Hyperglycemia and the Extra-pancreatic Effect of Incretins

Rigshospitalet, Denmark20 enrolled

Overview

Incretin hormones (GLP-1 and GIP) released from the intestine in response to meal ingestion augment insulin secretion from the pancreas to help maintain glycemic control. Studies in vitro and in vivo have shown that these incretin hormones also have functional effects in other tissues independent of the insulin secretory response. Both GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner, however the glucose-dependency of their extra-pancreatic effects has not been examined in vivo. By using pancreatic clamp methodology during euglycemic and hyperglycemic conditions we will test the hypothesis that extra-pancreatic effects of GLP-1 and GIP are glucose-dependent.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Extra-pancreatic Incretin Effect Glucose Effectiveness

Interventions

Eligibility

Sex: MALEMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * age 18-60 years * BMI 18-30 kg/m2 * Male * Normal glycemic control (fasting glucose \<5.6 mM) Exclusion Criteria: * Evidence of chronic disease * Smoking * Active weight loss (\>2 kg in previous 6 months) * Treatment with drugs known to affect our outcome varaibles

Outcomes

Primary Outcomes

Glucose metabolism

Pancreatic clamp will be performed including infusion of somatostatin and replacement of basal insulin, glucagon, and growth hormone. During pancreatic clamps, euglycemia (5 mM) will be maintained via exogenous glucose infusion for the first 2-hours, followed by hyperglycemia (+5 mM) for the final 2-hours. An infusion of the stable isotope \[U13C\]glucose will be performed to assess glucose kinetics. Expired air will be collected for the analysis of \[U13C\]glucose into 13CO2.

Time frame: up to 4 hours

Lipid metabolism

An infusion of the stable isotope \[D5\]glycerol will be performed to assess glycerol kinetics.

Time frame: up to 4 hours

Secondary Outcomes

Endothelial function

Ultrasound Doppler will be used to examine lower and upper limb blood flow and flow-mediated dilation

Time frame: Baseline, 2 hours, and 4 hours

Signaling

Skeletal muscle (vastus lateralis) and subcutaneous abdominal adipose biopsies will be obtained under local anaesthetic by the Bergstrom needle technique. Intracellular signalling related to glucose and lipid metabolism will be measured.