Impact of Plasma Lipids on β Cell Function and Insulin Sensitivity

Mild hypertriglyceridemia is associated with reduced glucose tolerance and increased risk of type 2 diabetes, independent of obesity, in both cross-sectional and prospective studies. It is unclear whether this association is direct or mediated by circulating lipid substrates of triglycerides (free fatty acids, or FFA) and which are the mechanisms involved.

To comprehensively examine the effects of mild acute hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression, two dual-labeled oral glucose tolerance tests (OGTT) during 5-hour intravenous infusions of either 20% Intralipid or normal saline will be performed in healthy lean volunteers. Lipid-induced changes in glucose tolerance and insulin metabolism will be evaluated.

• 20% Intralipid (Other): Participants will receive a 5 h primed (375 mL/m2)-continuous (25 mL h-1 m-2) i.v. infusion of 20% fat emulsion (Intralipid 20%), together with a 5 h primed (28 µmol/kg)-continuous (0.28 µmol min-1 kg-1) infusion of 6,6-\[2H2\]glucose. After 2 h, participants will consume within 5 min an oral glucose drink consisting of 147 mL of 50% dextrose solution (wt/vol) enriched with 1.5 g of \[U-13C\] glucose.
• Normal Saline (Other): Participants will receive a 5 h primed (375 mL/m2)-continuous (25 mL h-1 m-2) i.v. infusion of normal saline (Sodium Chloride 0.9%), together with a 5 h primed (28 µmol/kg)-continuous (0.28 µmol min-1 kg-1) infusion of 6,6-\[2H2\]glucose. After 2 h, participants will consume within 5 min an oral glucose drink consisting of 147 mL of 50% dextrose solution (wt/vol) enriched with 1.5 g of \[U-13C\] glucose.

Primary outcomes

• Glucose control [At the end of the 5-hour lipid infusion]: Incremental area under the curve (AUC) of plasma glucose in response to the oral glucose tolerance test (OGTT)
• Insulin secretion [At the end of the 5-hour lipid infusion]: Insulin secretion rate (ISR) estimated from C-peptide deconvolution at fasting and in response to the oral glucose tolerance test (OGTT)
• Beta cell glucose sensitivity [At the end of the 5-hour lipid infusion]: Beta cell glucose sensitivity calculated by mathematical modeling of insulin secretion rate (ISR) and plasma glucose concentrations during the oral glucose tolerance test (OGTT)
• Insulin sensitivity [At the end of the 5-hour lipid infusion]: Insulin sensitivity estimated by an OGTT-derived surrogate index (Matsuda index)
• Insulin clearance [At the end of the 5-hour lipid infusion]: Insulin clearance calculated as the ratio between insulin secretion rate (ISR) and plasma insulin levels
• Rate of oral glucose appearance (RaO) [At the end of the 5-hour lipid infusion]: The rate of oral glucose appearance (RaO) will be assessed from the time course of the plasma tracer/tracee ratio of 6,6-\[2H2\]glucose and \[U-13C\]glucose
• Endogenous glucose production (EGP) [At the end of the 5-hour lipid infusion]: The endogenous glucose production (EGP) will be assessed from the time course of the plasma tracer/tracee ratio of 6,6-\[2H2\]glucose and \[U-13C\]glucose

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

* age 18-65 years
* Body mass index (BMI) 18-35 kg/m2
* both women and men

Exclusion Criteria:

* chronic or acute diseases
* any medications
* pregnancy

• Andrea Natali, MD, Principal investigator, University of Pisa