Insulin itself may contribute to obesity. A high first-phase insulin response to intravenous glucose has been shown to be a risk factor for long-term weight gain, and this effect is particularly manifested in insulin-sensitive individuals. 76 Also, compared to normal children, Pima Indian children with elevated fasting insulin gain more weight over time. 77 Insulin inhibits hormone sensitive lipase thereby preventing fatty acid release from adipose tissue and encourages fat storage. 78
Elevated levels of insulin after a high glycemic meal can contribute to increased hunger and eating behavior that can contribute to obesity. 79 Evidence suggests that elevated insulin can induce insulin resistance by its degradation effects on insulin receptors. 80 It is the old “chicken and egg” question. Perhaps there is a bit of both—in some cases insulin resistance occurs which instigates or exacerbates weight gain while in others it’s the weight gain that instigates the insulin resistance. In either case, a high glycemic load can lead to chronically elevated CRP 81 and insulin levels 79, 82, 83 and exacerbate the situation. Insulin resistance in the brain may impair insulin’s ability to satisfy a satiety center which also could contribute to overeating, obesity, and diabetes. 84
Tumor necrosis factor-alpha (TNF-a)
Tumor necrosis factor-alpha is a cytokine secreted in proportion to the percentage of body fat. 85 It can damage the insulin-producing beta cells in the pancreas, inhibit secretion of insulin, and may also produce resistance to insulin, especially in fat and muscle. 85 86, 87 It also activates phospholipase A2 and synthesis of arachidonic and metabolites in endothelial cells which can play a role in inflammation, vasoconstriction, and thrombosis. 86, 87 TNFa can incite the immune system to attack healthy tissue throughout the body. Elevated TNF-a can cause diffuse inflammation that may result in painful arthritis along with vascular (blood-vessel) complications. It also induces breakdown of muscle, causing the cachexia or wasting that occurs in such chronic diseases as congestive heart failure, cancer, and pathological aging. 88-91
Fat’s role in inflammation
CRP and therefore inflammation are related to insulin resistance as well as to waist size and abdominal fat. These stores of fat are not just innocent bystanders hanging around doing nothing. Stored fat or adipose tissue contributes heavily to a low-level, chronic inflammatory state. Besides its connection to CRP, fatty tissue produces and releases other inflammatory substances, including interleukin-6 (IL-6) 72 and tumor necrosis factor alpha (TNFa) into the circulation. Omental or visceral fat cells in vitro have been shown to secrete as much as two to three times more IL-6 than cells derived from subcutaneous fat stores. 92 This may shed light on the connection between excess abdominal fat and insulin resistance in the liver and other metabolically active tissues since venous drainage from omental fat provides direct access to the liver’s portal system. 62 TNFa produced by fat cells also appears to be implicated in inducing resistance to insulin. 93, 94 Thus overweight people have excess body fat, which produces inflammatory substances and low-level, chronic inflammation that may induce endothelial dysfunction and resistance to insulin. This process links these conditions (endothelial dysfunction and insulin resistance) to obesity, cardiovascular disease, and diabetes.
At least 90 percent of patients with type 2 diabetes are overweight. While simply being overweight is a risk for type 2 diabetes, one must also bear in mind that a subset of non-obese adults without apparent glucose abnormalities can rapidly develop type 2 diabetes, which may be attributable to an autoimmune and inflammatory process. 95 Barzilay et al found that in those with lower BMI (less overweight), there was a stronger association with inflammation as glucose levels progressed. This suggests that inflammation in leaner patients with type 2 diabetes might not be due entirely to the production of inflammatory cytokines by fat cells. 61 There is a condition known as metabolically obese, normal weight, where individuals have a low BMI but are insulin resistant. However, there usually exists some excess abdominal fat for that given individual. 96 Even modest weight loss can prevent and reverse type 2 diabetes, 97 and sustained weight loss in obese women results in a reduction in elevated inflammatory cytokine levels and an amelioration of endothelial dysfunction. 98 Surgical removal of visceral fat may reduce insulin resistance and plasma insulin levels. 99
Could infectious agents play a role in type 2 diabetes?
Some chronic diseases follow the same pattern as in other epidemics that eventually were found to be caused by a biological agent. 100 An example is the induction of peptic-ulcer disease by Heliobacter. 101 Six viruses have been shown to cause obesity in animal models including Adenovirus Ad-36 which is a human pathogen. Sera of 360 obese and 142 nonobese subjects screened for the presence of Ad-36 revealed a significantly greater prevalence in the obese (30 percent) vs. the nonobese (11 percent). 102 Could infectious agents precipitate inflammation and trigger endothelial activation, leading to endothelial dysfunction, insulin resistance, weight gain, and diabetes? This is an intriguing possibility.
Reconsidering cholesterol and atherosclerosis
Consider the following facts. More than half of all MIs occur in people with normal plasma lipid levels and 40 percent have no warning symptoms 103 Eighty percent of people who develop CAD have the same blood cholesterol values as those who do not 104 develop CAD In fact, angiographic studies indicate that the average stenosis of lesions leading to acute MI is less than 50 percent, with infarction occurring due to rupture of non-occlusive plaques triggering acute thrombosis. 105
The beneficial effects of statin agents may be independent of serum lipid levels and can occur before lipid lowering. 106-109 In the CARE and other trials, the risk of an MI was reduced to the same degree whether the cholesterol level was lowered by a large or small amount, i.e., “lack of exposure response.” 110 Those who had their LDL lowered by the greatest amount, had the least protection against CHD events. In the Heart Protection Study, 111 statins protected against CHD even in people with normal LDL levels, and the study (as well as others, e.g. CARE, 112 LIPID, 113 APSCAP-TexCAPS, 114 and MIRACL 115 ) failed to demonstrate any dose-response effect on LDL lowering. 109
While a number of factors can damage the endothelium and accelerate atherosclerosis, oxidants and free radicals are major initiators of vessel wall damage as we will discuss below. Statins have been shown to prevent the activation of monocytes into macrophages, inhibit the production of pro-inflammatory cytokines, C- reactive protein, and cellular adhesion molecules, and decrease the adhesion of monocyte to endothelial cells. 116 The benefit of statins may be their anti-inflammatory effect, and the lowering of cholesterol may be an interesting side effect. LDLs appear to be harmful only when they are oxidized. Without a pro-oxidant or pro-inflammatory environment elevated lipids are significantly less of a threat, and perhaps harmless. Ridker et al showed that of 12 markers measured, including lipid profiles, plasma levels of highly sensitive C-reactive protein was the strongest univariate predictor of the risk of cardiovascular events. Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone. 64 Again, what we may be seeing is that an inflammatory milieu is the critical factor, and when lipids are elevated in this environment, only then do they become problematic, i.e., they become oxidized and contribute to the atherosclerosis process.
Recent evidence suggests that stress-induced increase in renal cholesterol accumulation, possibly unrelated to HMG-CoA reductase, may reflect a role for cholesterol as an acute phase inflammatory reactant. 117 Apolipoprotein E, a component of HDL cholesterol, is a strong predictor of CRP, 118 and HDL may have anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, pro-fibrinolytic, and plaque stabilizing activities. 119, 120 In addition to predicting CRP and inflammation, a low HDL may be a good marker for insulin resistance and endothelial dysfunction. 69