Inhaled insulin.

Inhalation of regular insulin for meal time glucose control has been found to be safe, efficacious and reliable in Type I and Type II diabetics. The administration of regular insulin through the human lungs by inhalation has been conducted in at least 14 short studies in both normal and diabetic subjects beginning as early as 1925. In all studies, significant insulin absorption and lowering of blood glucose was observed in the absence of penetration enhancers. Although a concern of variable dosing was raised in early studies, the development of new reproducible delivery systems has ensured that the variability of aerosol insulin can be as good, if not better, than subcutaneous (SC) injection. In the longest controlled studies in humans to date, both Type I and Type II insulin-dependent diabetics used a novel inhaled dry powder insulin delivery system for 3 months for meal time glucose control. The study results indicate that inhaled insulin provides equivalent glucose control, measured by hemoglobin A1c, when directly compared to SC injection. Interim results from an additional study with Type II diabetics who were failing oral hypoglycemic agents suggest that adjunctive therapy with inhaled insulin markedly improved glycemic control with a low risk of hypoglycemia. In all the 3 month studies the system was efficacious, well tolerated, well liked, and resulted in reproducible results. A potential advantage of aerosol insulin is that it is more rapidly absorbed (serum peak at 5-60 min) and cleared than SC injection (peak at 60-150 min), which provides a more relevant and convenient therapy for meal time glucose control. The relative efficiency of insulin delivery by aerosol, compared to SC injection, has been estimated from the dose measured at the exit point of the aerosol device, and found to range between 8 and 25% of SC, depending on the study.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a Phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection.

Loss of body mass, or wasting, is a major cause of morbidity and a contributor to mortality in human immunodeficiency virus-1 (HIV-1) infection. Dietary supplements and appetite adjuvants have had limited effectiveness in treating this condition. GH and insulin-like growth factor I (IGF-I) have been shown to be anabolic in many catabolic conditions, and limited data suggest similar efficacy in HIV wasting. In addition, it appears that GH and IGF-I may have complementary anabolic effects with opposing glucoregulatory effects. We report results from a 12-week randomized, placebo-controlled trial of combination recombinant human GH (rhGH; Nutropin; 0.34 mg, sc, twice daily) and rhIGF-I (5.0 mg, sc, twice daily) in individuals with HIV wasting and without active opportunistic infection, cancer, or gastrointestinal disease. A total of 142 subjects (140 males and 2 females) were randomized using a 2:1, double blind treatment scheme and assigned to receive either active treatment or placebo injections. Eighty subjects completed the 12-week protocol. Nutritional intake and demographic and clinical characteristics did not differ between the groups at any study time point. At 3 weeks, the treatment group had a significantly larger weight increase (P = 0.0003), but this difference was not observed at any later time point. Similarly, fat-free mass, calculated from skinfold measurements, increased transiently in the treatment group at 6 weeks (P = 0.002). No significant differences in isokinetic muscle strength or endurance testing or in quality of life were observed between the groups. Resting heart rate was significantly higher in the treatment group at each time point post-baseline. GH and IGF-binding protein-3 levels did not change; however, IGF-I levels were higher in the treatment group at 6 and 12 weeks. There were no significant between-group differences in any of the measured biochemical or immunological parameters. rhGH plus rhIGF-I treatment was associated with an increased incidence of peripheral edema and other side-effects, possibly related to fluid retention. We conclude that the combination of rhIGF-I and low dose rhGH used in this study had no significant anabolic effect in HIV wasting.

Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone.

