Actually, insulin resistance begins in the hypothalamus through a combination of ER stress and increased levels of palmitic acid interacting with fatty-acid receptors. In animal studies you can see increased insulin resistance in the hypothalamus within 24 hours of starting a high-fat diet. In humans, it appears to take 48 hours. If over-nutrition is the cause of insulin resistance, then calorie restriction is the cure. This is why the dietary guidelines of the Joslin Diabetes Center and the Zone Diet are virtually identical. Both are a calorie-restricted, hormonally balanced diet to maintain stable blood sugar levels.