The impact of smoking on inhaled insulin

OBJECTIVE: This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers. RESEARCH DESIGN AND METHODS: In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration ("acute smoking"); on the other dosing day, smokers had not smoked since midnight ("nonacute smoking"). After inhalation, 6-h serum insulin and serum glucose profiles were determined. RESULTS: Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6 h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose. CONCLUSIONS: Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.     

Inhaled insulin using the AERx Insulin Diabetes Management System in healthy and asthmatic subjects

OBJECTIVE: The AERx insulin Diabetes Management System (AERx iDMS) (Aradigm, Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for systemic absorption. This study examined the effects on pulmonary function, pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and nonasthmatic subjects without diabetes. RESEARCH DESIGN AND METHODS: A total of 28 healthy and 17 asthmatic (forced expiratory volume during the first second [ FEV(1)] 50-80% of predicted value) subjects were enrolled in a two-part, open-label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part 1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects on pulmonary function. RESULTS: Inhaled insulin showed area under the curve (AUC)((0-360 min)) values that were significantly greater for healthy subjects than for asthmatic subjects (P = 0.013), whereas no difference was observed for maximum concentration (C(max)) in the two groups. A greater reduction of serum glucose as indicated by area over the curve (AOC)((0-360 min)) was observed in healthy subjects (P = 0.007). Asthmatic subjects had greater intrasubject variations in insulin AUC((0-360 min)) and C(max) values than healthy subjects, but similar variations in glucose AOC((0-360 min)). No significant changes in FEV(1), forced vital capacity (FVC), and FEV(1)/FVC were observed from pre- to postdose times, and there were no observed safety issues. CONCLUSIONS: After inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No effects on airway reactivity were observed. Diabetic patients with asthma may need to inhale more insulin than patients with normal respiratory function in order to achieve similar glycemic control.     

Dose-response relationship of oral insulin spray in healthy subjects

OBJECTIVE: To evaluate the pharmacodynamic and pharmacokinetic properties and the dose-ranging effects of an oral insulin spray in comparison with subcutaneous regular insulin. RESEARCH DESIGN AND METHODS: In this randomized, five-way, cross-over study, seven healthy volunteers were assessed under euglycemic clamp and received four different doses of oral spray and one dose of subcutaneous regular insulin. RESULTS: The time to maximum insulin concentration was shorter for oral insulin than for subcutaneous insulin (25.9 +/- 9 vs. 145.7 +/- 49.5 min, P < 0.05). Maximum serum insulin levels (C(max)) were comparable between the subcutaneous and 20 puffs of oral insulin (39.1 +/- 19.6 vs. 34.0 +/- 7.4 microU/ml, NS). The Ins-AUC(0-120) (area under the curve from 0 to 120 min for serum insulin) (339.8 +/- 218, 681.3 +/- 407, and 1,586.7 +/- 8 microU/ml, P < 0.05) and C(max) (7.6 +/- 2.8, 16.4 +/- 9.3, and 39.1 +/- 19.6 microU/ml, P < 0.005) proved a dose-response relationship for the three doses of oral insulin (5, 10, and 20 puffs, respectively). Oral insulin had an earlier onset of action (31.7 +/- 12 vs. 77.8 +/- 3 min, P < 0.05), earlier peak (44.2 +/- 10 vs. 159.2 +/- 68 min, P < 0.05), and a shorter duration of action (85.1 +/- 25 vs. 319.2 +/- 45 min, P < 0.05) compared with subcutaneous insulin. The maximum metabolic effect (1.7 +/- 1.0, 3.09 +/- 1.7, and 4.6 +/- 1.5 mg . kg(-1) . min(-1), P < 0.05) and the GIR-AUC(0-120) (amount of glucose infused from 0 to 120 min) (106.7 +/- 74.3, 162.9 +/- 116.1, and 254 +/- 123 mg/kg) increased in a dose-dependent relationship for the three doses. CONCLUSIONS: Oral insulin was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with subcutaneous regular insulin. A dose-response relationship in the absorption and metabolic effect of the oral insulin was noted.     

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).     

Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans: implications for primary diabetes prevention

OBJECTIVE: We examined the determinants of impaired glucose tolerance (IGT) and type 2 diabetes in first-degree relatives of African-American type 2 diabetic patients over 5-8 years (median 6). RESEARCH DESIGN AND METHODS: A total of 81 healthy subjects (age 41.5 +/- 4.8 years; BMI 31.3 +/- 3.6 kg/m(2)) participated in the study. Each subject underwent an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test at baseline. Insulin sensitivity index (S(i)) and glucose effectiveness index (S(g)) were determined by the minimal model method. Homeostasis model assessment (HOMA) was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B). A total of 18 subjects progressed to either IGT or type 2 diabetes (progressors), whereas 19 subjects maintained normal glucose tolerance (nonprogressors). RESULTS: Comparing the progressors and nonprogressors, mean fasting serum glucose levels (95 +/- 8 vs. 80 +/- 14 mg/dl, P < 0.01) and 2-h serum glucose levels (149 +/- 27 vs. 100 +/- 60 mg/dl, P < 0.01) as well as 2-h serum insulin levels (117 +/- 81 vs. 72 +/- 87 microU/ml, P < 0.01) during OGTT were higher at baseline. Mean acute first-phase insulin secretion (205 +/- 217 vs. 305 +/- 230 microU/ml), HOMA-%B (148 +/- 60 vs. 346 +/- 372, P < 01), S(i) (1.61 +/- 1.13 vs. 2.48 +/- 1.25 x 10(-4). min(-1) [microU/ml](-1)), and S(g) (1.48 +/- 0.61 vs. 2.30 +/- 0.97 x 10(-2). min(-1)) were lower in the progressors than in the nonprogressors at baseline. Mean HOMA-IR (3.31 +/- 1.64 vs. 2.36 +/- 1.64) was significantly greater in the progressors than the nonprogressors. At the time of diagnosis of glucose intolerance (IGT + diabetes), HOMA-%B (101 +/- 48 vs. 148 +/- 60, P < 0.001) and HOMA-IR (5.44 +/- 2.55 vs. 3.31 +/- 1.64, P < 0.003) deteriorated in the progressors versus baseline. CONCLUSIONS: We conclude that nondiabetic, first-degree relatives of African-American type 2 diabetic patients who progressed to IGT and type 2 diabetes manifest triple defects (decreased insulin secretion, insulin action, and glucose effectiveness) that antecede the disease.     

Bronchoalveolar cell populations in acute sarcoidosis. Observations in smoking and nonsmoking patients.

Bronchoalveolar cells were obtained by segmental lung lavage from 14 patients with sarcoidosis and studied to determine changes in composition associated with acute disease and smoking history. In nonsmoking patients, both the proportion and number of lymphocytes recovered were significantly increased compared to nonsmoking controls (p less than 0.001 in both cases). Furthermore, the number of T cells was increased (4.19 +/- 0.72 vs. 0.896 +/- 0.107 x 10(6) cells/100 ml, p less than 0.001), and activated T cells were also increased (1.04 +/- 0.478 vs. 0.148 +/- 0.032 x 10(6) cells/100 ml, p less than 0.01). Less striking differences in these values were found when smoking sarcoid patients were compared to smoking controls, but there were no significant differences in these values for smoking and nonsmoking patients (p greater than 0.05). Thus acute sarcoidosis in both smoking and nonsmoking patients appears to be associated with a lymphocytosis of the bronchoalveolar space which results from increased numbers of T cells and activated T cells. The potential importance of this finding with regard to diagnosis and pathogenesis is discussed.     

Fenfluramine increases insulin action in patients with NIDDM

These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a significant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 +/- 1.2 vs. 8.4 +/- 0.89 mM, mean +/- SE, P less than .01) with no significant fall in fasting serum insulin (20 +/- 2 vs. 24 +/- 3 microU/ml) or C-peptide (1.3 +/- 0.2 vs. 1.3 +/- 0.1 nM). During euglycemic-hyperinsulinemic (1 mU.kg-1.min-1) clamp studies there was a significant increase in insulin action from 12.7 +/- 2.3 to 17.3 +/- 1.8 min-1.10(3) microU.ml-1 (P less than .05), although clamp insulin levels were lower after fenfluramine treatment (136 +/- 14 vs. 96 +/- 9 microU/ml, P less than .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 +/- 1.5 vs. 20.1 +/- 2.1 ml.kg-1.min-1, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of different durations of breath holding after inhalation of insulin using the AERx insulin diabetes management system