Weight loss is a common, persistent characteristic of long term human immunodeficiency virus (HIV-1) infection; its full etiology remains unknown. Because treatment with GH has induced nitrogen retention in various catabolic conditions, we designed this study to determine whether a moderate dose of insulin-like growth factor I (IGF-I) combined with a low GH dose could impede the catabolic response seen in HIV-1 infection. A double blind, placebo-controlled study design was used. Subjects in the GH/IGF-I treatment group (n = 44) and control group (n = 22) continued to receive their routine stable antiretroviral therapy. No patient had a recent history of opportunistic infection, malignancy, or Kaposi's sarcoma and had dietary intakes of at least 25 Cal/kg weight.day at study entry. During the 12-week study period, dietary instruction was given, and subjects were encouraged to maintain an intake of 35 Cal/kg and 1 g protein/kg. All subjects had a body mass index of 19.8 kg/m2 or less at the time of study entry or a weight loss of 10% or more of their premorbid weight and a body mass index below 26.1 kg/m2. The treatment group received 0.34 mg (0.68 mg/day) GH, twice daily, and 5.0 mg (10 mg/day) IGF-I, twice daily. Changes in body composition of total body potassium (TBK), total body nitrogen (TBN), fat-free mass (FFM), and body fat (Fat) were examined at 6 and 12 weeks during the treatment period. TBK, TBN, FFM, and Fat for the treatment and placebo groups were, on the average, below normal at study entry. At 6 weeks, the GH/IGF-I group showed a significant increase in FFM (P < 0.0001), a minimal increase in TBK (P < 0.05), and a substantial decrease in Fat (P < 0.01) compared with baseline values. The loss of body fat continued to be significant (P < 0.01) in the GH/IGF-I group treatment at 12 weeks, whereas the increase in FFM was minimal (P < 0.05). No significant changes in the mean body composition occurred at 6 or 12 weeks in the placebo group. By 12 weeks, neither TBK (body cell mass) nor TBN (total protein mass) had significantly increased relative to the values at baseline, although the FFM remained elevated. Thus, the combined GH and IGF-I doses used in this study in adult males with HIV-associated weight loss were ineffective in producing a sustained anabolic response and, in fact, resulted primarily in a significant loss of body fat.

Effect of recombinant human insulin-like growth factor I and early total parenteral nutrition on immune depression following severe head injury.

OBJECTIVE: To determine the effects of insulin-like growth factor I (IGF-I) and aggressive nutrition on CD4/CD8 ratios following head injury. DESIGN: Randomized controlled trial. SETTING: An urban level 1 trauma center. PARTICIPANTS: Head-injured patients with a Glasgow Coma Scale score of 4 to 10 within 6 hours of hospital admission requiring no major extracranial surgery with the exception of isolated lower-extremity fracture fixation. Fourteen patients were recruited and 11 completed the study. INTERVENTIONS: Patients were randomized to a continuous infusion of saline or 0.01 mg/kg per hour of recombinant human (rh) IGF-I. Both groups received parenteral nutrition and rapidly advanced to a total protein intake of 2 g/kg per day and a maximum nonprotein calorie intake of 40 kcal/kg per day. The nonprotein prescription was 1.25 times the metabolic energy expenditure determined by metabolic cart not to exceed a nonprotein calorie intake of 40/kcal. MAIN OUTCOME MEASURES: The CD4/CD8 ratios and serum IGF-I levels on days 1, 7, and 14. RESULTS: Administration of early aggressive nutrition eliminated the depressed CD4/CD8 ratio usually seen after head injury; administration of IGF-I increased the CD4/CD8 ratio while IGF-I levels were elevated. CONCLUSIONS: Infusion of rhIGF-I and aggressive early intravenous nutrition affects the immunologic response of patients with severe head injury.

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total circulating IGF-I without changing free IGF-I disposition or glycemic response. A 30-kilodalton IGFBP band, most likely IGFBP-1, appeared transiently following rhIGF-I administration, probably as a result of suppression of insulin levels. IGFBP-2, -3, and -4 were unaffected.

Frozen desserts and glycemic response in well-controlled NIDDM patients.

Fructose is known to elicit a lower glycemic response than sucrose, and high-fructose desserts have been recommended for a diabetic diet. We compared a cholesterol-free tofu-based frozen dessert (TFD) containing high-fructose corn syrups with a dairy-based sucrose-sweetened ice cream (IC). Six male and six female non-insulin-dependent diabetic patients (mean age 51 yr, mean ideal body weight 143%, fasting blood glucose less than 160 mg/dl) with well-controlled diabetes and managed on oral hypoglycemic agents were studied. Subjects underwent three trials. In the first trial they ingested 50 g glucose, and in the next two trials they ingested 50-g carbohydrate equivalents of either TFD or IC in random sequence. Venous blood was drawn at intervals during the 3-h trials for glucose and insulin determinations. Fasting plasma glucose was not statistically different between IC and TFD trials (130 vs. 121 mg/dl). Peak glucose responses were at 120 min in both trials (190 mg/dl for IC and 222 mg/dl for TFD), with those for TFD being significantly higher (P less than 0.01). Mean glucose area and glycemic index for TFD were significantly greater than for IC (P less than 0.01 and P less than 0.03, respectively). There was no significant difference between mean insulin areas. In summary, the TFD, which contains soybean curd and high-fructose corn syrup, might have been expected to produce more satisfactory postprandial blood glucose levels than IC, which contains sucrose, yet a higher glycemic response was elicited. This is related to the substantial amount of total glucose in this "fructose" dessert.(ABSTRACT TRUNCATED AT 250 WORDS)