Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study.

OBJECTIVE: To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5-10 microg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET). RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, active comparator-controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose

First-phase insulin secretion has limited impact on postprandial glycemia in subjects with type 2 diabetes: correlations between hyperglycemic glucose clamp and meal test.

BACKGROUND: Lack of first-phase insulin (INS) secretion is regarded as causative for high postprandial glucose excursions in subjects with type 2 diabetes. We aimed to determine the impact of early INS secretion on postprandial glycemia. METHODS: Twenty subjects with type 2 diabetes (age 54 +/- 8 years, body mass index 28.7 +/- 2.7 kg/m(2) [mean +/- SD]) underwent a hyperglycemic glucose clamp and a meal test twice separated by a washout period of 4 weeks. Multiple regression analysis was used to identify determinants of postprandial glycemia. RESULTS: During hyperglycemic glucose clamps eight subjects showed a preserved first-phase INS secretion (P1+), whereas 12 subjects showed none (P1-). Both subject groups differed in fasting blood glucose (BG) (116 +/- 7 vs. 147 +/- 31 mg/dL, P = 0.011) and glycosylated hemoglobin (6.0 +/- 0.4 vs. 6.7 +/- 0.8, P = 0.041). Total INS secretory response during glucose clamps was higher in P1+ than P1- (INS-area under the concentration vs. time curve [AUC](0-120 min) 6.7 +/- 2.7 vs. 3.2 +/- 2.1 mU.min/mL; P = 0.006). During meal tests, however, INS-AUC(0-120 min) was similar between P1+ and P1-, whereas early INS secretion was still different (INS-AUC(0-60 min) 3.9 +/- 1.8 vs. 2.1 +/- 1.0 mU.min/mL; P = 0.031). Despite higher INS-AUC(0-60 min) in P1+, early postprandial BG was comparable between groups (BG-AUC(0-60 min) 1.5 +/- 0.5 vs. 1.6 +/- 0.6 g.min/dL; difference not significant). Multiple regression analyses showed no impact of first-phase INS secretion on postprandial glycemia, either in P1+ or in P1-. Nevertheless, in P1-, but not in P1+, postprandial glycemia was negatively correlated with INS sensitivity (R(2) = 0.83, P < 0.001). CONCLUSIONS: This study, correlating results of hyperglycemic glucose clamps with meal tests, shows that a preserved first-phase INS secretion has only a limited impact on postprandial glucose excursions in a group of subjects in early-stage type 2 diabetes.

Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus.

AIMS: To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. METHODS: After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d.,effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. RESULTS: Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of -1.8 microU ml(-1), 95% confidence interval (CI) -7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C(max) and AUC(tau) (95% CI) and median t(max) (range) in this patient population were 180 ng ml(-1) (125, 260), 581 ng.h ml(-1) (422, 800) and 3.0 h (0.67, 4.3), respectively. CONCLUSIONS: The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes.

AIR insulin capsules of different dose strengths may be combined to yield equivalent pharmacokinetics and glucodynamics.

BACKGROUND: In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects. METHODS: Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose. RESULTS: Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range. CONCLUSIONS: AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.

Glycemic exposure is affected favorably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes.

BACKGROUND: The objective was to compare the effects on glycemia of adding either inhaled human insulin (Exubera [EXU] [insulin human (recombinant DNA origin) inhalational powder]) or subcutaneous insulin glargine (GLA) to the treatment regimens of patients with type 2 diabetes uncontrolled with oral antidiabetic drugs. METHODS: Forty patients were randomized to receive either EXU three times daily prior to meals or subcutaneous GLA once daily in a crossover design. Interstitial glucose concentrations were monitored using a continuous glucose monitoring system (CGMS) for the final 72-h period of 8 treatment days. RESULTS: Total insulin dosage on the last treatment day was approximately 40.1+/-18.1 units/day EXU compared with 16.4+/-4.8 units/day GLA. Serum insulin levels over the 72-h CGMS period were higher for EXU than for GLA (1,091+/-589 pmol/mL/h vs. 737+/-386 pmol/mL/h; ratio, 148; 95% confidence interval [CI], 130-169). The glucose exposure over this period was lower with EXU than with GLA (380+/-45 mmol/Lh vs. 426+/-89 mmol/Lh; ratio, 88.57; 95% CI, 84-93). The overall hypoglycemic event rate was 8.7 events per subject-month for EXU and 2.4 for GLA. CONCLUSIONS: Prandial insulin therapy with EXU, using a higher daily insulin dose, reduces total daily glucose exposure--in particular postmeal glycemia--more effectively than a basal insulin analog.

