allocated into 3 groups: i) Semaglutide (S), ii) VLCD (V), and iii) Semaglutide-plus-VLCD (SV). Semaglutide was administered once weekly gradually up titrated to a maximum dose of 1mg and VLCD regime was provided by LighterLife® total meal replacement. Beta cell function was assessed using intravenous glucose tolerance tests (IVGTT) performed at baseline and 12 weeks. First-phase insulin response was calculated as the incremental area under the suprabasal plasma insulin concentration curve during 0-10 minutes of the IVGTT (µU.min.ml-1). Data were analysed using GraphPad Prism 9.5.0 (La Jolla, USA). All groups were equally matched at baseline. Mean weight loss was 6.4, 14.1 and 14.9 kg in S, V and SV, respectively. A significant improvement in first phase response was observed in all groups (S: +398.5; V: +88.4; SV: +547.8 µU.min.ml-1, all p<0.05 vs. baseline). At 12 weeks, first phase response in SV was significantly higher than in V (583.9 vs. 169.2 µU.min.ml-1 respectively, p<0.05). These data suggest that combination of VLCD and Semaglutide results in a significantly greater improvement in first phase response than VLCD alone. This approach could result in a more robust remission of T2D in the longer-term, and may have important implications for the future design of interventions for the clinical management of T2D. Disclosure O. Anyiam: None. B. E. Phillips: None. D. J. Wilkinson: None. K. Smith: None. P. J. Atherton: None. I. R. Idris: None. Funding Medical Research Council Confidence in Concept Scheme

Progressive Acceleration of Insulin Exposure Over 7 Days of Infusion Set Wear.

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report insulin pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide <0.6 nmol/L, ≥6 months pump use) were enrolled in a crossover euglycemic clamp pilot study comparing conventional Teflon angled IISs with an investigational extended-wear IIS. PK/PD data from six participants were obtained for 5 h postbolus. Although PD data were unstable, PK profiles (pooled data from both groups) of insulin lispro (0.15 U/kg bolus) showed statistically significant progressive decreases from days 0 to 7 for tmax (P < 0.001), Cmax (P < 0.05), and mean residence time (P < 0.0001). Area under the insulin concentration curve (AUC0-300) declined by ∼24% from days 0 to 7 (P < 0.05). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. The study was registered in clinicaltrials.gov (NCT04398030).

Consumption of Cooked Black Beans Stimulates a Cluster of Some Clostridia Class Bacteria Decreasing Inflammatory Response and Improving Insulin Sensitivity.

There is limited information on the effect of black beans (BB) as a source of protein and resistant starch on the intestinal microbiota. The purpose of the present work was to study the effect of cooked black beans with and without high fat and sugar (HF + S) in the diet on body composition, energy expenditure, gut microbiota, short-chain fatty acids, NF-κB, occluding and insulin signaling in a rat model and the area under the curve for glucose, insulin and incretins in healthy subjects. The consumption of BB reduced the percentage of body fat, the area under the curve of glucose, serum leptin, LPS, glucose and insulin concentrations and increased energy expenditure even in the presence of HF + S. These results could be mediated in part by modification of the gut microbiota, by increasing a cluster of bacteria in the Clostridia class, mainly R. bromii, C. eutactus, R. callidus, R. flavefaciens and B. pullicaecorum and by an increase in the concentration of fecal butyrate. In conclusion, the consumption of BB can be recommended to prevent insulin resistance and metabolic endotoxemia by modifying the gut microbiota. Finally, the groups fed BB showed lower abundance of hepatic FMO-3, even with a high-fat diet protecting against the production of TMAO and obesity.

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine-A pharmacokinetic and pharmacodynamic study.

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof‐of‐concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto‐injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60‐80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10‐minute intervals between −20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule.

