Dyslipidaemia and Type Diabetes

With increasing obesity, in particular visceral obesity, fat cells become enlarged and apparently less responsive to insulin, i.e. insulin resistant (Frayn, 2001). Some investigators argue that adipocyte sensitivity to insulin is maintained until well after other organs become insulin resistant but such work generally derives from studies on subcutaneous tissues rather than the generally accepted more relevant visceral

Monocytes Cytokines?

Pancreas

Pancreas

Insulin

Endothelium

CRP, PAI-1

Figure 2.3 The relevance of insulin action extends beyond skeletal muscle, adipose tissue and liver, and includes effects on endothelium and immune cell function. In healthy insulinsensitive subjects, it helps maintain low levels of free fatty acids (FFAs), and thus normal lipids, healthy endothelium and low cytokine levels. By contrast, in insulin-resistant subjects, such tissues respond less well to insulin, and thus derangements in the above pathways are favoured. (HDL-C = HDL-cholesterol; TG = triglycerides.)

Insulin

Endothelium

>High blood pressure/ adhesion molecules/1

molecules/ t-PA

Adipose tissue

PAI-1, IL-6, TNF-a adiponectin

PAI-1, IL-6, TNF-a adiponectin

CRP, PAI-1

Figure 2.3 The relevance of insulin action extends beyond skeletal muscle, adipose tissue and liver, and includes effects on endothelium and immune cell function. In healthy insulinsensitive subjects, it helps maintain low levels of free fatty acids (FFAs), and thus normal lipids, healthy endothelium and low cytokine levels. By contrast, in insulin-resistant subjects, such tissues respond less well to insulin, and thus derangements in the above pathways are favoured. (HDL-C = HDL-cholesterol; TG = triglycerides.)

adipose sites. Regardless of adipocyte insulin sensitivities, a simple increase in the mass of visceral fat tissue in obese individuals would in itself enhance FFA release. Such excess release of FFAs into the portal circulation drives excess hepatic triglyceride accumulation and synthesis, in the form of very-low-density lipoprotein (VLDL) particles, with a resultant increase in plasma triglyceride concentrations. It is clear that this process predates type 2 diabetes since, other than glucose, elevated plasma triglyceride concentration is arguably the strongest biochemical predictor of incident type 2 diabetes (Freeman et al., 2002). Indeed, it is often not well appreciated but triglyceride levels are far stronger predictors of diabetes than of CVD (Wilson etal., 2005).

The rise in triglyceride in the form of VLDL, in turn, promotes numerous atherogenic changes in other lipid particles. Critically, VLDL exchanges triglyceride for both LDL-and HDL-cholesteryl ester and this is one of the major mechanisms leading to a decline in HDL-cholesterol concentrations in the face of rising triglyceride concentrations. The cholesteryl esters transferred to triglyceride-rich lipoproteins (i.e. VLDL particles) render these 'remnant' particles more resistant to lipolytic breakdown and as a result more atherogenic, whereas hydrolysis of the accumulated triglyceride in LDL and HDL results in smaller, denser particles (Packard, 2006). Small, dense LDL particles are particularly atherogenic, whereas smaller HDL particles are less cardioprotective.

The above atherogenic lipoprotein perturbations are significantly exaggerated in the postprandial period, promoting enhanced plasma accumulation of cholesterol-enriched VLDL remnants, a further lowering in HDL-cholesterol and a further reduction in LDL particle size. Triglyceride intolerance (impaired clearance of postprandial lipaemia) is independently predictive of the presence of CVD (Eberly etal., 2003). Overall, the pattern of elevated FFAs and triglyceride, low HDL-cholesterol and increased preponderance of small, dense LDL is strongly associated with type 2 diabetes and insulin resistance. There exist multiple mechanisms by which this lipid pattern can accelerate atherogenesis, as recently reviewed and described in detail in Table 2.1 (modified from Sattar etal., 1998). In particular, small, dense LDL particles more

Table 2.1 Evidence linking atherogenic lipoprotein pertubations to endothelial dysfunction.

Particles

Potential mechanisms of endothelial damage

Triglyceride-rich lipoproteins and remnant particles

Small, dense LDL

Free fatty acids

High-density lipoproteins

Increase oxidative burden Directly toxic to endothelium Can cross endothelial barrier Stimulate endothelial cell PAI-1

production Activate Factor VII Increase endothelial cell expression of adhesion molecules Increase susceptibility to oxidative damage

Greater lysophosphatidylcholine content upon oxidisation Increase arterial residence time Increase penetration of arterial intima Increase affinity for endothelial proteoglycans Increase oxidative stress Facilitate endothelial transfer of LDL and cholesterol-rich remnant particles Reduce albumin's protective properties, thereby allowing expression of VLDL toxicity

Reduce endothelial cell production of prostacyclin and nitric oxide Impair ability of endothelial cells to inhibit platelet aggregation Antioxidant roles bind free transition metals

Intrinsic antioxidant enzymes Shuttle reactive hydroperoxides from endothelium to liver for excretion Limit endothelial toxicity of VLDL remnants readily enter the arterial intima due to their smaller size. Once entered, they are more likely to be retained or anchored by proteoglycans, and thus more likely to be oxidised, whereupon they become antigenic and will release signals to recruit monocytes and favour their transformation into foam cells through a receptor-mediated intake (scavenger pathway). In other words, oxidised LDL is the key signal initiating the atherosclerotic plaque. Oxidised LDL particles also show cytotoxic potential, which is in part responsible for endothelial cell damage and macrophage degeneration in the atherosclerotic human plaque.

Of interest, recent prospective population studies have demonstrated better CVD prediction from a high apolipoprotein B (ApoB) to ApoAI ratio compared to the traditionally accepted cholesterol to HDL-cholesterol ratio (Walldius etal., 2001; Sniderman, 2004). Apolipoprotein B is the key protein within LDL particles and rises with particle number, whereas ApoAI is the key protein within HDL particles responsible for its anti-atherogenic properties. It has recently been demonstrated that high ApoB correlates more strongly than LDL-cholesterol to insulin resistance, an observation that explains why ApoB levels are elevated in diabetes patients and why ApoB may better predict vascular events.

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