BACKGROUND: The AERx insulin diabetes management system (iDMS) is a new technology for the administration of insulin by inhalation. OBJECTIVE: This study assessed the effects of different durations of breath holding (0, 3, and 10 seconds after inhalation) on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of insulin. METHODS: This was an open-label, randomized, 3-period crossover study in which healthy subjects received a single inhalation of 45 IU regular human insulin followed by breath holding for 0, 3, and 10 seconds on 3 separate study days. Blood levels of insulin and glucose were assessed for 6 hours. RESULTS: Twenty-one healthy subjects (8 men, 13 women; mean [SD] age, 32.1 [6.9] years; mean body mass index, 24.8 [3.2] kg/m(2)) took part in the study. No significant differences were observed in any PK or PD parameter with the 3 durations of breath holding. Values for mean serum insulin area under the curve from 0 to 360 minutes were 8218, 8244, and 8404 microU/mL x min for the 0-, 3-, and 10-second durations of breath holding, respectively. Mean maximum insulin concentrations were a respective 44.9, 44.2, and 45.5 microU/mL. Values for mean plasma glucose area over the curve and below baseline from 0 to 360 minutes were a respective 3512, 4033, and 3708 mg/dL x min. Pairwise comparisons of serum insulin and plasma glucose concentrations showed no significant changes with the different durations of breath holding. Few adverse events were observed. CONCLUSIONS: The duration of breath holding after a single inhalation of insulin using the AERx iDMS had no significant effect on the PK or PD parameters of insulin. On the basis of the results in these healthy subjects, breath holding may not be necessary after inhalation of insulin using the AERx iDMS.     

Chronic cigarette smoking is associated with increased plasma circulating intercellular adhesion molecule 1 levels in young type 1 diabetic patients.

OBJECTIVE: The purposes of this study were to compare plasma concentrations of circulating intercellular adhesion molecule 1 (cICAM-1), a marker of endothelial dysfunction, in nondiabetic subjects and type 1 diabetic patients and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma cICAM-1 levels in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Plasma cICAM-1 concentrations were measured in 54 young type 1 diabetic patients without clinical macroangiopathy and in 20 healthy control subjects who were matched for age, sex, BMI, and smoking habit. RESULTS: Type 1 diabetic patients had significantly higher plasma levels of cICAM-1 than control subjects (280.4 +/- 59 vs. 224 +/- 53.6 ng/ml, respectively) (P < 0.001). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, blood pressure, glycemic control, diabetes duration, and chronic complications of diabetes that were super-imposable on their nonsmoking counterparts. Nevertheless, plasma cICAM-1 levels were markedly elevated in type 1 diabetic smokers (321.4 +/- 64.2 vs. 257.3 +/- 41.5 ng/ml, respectively) (P < 0.001) in a dose-dependent fashion (P < 0.001 by analysis of variance when subjects were categorized by number of cigarettes smoked per day). CONCLUSIONS: Chronic cigarette smoking has a deleterious effect on plasma cICAM-1 levels in young type 1 diabetic patients, which further supports the clinical importance of discouraging the initiation of smoking and promoting its cessation in people with type 1 diabetes.     

Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes

OBJECTIVE: To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36-80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. RESULTS: Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T(max) 77 +/- 66 vs. 193 +/- 104 min, P < 0.001) and time-to-peak metabolic effects (T(GIRmax) 240 +/- 94 vs. 353 +/- 60 min, P < 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P = 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed. CONCLUSIONS: The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection.     

Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes: a single-center, randomized, single-blind, 5-way crossover study

OBJECTIVE: This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus. METHODS: This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique. RESULTS: The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05). CONCLUSIONS: In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.     