Glucose and Insulin Responses to an Intravenous Glucose Load in Thoroughbred and Paso Fino Horses

Certain breeds of horses may be genetically predisposed to developing insulin dysregulation, which is a risk factor for development of endocrinopathic laminitis in horses. This study was performed to test the hypotheses that Paso Fino horses exhibit evidence of insulin dysregulation compared with Thoroughbred horses and that obesity exaggerates the insulin dysregulation. Intravenous glucose tolerance tests were performed in 14 moderate-weight Thoroughbreds, 12 moderate-weight Paso Finos, and 12 overweight Paso Finos. Moderate Paso Finos had greater baseline serum insulin concentrations, area under the insulin concentration curve, peak insulin, insulin-to-glucose ratio, area under the insulin to glucose curve, and modified glucose-to-insulin ratio compared with moderate Thoroughbreds. The reciprocal inverse square of basal insulin (RISQI) and glucose-to-insulin ratio were significantly lower in moderate Paso Finos compared with moderate Thoroughbreds. Overweight Paso Finos had greater baseline insulin concentrations, area under the insulin concentration curve, time to peak insulin, baseline plasma glucose concentration, insulin-to-glucose ratio, and area under the insulin to glucose curve compared with moderate Paso Finos. The RISQI and glucose-to-insulin ratio were significantly lower in overweight Paso Finos compared with moderate Paso Finos. In conclusion, moderate-weight Paso Finos had higher baseline serum insulin concentrations and an excessive hyperinsulinemic response to an intravenous glucose load when compared with moderate-weight Thoroughbreds. Overweight Paso Finos had even greater baseline insulin concentrations and hyperinsulinemic responses to glucose compared with moderate Paso Finos, as well as greater baseline plasma glucose concentrations. Paso Finos exhibit insulin dysregulation compared with Thoroughbreds.

SAT-171 Effective Intrajejunal Wall Delivery of Recombinant Human Insulin via a Self-Deployed Ingestible Capsule in Anesthetized Swines: A Pharmacokinetic and Pharmacodynamic Study

BACKGROUND: Biotherapeutic agents must be administered parenterally to reach and maintain therapeutic blood concentrations, lowering patient compliance and complicating long-term care. We have developed an ingestible robotic pill capable of delivering a variety of drugs directly into the wall of the proximal small intestine. METHODS: This observational, pilot study was performed in 17 juvenile anesthetized pigs under a 60-80 mg/dl euglycemic glucose clamp. All animals underwent midline, abdominal laparotomies. In a TEST group of 8 pigs (mean weight = 17.4±1.2 kg), 20 IU of recombinant human insulin (RHI) were auto-injected into the jejunal wall by inserting the pill into the proximal jejunum via a 1-cm enterotomy. A CONTROL group of 9 pigs (17.0±0.4 kg) received 20 IU of RHI injected subcutaneously. In both study groups, blood samples were collected at 10-min intervals, between -20 and +420 min after RHI administration for measurements of blood concentrations of glucose, using a handheld glucometer, and serum insulin, using the ELISA method. RESULTS: The peak serum concentrations (Cmax) of RHI were 517±109 and 342±50 pM for the jejunal wall and the subcutaneous groups, respectively (ns). The area under the insulin concentration curves (83±18 and 81±10 nmol/l.min) were likewise similar in both groups. The mean time to peak serum concentration of insulin (Tmax) was 139±42 min in the jejunal wall group, shorter than in the subcutaneous group (227±24 min). CONCLUSIONS: 1) The bioactivity of RHI was preserved after its delivery into the jejunal wall, 2) the jejunal wall route provided a more rapid and physiologic uptake of insulin compared with the subcutaneous route, though the difference (p=0.097) was not statistically significant, and 3) the pharmacokinetic and pharmacodynamic profile of RHI after its jejunal wall delivery suggests that drugs such as basal insulin, currently administered parenterally, could be successfully delivered into the proximal intestinal wall via the ingestible robotic capsule.

United States experience of insulin degludec alone or in combination for type 1 and type 2 diabetes.

Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program which began with the release of insulin detemir. The goal was to produce a long-lasting basal insulin with low individual variability. Certainly, this goal has been achieved. Degludec has a duration of action approaching twice that of glargine. Another advantage of degludec is in its lack of unpredictable copolymerization of added aspart. In several studies, degludec has shown lower rates of nocturnal hypoglycemia than glargine. Degludec can be administered flexibly with a very flat insulin concentration curve at any time of day. Initial US Food and Drug Administration concerns about a possible increase in cardiac events in degludec-treated patients have been allayed by the results of a study targeting individuals with high cardiac risk. Degludec is now marketed in the US competing with glargine. Despite the long duration of action of degludec, attempted administration three times weekly resulted in less effective lowering of glycated hemoglobin and an increased incidence of hypoglycemia compared to daily glargine. Conversely the coformulation of degludec and liraglutide has proven very successful in reducing glycated hemoglobin levels with less hypoglycemia and less weight gain than with degludec alone and with less gastrointestinal symptoms than with liraglutide alone. A large study comparing glargine insulin and degludec in patients with increased cardiac risk is now ongoing. This study may or may not prove superiority of one or the other insulin, but, with the coming of biosimilar glargine insulin, cost factors may be dominant in determining which basal insulin is to be used. Nonetheless, the coformulation with liraglutide will likely insure the future of degludec insulin in the treatment of type 2 diabetes.

Effects of rumen-protected Capsicum oleoresin on productivity and responses to a glucose tolerance test in lactating dairy cows

The objective of this experiment was to investigate the effects of rumen-protected Capsicum oleoresin (RPC) supplementation on feed intake, milk yield and composition, nutrient utilization, fecal microbial ecology, and responses to a glucose tolerance test in lactating dairy cows. Nine multiparous Holstein cows were used in a replicated 3 × 3 Latin square design balanced for residual effects with three 28-d periods. Each period consisted of 14 d for adaptation and 14 d for data collection and sampling. Treatments were 0 (control), 100, and 200 mg of RPC/cow per day. They were mixed with a small portion of the total mixed ration and top-dressed. Glucose tolerance test was conducted once during each experimental period by intravenous administration of glucose at a rate of 0.3 g/kg of body weight. Dry matter intake was not affected by RPC. Milk yield tended to increase for RPC treatments compared to the control. Feed efficiency was linearly increased by RPC supplementation. Concentrations of fat, true protein, and lactose in milk were not affected by RPC. Apparent total-tract digestibility of dry matter, organic matter, and crude protein was linearly increased, and fecal nitrogen excretion was linearly decreased by RPC supplementation. Rumen-protected Capsicum oleoresin did not affect the composition of fecal bacteria. Glucose concentration in serum was not affected by RPC supplementation post glucose challenge. However, compared to the control, RPC decreased serum insulin concentration at 5, 10, and 40 min post glucose challenge. The area under the insulin concentration curve was also decreased 25% by RPC. Concentration of nonesterified fatty acids and β-hydroxybutyrate in serum were not affected by RPC following glucose administration. In this study, RPC tended to increase milk production and increased feed efficiency in dairy cows. In addition, RPC decreased serum insulin concentration during the glucose tolerance test, but glucose concentration was not affected by treatment.

Insulin Injection Into Lipohypertrophic Tissue: Blunted and More Variable Insulin Absorption and Action and Impaired Postprandial Glucose Control.

