Half-maximal Glucose Infusion Rate Research Articles

U‐100, pH‐Neutral formulation of VIAject®: faster onset of action than insulin lispro in patients with type 1 diabetes

VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Effects of Dietary Starch and Sucrose on Tissue Responsiveness and Sensitivity to Insulin in Goats Fed a High-concentrate Diet

A glucose clamp technique was used to compare dietary starch (ST), starch plus sucrose (ST+SU) and sucrose (SU) with regard to the effect on tissue responsiveness and sensitivity to insulin in intact adult male goats. The goats were fed diets containing 1.2 times of ME and CP for maintenance requirements twice daily for 21 d. Of the energy intake, 30% was offered with ST, ST+SU or SU for the respective diets, and 70% as alfalfa hay, ground corn and ground soybean meal at the respective weight ratio of 1, 1, and 0.3 for all diets. Tissue responsiveness and sensitivity to insulin were evaluated using a hyperinsulinemic euglycemic clamp technique with four levels of insulin infusion beyond 13 h after feeding. The concentrations of plasma metabolites and insulin were also determined at 3, 6 and 13 h after feeding to evaluate the effects of different carbohydrates on metabolic states in the body. Plasma glucose concentration was higher (p = 0.01) for SU diet than for ST and ST+SU diets. Increasing SU intake decreased (p<0.01) plasma acetate concentration across the time. At 3 h but not 6 and 13 h after feeding, high lactate (p = 0.01), and non-significant high propionate (p = 0.14) and low urea nitrogen (p = 0.19) concentrations were observed in plasma on SU compared with ST and ST+SU diets. Plasma insulin concentration was not different (p = 0.44) between ST and SU fed animals. In the glucose clamp experiment, considering the effects on the maximal glucose infusion rate (tissue responsiveness to insulin, p = 0.54) and the plasma insulin concentration at half-maximal glucose infusion rate (insulin sensitivity, p = 0.54), SU was not different from ST. It is concluded that SU may not be greatly different from ST with regard to the effect on tissue responsiveness and sensitivity to insulin in adult goats when fed twice daily as part of a high-concentrate diet. The possible greater effects of SU on plasma metabolites concentrations at 3 h than at 6 and 13 h after feeding suggest that a lack of persistency of SU effects during the postfeeding period may be associated with the poor response to SU in insulin action.

Effects of Non-protein Energy Intake on the Concentrations of Plasma Metabolites and Insulin, and Tissue Responsiveness and Sensitivity to Insulin in Goats

A glucose clamp technique was used to investigate the effects of non-protein energy intake on tissue responsiveness and sensitivity to insulin for glucose metabolism in intact adults male goats. Three goats were fed diets at 1.0, 1.5 and 2.0 times of ME for maintenance, each for 21 d. Crude protein intake was 1.5 times of maintenance requirement in each treatment. Tissue responsiveness and sensitivity to insulin were evaluated using a hyperinsulinemic euglycemic clamp technique with four levels of insulin infusion, beginning at 13 h after feeding. Concentrations of plasma metabolites and insulin were also measured at 3, 6 and 13 h after feeding, for evaluating effects of non-protein energy intake on the metabolic status of the animals. Increasing non-protein energy intake prevented an increase in plasma NEFA concentration at 13 h after feeding (p = 0.03). Plasma urea-nitrogen and total amino-nitrogen concentrations decreased (p<0.01) and increased (p = 0.03), respectively, with increasing non-protein energy intake across time relating to feeding. Plasma insulin concentration was unaffected (p = 0.43) by non-protein energy intake regardless of time relating to feeding. In the glucose clamp experiment, increasing non-protein energy intake decreased numerically (p = 0.12) the plasma insulin concentration at half-maximal glucose infusion rate (insulin-sensitivity), but did not affect (p = 0.60) maximal glucose infusion rate (tissue responsiveness to insulin). The present results suggest that an increase in non-protein energy intake may enhance insulin sensitivity for glucose metabolism, unlike responsiveness to insulin, in adult male goats. The possible enhancement in insulin sensitivity may play a role in establishing anabolic status in the body, when excess energy is supplied to the body.