The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin: a prospective randomized pharmacodynamic study

OBJECTIVE: To assess the impact of the development of high- or low-affinity insulin antibodies (IABs) on postprandial glucose tolerance, duration of insulin action, and clinical safety in patients with type 1 diabetes receiving inhaled insulin (Exubera). RESEARCH DESIGN AND METHODS: This study consisted of a prospective, randomized, open-label, parallel-group trial in which 47 patients with type 1 diabetes received NPH insulin twice daily plus either premeal inhaled insulin (INH group; n = 24) or pre-meal subcutaneous regular insulin (SC group; n = 23) for 24 weeks. Meal challenge and euglycemic clamp studies were performed on consecutive days at baseline, week 12, and week 24. Adverse events were monitored. RESULTS: For the INH and SC groups, mean (+/-SD) IAB levels were 3.5 +/- 3.9 and 2.6 +/- 4.1 muU/ml at baseline, respectively, compared with 101.4 +/- 140.4 and 4.3 +/- 9.4 microU/ml at week 24. At week 24, the changes from baseline were similar for the INH and SC groups for maximal plasma glucose concentration (C(max)) (adjusted ratio for treatment group difference 0.99 [90% CI 0.95-1.03]), area under the plasma glucose concentration time curve (adjusted ratio for treatment group difference 0.98 [0.88-1.08]), and duration of insulin action (adjusted treatment group difference 29 min [-49 to 108]). No adverse events were attributed to IABs. CONCLUSIONS: In patients with type 1 diabetes treated with inhaled insulin, development of high- or low-affinity IABs did not impair postprandial glucose tolerance, alter the time-action profile of insulin, or impact tolerability. No clinical relevance of IABs was identified in this study.     

Effects of long-term fasting on insulin responses to fatty acids in man

OBJECTIVE: To investigate whether the prolonged physiological elevation of nonesterified fatty acids (NEFA) seen in man during fasting associates with an altered acute insulin response to NEFA. SUBJECTS AND METHODS: Fourteen non-diabetic subjects, age 18-25 years, BMI 23.2 +/- 0.8 kg/m2 underwent hyperglycemic clamps (blood glucose 11 mM) for 120 min, during which either saline or Intralipid was administered in the last 60 min. Subjects were tested after an overnight as well as after a 58 h fast. RESULTS: After the overnight fast, insulin levels increased during Intralipid infusion, at min 120 reaching an increment of 33.0 +/- 8.5 microU/ml vs. 9.5 +/- 4.4 microU/ml during saline; p<0.05 for difference. Conversely, after the 58 h fast. Intralipid failed to promote a successive increase of insulin levels (increment during Intralipid at min 120: 0.5 +/- 5.8 microU/ml vs. -4.3 +/- 2.5 microU/ml during saline, NS). Insulin sensitivity as assessed by the amount of infused glucose and its ratio to insulin was enhanced by Intralipid after an overnight fast, but was decreased after a 58 h fast. CONCLUSION: Long-term elevated NEFA during fasting associates with diminished beta cell responsiveness to an acute elevation of fatty acids in conjunction with negative effects on insulin sensitivity.     

Comparison of pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and subcutaneous insulin injection in healthy subjects using the euglycemic clamp technique

BACKGROUND: Oral insulin spray is a new, noninjectable method of insulin delivery. This system delivers an aerosol of uniform-sized droplets containing regular human insulin at a high velocity into the oropharyngeal cavity for local transmucosal absorption. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and SC insulin injection in healthy subjects. METHODS: Healthy male volunteers aged 21 to 25 years participated in this open-label study conducted at the Diabetes Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel. Subjects presented at 2 visits separated by 7 to 14 days. At both visits, the euglycemic clamp technique was used to maintain a constant blood glucose level. At one visit, subjects received regular human insulin 0.1 U/kg by SC injection. At the other visit, subjects received 15 puffs (150 U) of oral insulin spray. The pharmacokinetic (insulin absorption) and pharmacodynamic (glucose uptake) properties of the drugs were evaluated using blood analyses over the subsequent 360 minutes. RESULTS: Six volunteers were enrolled (mean [SD] age, 22.8 [1.2] years; mean [SD] body mass index, 23.2 [2.2] kg/m(2)). The mean (SD) baseline-corrected C(max) was significantly higher with oral insulin spray compared with SC insulin (54.0 [20.3] vs 30.8 [6.1] microU/mL; P = 0.028). Mean (SD) T(max) was significantly shorter with oral insulin spray compared with SC insulin (23.3 [5.2] vs 83.3 [42.2] minutes; P = 0.027). The mean (SD) time to maximal metabolic effect (maximum glucose infusion rate [GIR(max)]) (44.2 [8.6] vs 100.0 [35.6] minutes) and late time to half-maximal effect (101.0 [41.0] vs 257.2 [27.8] minutes) were shorter with oral insulin spray compared with SC insulin (both, P = 0.028). The baseline-corrected GIR(max) (6.8 [3.3] vs 6.2 [2.3] mg/kg . min) and glucose consumption (396.7 [178.0] vs 432.1 [226.0] mg/kg) during the 120 minutes after study drug administration were comparable between oral and SC insulin, respectively. CONCLUSIONS: In this study in a small, selected population of healthy male subjects under euglycemic conditions, oral insulin spray was associated with a higher C(max), shorter T(max), and faster time to peak glucose uptake compared with SC insulin. The short T(max) and the 120-minute duration of effect of oral insulin spray suggest it may be a promising alternative for fulfilling meal-related insulin requirements in persons with diabetes.     