An analysis of how to measure glucose during glucose clamps: are glucose meters ready for research?

This article provides a perspective on the challenges of appropriate glucose measurement in the context of glucose clamp experiments. In a first step, the core outcome parameters of a clamp experiment, the blood glucose target level, and the glucose infusion rate will be identified. The relation of these core parameters to glucose measurement are discussed. From there, the core quality parameters of glucose measurement within a clinical research setting are identified and assessed in light of their practical implications, with a specific consideration of the work presented by Cohen et al. in this issue of the Journal of Diabetes Science and Technology.

Inhaled Technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes.

BACKGROUND: This study assessed time action profile and within- and between-subject variability of inhaled Technosphere Insulin (TI) compared with subcutaneous regular human insulin (sc RHI). METHODS: Thirteen subjects with type 2 diabetes (age 56 +/- 7 years, body mass index 30.4 +/- 3.0 kg.m(-2); hemoglobin A1c 6.9 +/- 0.9%; mean +/- SD) participated in this six-period crossover isoglycemic glucose clamp study. In randomized order, each subject received three single doses of TI and sc RHI on separate study days. RESULTS: Inhalation of TI resulted in a higher maximum serum insulin concentration (858 vs 438 pmol.liter(-1); p = 0.0001) and shorter intervals to maximum insulin concentration (17 vs 135 minutes; p = 0.0001) than sc RHI. Overall, 48 units of TI and 24 units of sc RHI provided comparable 3-hour insulin exposure (INS area under the curve(0-3 h) 55.8 vs 60.0 nmol.min.liter(-1), respectively). Time to maximum metabolic effect was shorter (79 vs 293 minutes; p < 0.0001), and percentage of glucose disposal during the first 3 hours was higher for TI compared with sc RHI (59 vs 27%). Within-subject variabilities of insulin exposure following inhalation of TI for 2 and 3 hours and end of study period were 19, 18, and 16% as compared with 27, 25, and 15% after sc RHI injection (p = not significant). CONCLUSION: Technosphere Insulin has a more rapid onset of action than sc RHI. About 60% of the glucose-lowering effect of TI occurs during the first 3 hours after application. In contrast, <30% of the glucose-lowering effect of sc RHI occurs in this period. Technosphere Insulin demonstrated a lower intrasubject variability during the 3-hour postprandial period, without reaching statistical significance.

Improvement of insulin resistance after diet with a whole-grain based dietary product: results of a randomized, controlled cross-over study in obese subjects with elevated fasting blood glucose.