Effect of supplemental calcium propionate on insulin action to blood glucose metabolism in adult sheep

An experiment combining a hyperinsulinemic euglycemic clamp procedure of four sequential 2-h periods and an isotope dilution method of [U-13C]glucose determined the effect of supplemental calcium propionate on blood glucose metabolism during insulin and glucose infusions in adult sheep. They were fed lucerne hay cubes and commercial concentrate with and without supplementary calcium propionate (Prop and Cont diets, respectively) in a crossover design for each 21-day period. At the preinfusion period, blood glucose turnover rate (GTR) was greater (P < 0.05) for the Prop diet than for the Cont diet. Blood GTR, endogenous glucose production rate (EGPR) and the ratio of EGPR to blood GTR were greater (P < 0.01, P < 0.05 and P < 0.05, respectively) for the Prop diet than for the Cont diet. Blood GTR and glucose infusion rate (GIR) increased (P < 0.001) and the ratio of EGPR to blood GTR was reduced (P < 0.01) with increased insulin infusion rates. The maximal GIR tended to be (P < 0.10) greater for the Prop diet than for the Cont diet but plasma insulin concentration at half maximal GIR did not differ between diets. It is suggested that in adult sheep, dietary propionate supplementation enhances insulin action on glucose metabolism, however, changes in measures of tissue responsiveness and sensitivity were not significant.

Tissue responsiveness and sensitivity to insulin in sheep fed plantain and orchardgrass and exposed to cold

To assess the effect on insulin action of feeding a forage herb to sheep exposed to a cold environment, eight sheep were fed either plantain (PL), a forage herb, or orchardgrass (OR), a forage. A hyperinsulinaemic euglycaemic clamp procedure was applied to determine tissue responsiveness and sensitivity to insulin in both the thermoneutral (20°C) and cold (0–4°C) environments. For the glucose clamp procedure, insulin was infused over four sequential 2‐h periods at rates of 0.64, 1.6, 4.0, and 10 mU kg‐0.75 body weight min−1 and glucose was infused at variable rates to maintain euglycaemia. The maximal glucose infusion rate (tissue responsiveness to insulin) was greater (P = 0.04) for the PL diet than for the OR diet, and was enhanced (P = 0.001) during cold exposure. The plasma insulin concentration at half maximal glucose infusion rate (tissue sensitivity to insulin) was influenced by neither diet nor environment. No significant diet by environment interaction was observed for these variables. It is possible that in sheep the forage herb PL enhances insulin action through enhanced tissue responsiveness. Insulin action in response to cold exposure was comparable between the PL and OR diets.

Effects of dietary protein level and cold exposure on tissue responsiveness and sensitivity to insulin in sheep

The effects of dietary crude protein (CP) level and cold exposure on tissue responsiveness and sensitivity to insulin were studied in sheep. Nine rams were assigned to one of three isoenergetic diets which contained 70, 100, and 140% of CP for maintenance. They were exposed from a thermoneutral environment (20 degrees C) to a cold environment (0 degrees C) for 7 days. A hyperinsulinemic euglycemic clamp approach was applied for the determination of tissue responsiveness to insulin (the maximal glucose infusion rate, GIRmax) and tissue sensitivity to insulin (the plasma insulin concentration at half maximal glucose infusion rate, ED50). Dietary CP level influenced digestibilities of dry matter and CP (P=0.002 and P=0.001, respectively), and cold exposure decreased (P=0.01) CP digestibility. The GIRmax and ED50 tended to be influenced (P=0.08) by dietary CP level. The GIRmax was enhanced (P=0.0001) during cold exposure. Significant interactions between diet and environment were found for the GIRmax (P=0.04), but not for ED50 (P=0.07). It is concluded that in sheep dietary CP level can modify insulin action in response to cold exposure.

