fryone, I can send you a copy of my these if you like! There are a couple of very clear links between obesity and insulin resistance.\
I quote:
1.3 Pathogenesis of insulin resistance
There are at least two currently prevailing hypotheses for the pathogenesis of insulin resistance. These are not mutually exclusive and in many respects probably complementary.
1.3.1 White adipose tissue inflammation
It is well recognised that obesity affects the metabolic and endocrine functions of white adipose tissue. The subsequent release of fatty acids, hormones and proinflammatory molecules are thought to result in complications, such as insulin resistance and T2DM. This can be seen in infiltration of adipose tissue by the increased number of macrophages and other inflammatory cell types seen in obesity with the subsequent activation of inflammatory pathways21,22 (Figure 1).
This response is believed to depend upon the production of chemotactic factors by adipocytes and stromovascular cell types. The chemotaxins are released in response to metabolic stress, including mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and the production of reactive oxygen species (ROS). Ultimately adipocyte stress appears to lead to cell death, with rupture of the plasma membrane, dilatation of the endoplasmic reticulum, and release of cell debris into the extracellular space. This differs from normal apoptosis, when cell constituents are packaged into inflammation-suppressive bodies. A significant component of the inflammatory response involves macrophages surrounding these dead or dying cells to ‘mop up’ cell debris23.
Subsequent release of cytokines, such as TNF-?, monocyte chemotactic protein-1 (MCP-1) and interleukin-1 (IL-1), then cause white adipose tissue endocrine dysfunction, impaired muscular glucose disposal, impaired pancreatic beta cell function and cell regeneration, and reduced suppression of hepatic glucose production.
1.3.2 The ‘overflow’ hypothesis
The other theory proposes that the capacity of adipocytes to accommodate all the triglyceride generated in states of sustained positive energy balance through a combination of hypertrophy and hyperplasia is ‘finite’ and that sustained positive energy balance ultimately leads to adipocyte dysfunction and ‘lipid overflow’ to other sites such as the liver, skeletal muscle, and even pancreatic ?-cells (Figure 2)24,25,26. Obesity, a state in which the capacity of adipose tissue to store surplus energy as triglyceride is eventually exceeded, is the most common cause for ectopic lipid accumulation (‘the ‘overflow’ hypothesis’).
Triglyceride accumulation in the liver and skeletal muscle can be precisely quantified by magnetic resonance spectroscopy and has been convincingly shown to correlate very tightly with insulin resistance (r ? 0.6-0.7)27. While triglyceride itself is not thought to cause insulin resistance, accumulation of more reactive lipid species, such as diacylglycerol and ceramide, in ‘ectopic’ sites, such as the liver and skeletal muscle, activates a range of serine kinases (e.g. Protein kinase C theta type (PKC?) and c-Jun N-terminal kinases (JNK)) triggering increased phosphorylation of insulin receptor substrate 1 (IRS-1) on serine residues, which then inhibits insulin receptor kinase phosphorylation of IRS-1 on critical tyrosine sites required for phosphatidylinositol 3-kinase (P13K) activation, ultimately inhibiting insulin stimulated glucose uptake3.
Adipose tissue dysfunction is likely to lead to excess lipid flux to liver and muscle, but lipid accumulation in these sites may also be a consequence of impaired lipid oxidation or disposal. Since fatty acid oxidation primarily takes place within mitochondria, defects in mitochondrial function are likely to lead to lipid accumulation. This is consistent with the finding of lipodystrophy in patients with some mitochondrial diseases, such as in multiple symmetric lipomatosis where multiple large subcutaneous lipomas are associated with mutations in mitochondrial DNA28.
There is considerable support for this hypothesis from a number of human and murine studies, demonstrating mitochondrial abnormalities, in both insulin-resistant pre-diabetic and diabetic states, and the potential role of mitochondrial dysfunction in ectopic fat deposition. These include ex vivo morphological and biochemical analyses of muscle biopsies demonstrating smaller mitochondria in diabetic individuals, a finding also seen in a number of myopathies known to result in mitochondrial dysfunction29, reduced mitochondrial density of young, lean, insulin resistant offspring of parents with T2DM30, significantly reduced activity of nicotinamide adenine dinucleotide (NADH) oxidase indicating reduced mitochondrial electron transport chain activity in obese and diabetic volunteers31, reduced functional capacity and number of subsarcolemmal mitochondria in diabetic and obese volunteers32, and decreased expression of genes involved in oxidative phosphorylation or mitochondrial metabolism in diabetic muscle33,34,35,36. This has also been demonstrated in vivo by magnetic resonance spectroscopy studies, showing reduced mitochondrial oxidation and phosphorylation in elderly insulin-resistant volunteers37, reduced mitochondrial phosphorylation in insulin-resistant offspring of parents with T2DM38, and impaired mitochondrial function as measured by phosphocreatine (PCr) recovery half-time after exercise39,40 and adenosine triphosphate (ATP) flux41 in patients with T2DM.
References available on request!