Subjects with obesity and elevated fasting blood glucose are at high risk of developing type 2 diabetes which may be reduced by a dietary intervention leading to an improvement of insulin resistance. We investigated the potential of a whole-grain based dietary product (WG) with reduced starch content derived from double-fermented wheat during a hypo-energetic diet to positively influence body weight, fasting blood glucose, insulin resistance and lipids in comparison to a nutrient-dense meal replacement product (MR) in a randomized two-way cross-over study with two 4-week treatment periods separated by a 2-week wash-out. Subjects replaced at least two daily meals with WG and MR, respectively, targeting for a consumption of 200 g of either product per day. Total daily energy intake was limited to 7120 kJ. Thirty-one subjects (BMI 33.9 (SD 2.7) kg/m2, fasting blood glucose 6.3 (SD 0.8) mmol/l) completed the study. In both treatment groups body weight (-2.5 (SD 2.0) v. - 3.2 (SD 1.6) kg for WG v. MR), fasting blood glucose (-0.4 (SD 0.3) v. -0.5 (SD 0.5) mmol/l), total cholesterol (-0.5 (SD 0.5) v. -0.6 (SD 0.5) mmol/l), TAG (-0.3 (SD 0.9) v. -0.3 (SD 1.2) mmol/l) and homeostasis model assessment (HOMA) insulin resistance score (-0.7 (SD 0.8) v. -1.1 (SD 1.7) microU/ml x mmol/l) improved (P < 0.05) with no significant differences between the treatments. After statistical adjustment for the amount of body weight lost, however, the comparison between both groups revealed that fasting serum insulin (P = 0.031) and HOMA insulin resistance score (P = 0.049) improved better with WG than with MR. We conclude that WG favourably influences metabolic risk factors for type 2 diabetes independent from the amount of body weight lost during a hypo-energetic diet.

AIR inhaled insulin in subjects with chronic obstructive pulmonary disease: pharmacokinetics, glucodynamics, safety, and tolerability.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Advantage of premeal-injected insulin glulisine compared with regular human insulin in subjects with type 1 diabetes.

OBJECTIVE: Insulin glulisine, a rapid-acting insulin analog, provides prandial insulin replacement. In this study, we compared postprandial blood glucose control after pre- and postmeal insulin glulisine with regular human insulin (RHI). RESEARCH DESIGN AND METHODS: In a single-dose, randomized, four-way complete cross-over study, subjects received standardized, 15-min meals, covered by subcutaneous injections of either insulin glulisine (immediately premeal or 15 min postmeal; 0.15 unit/kg per injection) or RHI (30 min or immediately premeal; 0.15 unit/kg per injection). Twenty-one patients with type 1 diabetes (mean age 36.4 years; mean BMI 26.0 kg/m(2)) were enrolled; 20 patients completed the study. Postprandial baseline-subtracted blood glucose exposure, maximum excursion, maximum and minimum blood glucose concentrations, and time to the maximum excursion and minimum concentration were assessed, along with serum insulin concentrations. RESULTS: Lower maximum blood glucose excursion (65 vs. 89 mg/dl), total blood glucose exposure within 2 h (279 vs. 334 mg . h/dl, maximum blood glucose concentration (180 vs. 209 mg/dl), and less time to maximum blood glucose excursion (48 vs. 70 min) were seen with immediately premeal insulin glulisine versus immediately premeal RHI. The maximum serum concentration of insulin glulisine was almost double that of RHI (82 vs. 45 microU/ml), achieved in approximately half the time (55 vs. 97 min). Conversely, insulin glulisine (15 min postmeal) versus RHI (immediately premeal) and RHI (30 min premeal) versus insulin glulisine (immediately premeal) resulted in comparable blood glucose control. CONCLUSIONS: Insulin glulisine renders postprandial glucose disposal closer to physiologic requirements compared with RHI and enables appropriate timing of prandial insulin administration.

Renal glucose excretion as a function of blood glucose concentration in subjects with type 2 diabetes--results of a hyperglycaemic glucose clamp study.