Effect of hypomagnesemia and cold exposure on tissue responsiveness to insulin in sheep given a low magnesium and high potassium diet

Hypomagnesemia in ruminants has been shown to be associated with cold stress and with altered insulin secretion and sensitivity. However, the relationship between hypomagnesemia and tissue responsiveness to insulin in ruminants exposed to cold environment is still unclear. The hyperinsulinemic euglycemic clamps, four insulin infusion rates (1, 2, 4 and 8 mU · kgBW -1 · min -1 for four sequential periods of 2-h each) were performed to determine combined effects of hypomagnesemia and cold exposure (0°C) on tissue responsiveness to insulin in sheep. The low magnesium (0.05% Mg) and high potassium (4.20% K) diet and cold exposure decreased (P < .05) plasma Mg levels compared with those of the control diet (0.28% Mg/0.52% K) and the thermoneutral environment (20°C). In the euglycemic clamps, cold exposure increased (P < .01) the pooled glucose infusion rate (GIR) across various insulin infusion rates in both diet treatments, though the increases in GIR were small for the low Mg/high K diet. In the cold environment, the GIR was lower (P < .01) for the low Mg/high K diet-fed sheep than for the control diet-fed sheep. The maximal insulin-induced increase in GIR was lower (P < .01) in the hypomagnesemic sheep than in the control sheep during cold exposure, and the insulin level resulting in half-maximal GIR tended to be higher in the hypomagnesemic sheep than in the control sheep. These results indicated that hypomagnesemia in ruminants depressed the enhanced tissue responsiveness to insulin in the cold environment, and decreased insulin-mediated glucose disposal.

Effects of supplemental chromium and heat exposure on glucose metabolism and insulin action in sheep

An isotope dilution method using [U-13C]glucose and a glucose clamp approach were applied to determine the effects of supplemental chromium (Cr) and heat exposure on blood glucose metabolism and tissue responsiveness and sensitivity to insulin in sheep. The sheep consumed diets with either 0 or 1 mg of Cr/kg (Control and +Cr diet, respectively) from high-Cr-yeast, and were exposed from a thermoneutral environment (20 °C) to a hot environment (30 °C) for 5 days. Blood glucose turnover rate did not differ between the diets, and was lower (P &lt; 0·05) during heat exposure than in the thermoneutral environment. The maximal glucose infusion rate (tissue responsiveness to insulin) tended to be lower (P = 0·06) for the +Cr diet than for the Control diet, but did not change with heat exposure. The plasma insulin concentration at half maximal glucose infusion rate (tissue sensitivity to insulin) did not differ between the diets, and was greater (P &lt; 0·05) during heat exposure than in the thermoneutral environment. No significant diet × environment interactions were observed. There was no significant evidence that Cr supplementation moderated heat stress in sheep from the measures of blood glucose metabolism and insulin action.

Effects of Supplemental Energy as Starch on Tissue Responsiveness and Sensitivity to Insulin in Goats

Intact adult male goats were fed diets at 1.0, 1.5 and 2.0 times the metabolizable energy for maintenance, each for 21 days. Supplemental energy above maintenance was supplied as corn starch. Tissue responsiveness and sensitivity to insulin were evaluated using a hyperinsulinemic euglycemic clamp technique with four levels of insulin infusion. The concentrations of plasma metabolites and insulin were also measured at 6h after feeding. At 6h after feeding, plasma total amino-nitrogen, acetate and propionate concentrations were increased (P<0.05) with increasing energy intake, but plasma insulin concentration was unchanged. In the clamp experiment, basal blood glucose and plasma insulin concentrations were unaffected by energy intake. Maximal glucose infusion rate (tissue responsiveness to insulin) increased (P<0.05) with increasing energy intake, but the plasma insulin concentration at half-maximal glucose infusion rate (insulin sensitivity) was unaffected by energy intake. These results suggest that in adult male goats energy supplementation with starch enhances tissue responsiveness to insulin, but has no effect on insulin sensitivity as determined by the glucose clamp approach.

