De Novo Lipogenesis and Cholesterol Synthesis in Humans with Long-Standing Type 1 Diabetes Are Comparable to Non-Diabetic Individuals

<div><p>Background</p><p>Synthesis of lipid species, including fatty acids (FA) and cholesterol, can contribute to pathological disease. The purpose of this study was to investigate FA and cholesterol synthesis in individuals with type 1 diabetes, a group at elevated risk for vascular disease, using stable isotope analysis.</p><p>Methods</p><p>Individuals with type 1 diabetes (n = 9) and age-, sex-, and BMI-matched non-diabetic subjects (n = 9) were recruited. On testing day, meals were provided to standardize food intake and elicit typical feeding responses. Blood samples were analyzed at fasting (0 and 24 h) and postprandial (2, 4, 6, and 8 hours after breakfast) time points. FA was isolated from VLDL to estimate hepatic FA synthesis, whereas free cholesterol (FC) and cholesteryl ester (CE) was isolated from plasma and VLDL to estimate whole-body and hepatic cholesterol synthesis, respectively. Lipid synthesis was measured using deuterium incorporation and isotope ratio mass spectrometry.</p><p>Results</p><p>Fasting total hepatic lipogenesis (3.91±0.90% vs. 5.30±1.22%; P = 0.41) was not significantly different between diabetic and control groups, respectively, nor was synthesis of myristic (28.60±4.90% vs. 26.66±4.57%; P = 0.76), palmitic (12.52±2.75% vs. 13.71±2.64%; P = 0.65), palmitoleic (3.86±0.91% vs. 4.80±1.22%; P = 0.65), stearic (5.55±1.04% vs. 6.96±0.97%; P = 0.29), and oleic acid (1.45±0.28% vs. 2.10±0.51%; P = 0.21). Postprandial lipogenesis was also not different between groups (P = 0.38). Similarly, fasting synthesis of whole-body FC (8.2±1.3% vs. 7.3±0.8%/day; P = 0.88) and CE (1.9±0.4% vs. 2.0±0.3%/day; P = 0.96) and hepatic FC (8.2±2.0% vs. 8.1±0.8%/day; P = 0.72) was not significantly different between diabetic and control subjects.</p><p>Conclusions</p><p>Despite long-standing disease, lipogenesis and cholesterol synthesis was not different in individuals with type 1 diabetes compared to healthy non-diabetic humans.</p></div

Schematic of the testing day design.

<p>Blood samples were taken at fasting (0 h) and every 2 h for 8 h after the D₂O administration and breakfast completion. A lunch meal was provided after the 4 h sample, and take-away foods were provided for the subject to consume at home during the evening, before returning the following morning for a fasting 24 h blood sample.</p

Synthesis of cholesterol determined from whole-body and hepatic free cholesterol (FC) and cholesteryl ester (CE) fractions at fasting and postprandial timepoints.

<p>Fasting FC-FSR was 7.3±0.8% in Control subjects compared to 8.3±1.2% in diabetic subjects (P = 0.65), VLDL-FC-FSR was 8.1±0.8% vs. 8.2±2.0% (P = 0.72), and CE-FSR was 2.0±0.3% vs. 1.9±0.3% (P = 0.93) (<b>A</b>). Postprandial FC-FSR (<b>B</b>) at 4 h (1.8±0.9% vs. 2.2±1.1%, P = 0.36) and 8 h (2.8±1.3% vs. 2.9±1.5%, P = 0.65) was similar between groups, as was CE-FSR (<b>C</b>) at 4 h (0.11±0.12% vs. 0.31±0.37%, P = 0.37) and 8 h (0.37±0.24% vs. 0.33±0.34%, P = 0.71). Black bars, control non-diabetic subjects; white bars, type 1 diabetic subjects; data presented as mean ± SEM.</p

Fasting hepatic de novo fatty acid synthesis (DNFA) of total and individual fatty acids, postprandial synthesis of palmitate, and VLDL-TG fatty acid composition in control and type 1 diabetic subjects.

<p><i>Panel A</i> - Fasting (24 h) total hepatic FA synthesis was similar between control and diabetic subjects (5.30±1.22% vs. 3.91±0.90%, respectively; P = 0.41), and was similar for individual FA including myristic acid (14∶0; 26.66±4.57% vs. 28.60±4.90%, P = 0.76), palmitic acid (16∶0; 13.71±2.64% vs. 12.52±2.75%, P = 0.65), palmitoleic acid (16∶1; 4.80±1.22% vs. 3.86±0.91%, P = 0.65), stearic acid (18∶0; 6.96±0.97% vs. 5.55±1.04%, P = 0.29), and oleic acid (18∶1; 2.10±0.51% vs. 1.45±0.28%, P = 0.21). <i>Panel B</i> – Similar to fasting, postprandial synthesis of palmitate, the major product of de novo lipogenesis, was not significantly different in diabetic compared to control subjects (P = 0.38). <i>Panel C</i> – Fatty acid composition of VLDL-TG was not different between groups except for 16∶0, which was significantly lower in diabetic subjects compared to controls (P = 0.015). Arrows and “meal” on Panel B indicate when a meal was fed at breakfast (time 0) and lunch (time 4 h). Black bars or circles, control non-diabetic subjects; white bars or circles, type 1 diabetic subjects; data presented as mean ± SEM.</p

Anthropometric and biochemical characteristics of control and diabetic subjects.

*<p>Dietary intake estimated from 3-day food records; dietary carbohydrate, protein, and fat are described as percent total energy intake. Data reported mean ± SD.</p