BACKGROUND: The purpose of this study was to investigate renal glucose excretion as a function of blood glucose concentration and to evaluate the within-subject variability and between-subject variability in subjects with type 2 diabetes. METHODS: Twenty-two subjects with type 2 diabetes [age 58 (12) years, diabetes duration 7 (6) years, endogenous creatinine clearance 117 (38) ml min(-1) 1.73 m(-2); median (inter-quartile range, IQR)] underwent two five-period hyperglycaemic glucose clamp experiments at intervals of 7-21 days. Starting from an initial blood glucose level of 12.2 mmol l(-1), subsequent glucose clamp levels were chosen using an algorithm based on urinary glucose concentrations measured at the end of the preceding glucose clamp period. That is, blood glucose was either stepwise decreased or increased depending on whether urinary glucose concentration was above or below 11.1 mmol l(-1), respectively. RESULTS: As expected, increasing the blood glucose from 7.8 to 13.3 mmol l(-1) during the glucose clamps resulted in a steep increase of urinary glucose excretion from 0.06 to 0.77 mmol min(-1). With decreasing blood glucose, a measurable glucosuria persisted up to a blood glucose level of 7.8 mmol l(-1). When defining the (pseudo)threshold for renal glucose excretion (PRT(G)) as the highest blood glucose level during glucose clamps associated with a concomitant glucose concentration in urine of <2.8 mmol l(-1), median (IQR) PRT(G) was 11.0 (1.1) mmol l(-1). The within-subject variability of PRT(G), i.e. the difference between two assessments, was low, 0.1 (0.0) mmol l(-1) while the between-subject variability of PRT(G) was high, ranging from 7.7 to 12.2 mmol l(-1). CONCLUSION: Renal glucose excretion increases in a proportional manner with increasing blood glucose. When decreasing blood glucose to euglycaemic blood glucose levels, glucosuria persists so that the classical concept of a renal threshold for glucose excretion cannot be upheld in subjects with type 2 diabetes.

Dose response of inhaled dry-powder insulin and dose equivalence to subcutaneous insulin lispro.

OBJECTIVE: To determine the pharmacokinetic (PK) and glucodynamic (GD) dose response of human insulin inhalation powder (HIIP) delivered via AIR particle technology and dose equivalence to subcutaneous (SC) insulin lispro. RESEARCH DESIGN AND METHODS: Twenty healthy, nonsmoking, male or female subjects (aged 29.6 +/- 6.9 years, BMI 23.2 +/- 2.3 kg/m2, means +/- SD) with normal forced vital capacity and forced expiratory volume were enrolled in an open-label, randomized, seven-period, euglycemic glucose clamp, cross-over trial. Each subject received up to four single doses of HIIP (2.6, 3.6, 5.2, or 7.8 mg) and three doses of SC lispro (6, 12, or 18 units) from 5 to 18 days apart. RESULTS: HIIP demonstrated a similar rapid onset but an extended time exposure and a prolonged duration of effect (late t(50%) 412 vs. 236 min, P < 0.001) compared with SC lispro. The HIIP versus SC lispro doses of 2.6 mg vs. 6 units, 5.2 mg vs. 12 units, and 7.8 mg vs. 18 units achieved similar PK area under the serum immunoreactive insulin (IRI) concentration-versus-time curve from time zero until the serum IRI concentrations returned to the predose baseline value [AUC(0-t')] and GD (G(tot)) responses. The median insulin (t(max)) was not different between HIIP and SC lispro (45 min for both), although the median time of return to baseline for PK was apparently longer for HIIP compared with SC lispro (480 vs. 360 min). Relative bioavailability and relative biopotency of HIIP were consistent across doses (8 and 9%). CONCLUSIONS: While the time-action profile was longer for HIIP than for SC lispro, both treatments showed rapid initial absorption and similar overall PK exposure and GD effect. HIIP was as well tolerated as SC lispro, thereby offering a promising alternative to injectable insulin therapy.

Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics, postprandial blood glucose excursions, and safety of insulin glulisine as compared with regular human insulin (RHI), both administered immediately before meals in pediatric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 10 children (aged 5-11 years) and 10 adolescents (aged 12-17 years) were enrolled in a randomized, single-center, single-dose, double-blind, cross-over study. The blood glucose of fasting patients was stabilized with intravenous insulin, following which patients received 0.15 IU/kg of subcutaneously injected insulin glulisine or RHI 2 min before a weight-adjusted standardized liquid meal. RESULTS: For insulin glulisine versus RHI, maximum insulin concentrations (58 vs. 33 microIU/ml, P < 0.05) and initial insulin concentrations (insulin [area under the curve] AUC(0-2h) 5,232 vs. 2,994 microIU.min(-1).ml(-1), P < 0.05; data are geometric means) were higher after insulin glulisine than RHI. Both time to maximum insulin concentration (54 vs. 66 min) and mean residence time (88 vs. 137 min, P < 0.05) were shorter with insulin glulisine versus RHI. Postprandial glucose excursions after insulin glulisine were lower than after RHI (glucose AUC(0-6h) 641 vs. 801 mg.h(-1).dl(-1), P < 0.05). The pharmacokinetic profile for insulin glulisine was similar for children and adolescents, whereas the pharmacokinetic profile for RHI demonstrated a 64% higher concentration in adolescents. Insulin glulisine was safe and well tolerated. CONCLUSIONS: The rapid-acting properties of insulin glulisine that have been previously demonstrated in adults are also observed in children and adolescents with type 1 diabetes. Further, these initial data indicate that insulin glulisine is safe and well tolerated in this patient population.

Enhancement of blood glucose lowering effect of a sulfonylurea when coadministered with an ACE inhibitor: results of a glucose-clamp study.

BACKGROUND: To investigate if coadministration of enalapril alters the metabolic effect of glibenclamide by employing an euglycemic glucose-clamp technique in healthy volunteers. METHODS: A double-blind crossover study with nine healthy normotensive volunteers (age 27 +/- 3 y, BMI 23.3 +/- 2.0 kg m(-2); mean +/- SD)-randomly assigned to a 3-day treatment of either 5 mg enalapril or placebo. In the morning of the fourth day, volunteers orally received 3.5 mg glibenclamide together with either 10 mg enalapril or placebo. Blood glucose levels of volunteers were allowed to fall by 10% from fasting levels and were kept constant thereafter by employing a Biostator-based euglycemic glucose clamp. RESULTS: Coadministration of enalapril-compared with placebo-resulted in a temporarily higher metabolic effect of glibenclamide (AUC GIR(0-120)229 +/- 173 vs 137 +/- 44 mg kg(-1), p < 0.01; mean +/- SD), which lasted from 120 min to 240 min after enalapril administration. In parallel, the maximal metabolic effect of glibenclamide tended to be higher with enalapril (GIR(max)5.2 +/- 1.9 vs 4.1 +/- 1.3 mg kg(-1) min(-1); p = 0.19). However, the total metabolic effect of glibenclamide was almost identical between volunteers taking enalapril or placebo (AUC GIR(0-600)1267 +/- 334 vs 1286 +/- 249 mg kg(-1), ns). In contrast, serum insulin levels, C-peptide levels, and serum glibenclamide profiles were not significantly different between enalapril and placebo. CONCLUSIONS: The results of this study may explain the higher incidence of hypoglycemic episodes observed in patients with type 2 diabetes when taking ACE inhibitors together with sulfonylureas or insulin. ACE inhibitors may cause a temporary increase of the insulin sensitivity, which leads to an increased risk of hypoglycemia under these conditions.

Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin.

OBJECTIVE: This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS: In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. RESULTS: INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg . kg(-1) . min(-1), respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed. CONCLUSIONS: INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.

Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.