Chromium supplementation does not influence glucose metabolism or insulin action in response to cold exposure in mature sheep.

An isotope dilution method using [U-(13)C] glucose infusion and a glucose clamp approach were applied to determine the effects of supplemental Cr and cold exposure on blood glucose turnover rate and tissue responsiveness and sensitivity to insulin in eight sheep. The daily profiles of blood metabolites and hormones were also determined. The sheep consumed diets containing either 0 or 1 mg of Cr/kg from a high-Cr yeast and were exposed from a thermoneutral environment (20 degrees C) to a cold environment (0 to 4 degrees C) for 9 d. The experiment used a crossover design. Body weight was lost (P = 0.02) during cold exposure, regardless of Cr supplementation. Blood glucose turnover rate and the maximal glucose infusion rate did not differ between diets, but both were higher (P = 0.0004 and P = 0.0001, respectively) during cold exposure than in the thermoneutral environment. The plasma insulin concentration at half-maximal glucose infusion rate changed with neither diet nor environment. Plasma concentrations of glucose and NEFA increased (P < 0.05) during cold exposure for both diets. In sheep, Cr supplementation, 1 mg/kg of diet as high-Cr yeast, has little influence on blood glucose metabolism and insulin action, whereas cold exposure enhances both without further modification by Cr supplementation.

Effects of supplemental chromium and isolation stress on tissue responsiveness and sensitivity to insulin in sheep

The hyperinsulinemic euglycemic clamp approach was used to study the effects of supplemental chromium (Cr) and isolation stress on tissue responsiveness and sensitivity to insulin in sheep. The sheep ( n = 4) were housed together in individual cages in an animal room and were fed a basal diet with either 0 or 0.5 mg of Cr/kg from Cr yeast. Therefore, the sheep consumed 14 and 24 μg of Cr/kg BW/day for the Control and +Cr diets, respectively. Blood metabolites and endocrine hormone responses were measured over the 2 h period of isolation stress. Plasma cortisol and lactate concentrations, however, increased ( p < 0.01) transiently in response to isolation stress regardless of Cr supplementation. The hyperinsulinemic euglycemic clamp was carried out 1 week before and 2 h after the initiation of isolation stress for both dietary treatments. Insulin was infused over four sequential 2 h periods at rates from 0.64 to 10 mU kg −1 min −1 with concomitant glucose infusion, to maintain pre-infusion blood glucose concentrations. Plasma insulin concentrations and glucose infusion rates increased ( p < 0.001) with insulin infusion rates. The maximal glucose infusion rate and the plasma insulin concentration at the half-maximal glucose infusion rate did not change with either Cr supplementation or isolation stress. These results suggest that in sheep supplemental Cr and isolation stress have a limited influence on tissue responsiveness and sensitivity to insulin. Chromium supplementation did not influence blood metabolite and endocrine hormone responses to isolation stress.

Effects of feed restriction and cold exposure on glucose metabolism in response to feeding and insulin in sheep.

