Features of diabetic dyslipidaemia in non-insulin-dependent diabetes mellitus (NIDDM), such as a low HDL cholesterol concentration, the preponderance of small dense LDL and postprandial fat intolerance are considered to be metabolic consequences of elevated plasma triglycerides [1]. The mechanism underlying hypertriglyceridaemia in NIDDM is still unclear. A majority of studies indicate that the elevation of plasma triglycerides in NIDDM result from an overproduction of VLDL triglyceride [2,3] and apo B [4,5] but it is unclear and a matter of controversy whether the increased production of VLDL particles is driven by a direct effect of hyperinsulinaemia or is a consequence of defective suppression of VLDL production by insulin [1]. In healthy subjects acute insulin administration suppresses VLDL apo B production [6][7][8]. Data on the suppression of VLDL production by insulin in insulin resistant states are controversial. Lewis et al. [6] showed an impaired suppression of VLDL apo B production in obese subjects while Cummings et al. [9] did not find any defect in the ability of insulin to suppress VLDL apo B production in patients with NIDDM.Two major subclasses of VLDL particles are recognised, large triglyceride-rich VLDL1 particles Diabetologia (1997) 40: 454-462 Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM Summary Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) subclass. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 ± 3 years, body mass index 27.0 ± 1.0 kg/m 2 , plasma triglycerides 1.89 ± 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin ∼ 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper-and normoglycaemic conditions. [3-2 H]-leucine was used as tracer and kinetic constants derived using a non-steadystate multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 ± 8 % after 8.5 h of hyperinsulinaemia (701 ± 102 vs 672 ± 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 ± 21 % under normoglycaemic conditions (603 ± 145 mg/day). In contrast, in normal subjects insulin induced a 50 ± 15 % decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids. [Diabetologia (1997) 40: 454-462]

The mechanism by which acute insulin administration alters VLDL apolipoprotein (apo) B subclass metabolism and thus plasma triglyceride concentration was evaluated in 7 normolipidemic healthy men on two occasions, during a saline infusion and during an 8.5-hour euglycemic hyperinsulinemic clamp (serum insulin, 490 +/- 30 pmol/L). During the insulin infusion, plasma triglycerides decreased by 22% (P < .05), and serum free fatty acid decreased by 85% (P < .05). The plasma concentration of VLDL1 apo B fell 32% during the insulin infusion, while that of VLDL2 apo B remained constant. A bolus injection of [3-(2)H]leucine was given on both occasions to trace apo B kinetics in the VLDL1 and VLDL2 subclasses (Svedberg flotation rate, 60-400 and 20-60, respectively), and the kinetic basis for the change in VLDL levels caused by insulin was examined using a non-steady-state multicompartmental model. The mean rate of VLDL1 apo B synthesis decreased significantly by 35% (P < .05) after 0.5 hour of the insulin infusion (523 +/- 87 mg/d) compared with the saline infusion (808 +/- 91 mg/d). This parameter was allowed to vary with time to explain the fall in VLDL1 concentration. After 8.5 hours of hyperinsulinemia, the rate of VLDL1 apo B synthesis was 51% lower (321 +/- 105 mg/d) than during the saline infusion (651 +/- 81 mg/d, P < .05). VLDL2 apo B production was similar during the saline (269 +/- 35 mg/d) and insulin (265 +/- 37 mg/d) infusions. No significant changes were observed in the fractional catabolic rates of either VLDL1 or VLDL2 apo B. We conclude that acute hyperinsulinemia lowers plasma triglyceride and VLDL levels principally by suppressing VLDL1 apo B production but has no effect on VLDL2 apo B production. These findings indicate that the rates of VLDL1 and VLDL2 apo B production in the liver are independently regulated.

The objective of the study was to examine the potential differential effect of insulin and acipimox (both of which reduce free fatty acid [FFA] availability) on VLDL apolipoprotein (apo) B metabolism. We studied eight healthy men (age 40 +/- 4 years, BMI 25.8 +/- 0.9 kg/m2, plasma triglycerides 1.30 +/- 0.12 mmol/l) after an overnight fast (control study, n = 8), during inhibition of lipolysis with an antilipolytic agent, acipimox (n = 8), and under 8.5-h euglycemic-hyperinsulinemic conditions (n = 5). Plasma FFAs were similarly suppressed in the acipimox and insulin studies (approximately 70% suppression). 2H3-leucine was used to trace apo B kinetics in VLDL1 and VLDL2 subclasses (Svedberg flotation rates: 60-400 and 20-60), and a non-steady-state multicompartmental model was used to derive the kinetic constants. The mean rate of VLDL1 apo B production was 708 +/- 106 mg/day at the beginning and 602 +/- 140 mg/day at the end of the control study. Production of the lipoprotein decreased to 248 +/- 93 mg/day during the insulin study (P < 0.05 vs. control study) and to 375 +/- 92 mg/day (NS) during the acipimox study. Mean VLDL2 apo B production was significantly increased during the acipimox study (399 +/- 42 vs. 236 +/- 27 mg/day, acipimox vs. control, P < 0.05) but not during the insulin study (332 +/- 51 mg/day, NS). The fractional catabolic rates of VLDL1 and VLDL2 apo B were similar in all three studies. We conclude that acute lowering of FFAs does not change the overall production rate of VLDL particles, but there is a shift toward production of smaller and denser VLDL2 particles, and, thus, the amount of total VLDL particles secreted remained constant. Insulin acutely suppresses the total production rate of VLDL apo B by decreasing the production of large triglyceride-rich VLDL1 particles. Based on these findings, we postulate that insulin has a direct suppressive effect on the production of VLDL apo B in the liver, independent of the availability of FFAs.

Insulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with noninsulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51 +/- 3 years, BMI 26.3 +/- 0.6 kg/m2, fasting plasma glucose 5.6 +/- 0.2 mmol/l) and seven patients with NIDDM (age 54 +/- 2 years, 27.0 +/- 0.9 kg/m2, 11.1 +/- 0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r = 0.72, p < 0.005), even after adjusting for the percentage of body fat (p < 0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37 +/- 14%; 5.2 +/- 0.8. vs 3.9 +/- 0.6 ng/ml, 6 vs 0 h, p < 0.05) in the normal subjects and after 8.5 h (38 +/- 11%; 7.1 +/- 1.0 vs 5.5 +/- 0.9 ng/ml, 8.5 vs 0 h, p < 0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11 +/- 1% (p < 0.005) and in the patients with NIDDM by 14 +/- 1% (p < 0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32 +/- 13 (p < 0.05), 53 +/- 14 (p < 0.001), 106 +/- 15 (p < 0.001) and 165 +/- 21 (p < 0.001) % higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11 +/- 9 (p < 0.05), 27 +/- 10 (p < 0.05), 58 +/- 7 (p < 0.001) and 106 +/- 13 (p < 0.001) % higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.