The effects were compared of varying aerosol particle size and aerosolization time within each breath on the metabolic effect elicited by inhalation of a liquid insulin aerosol in comparison with that after subcutaneous injection (s.c.) of regular insulin. In this single-center, open-label euglycemic glucose clamp study, 13 healthy non-smoking subjects received five administrations of insulin in randomized order on separate study days, once by s.c. (0.15 U/kg of regular insulin) and four times by inhalation. Subjects inhaled 1.5 U/kg of liquid insulin aerosol administered by the Aerodose Insulin Inhaler (Aerogen Inc., Mountain View, CA) configured to deliver two aerosol particle sizes--fine [F, 4.4 +/- 0.3 microm (mean +/- SD)] or very fine (VF, 3.5 +/- 0.2 microm)--and two aerosolization times (aerosol released for the first 2 or 4 s after the start of each 5-s inhalation). Glucose infusion rate (GIR) values necessary to keep blood glucose concentrations constant at 5.0 mmol/L were determined over a 6-h period following insulin administration. After inhalation of insulin, the onset of action was substantially more rapid on all four inhalation study days than after s.c. insulin, and the time to maximal action [t(GIRmax) (min)] was reached earlier: F/2 s, 127 +/- 54; F/4 s, 128 +/- 55; VF/2 s, 158 +/- 91; VF/4 s, 132 +/- 72; s.c., 175 +/- 69 (P < 0.0001). The longer aerosolization time (4 vs. 2 s) resulted in higher maximal metabolic action [GIR(max) (mg/kg/min), F/4 s 8.1 +/- 3.6, VF/4 s 8.4 +/- 2.7 vs. F/2 s 6.6 +/- 2.4, VF/2 s 7.2 +/- 2.4 (P = 0.01 for 4 s vs. 2 s, grouped data)], total metabolic activity [area under the curve of GIR 0-6 h (g/kg), F/4 s 1.97 +/- 0.92, VF/4 s 2.14 +/- 0.86 vs. F/2 s 1.56 +/- 0.68, VF/2 s 1.78 +/- 0.60 (P = 0.01)], and relative biopotency [F/4 s 10.6 +/- 4.0%, VF/4 s 11.7% +/- 4.1% vs. F/2 s 8.5 +/- 3.2%, VF/2 s 9.7 +/- 2.4% (P = 0.01)]. None of these summary measures was significantly affected by particle size. No drug- or device-related adverse events were observed. This study shows that aerosolization time, but not particle size, in the ranges studied, had an impact on the metabolic effect elicited by inhaled insulin, allowing rational selection of delivery parameters for further clinical testing. Based on the observed biopotency and the rapid onset of action, inhalation of a liquid insulin aerosol generated by the Aerodose Insulin Inhaler shows promise for covering prandial insulin requirements.

Correlation between anthropometric parameters and abdominal fat volumes assessed by a magnetic resonance imaging method in patients with diabetes.

BACKGROUND: Anthropometric measurements such as body mass index (BMI), waist-to-hip ratio, or waist circumference are used in clinical settings as a rough estimation of abdominal fat volumes. In contrast, abdominal magnetic resonance imaging (MRI) allows a precise and noninvasive imaging modality to measure the whole abdominal fat volumes. The main difference between the two methods is that only MRI provides detailed anatomical information about fat distribution in terms of a three-dimensional volumetric model. The aim of this study was to evaluate the relationship between selected anthropometric parameters and MRI-estimated abdominal fat volumes in patients with diabetes. METHODS: Total fat volume coverage of the abdomen was obtained in a total of 37 patients with diabetes (mean +/- SD age, 48 +/- 13 years) with a BMI of 27.9 +/- 3.6 kg/m2 and a waist-to-hip ratio of 0.94 +/- 0.01 using T1-weighted magnetic resonance images. Quantification of intraabdominal, subcutaneous, and total abdominal fat volumes was performed using a semiautomated computer-assisted analysis of the images. Anthropometric parameters (height, weight, BMI, circumference hip, waist circumference, and waist-to-hip ratio) of all patients and abdominal fat volumes estimated by the MRI method proposed were correlated. RESULTS: The volumes estimated were as follows: intraabdominal fat, 10.5 +/- 5.0 L; subcutaneous fat, 15.2 +/- 7.3 L; and total abdominal fat, 25.7 +/- 11.5 L. The correlation coefficients between BMI and the three different fat volumes were, respectively, r = 0.38, r = 0.31, and r = 0.36. For the waist-to-hip ratio the respective correlation coefficients were r = 0.46, r = 0.14, and r = 0.29. CONCLUSIONS: Correlation in patients with diabetes of abdominal fat volumes estimated with a reliable MRI method with conventionally applied anthropometric parameters revealed poor correlation coefficients. In contrast, the fat volume determination by means of the novel MRI analysis method is rapid and reliable. Therefore, this method has the potential to be of high value in studies in patients with diabetes.