The effects of feed restriction, cold exposure, and the initiation of feeding on blood glucose metabolism, other blood metabolites, hormones, and tissue responsiveness and sensitivity to insulin were measured in sheep. The sheep consumed orchardgrass hay ad libitum (AL) or were restricted to 82% of the ME requirement for maintenance (RE) and were exposed to a thermoneutral (20 degrees C) or a cold environment (2 degrees C). An isotope dilution method and a glucose clamp approach were applied to determine blood glucose metabolism and insulin action, respectively. Plasma NEFA and insulin concentrations were influenced by feed restriction. Concentrations of plasma glucose, NEFA, insulin, and glucagon were influenced by cold exposure. Plasma NEFA concentration for RE decreased after the initiation of feeding and plasma insulin concentration increased transiently for all treatments. [U-13C]Glucose was continuously infused for 8 or 7 h after a priming injection starting 3 h before the initiation of either feeding or insulin infusion, respectively. When responses to feeding were studied, blood glucose turnover rate was less (P < .001) for RE than for AL, and it was greater (P < .001) during cold exposure than in the thermoneutral environment. The rate changed little after the initiation of feeding. For the glucose clamp approach, insulin was infused over four sequential 1-h periods at rates from .64 to 10 mU x kg BW(-1) x min(-1), with concomitant glucose infusion to maintain preinfusion plasma glucose concentrations. The rates of glucose infusion and blood glucose turnover increased (P < .001) dose-dependently with insulin infusion rate. The maximal glucose infusion rate was greater (P < .05) for RE than for AL and was greater (P < .001) during cold exposure than in the thermoneutral environment. The plasma insulin concentration at half-maximal glucose infusion rate was lower (P < .1) during cold exposure. Blood glucose turnover rate tended to be greater (P = .10) for RE than for AL, and it was greater (P < .001) during cold exposure than in the thermoneutral environment. The ratio of endogenous production to utilization of glucose was suppressed by insulin infusion. In sheep fed a roughage diet, blood glucose turnover rate seems to be influenced by both intake level and environmental temperature, but not by the act of feeding. Moreover, the action of insulin on glucose metabolism is enhanced during cold exposure, and the effect of feed restriction is somewhat enhanced.

Slower activation of insulin action in hypertension associated with obesity.

To determine whether kinetic abnormalities in the onset of insulin action contribute to the insulin resistance in obesity-associated hypertension. We monitored the rate of increase in glucose infusion during 6 h of hyperinsulinemic (40 mU/m2 per min) euglycemic clamps in hypertensive and normotensive obese subjects. The two groups of hypertensive (n=9) and normotensive (n=9) subjects were matched for age (48+/-2 versus 45+/-5 years), sex (five males and four females versus four males and five females) and body mass index (42+/-3 versus 40+/-2 kg/m2). In all subjects, the glucose infusion rate required to maintain euglycemia increased progressively during the clamp studies to achieve maximal, steady-state values within the fifth hour. During the first 2 h of the clamp, mean glucose infusion rate, the traditional approach to assessing insulin sensitivity, was lower in the hypertensive than in the normotensive obese patients (2.04+/-0.13 versus 3.29+/-0.41 mg/kg per min, respectively; P < 0.05). In contrast, the maximal steady-state glucose infusion rate, calculated as the mean value during the sixth hour of clamping, was similar in the hypertensive and in the normotensive obese patients (4.48+/-0.43 versus 4.81+/-0.45 mg/kg per min, respectively; NS). The time required to reach the half-maximal glucose infusion rate was greater in the hypertensive than normotensive obese patients (91+/-12 versus 38+/-5 min, respectively; P< 0.05). In obesity, hypertension was associated with a slower rate of activation of the insulin effect on glucose metabolism, whereas the maximal steady-state insulin effects were not altered by elevated blood pressure. Thus, the link between obesity and hypertension may be associated with the kinetics of onset of insulin action.

Interstitial muscle insulin and glucose levels in normal and insulin-resistant Zucker rats.

