Four-Stage Evolution of Diabetes or Whole-Body Insulin Resistance (WBIR): Debunking of The Lipid-Induced Insulin Resistance (LIIR) and Proposing of the Glycation-Induced Insulin Resistance (GIIR)

Abstract

Song Jae Lee and Sang Won Shin

Insulin resistance (IR) would develop first preferentially in the muscle tissue with a relatively low cell turnover and then progress in sequence to the subcutaneous adipose tissue, then to the visceral adipose tissue, and then to the liver with higher cell turnovers. Moreover, metabolic disruptions due to IR would vary widely from tissue to tissue, contrary to the widespread notion that IR impairs merely glucose uptake in tissues. This warrants that IR be divided better into four distinct tissue-specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s-AIR), visceral adipose insulin resistance (v-AIR), and hepatic insulin resistance (HIR). Tissue-specific IRs developing in the order of MIR, s-AIR, v-AIR, and HIR with uniquely tissue-specific metabolic disruptions would amount to nothing but the whole-body insulin resistance (WBIR) evolving in four distinctively insulin-resistant stages, IR-I to IR-IV stage. The four-staged metabolic evolution from rapid weight gain (IR-I stage) to visceral obesity (IR-II stage), then to rapid weight loss (IR-III stage), and then to full-blown diabetes (IR-IV stage) not only complies well with the natural development history of diabetes but also resolves many controversies regarding obesity or diabetes, including visceral obesity, obe- sity paradox, and dawn phenomenon that have long remained metabolic puzzles. In addition, the entrenched notion of the lipid-induced insulin resistance (LIIR), which is refuted by four-stage WBIR evolution and believed to be the main culprit for the current epidemic of obesity and diabetes around the world, was debunked thoroughly. Then, in order to replace the LIIR, the glycation-induced insulin resistance (GIIR) was proposed and verified to be compatible to the four- stage WBIR evolution.

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