In his last post Loren Cordain wrote: '....Neel's hypothesis has become "one of the orienting concepts of nutritional and biomedical anthropology" ..... So very true, and not just anthropology but nutritional biochemistry and molecular biology too. Just about every paper on the origins of obesity and diabetes mentions it. It's as if Neel's hypothesis is considered proven beyond reasonable doubt. Loren suggested I might elaborate on the mechanisms behind our hypothesis (1) that 'ultra' high protein diets selected for the insulin resistant genotype rather than cycles of feast and famine (ie the thrifty genotype hypothesis). The mechanism relates to both the high protein intake as well as the simultaneously low carbohdyrate intake. We hypothese that the need to spare carbohdyrate for the brain and fetus which use glucose as their preferred fuel would have required metabolic mechanisms that re-directed glucose away from the muscles. That's exactly what insulin resistance does best! What's more insulin resistance in the liver promotes gluconeogenesis even in the face of the moderate insulinaemia which accompanies high protein meals. We have had the opportunity to revise the hypothesis for World Review of Nutrition and Dietetics (in press). Here is the abstract from that paper (I'd appreciate any new feedback): TimesInsulin resistance may provide valuable insights into past human existence and diet. A critical role is proposed for the quantity and quality of dietary carbohydrate in the pathogenesis of the insulin resistance and hyperinsulinemia which characterise the metabolic syndrome, non-insulin-dependent diabetes mellitus (NIDDM) and heart disease. Our hypothesis, the carnivore connection, proposes that an insulin-resistant genotype evolved to provide survival and reproductive advantages to populations adapted to a high meat, low plant food (low carbohydrate) nutritional environment. Unlike true carnivores, humans have a limited capacity for gluconeogenesis even on a high protein diet. Insulin resistance would have maximised gluconeogenesis and redirected glucose away from muscles facilitating the preferential utilisation of glucose by the brain, fetus and mammary gland. But about 10,000 years ago, following the end of the last Ice Age, carbohydrate intake increased with the development of agriculture in the Middle East and Europe and the selection pressure for insulin resistance was relaxed. Hence the prevalence of the insulin-resistant genotype decreased in Europeans and other groups exposed to a high carbohydrate diet for sufficiently long. The Mongoloid ancestors of both Pima Indians and Nauruans occupied the Siberian mammoth steppe during the final 20,000 years before the end of the last Ice Age. These groups depended on a high meat diet and did not develop agriculture until 2,000 years ago. Australian Aborigines never developed agriculture and until this century ate an animal-based diet. Thus Pima Indians, Nauruans and Australian Aboriginals have had only recent exposure to a high carbohydrate diet and currently have among the highest rates of NIDDM in the world. While their traditional carbohydrate foods have a low glycaemic index and stimulate only modest increases in plasma insulin, westernisation is associated with the intake of refined, high glycaemic index carbohydrate which results in pronounced postprandial hyperinsulinemia. In this context the insulin resistant genotype is disadvantageous and predisposes to the development of the metabolic syndrome, NIDDM and heart disease. (1) Brand Miller JC, Colagiuri S. The carnivore connection: dietary carbohydrate in the evolution of NIDDM. Diabetologia 37: 1280-1286, 1994. Best wishes Jennie Jennie Brand Miller PhD Associate Professor in Human Nutrition Department of Biochemistry G08 University of Sydney NSW 2006 Australia Phone: (61 2) 9351 3759 Fax: (61 2) 9351 6022