To study interstitial insulin and glucose concentrations, microdialysis was performed in the medial femoral muscles in normal SD rats as well as in insulin-resistant obese Zucker rats during a euglycemic insulin clamp. [14C]inulin was given (0.1 mCi/rat) as a constant subcutaneous infusion 24 h before the insulin clamp. Insulin infusion rates were 5-8 mU x kg(-1) x min(-1) (low rate) for 140 min and 10-20 mU x kg(-1) x min(-1) (high rate) for another 100 min. The relationship between insulin and [14C]inulin dialysate recoveries was evaluated in vivo and in vitro in plasma to calculate interstitial insulin concentration. Relative microdialysis recovery of interstitial insulin in vivo was 3.0 +/- 0.3% (mean +/- SE, n = 68). In normal SD rats, plasma and interstitial insulin concentrations were identical when plasma insulin was < or =250 mU/ml, whereas interstitial insulin was lower when plasma insulin was > or =350 mU/ml. Half-maximal glucose infusion rate was achieved in the presence of plasma and interstitial insulin concentrations of approximately 140 mU/ml, whereas maximal glucose disposal was seen at interstitial insulin concentrations of approximately 325 mU/ml, corresponding to approximately 500 mU/ml in plasma. In electrically stimulated and contracting (1 Hz) normal muscle with markedly increased blood flow, the dialysate insulin concentration was significantly higher at high rates, but not at low rates, of insulin infusion. In insulin-resistant obese Zucker rats, the interstitial insulin concentration was similar to that in plasma, even at pharmacological concentrations. The glucose infusion rate was significantly lower in the obese Zucker rats at both insulin infusion rates than in the lean animals. The glucose content in dialysates from skeletal muscle was equal in both obese and lean rats during the low insulin infusion rate. During the high insulin infusion rate, dialysate glucose concentrations decreased significantly in both groups but were significantly higher in the obese Zucker rats. The data suggest that transport of insulin and glucose diffusion across the capillary wall are rate limiting for insulin as well as for glucose metabolism in muscle in normal rats. This does not appear to be the case in the insulin-resistant obese Zucker rats, where the reduced insulin responsiveness in muscle is due to muscular cellular defects rather than an inhibited transcapillary delivery of insulin.

Insulin responsiveness, action and sensitivity in growing lambs and mature rams

Insulin responsiveness, action and sensitivity, using the glucose clamp technique, were measured in ruminating growing lambs (5 and 9 mo old) and mature rams (3 yr old). In the hyperglycemic clamp experiment, blood glucose concentrations were designed to remain 50 mg dL−1 above basal concentrations for more than 1 h. Plasma insulin concentrations during glucose infusion were lower (P &lt; 0.05) for 5 mo-old lambs than for 9 mo-old lambs and mature rams and were higher (P &lt; 0.05) for 9 mo-old lambs than for 5 mo-old lambs and mature rams. In the hyperinsulinemic euglycemic clamp experiment, insulin was infused over five sequential 1-h periods at rates from 0.64 to 25 mU kg−1 min−1 with concomitant glucose infusion to maintain preinfusion blood glucose concentrations. Glucose infusion rates during insulin infusion were lower (P &lt; 0.05) for 5 mo-old lambs than for 9 mo-old lambs and plasma insulin concentration at half-maximal glucose infusion rate was numerically lower for 5 mo-old lambs, whereas maximal glucose infusion rate did not differ among growth stages. It is likely that in ruminating sheep insulin responsiveness, action and sensitivity may change with growth stage. Key words: Development, insulin response, insulin sensitivity, sheep, glucose clamp technique

Action profiles of fast onset insulin analogues

Recombinant DNA technology allows the production of insulin analogues with faster absorption rates from subcutaneous tissue as compared to conventional human regular insulin. We report the time-action profiles of 12 U subcutaneously injected insulin analogues (B9Asp + B27Glu or B10Asp) as evaluated against human regular insulin by means of the euglycaemic clamp technique (blood glucose 5.0 mmol/l) in healthy men. After injection of 12 U of either insulin preparation identical values were found for maximal insulin action (maximal glucose infusion rate, time to peak action), total amount of glucose infused as well as area under the curve of glucose infusion rate. Half-maximal glucose infusion rate was reached significantly earlier after injection of modified insulins (mean +/- SD 38 +/- 7 and 43 +/- 5 min) as compared to regular insulin (56 +/- 14 min, p less than 0.01). Forty-five min after injection of both insulin analogues glucose infusion rate had increased by 7.4 +/- 1.8 or 6.1 +/- 1.8 mg.kg-1.min-1, reflecting 83 +/- 27 or 67 +/- 15% of maximal regular insulin action. In conclusion, the two tested insulin analogues showed similar action profiles, but a significantly faster onset of action as compared to regular insulin.