Our study offers a novel insight into the pathogenesis of prediabetes in obese children and adolescents—namely, that changes in glucose homoeostasis are closely linked with altered partitioning of fat in both skeletal muscle and adipose tissues. We found that obese children and adolescents with impaired glucose tolerance had: profound peripheral insulin resistance with major defects in the non-oxidative pathway of glucose metabolism; no compensatory increases in insulin secretion; low adiponectin concentrations; and similar magnitude of suppression of total body lipid oxidation, plasma fatty acids, and glycerol turnover. Most importantly, early in the development of type 2 diabetes in obese young people, increased intramyocellular lipid accumulation, along with an increased visceral fat mass, are related to insulin resistance. These differences are unlikely to be due to differences in percentage body fat, age, sex, or pubertal stage of development, because the two groups had similar distributions of these variables and we adjusted for them in the analysis.
Obese children and adolescents with prediabetes are a useful group for studying the initial pathophysiological changes relevant to the alterations in glucose metabolism, because they are free from the confounding effects of ageing on insulin sensitivity and secretion and reflect the earliest stage of prediabetes. Our study clearly showed that obese young people with impaired glucose tolerance show pronounced defects in the nonoxidative pathway of glucose metabolism. This metabolic defect is similar to that observed in adults with overt type 2 diabetes.28
Our study showed also that intramyocellular lipid accumulation is associated with insulin resistance in children with prediabetes, thus further supporting the view that increased lipid content in myocytes is a marker of impaired insulin action.10
Indeed, abnormalities in insulin signalling have been found to arise as a result of overaccumulation of various lipid moieties in myocytes, such as long-chain fatty acyl-CoA, which interferes directly with insulin signalling and glucose transport.11–14
Consistent with these findings is the inverse relation between intramyocellular lipid content and non-oxidative glucose disposal we found. Further evidence of cause and effect between intramyocellular lipid and insulin resistance came from a study by Greco and colleagues,29
which showed that selective depletion of intramyocellular fat stores restored normal insulin sensitivity in obese adults, despite a persistent excess of total body fat mass. In our study, sex and ethnicity did not significantly affect the intramyocellular lipid content. No differences in extramyocellular lipid between our groups were found, perhaps because the 1
H-NMR technique is limited in its ability to quantify extramyocellular fat.30
As a possible mediator of triglyceride accumulation, the adipocyte-derived hormone adiponectin has emerged as an important player in the genesis of insulin resistance.31
The low adiponectin concentrations found in the obese children with impaired glucose tolerance imply a role of adiponectin in the genesis of insulin resistance in such individuals.
In this study, baseline plasma fatty acid concentrations did not differ significantly between the groups. This finding should, however, be interpreted in light of the hyperinsulinaemia in the group with impaired glucose tolerance, which suggests that baseline lipolysis may be resistant to the suppressive effects of insulin. However, both fatty acid concentrations and glycerol turnover during the low-dose and high-dose insulin infusions were similar in the two groups, which argues against a reduced antilipolytic effect of insulin in prediabetes. Similarly, the suppression of lipid oxidation rates was of similar magnitude in both groups. These findings suggest that insulin resistance is mainly confined to muscle tissue and that defective suppression of lipolysis may not contribute to the increased intramyocellular lipid content in these young people. The baseline hepatic glucose production rates were similar in the two groups, suggesting that hepatic insulin resistance did not have a major role in early prediabetes in our participants.
Visceral fat accumulation is known to be associated with features of the insulin resistance syndrome in adults and obese children,6
although the nature of this association and the relative importance of visceral and subcutaneous abdominal fat remains a matter of debate. An intriguing suggestion in this study was that altered distribution of fat between the abdominal subcutaneous and visceral compartments is associated with the development of impaired glucose tolerance. The participants with impaired glucose tolerance had more visceral fat and less abdominal subcutaneous fat than those whose glucose tolerance was normal. Therefore, the visceral-to-subcutaneous ratio was significantly greater in those with impaired glucose tolerance. Both the enlarged visceral depot and the visceral-tosubcutaneous ratio were inversely related to the insulin-stimulated glucose metabolism after adjustment for overall adiposity. Although the two groups participating in the MRI study had similar percentages of body fat, there were some differences—albeit small—in the sex and ethnic distribution. Therefore, these differences in abdominal fat partitioning between the two groups require further investigation. Owing to the small sample size, we were unable to detect any significant sex or ethnic differences in visceral adipose tissue and intramyocellular lipid content within or between groups. Adequately powered studies are warranted to address these important issues.
First-phase and second-phase insulin secretion rates were similar in both groups. These data should be viewed cautiously, because they are absolute measurements. When we estimated insulin secretion in the context of the “resistant milieu” of the participants with impaired glucose tolerance, the secretion of insulin was not able to compensate for the increased resistance, resulting in a pronounced decrease in insulin-stimulated glucose metabolism. This feature can be viewed as a “relative” β-cell failure due to the inability of these participants to overcome the extraordinary insulin resistance.
The results of this study shed new light on the findings of Weyer and colleagues,32
who studied progression to diabetes in adult Pima Indians. As in their findings, a reduction in insulin-stimulated glucose disposal, mainly in the nonoxidative pathway, characterised the progressors to diabetes. In that study, progressors gained more weight, but the tissue localisation of lipid deposition was not directly assessed. Our results emphasise that lipid deposition in intramyocellular and visceral compartments—and not necessarily increased weight per se—are related to the reduction in insulin sensitivity. In contrast to Weyer and colleagues’ findings, we did not detect an absolute reduction in the acute insulin response in patients with impaired glucose tolerance, although the cross-sectional design of our study limits the comparison. This discrepancy may imply that β-cell failure is a late development in adolescents. The differences in the populations studied may explain other differences in their metabolic profiles.
In summary, early in the natural history of type 2 diabetes in obese young people, altered partitioning of fat in both skeletal muscle and abdominal adipose tissues is closely linked to insulin resistance. Increased intramyocellular and intra-abdominal fat accumulation is strongly related to post-glucose hyperglycaemia in obese prediabetic young people.