Glucose Metabolism Disorders
Conditions
Keywords
postprandial glucose metabolism, brain insulin action, insulin sensitivity, insulin secretion, endogenous glucose production, menstrual cycle, sex differences, proglucagon cleavage products
Brief summary
The goal of this clinical trial is to clarify (i) the contribution of brain insulin action on regulation of systemic metabolism, (ii) sex-specific differences in the central regulation and (iii) the influence of the menstrual cycle in women. Therefore, participants will undergo oral glucose tolerance tests combined with a double tracer dilution technique. This approach will be compared between days with insulin delivery to the brain as nasal spray and days with placebo spray.
Detailed description
This research project aims to investigate to what extent brain insulin action is responsible for the control of postprandial metabolism compared to direct effects of insulin in peripheral target tissues. Furthermore, the study will investigate sex differences and the influence of the menstrual cycle on brain-derived coordination of postprandial signaling for metabolic control. Therefore, insulin action in the brain will be introduced by application of insulin as nasal spray (on one day) versus carrier solution as placebo nasal spray (on another day) in a randomized, blinded fashion. Spray administration will be performed 15 minutes before a 75 gram oral glucose tolerance test that will introduce a postprandial state. On placebo day, the known spillover of tiny amounts of nasal insulin into the systemic circulation will be mimicked by an appropriate i.v. insulin bolus. This approach will be combined with a double-tracer dilution technique. Labeled glucose (\[6,6-2H\]glucose) will be infused 120 minutes before and during the OGTT (180 min) and will be used to address endogenous glucose production. The glucose drink from the OGTT will be enriched with \[U-13C6\]glucose to compute the glucose appearance rate (Ra). Basal endogenous glucose production will be calculated as well as post-load endogenous glucose production and rates of glucose disappearances (Rd). Using this approach, brain-derived regulation of postprandial metabolism including endogenous glucose production, glucose disappearance, insulin secretion, and secretion of proglucagon-cleavage products (incretins) will be examined.
Interventions
OTHEROral glucose tolerance test with double-tracer dilution and intranasal insulin spray
Subjects will undergo a 75 g OGTT (180 min) combined with a double tracer dilution. The double-tracer dilution technique will be used to quantify endogenous glucose production, glucose appearance and disappearance rate. \[6,6-2H\]glucose will be infused for a total of 300 minutes,while the infusion will start 120 minutes prior the OGTT and will last until the end of the OGTT. Intranasal insulin will be administered 15 minutes prior to the start of the OGTT. The drink consumed at time point 0 min contains 75 gram glucose, enriched with \[U-13C6\]-glucose.
OTHEROral glucose tolerance test with double-tracer dilution and intranasal placebo spray
Subjects will undergo a 75 g OGTT (180 min) combined with a double tracer dilution. The double-tracer dilution technique will be used to quantify endogenous glucose production, glucose appearance and disappearance rate. \[6,6-2H\]glucose will be infused for a total of 300 minutes,while the infusion will start 120 minutes prior the OGTT and will last until the end of the OGTT. Placebo spray will be administered 15 minutes prior to the start of the OGTT. The drink consumed at time point 0 min contains 75 gram glucose, enriched with \[U-13C6\]-glucose. To mimic insulin spill-over from nasal spray into systemic circulation, an i.v. insulin bolus of 3 mU × kg-1. will be administered over ten minutes starting at time point -15 minutes on the placebo spray day. On the insulin spray day a comparable amount of saline will be infused.
Sponsors
University of Ulm
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Intervention model description
Randomized, controlled, cross-over design for men. Randomized, controlled, 2x2 factorial cross-over design for women taking the menstrual cycle phase into account.
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI \< 24 kg/m2 * no known primary diseases * no hormonal contraception
Exclusion criteria
* Alcohol or drug abuse * Smoking * At screening: Hb \< 12 g/dl for women and Hb \< 14 g/dl for men * Any (clinical) condition that would endanger participant's safety or question scientific success according to a physician's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous glucose production | -120 minutes - 180 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on endogenous glucose production assessed with Steele's non-steady state model during an oral glucose tolerance test combined with double-tracer dilution technique. |
| Rate of glucose disappearance | -120 minutes - 180 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on rate of glucose disappearance (Rd) assessed with Steele's non-steady state model during an oral glucose tolerance test combined with double-tracer dilution technique. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proglucagon cleavage products | 0-120 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on secretion of proglucagon cleavage products assessed by oral glucose tolerance test. |
| Glucose tolerance | 0-120 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on glucose tolerance assessed as area under the glucose curve (0-120 minutes) and glucose levels at timepoint 120 minutes during the 75 g oral glucose tolerance test. |
| Whole-body insulin sensitivity | 0-120 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on whole-body insulin sensitivity, assessed from glucose and insulin measurements during the 75 g OGTT. |
| Insulin secretion | 0-180 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on insulin secretion assessed from glucose and insulin/C-peptide measurements during the 75 g oral glucose tolerance test. |
| Post-absorptive energy expenditure | 30 minutes and 180 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on post-absorptive energy expenditure assessed by indirect calorimetry at timepoint 30 min and 180 min during an oral glucose tolerance test combined with double-tracer dilution technique. |
| Sex differences | -120 minutes - 180 minutes during oral glucose tolerance test | Explore sex differences in the brain-derived regulation of postprandial metabolism during the 75 g oral glucose tolerance tests. Outcomes 1-7 will be compared between sexes. |
| Menstrual cycle effects | -120 minutes - 180 minutes during oral glucose tolerance test | Differences between the follicular and the luteal phase of the menstrual cycle in the brain-derived regulation of postprandial metabolism during the 75 g oral glucose tolerance tests: Outcomes 1-7 will be compared between the phases of the menstrual cycle. |
| Autonomic nervous system activity | -15 minutes - 180 minutes during oral glucose tolerance test | Effect of intranasal insulin versus placebo on autonomic nervous system activity assessed by heart rate variability using an 3-channel ECG at timepoint -15 min until 180 min during an oral glucose tolerance test combined with double-tracer dilution technique. |
Countries
Germany
Contacts
PRINCIPAL_INVESTIGATORMartin Heni, MD
University of Ulm
Outcome results
None listed