Study of insulin metabolism in hyperthyroid patients

Hyperthyroidism is associated with degradation of carbohydrate metabolism. The insulin metabolism in 12 hyperthyroid patients is compared with 10 control subjects. The patients were connected to an artificial beta cell (Biostator GCIIS Miles) for two hours of insulin infusion (40 mU/m2/mn) while glycemia was maintained at its basal level by a modulated glucose infusion. Blood samples were taken, every 15 minutes for insulin and C peptide dosage. In control subjects the insulin steady state level was 93.3 +/- 5 microU/ml whereas this ranged from 42 +/- 3.4 microU/ml to 68 +/- 3.9 microU/ml in hyperthyroid patients. After treatment the insulin level was not quite normal, and ranged from 52 +/- 4.8 microU/ml to 82.2 +/- 9 microU/ml. A glucose intake not corresponding to the same insulin steady state is not therefore to be interpreted. Here there is no evidence of a correlation between the percentage decrease in the insulin test level and the thyroid hormone levels. An impairment of insulin metabolism is suggested in hyperthyroid patients, which might contribute to the decrease in carbohydrate tolerance.     

Does C‐reactive protein identify a subclinical metabolic disease in healthy subjects?

BACKGROUND: Highly sensitive C-reactive protein (hs-CRP) levels are significant predictors of subsequent diabetes and metabolic syndrome (MS). Owing the strong correlations between components of the MS and obesity with hs-CRP levels, previous studies about the associations of hs-CRP with insulin resistance might have been confounded by the inclusion of overweight or dysmetabolic subjects. DESIGN: Our aim was to evaluate the associations between hs-CRP levels and fasting insulin and insulin resistance (evaluated by the Homeostasis Model Assessment: HOMA IR) in a subgroup of subjects with normal body mass index (BMI) and without any metabolic abnormalities. Out of a cohort of 1658 middle-aged subjects, representative of the local sanitary districts of the province of Asti (north-western Italy) enrolled for metabolic screening: 241 (14.5%) showed normal BMI, glucose tolerance, blood pressure and waist values and no dyslipidaemia. RESULTS: In this subgroup of subjects, those with hs-CRP levels > or = 3 mg L(-1) showed significantly higher median insulin and HOMA-IR values (respectively: 20.4 vs. 6.0 pmol L(-1), and 0.8 vs. 0.2 microU mL(-1)x mmol L(-1)). In a multiple regression model, insulin and insulin resistance remained significantly and independently related to hs-CRP levels, after adjustments for age, sex, BMI, waist, alcohol consumption, level of physical activity and smoking habits. Very few individuals within lower fasting insulin quartiles showed hs-CRP values > or = 3 mg L(-1) when compared with approximately 60% of those within the highest quartile. CONCLUSIONS: The novel finding is that a state of low-grade systemic inflammation is present in normal BMI subjects who show subclinical insulin resistance but no other metabolic abnormalities.     