Lipohypertrophy (LHT) is common in insulin-treated patients but its exact impact on insulin absorption and action is unclear. In this crossover study, 13 patients with type 1 diabetes received subcutaneous abdominal injections of 0.15 units/kg insulin lispro into LHT (confirmed by examination and ultrasound) and normal adipose tissue (NAT). On one day, a euglycemic clamp was performed with two injections each into LHT and NAT, and on another day one injection per region was given before a standardized mixed meal (75 g carbohydrates), all in randomized order. Compared with NAT, LHT reduced insulin absorption (mean area under the insulin concentration curve [AUCINS0-4h] 131 vs. 165 h * mU/L [LHT vs. NAT]; Cmax 61 vs. 79 mU/L, P < 0.02, respectively) and effect (areas under glucose infusion rate [GIR] curves [AUCGIR0-4h 625 vs. 775 mg/kg, P < 0.05]) but increased intrasubject variability ([coefficient of variation] AUCINS0-4h 52 vs. 11%, Cmax 55 vs. 15%, AUCGIR0-4h 57 vs. 23%, all P < 0.01). Postprandial blood glucose (BG) concentrations were ≥26% higher with LHT (AUCBG0-5h 731 vs. 513 mg * h/dL, BGmax 199 vs. 157 mg/dL, 2-h BG 150 vs. 104 mg/dL, 5-h BG 145 vs. 81 mg/dL, all P < 0.05) and maximum concentrations occurred later. Hypoglycemia (BG ≤50 mg/dL) occurred numerically less frequently with LHT injection (two vs. six patients), whereas profound hyperglycemia (BG ≥300 mg/dL) only occurred with LHT injection (two patients). Tmax-INS did not differ between LHT and NAT in either study. Insulin absorption and action are blunted and considerably more variable with LHT injection, leading to profound deterioration in postprandial glucose control.

Conjoint regulation of glucagon concentrations via plasma insulin and glucose in dairy cows

Insulin and glucagon are glucoregulatory hormones that contribute to glucose homeostasis. Plasma insulin is elevated during normoglycemia or hyperglycemia and acts as a suppressor of glucagon secretion. We have investigated if and how insulin and glucose contribute to the regulation of glucagon secretion through long term (48 h) elevated insulin concentrations during simultaneous hypoglycemia or euglycemia in mid-lactating dairy cows. Nineteen Holstein dairy cows were randomly assigned to 3 treatment groups: an intravenous insulin infusion (HypoG, n = 5) to decrease plasma glucose concentrations (2.5 mmol/L), a hyperinsulinemic-euglycemic clamp to study effects of insulin at simultaneously normal glucose concentrations (EuG, n = 6) and a 0.9% saline infusion (NaCl, n = 8). Plasma glucose was measured at 5-min intervals, and insulin and glucose infusion rates were adjusted accordingly. Area under the curve of hourly glucose, insulin, and glucagon concentrations on day 2 of infusion was evaluated by analysis of variance with treatments as fixed effect. Insulin infusion caused an increase of plasma insulin area under the curve (AUC)/h in HypoG (41.9 ± 8.1 mU/L) and EuG (57.8 ± 7.8 mU/L) compared with NaCl (13.9 ± 1.1 mU/L; P < 0.01). Induced hyperinsulinemia caused a decline of plasma glucose AUC/h to 2.3 ± 0.1 mmol/L in HypoG (P < 0.01), whereas plasma glucose AUC/h remained unchanged in EuG (3.8 ± 0.2 mmol/L) and NaCl (4.1 ± 0.1 mmol/L). Plasma glucagon AUC/h was lower in EuG (84.0 ± 6.3 pg/mL; P < 0.05) and elevated in HypoG (129.0 ± 7.0 pg/mL; P < 0.01) as compared with NaCl (106.1 ± 5.4 pg/mL). The results show that intravenous insulin infusion induces elevated glucagon concentrations during hypoglycemia, although the same insulin infusion reduces glucagon concentrations at simultaneously normal glucose concentrations. Thus, insulin does not generally have an inhibitory effect on glucagon concentrations. If simultaneously glucose is low and insulin is high, glucagon is upregulated to increase glucose availability. Therefore, insulin and glucose are conjoint regulatory factors of glucagon concentrations in dairy cows, and the plasma glucose status is the key factor to decide if its concentrations are increased or decreased. This regulatory effect can be important for the maintenance of glucose homeostasis if insulin secretion is upregulated by other factors than high glucose such as high plasma lipid and protein concentrations at simultaneously low glucose.

Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome

To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). 6 healthy adult mares and 6 horses with EMS. Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.

Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects

OBJECTIVEHuman regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL).RESEARCH DESIGN AND METHODSThis was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects.RESULTSBoth overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05).CONCLUSIONSOverall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

A Solid High‐Protein Meal Evokes Stronger Hunger Suppression Than a Liquefied High‐Protein Meal

Hunger is a potential problem for compliance with an energy-restricted diet. Relatively high-protein meal-replacement products have been shown to diminish this problem; they are available as liquid and solid meals, yet their physical state can affect hunger suppression. The objective was to investigate the differences in appetite profile and physiological parameters after consumption of a single-macronutrient, subject-specific, high-protein meal in liquefied vs. solid form, controlled for energy density, weight, and volume. Ten male subjects (age: 21.1 ± 3.9 years; BMI: 22.4 ± 1.2 kg/m²) were offered lunch subject-specifically as 15% of daily energy requirement (DER), consisting of solid (steamed chicken breast + 750 ml water) or liquefied protein (steamed chicken breast blended in 500 ml water + 250 ml water). Appetite profiles, insulin, glucose, and ghrelin were measured over 3 h. Comparing the solid vs. liquefied condition, oral exposure time did not differ between conditions (19.2 ± 0.4 and 18.8 ± 0.6 min, respectively; P = 0.13). Area under the curve (AUC) effects were observed for thirst; statistically significant condition × time interactions and statistically significant differences at several time points were observed for desire to eat (condition × time P < 0.05; 31 ± 6 mm vs. 53 ± 8 mm; P < 0.04 at 115 min) and thirst (condition × time P < 0.01; 27 ± 8 mm vs. 41 ± 8 mm; P < 0.05 at 30 min and 23 ± 6 mm vs. 41 ± 8 mm; P < 0.02 at 70 min) to be lower, while hunger suppression (79 ± 3 mm and 52 ± 10 mm; P < 0.03 at 20 min and 61 ± 7 mm and 44 ± 8 mm; P < 0.03 at 115 min) was higher in the solid condition. Glucose, insulin, and ghrelin concentration curves were similar for both conditions. In conclusion, solid protein evokes a stronger suppression of hunger and desire to eat than liquefied protein.

Insulin Responses to Administrations of Amino Acids and Fatty Acids in Healthy Cats

In order to compare the stimulation ability of insulin secretion, we determined changes in plasma glucose and insulin concentrations after intravenous administration of various amino acids and essential fatty acids in clinically healthy adult cats. Plasma glucose concentrations were within the normal ranges after injection of amino acids and fatty acids. Plasma insulin concentrations increased rapidly 2 to 4 min after injection of arginine, then decreased to the basal levels at 20 min in all five cats. Insulin peak responses were significantly greater in arginine injections than in normal saline (P<0.01). Areas under the curve (AUC) of plasma insulin concentrations from 0 to 10 min after injection of arginine were significantly larger than after injection of normal saline (P<0.01) and glucose (P<0.05). Increases in AUC of plasma insulin concentration from 0 to 60 min were observed after injection of arginine, leucine, alanine, and fat emulsion. Arginine had a strong insulinotropic effect, and leucine, alanine, and fatty acids had weak ones. Besides, valine, methionine, taurine and glutamine had no stimulant activity of insulin. Given the risk of glucose toxication and required time for testing, the intravenous arginine tolerance test may be useful for estimation of insulin responses in cats.

