PreDiabetes
Conditions
Keywords
Insulin secretion, glucagon secretion, endogenous glucose production, glucose disappearance
Brief summary
Fasting hyperglycemia contributes disproportionately to nonenzymatic glycosylation and the microvascular complications of type 2 diabetes. However, little is known about the regulation of glucose concentrations in the fasting state relative to what is known about the postprandial state. The proposed experiment is part of a series of experiments designed to establish how glucagon and insulin interact with their receptors to control fasting glucose in health and in prediabetes.
Detailed description
The interaction between α-cell and β-cell function to regulate fasting glucose is incompletely understood. This is an important gap in our knowledge as fasting glucose contributes disproportionately to HbA1c and the microvascular complications of type 2 diabetes (T2DM). The regulation of fasting glucose in health and disease is relatively understudied. Insulin and glucagon should regulate glucose reciprocally through direct interaction; insulin restrains α-cell secretion while glucagon directly stimulates β-cell secretion. In addition, there are indirect interactions via changes in glucose. Glucagon increases endogenous glucose production (EGP) increasing glucose (and insulin secretion). Conversely, insulin stimulates glucose disappearance (Rd) and suppresses EGP, lowering glucose (and stimulating glucagon). However, this does not appear to occur uniformly in prediabetes. For example, in impaired fasting glucose (IFG), glucagon secretion rate (GSR) is inappropriate for the prevailing glucose. This is not accompanied by reciprocal changes in insulin secretion rate (ISR). Variability in the hepatic response to glucagon and to insulin further compound the dysregulation of fasting glucose. The net effect of these variables is unknown. This experiment is intended to test the hypothesis that impaired glucagon-induced insulin secretion contributes to fasting hyperglycemia in IFG.
Interventions
OTHERGlucagon
a variable rate glucagon infusion
OTHERGlucose
a variable rate glucose infusion
Sponsors
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All participants will complete two experiments conducted in random order. On one day they will receive a graded glucagon infusion while on the other they will receive a glucose infusion that replicates the glucose concentrations observed in the first study day
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Individuals with normal or impaired fasting glucose and normal or impaired glucose tolerance
Exclusion criteria
* HbA1c less than 6.5% * Use of any glucose-lowering agents including metformin or sulfonylureas. * For female subjects: positive pregnancy test at the time of enrollment or study * History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy. * Active systemic illness or malignancy. * Symptomatic macrovascular or microvascular disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in beta-cell responsivity induced by glucagon | Beta-cell responsivity will be calculated as the gradient of the relationship between glucose concentrations and insulin secretion rate during the study day over the 4 hours (0 to 240 minutes) of the study | The beta-cell responsivity observed during glucagon infusion will be compared to that observed during glucose infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| change in endogenous glucose production induced by glucagon | The rate of endogenous glucose production at the end of the study (240 minutes) will be expressed as a percentage of that at the beginning of the study (0 minutes). The % change for each study day will then be compared | The endogenous glucose production observed during glucagon infusion will be compared to that observed during glucose infusion |
| change in glucose disappearance induced by glucagon | The rate of glucose disappearance at the end of the study (240 minutes) will be expressed as a percentage of that at the beginning of the study (0 minutes). The % change for each study day will then be compared | The glucose disappearance observed during glucagon infusion will be compared to that observed during glucose infusion |
Countries
United States
Contacts
CONTACTKim Osmundson, CCRP
CONTACTJeanette Laugen
PRINCIPAL_INVESTIGATORAdrian Vella, MD
Mayo Clinic
Outcome results
None listed