Catch-up growth, while crucial for recovery from growth impairment, is linked to increased risks of type 2 diabetes and cardiovascular disease later in life. This is often characterized by disproportionately higher fat recovery compared to lean tissue, with hyperinsulinemia as an early marker. Previous studies using a rat model of semistarvation-refeeding showed that despite skeletal muscle insulin resistance, animals refed on a low-fat diet maintained blood glucose homeostasis through increased insulin-stimulated glucose uptake in adipose tissue and enhanced de novo lipogenesis. However, a high-saturated and monounsaturated fat diet blunted adipose tissue insulin sensitivity, leading to hyperinsulinemia and glucose intolerance. Prior research from the same laboratory indicated that diets enriched with essential polyunsaturated fatty acids (ePUFA) – linoleic and α-linolenic acid – prevented excessive fat deposition and improved glucose homeostasis during catch-up growth. This study aimed to investigate the mechanism of this improvement, specifically testing the hypothesis that the high ePUFA diet would enhance insulin sensitivity in skeletal muscle and adipose tissues by measuring in vivo glucose utilization during hyperinsulinemic-euglycemic clamps.

Extensive epidemiological data and clinical studies have established a link between catch-up growth and increased risks of type 2 diabetes and cardiovascular diseases in adulthood. The underlying mechanisms remain unclear, but a common feature is the preferential accumulation of body fat relative to lean tissue during this period, often accompanied by hyperinsulinemia. Previous work by the authors and others has explored the role of dietary fat composition in modulating these metabolic responses. Studies using rat models of semistarvation and refeeding demonstrated the importance of adipose tissue insulin sensitivity and de novo lipogenesis in maintaining glucose homeostasis during catch-up growth. Furthermore, earlier research from this lab showed that high-fat diets rich in ePUFA could mitigate the negative metabolic effects associated with catch-up growth on high-saturated and monounsaturated fat diets.

Male Sprague-Dawley rats (6 weeks old) were subjected to a 2-week period of caloric restriction (approximately 50% of ad libitum intake), followed by 1–2 weeks of isocaloric refeeding. Three dietary groups were compared: a low-fat (LF) diet, a high-fat diet rich in saturated and monounsaturated fatty acids (HF-SMFA), and a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) from safflower and linseed oils. Body composition (fat mass, lean mass, body water) was assessed via carcass drying and Soxhlet extraction. Glucose tolerance tests were performed on days 7–8 of refeeding to evaluate glucose and insulin responses to a glucose load. Hyperinsulinemic-euglycemic clamps, using two different insulin doses (high and low), were conducted on days 7–8 of refeeding to measure whole-body and tissue-specific insulin-stimulated glucose utilization. The in vivo glucose utilization index was determined using the labeled 2-deoxy-glucose technique. Activities of key de novo lipogenic enzymes (fatty acid synthase and glucose-6-phosphate dehydrogenase) were measured in adipose tissue samples. Statistical analyses included one-way ANOVA and Scheffe's post-hoc test (p<0.05).

Semistarvation resulted in a significant reduction in body fat but not lean mass. Refeeding with the HF-SMFA diet led to significantly greater fat gain compared to the LF diet. The HF-ePUFA diet, however, prevented the excessive fat gain and resulted in a higher lean mass compared to both the LF and HF-SMFA groups. The glucose tolerance test showed higher glucose and insulin responses in the HF-SMFA group compared to the LF and HF-ePUFA groups, with no difference between LF and HF-ePUFA. Hyperinsulinemic-euglycemic clamps revealed significantly lower glucose infusion rates (GIR) in both HF groups compared to the LF group, suggesting lower whole-body insulin sensitivity. Although the HF-ePUFA group tended to have a higher GIR than the HF-SMFA group, this difference was not statistically significant. Tissue-specific analysis showed no increase in insulin-stimulated glucose utilization index (GUI) in any skeletal muscle studied with the HF-ePUFA diet. GUI in white adipose tissue depots was only marginally higher in the HF-ePUFA group compared to the HF-SMFA group. De novo lipogenic enzyme activities tended to be higher in the HF-ePUFA group compared to the HF-SMFA group, but this was not consistently statistically significant across all adipose tissue depots.

The study confirmed that high-fat diets rich in ePUFA effectively counter the impaired glucose homeostasis and excessive fat deposition observed during catch-up growth with high-saturated and monounsaturated fat. However, the mechanism does not appear to be primarily through increased insulin sensitivity. Despite a tendency for lower basal insulin and improved glucose tolerance in the HF-ePUFA group, whole-body and tissue-specific insulin sensitivity, as assessed by the glucose infusion rate and glucose utilization index, showed only marginal improvement in adipose tissue, and no improvement in skeletal muscle. These results suggest that other mechanisms beyond enhanced insulin sensitivity are crucial for the beneficial effects of ePUFA. The authors propose potential mechanisms like insulin-independent glucose uptake pathways in skeletal muscle or other tissues (stimulated by ePUFA) and the positive influence of increased lean mass due to ePUFA-rich diet, thus providing a larger glucose buffering capacity.

The study demonstrates that the beneficial effects of high-ePUFA diets in preventing impaired glucose homeostasis during catch-up growth are not primarily mediated by increased insulin sensitivity in skeletal muscle or adipose tissue. Instead, insulin-independent mechanisms and increased lean mass may play more significant roles. Future research should investigate these alternative mechanisms, particularly the role of insulin-independent glucose uptake pathways, and the impact of specific ePUFA components and their metabolites on various metabolic pathways.

The study used a rat model, which may not perfectly replicate human physiology. The study focused on a specific type of high-fat ePUFA diet (safflower and linseed oil), and the results may not be generalizable to other ePUFA sources. The sample size, while sufficient based on prior studies, could be increased for greater statistical power.