Pharmacodynamic and pharmacokinetic properties of a premixed 85/15 human insulin preparation

BACKGROUND: Many patients with diabetes use mixtures of fast-acting (regular human) insulin and intermediate-acting (neutral protamine Hagedorn [NPH]) insulin to control their blood glucose levels. Premixed insulin is available in a 70%/30% mixture and a 50%/50% mixture of NPH/regular human insulin. For some patients, however, a premixed formulation containing > or =30% regular human insulin can provide too much fast-acting insulin, potentially causing an increased risk for hypoglycemia in the early hours after injection. OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of a premixed formulation of 85% NPH insulin and 15% regular human insulin (85/15) were compared with those of a premixed 70%/30% NPH/regular human insulin preparation and 100% NPH insulin. METHODS: A 12-hour euglycemic clamp approach was used to assess glucose-lowering effects and serum insulin levels in 36 healthy male volunteers in a single-dose (0.5 U/kg), randomized, double-blind, 3-period, crossover study. RESULTS: From 0 to 8 hours after injection, the glucose-lowering effects and serum insulin levels for the 85/15 premixed insulin preparation were significantly greater than those for NPH insulin (P < or = 0.05) but significantly less than those for the 70/30 premixed insulin preparation. The mean (+/- SEM) maximum glucose infusion rate (GIRmax) was 8+/-0.6 mg/(min x kg) for the 85/15 preparation, 7+/-0.6 mg/(min x kg) for NPH, and 9+/-0.6 mg/(min x kg) for the 70/30 preparation, with time to peak GIR (tmax(GIR)) occurring at 313, 360, and 272 minutes, respectively. Time to peak insulin levels did not differ significantly for the 3 preparations, but maximum serum insulin concentration (Cmax(ins)) was significantly different between the groups (70/30 premix: 54+/-2.2 microU/mL; 85/15 premix: 44+/-2.4 microU/mL; NPH: 35+/-1.7 microU/mL). Glucodynamic effect and serum insulin levels did not differ significantly among preparations during the interval from 8 to 12 hours after injection. Mean serum C-peptide levels ranged from -0.6 to 1.0 ng/mL for each preparation during the 12-hour period after injection. CONCLUSIONS: The 85/15 premixed insulin preparation demonstrated clinical pharmacokinetic and pharmacodynamic properties that were intermediate between, and significantly different from, those of NPH insulin and the 70/30 premixed insulin preparation.     

Maintenance of basal insulin secretion in severe non-insulin-dependent diabetes

It has been postulated that glucose regulation is secondary to maintenance of normal basal insulin secretion. Serum glucose, insulin, and C-peptide levels were measured at fasting in 209 consecutive non-insulin-dependent diabetic patients and after glucose stimulation in 193 patients. The basal serum insulin C-peptide levels were not significantly different in control subjects (mean 22 +/- 8.8 microU/ml) and in patients with varying severity of diabetes (mean 24 +/- 9.6 microU/ml) except in the most severely diabetic group [fasting serum glucose greater than 350 mg/dl (19.4 mmol/L), mean 19 +/- 7 microU/ml]. In 39 patients who developed ketonuria without acidosis during follow-up, the mean basal serum insulin was 22 microU/ml during the episode of ketonuria, 21 microU/ml during the glucose tolerance test, and 25 microU/ml after glucose stimulation (statistically nonsignificant differences). Our data suggest that hyperglycemia compensates for beta-cell impairment so that basal insulin secretion usually stays above the threshold for ketoacidosis unless there is marked beta-cell impairment. Patients who fail to increase insulin in response to nutrient challenge are at risk of developing ketosis.     

Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism.

To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present.     

A comparison of cutaneous vascular responses to transient pressure loading in smokers and nonsmokers

Smoking has been recognized as a risk factor for pressure ulcer development. This study investigated the hypothesis that smoking causes alterations in cutaneous vascular perfusion, which may contribute to this increased risk. With the use of the laser Doppler fluximetry (LDF), the adaptive vasodilatory response to a transient pressure load at the sacrum was measured in nine healthy female smokers and their age, sex, body mass index (BMI), and menstrual cycle matched nonsmoker controls. In all subjects, removal of the pressure load resulted in a reactive hyperaemic response. The total hyperaemic response was approximately 45% smaller in smokers compared to nonsmoker controls. The reduction was due to a shortening of the duration of the response predominantly through an increase in the rate of recovery from peak, which was twice as fast in the smokers (2.4 +/- 1.7 AU x seconds) compared with the nonsmoking controls (1.1 +/- 0.9 AU x seconds) (p < 0.005). We conclude that changes in the vascular responsiveness can be measured objectively at skin sites at risk of pressure ulcers. We have also shown that vascular responsiveness is altered in light smokers compared to control subjects. These preliminary data open the way for further investigation into the risk factors associated with pressure ulcer development.