The two-edged sword.

Unlike most chronic illnesses which have been declining or stabilizing in prevalence, incidence of type 2 diabetes has been increasing in the Western Hemisphere, and is now increasing at alarming rates in Asia1. While all causes of these increases cannot be identified, without question the increase in adiposity is an important contributor. The latter is due to increased caloric intake and reduced energy expenditure, although other factors may contribute2. Adiposity leads to insulin resistance, which in normal individuals elicits an hyperinsulinemic response, which compensates for the insulin resistance. Unresolved questions relate to whether fat storage in specific depots is particularly egregious, what mechanisms are responsible for the pancreatic islet-cell compensation, and why said compensation can fail, leading to diabetes in some, but not all individuals. Epidemiological studies suggest that visceral fat is particularly detrimental to metabolic health. Direct evidence favoring the importance of visceral fat is the result of surgical extirpation of the superior omentum in the canine model. While eliminating only 7% of total visceral fat in the dog, insulin sensitivity increased over 50%. This study compliments human data from Klein et al that evisceration of subcutaneous fat did not alter insulin resistance. Why is visceral fat detrimental? Induction of visceral adiposity by feeding of an hypercaloric high fat diet leads to insulin resistance for several reasons: a) increase of stored visceral fat in adipocytes which are themselves insulin resistant resulting in flux of free fatty acids (FFA) from viscera to liver and extrasplanchnic tissues; b) action of the sympathetic nervous system (SNS) which favors lipolysis and causes pulsatile release of FFA from visceral fat into the portal circulation; c) effects of pulsatile release of FFA which results in hepatic insulin resistance, associated with upregulation of liver gluconeogenic enzymes (fig. 1). Interestingly, the resultant insulin resistance of liver can be successfully reversed by antagonism of the cannabanoid system with rimonabant. The role of FFA in pathogenesis of insulin resistance has been questioned, as evidence was lacking for increased fasting FFA in obese individuals. Recently we reported a powerful circadian rhythm in FFA levels, with a peak in levels between 2 and 4 AM. We propose that it is the nocturnal surge in plasma FFA which is responsible for onset of insulin resistance in the overweight subject (fig. 2). This surge is due at least in part to a night-time outpouring of FFA from the visceral fat depot. We propose that omentectomy reduces this outpouring and increases insulin sensitivity. Not all insulin obese, insulin resistant individuals develop Type 2 diabetes, and induction of insulin resistance per se does not cause Diabetes mellitus hoy