Inhaled insulin: overview of a novel route of insulin administration.
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ABSTRACT:
SUBMITTER: Mastrandrea LD
PROVIDER: S-EPMC2835554 | biostudies-literature | 2010 Mar
REPOSITORIES: biostudies-literature
Publications
Inhaled insulin: overview of a novel route of insulin administration.
Vascular health and risk management 20100303
Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular disease, both of which are affected by optimal diabetes control. Many individuals with diabetes rely on subcutaneous insulin administration by injection or continuous infusion to control glucose levels. Novel routes of insulin administration are an area of interest in the diabetes field, given that insulin injection therapy ...[more]
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Project description:Aims/hypothesisThe small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels.MethodsIn this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment.ResultsGlucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min-1 kg-1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min-1 kg-1 (nmol/l)-1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration.Conclusions/interpretationOur study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance.Trial registrationClinicalTrials.gov NCT03223129. Graphical abstract.
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Project description:BackgroundAlong with general measures of treatment satisfaction, treatment-specific and device-specific treatment satisfaction should be assessed in clinical trials, because these latter measures may be more strongly correlated with clinical outcomes.MethodsStudy participants were 1076 adults (type 1 = 509, type 2 = 567) in clinical trials of Technosphere Insulin(R), who completed the SF-36 health-related quality of life questionnaire and the Inhaled Insulin Treatment Questionnaire (IITQ), a new instrument assessing diabetes worries, perceptions of insulin therapy, treatment satisfaction, treatment preference, and inhaler performance. The IITQ was administered twice prior to treatment initiation in the clinical trials, 1-2 weeks apart, and several times during the trials. Inhaler performance was assessed at follow-up visits, after participants had used the device.ResultsIITQ subscales had acceptable reliability (alpha = 0.68-0.87, median 0.83) and test-retest correlations (intra-class correlation coefficient = 0.67-0.90, median 0.82); floor effects (0.2-2.8%) and ceiling effects (0-9.3%) were minimal. Reliabilities for inhaler performance measures were acceptable (alpha = 0.73-0.90, median 0.85); there were no floor effects (0.0%) and ceiling effects (4.9-39.0%) were moderate. There were several modest associations between IITQ scores and measures of health status. Diabetes worries were lower for participants who had better mental health (type 2) and for those with higher BMI; perceptions of insulin therapy were more favorable for participants who had better physical and mental health; treatment satisfaction was higher for patients who had lower BMI (type 2), lower A1c levels, and better physical health (type 2); treatment preference was higher for patients with lower BMI (type 2) and better mental health (type 1). CONCLUSIONS -: Preliminary findings suggest that the IITQ is a comprehensive, reliable measure of the experience of patients treated with inhaled insulin.
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Project description:Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.
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