Obesity, Body Fat Distribution, Insulin Sensitivity and Islet β-Cell Function as Explanations for Metabolic Diversity

Abstract

Studies of metabolic processes have been enhanced by our understanding of the relationships among obesity, body fat distribution, insulin sensitivity and islet beta-cell function. Thus, we have learned that although insulin resistance is usually associated with obesity, even lean subjects can be insulin resistant due to the accumulation of visceral fat. Insulin sensitivity and beta-cell function are also intimately linked. The hyperbolic relationship between these two parameters explains why insulin-resistant individuals have markedly enhanced insulin responses, whereas subjects who are insulin sensitive exhibit very low responses. Failure to take into account this relationship will lead to erroneous conclusions. By accounting for this important interaction, it has been clearly demonstrated that subjects at high risk of developing type 2 diabetes (older individuals, women with a history of gestational diabetes or polycystic ovary syndrome, subjects with impaired glucose tolerance and first-degree relatives of individuals with type 2 diabetes) have impaired beta-cell function. Furthermore, the progression from normal glucose tolerance to impaired glucose tolerance and type 2 diabetes is associated with declining insulin secretion.

Adult BMI and fat distribution but not height amplify the effect of low birthweight on insulin resistance and increased blood pressure in 20-year-old South Africans

“…In this study, waist circumference, as a marker for abdominal fat distribution and fat mass, as a marker of general fat distribution, had similar associations with the cardiovascular risk factors. This is contrary to current evidence that visceral fat is a better marker of insulin resistance and cardiovascular risk than generalised fat [32]. Possible explanations for our findings include the fact that waist circumference reflects visceral, as well as deep and superficial subcutaneous fat.…”

Early disturbances in insulin secretion in the development of type 2 diabetes mellitus

“…'Second' phase secretion has been shown to be lower than secretion occurring in non-diabetic controls at identical plasma glucose. It is of note, that insulin resistance itself has been shown to lead to 'upregulation' of the B-cell secretion (Tayek et al, 1997;Kahn et al, 2001), which underlines the importance of matching study subjects for obesity and age.…”

“…In studies in 283 non-diabetic subjects in whom insulin sensitivity and beta cell function were assessed with hyperglycemic clamps, we found that both are important for fasting and 2 h post OGTT plasma glucose levels, with tissue insulin sensitivity having the largest impact . One of the intrinsic problems is that insulin sensitivity has a marked impact on beta cell function (Tayek et al, 1997;Kahn et al, 2001); it may, therefore, remain cumbersome to dissect the impact of each of them.…”

“…Again, matching for obesity (and age) is important for the interpretation of these results (Kahn et al, 2001). Indeed, in studies in which obesity and insulin resistance was taken into account acute insulin release was reported to be inappropriately low in insulin-resistant FDRs of diabetes patients (Nyholm et al, 2000).…”

The changing phenotype of the human species (affluent variety)

“…Seen from this perspective, it is not surprising that major genes conferring susceptibility to obesity or Type 2 diabetes are rare. Instead we encounter a complex patchwork of genetic and developmental influences upon insulin secretion, insulin resistance, fat deposition and inflammation [16]. The pioneers of diabetes genetics tended to view the body as a malfunctioning machine, on the assumption that correction of faulty genes or the pathways they controlled would restore a state of healthy normality.…”