Plasma soluble tumour necrosis factor‐α receptor 2 is elevated in obesity: specific contribution of visceral adiposity

We examined the obesity phenotype most strongly associated with increased plasma concentrations of sTNFR2, and compared which of the two markers, TNF-alpha or sTNFR2, better predicts indices of plasma glucose-insulin homeostasis. Plasma sTNFR2 levels were measured in a sample of 287 healthy nondiabetic men [age: 43.9 +/- 8.0 years (mean +/- SD)], covering a wide range of adiposity values (BMI: 29.0 +/- 4.4 kg/m(2); waist girth: 100.0 +/- 11.7 cm). Plasma sTNFR2 levels correlated positively and significantly with BMI (r = 0.36; P < 0.0001), fat mass (r = 0.42; P < 0.0001), waist girth (r = 0.38; P < 0.0001) as well as with visceral (r = 0.37; P < 0.0001) and subcutaneous adipose tissue (AT) (r = 0.40; P < 0.0001) areas measured by computed tomography. Two subgroups (n = 27 in each group) of overweight men (BMI >or=25 kg/m(2)) were individually matched for similar BMI values, but with markedly different levels of visceral AT (< or >or=130 cm(2)) and then compared with a control group of 46 lean subjects (with both BMI <25 kg/m(2) and visceral AT <130 cm(2)). This analysis revealed that men characterized by high levels of visceral AT had significantly higher concentrations of sTNFR2 compared with obese men with low visceral AT (1861 +/- 457 pg/ml vs. 1722 +/- 400; P < 0.05) and with lean controls (1570 +/- 291 pg/ml; P < 0.001). Whereas subjects classified across tertiles of TNF-alpha levels showed no difference in glucose tolerance and insulin levels, subjects in the upper tertile of plasma sTNFR2 levels were characterized with the highest plasma insulin concentrations during the OGTT and had the highest area under the curve of insulin concentrations. These results indicate that sTNFR2 levels are more closely related to abdominal AT accumulation than to total adiposity. Furthermore, plasma concentrations of sTNFR2 are independently related to plasma glucose-insulin homeostasis beyond the known contribution of visceral adiposity.

The increase in plasma PAI-1 associated with insulin resistance may be mediated by the presence of hepatic steatosis

Objective Recent evidence suggests that plasminogen-activator inhibitor-1 (PAI-1) is abundantly produced by the fatty liver, but it is unclear whether hepatic steatosis (HS) can mediate the increase in plasma PAI-1 induced by insulin resistance/compensatory hyperinsulinemia (IR/CH). Methods and results To address this issue, we cross-sectionally evaluated IR/CH as area under the curve of plasma insulin (AUC-PI) concentrations during OGTT, metabolic profile, and ultrasound degree of HS in 235 healthy volunteers (132 M, age: 60 ± 7 years) with normal transaminase concentrations. Circulating PAI-1 was increased in subjects with classical features of IR/CH (overweight, high fasting and post-OGTT insulin and glucose, high triglycerides (TG), and low HDL-cholesterol), and significantly correlated to prevalence and degree of HS, but not to alcohol intake. In a multivariate model, AUC-PI, TG and degree of HS were independent predictors of plasma PAI-1 ( R 2 = 0.32). However, AUC-PI was significantly correlated to PAI-1 only in subjects with HS, suggesting an interaction between AUC-PI and HS. In addition, in the presence of HS and IR/CH, PAI-1 concentrations were increased to a similar extent both in heavy and moderate drinkers, suggesting that metabolic and alcoholic steatosis have a similar effect on the relationship between IR/CH and PAI-1. Conclusion These results support the hypothesis that HS has a major impact on the relationship between IR/CH and plasma PAI-1 concentrations, and this effect seems to be unaffected by the etiology of the HS.

