Effects of Hypertriglyceridemia With or Without NEFA Elevation on β-cell Function and Insulin Clearance and Sensitivity

Abstract

Context: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of nonesterified fatty acids (NEFAs).

Objective: This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in subjects without diabetes.

Methods: Twenty-two healthy lean volunteers underwent 5-hour intravenous infusions of either saline or Intralipid, without (n = 12) or with heparin (I + H; n = 10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3 hours of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2 hours of lipid infusion and during the OGTTs.

Results: In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I + H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (ie, β-cell glucose sensitivity) and increased β-cell potentiation, whereas I + H had neutral effects on these β-cell functions.

Conclusion: In healthy nonobese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance and insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.

Keywords: hypertriglyceridemia; insulin clearance; insulin secretion; insulin sensitivity; nonesterified fatty acids; oral glucose tolerance; type 2 diabetes.

Figure 1.

Protocols of the 2 crossover, randomized controlled trials with 75 g oral glucose tolerance tests (OGTT) performed during continuous intravenous infusion of normal saline (0.9% NaCl) or either 20% Intralipid (Intralipid group) or 20% Intralipid plus heparin (I + H group) in healthy volunteers.

Figure 2.

Plasma levels of triglycerides (A) and NEFAs (B) in response to a 75-g oral glucose tolerance test (OGTT, time 0-180 minutes) during continuous intravenous infusion (time −120 to 180 minutes) of normal saline (dashed lines) or either 20% intralipid (white circles) or 20% intralipid plus heparin (black circles). The dotted line at time 0 minutes indicates glucose ingestion at the beginning of the OGTT. Data are mean ± SEM.

Figure 3.

Plasma glucose (A), insulin (B), insulin secretion rate (C), and relationship between plasma glucose and insulin secretion rate (D) in response to a 75-g oral glucose tolerance test (OGTT, time 0-180 minutes) during continuous intravenous infusion (time −120 to 180 minutes) of normal saline (dashed lines) or either 20% intralipid (white circles) or 20% intralipid plus heparin (black circles). The dotted line at time 0 minutes indicates glucose ingestion at the beginning of the OGTT. Data are mean ± SEM.

Figure 4.

Percent changes from saline to Intralipid infusion, the latter without or with heparin, in baseline and postglucose plasma glucose levels, plasma insulin, insulin secretion, insulin sensitivity, insulin clearance, and main β-cell function parameters. Baseline values were measured after 120 minutes of saline/lipid infusion before glucose ingestion. Postglucose values are the average of measurements during a 180-minute 75-g oral glucose tolerance test (OGTT) with saline/lipid infusion, with plasma glucose calculated as the incremental plasma glucose level from the baseline value. Insulin sensitivity was estimated by the HOMA-IR⁻¹ at baseline and by the Matsuda index during the OGTT. Data are median and interquartile range. *P < .05 for difference with saline infusion in all subjects (Wilcoxon signed rank test). °P < .05 for group differences (Mann–Whitney test).