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To be predisposed to insulin resistance and type 2 diabetes

It has long been recognized that some people in some families are predisposed to insulin resistance and type 2 diabetes from birth, and because insulin resistance consistently has been found in first degree relatives and offspring of patients with type 2 diabetes, the prevailing view has been that insulin resistance is an at least partly genetically determined trait playing a key role in the development of type 2 diabetes (Beck-Nielsen & Groop, 1994). Zhu et al. report in this issue of The Journal of Physiology that obesity in pregnant sheep (ewes) induced by over-nutrition from 60 days before to 75 days after conception was associated with the development of whole-body insulin resistance and glucose intolerance in the ewes, and most importantly with impaired signalling of the crucial AMP-activated protein kinase 8AMPK, as well as insulin receptor substrate-1 (IRS-1)-associated phospho-inositide-3 kinase (PI3K) pathways in fetal skeletal muscle (Zhu et al. 2008). Insulin signalling through PI3K mediates the majority of the metabolic effects of insulin including membrane glucose transport and glycogen synthesis, and AMPK acts as an intracellular sensor that once activated, promotes membrane glucose uptake and mitochondrial energy (ATP) production. 
 
The implications for our current understanding of the origin of insulin resistance and type 2 diabetes are numerous. Firstly, the study provides further evidence that under-nutrition in utero and low birth weight are not the only metabolic and nutritional challenges operating early in life increasing risk of later development of insulin resistance and type 2 diabetes (Hales & Barker, 2001). While under-nutrition in utero may be relevant to some current and historical life circumstances and populations, the propagation of Western life style, over-nutrition and obesity in virtually all parts of the world has gradually changed the focus and quantitative relevance away from under-nutrition and over to the potential deleterious effects of over-nutrition and obesity in pregnancy. Thus, it is most likely that the consequences of programming induced by over-nutrition in utero may contribute significantly to the enormous burden of disease associated with type 2 diabetes and the metabolic syndrome in countries like the United States. 
 
As mentioned by Zhu et al. (2008), Warram et al. reported almost two decades ago that insulin resistance predicts the development of type 2 diabetes in the offspring of diabetes parents (Warram et al. 1990). Indeed, young and otherwise healthy offspring of diabetic parents commonly exhibit insulin resistance and impaired muscle insulin signalling and glycogen synthesis many decades before onset of overt type 2 diabetes (Vaag et al. 1992), and it has for a long time been thought that muscle insulin resistance may represent an inherited or genetic trait in type 2 diabetes (Beck-Nielsen & Groop, 1994). Much to the surprise of many investigators in the field, recent large-scale genome-wide association (GWA) studies failed to identify any polymorphisms of genes involved in insulin action or insulin signalling contributing to the development of type 2 diabetes (Frayling, 2007). Instead, a number of genes thought to be involved in the control of insulin secretion showed polymorphisms that conferred marginally but statistical significantly increased susceptibility to type 2 diabetes (Frayling et al. 2007). With the report by Zhu et al. it may now be speculated that insulin resistant offspring of diabetic mothers to some unknown extent may be due to obesity and/or mild glucose intolerance during pregnancy per se, and not necessarily to genetics. Indeed, it is likely that the women who later develop type 2 diabetes may have been obese many years before onset of overt disease, and/or that they due to genetics (including genetic beta cell dysfunction) may have had glucose intolerance or overt (gestational) diabetes during pregnancy (even without knowing it) decades before they had the diagnosis of type 2 diabetes. Although many genes involved in the development of type 2 diabetes are yet to be discovered, the possibility that ‘genetic insulin resistance’ to some extent may be due to intrauterine programming should be kept in mind in the future. Similarly, heritability estimates of insulin resistance and related diseases inherent in the metabolic syndrome including besides type 2 diabetes (abdominal) obesity, hypertension, dyslipidaemia and even premature cardiovascular disease, as obtained from family studies should keep the possibility open that the trait in focus may not necessarily have a genetic origin, in particular if the criteria of a positive family history includes having a mother as a – or the – proband.