Early Detection of Insulin Sensitivity and β-Cell Function with Simple Tests Indicates Future Derangements in Late Pregnancy

Insulin sensitivity and secretion during early and late pregnancy were assessed in women with normal glucose tolerance and gestational diabetes mellitus (GDM). The oral glucose tolerance test (OGTT) was performed in 903 women at 16-20th gestational week, of whom 37 had GDM (GDM1 group), and 859 repeated the OGTT at wk 26-30. At the second test, 55 had GDM (GDM2 group); the others remained normotolerant (ND group). Insulin sensitivity from OGTT (as quantitative insulin sensitivity check index and OGTT insulin sensitivity) and beta-cell function (as the ratio of the areas under the insulin and glucose concentration curves, adjusted for insulin sensitivity) were assessed in both tests. In early pregnancy the quantitative insulin sensitivity check index was not different in the three groups, whereas OGTT insulin sensitivity was lowest in GDM2, intermediate in GDM1, and highest in ND. In late pregnancy both indices were reduced in GDM compared with ND and lower than in early pregnancy. In early pregnancy GDM1, but not GDM2, had lower beta-cell function than ND. During the late visit, GDM2 also showed impaired beta-cell function compared with ND; furthermore, the adaptation to the increase to insulin resistance from early to late pregnancy was defective in GDM2. In early pregnancy insulin sensitivity, as assessed from the OGTT but not from fasting measurements, is impaired in women who developed GDM. beta-Cell function impairment is evident only when GDM is manifest and is characterized by inappropriate adaptation to the pregnancy induced increase in insulin resistance.

Effect of Upper Respiratory Tract Infection on AIR Inhaled Insulin Pharmacokinetics and Glucodynamics in Healthy Subjects

The suitability of employing AIR Inhaled Insulin (AIR Insulin; AIR is a registered trademark of Alkermes) during acute upper respiratory tract infection (URI) has not been determined. Twenty-one healthy, non-diabetic subjects were enrolled in a single-sequence, two-period, euglycemic clamp study. Subjects received a single 12 U-equivalent dose of AIR Insulin before rhinovirus (RV16) inoculation and during symptomatic infection. Spirometry was used to evaluate pulmonary safety. AIR Insulin exposure (the area under the immunoreactive insulin (IRI) concentration vs time curve from time zero until the IRI concentrations returned to the predose baseline value (AUC(0-t'))) and glucodynamic response (total amount of glucose infused (G(tot))) were comparable before and during RV infection (AUC(0-t') 46,300 vs 52,600 pmol min/l, P=0.21; G(tot) 61,800 vs 68,700 mg, P=0.42, respectively). Variability of pharmacokinetic and pharmacodynamic parameters did not change during URI; either did the number or intensity of adverse events. No significant change in forced expiratory volume or forced vital capacity was observed following AIR Insulin administration or during URI. The AIR Insulin system provides similar pharmacokinetic and glucodynamic responses under conditions of an experimentally induced RV infection and is regarded as suitable for use in diabetic patients during URIs.

AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

In this open-label, randomized, crossover study, pharmacokinetic and glucodynamic responses were compared in healthy subjects versus subjects with moderate chronic obstructive pulmonary disease (COPD), following administration of 12 units equivalent AIR inhaled insulin versus 12 units subcutaneous insulin lispro. Three nonsmoking groups (n = 15 each)--healthy subjects (baseline mean +/- SD age 38 +/- 13 years, forced expiratory volume in 1 s [FEV1] 4.06 +/- 1.04 l), subjects with chronic bronchitis (aged 53 +/- 9 years, FEV1 2.14 +/- 0.60 l), and subjects with pulmonary emphysema (aged 58 +/- 6 years, FEV1 1.67 +/- 0.61 l)--were randomly assigned to one of three treatment sequences. Three euglycemic glucose clamp procedures were performed. In subjects with chronic bronchitis and emphysema, AIR inhaled insulin administration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC(0-t')]) (55.7%, P = 0.13 and 78.5%, P < 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P < 0.01 and 67.1%, P < 0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and metabolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre- and postclamp pulmonary function tests. During clamps, FEV1 and forced vital capacity declined modestly in both COPD groups, with no difference between AIR insulin and subcutaneous insulin lispro. Short-term exposure to AIR inhaled insulin was well tolerated by COPD subjects, showing similar time-exposure and time-action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. Further clinical evaluation is warranted in patients with comorbid diabetes and COPD.