Role of insulin resistance in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man

Abstract

Studies were performed to evaluate the relative importance of enhanced adipose tissue lipolysis and increased insulin levels in modulating hepatic VLDL production in patients with endogenous hypertriglyceridaemia. Eight control subjects and nine patients with hypertriglyceridaemia were investigated. The latter group comprised four patients with idiopathic hypertriglyceridaemia, three maturity onset diabetics, and two siblings with diabetic lipodystrophy. Each individual's plasma VLDL was selectively labelled with I131 in the apoprotein moiety and then reinjected to assess the turnover of these molecules. This was correlated with the insulin response to an oral glucose load and with the plasma FFA flux measured by a continuous infusion of 14C palmitate. In the patients with idiopathic hypertriglyceridaemia and in the adult onset diabetics, plasma VLDL-appoprotein turnover was increased suggesting enhanced hepatic production of these molecules. Although the insulin levels in these patients were higher than normal, no significant correlation was demonstrable between the plasma insulin and the turnover of VLDL-B-apoprotein. Furthermore, in the two patients with lipo-dystrophy the turnover of plasma VLDL was within the normal range, whereas the plasma insulin responses were the highest among all the patients. These results suggest that hyperinsulinaemia alone is not sufficient to account for the increased VLDL production seen in some of our patients. The plasma FFA flux was raised in the patients with idiopathic hypertriglyceridaemia and in the maturity onset diabetics, and was within the normal range in the two patients with lipodystrophy. Indded, in all the subjects studied a significant correlation was observed between the turnover of plasma VLDL-B-apoprotein and the plasma FFA flux. The results thus indicate that the rate of FFA release to plasma constitutes the predominant factor in determining hepatic output of VLDL and that in the majority of patients with endogenous hypertriglyceridaemia the increased FFA flux resulting from insulin resistance in adipose tissue could effectively increase VLDL production. This process appears to be independent of the prevailing insulin levels, and could occur in the presence of insulin resistance in the liver. The latter, however, could be responsible for the impaired glucose tolerance observed in some patients.

Relation of plasma triglyceride and apoB levels to insulin-mediated suppression of nonesterified fatty acids. Possible explanation for sex differences in lipoprotein pattern.

“…In contrast, apoB levels were correlated with NEFAs only, consistent with findings that plasma VLDL apoB turnover is correlated with plasma NEFA flux but not with plasma insulin. 18 Although impaired clearance by lipoprotein lipase could account for the association of elevated triglyceride levels with impaired insulin-mediated NEFA suppression, such a mechanism would not account for the correlation of postload NEFAs with apoB, which is not cleared by lipoprotein lipase. Experimental studies have demonstrated that elevated NEFA levels increase triglyceride synthesis and apoB secretion by hepatocytes in vitro.…”

Biological Effects of Allium monanthum Extracts on Lipid Metabolism, Anti-oxidation and the Production of Pro-inflammatory Cytokines in Rats Fed a High-Fat Diet

“…FFA, total cholesterol, LDL cholesterol and TG concentrations in the blood are increased in obesity (Considine et al, (Kissebah et al, 1976).…”

“…In addition, cytokines released from fat cells, including leptin, TNF-α and IL-6, are closely related to insulin resistance (Weigle, 1994;Nielsen and Jensen, 1997;Kissebah et al, 1976), and they are known as major causes for diabetes (Mohamed-Ali et al, 1997;Mohamed-Ali et al, 1998).…”

“…The typical clinical symptoms of obesity-induced diseases include diabetes (Mohamed-Ali et al, 1997;Mohamed-Ali et al, 1998), which is induced by the cytokines TNF-α and IL-6, which are released by adipocytes and directly affect insulin resistance (Weigle, 1994;Nielsen and Jensen, 1997;Kissebah et al, 1976). Additionally, excessively accumulated adipocytes may cause the abnormal production, decomposition and release of fatty acid in the liver and may lead to liver diseases.…”

Relationship of metabolic variables to abdominal adiposity measured by different anthropometric measurements and dual-energy X-ray absorptiometry in obese middle-aged women

“…1 Increased portal FFA availability may result in reduced hepatic insulin clearance, 2,3 increased hepatic glucose production 4 and increased very-low-density-lipoprotein (VLDL) triglyceride synthesis. 5 All these abnormalities provide a conceptual rationale for examining the relationship between various metabolic disturbances and adipose tissue distribution.…”