DOM: A low n-6/n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinemia by restoring insulin clearance in obese youth

Background: Hyperinsulinemia due to reduced insulin clearance and excess insulin secretion is a key feature of insulin resistance and is influenced by multiple factors, such as hepatic response to insulin action, dietary and circulating fat, and ethnic background
.
Reduced insulin clearance is associated with intrahepatic fat accumulation and hepatic insulin resistance in most ethnic groups in a complex metabolic network that is associated with beta-cell damage and increased risk of prediabetes and type 2 diabetes
.
Decreased dietary intake of omega-3(n-3) polyunsaturated fatty acids (PUFAs) and excessive intake of n-6 PUFAs can lead to adverse metabolic profiles
.
Recently, we found that a 12-week normocaloric dietary intervention (characterized by a low n-6 to n-3 PUFA ratio (4:1)) in the absence of weight change was associated with nonalcoholic fatty liver disease (NAFLD) obese youth had approximately 30% lower liver fat content
.
Notably, the diet also reduced fasting and oral glucose tolerance test (OGTT) plasma insulin levels by approximately 25% and improved systemic insulin sensitivity by 34%, without affecting fasting or postprandial blood glucose concentrations
.
This suggests a potential role for a low n–6:n–3 PUFA ratio diet as a therapeutic strategy to reduce obesity-related hyperinsulinemia by reducing liver fat
.

Objectives: Here, we tested the hypothesis that, in the absence of significant changes in body weight, a low n–6:n–3 PUFA ratio diet could alter the metabolic phenotype of obese youth with NAFLD by increasing insulin clearance
.
To achieve our goals, in a second analysis, we measured plasma C-peptide levels during the frequently sampled OGTT and compared glucose, insulin and C Peptide data were mathematically modeled to estimate parameters for insulin secretion, beta cell function, and insulin clearance
.

Materials and methods
.
Insulin secretion and clearance were assessed by measuring and simulating plasma insulin and C-peptide in 17 obese youths who underwent 9:180 min oral glucose before and after a 12-week low-calorie n–6:n–3 PUFA ratio diet Tolerance Test (OGTT)
.
Liver fat content was assessed by repeated abdominal magnetic resonance imaging (MRI)
.

result
.
Insulin clearance during fasting and OGTT was significantly increased after eating, whereas model parameters of absolute and glucose-dependent insulin secretion and beta-cell function were not affected
.
Diet-induced changes in insulin clearance were positively associated with changes in systemic insulin sensitivity and beta-cell glucose sensitivity, but not with changes in liver fat
.
Subjects with greater increases in insulin clearance exhibited poorer metabolic status at enrollment, characterized by impaired insulin clearance, beta-cell glucose sensitivity, and glucose tolerance, and benefited the most from the diet, with glucose-stimulated greater improvement in hyperinsulinemia, insulin resistance, and beta cell function
.

Figure 1 Plasma insulin (A), glucose (B) and C-peptide concentrations (C); insulin secretion rate (ISR) (D); 180-minute area under the curve of ISR (AUC0-180 minutes) (E); relative to plasma ISR of glucose (F); β-cell glucose sensitivity (β-GS) (G); ISR at a fixed fasting glucose of 5 mmol/L (ISR @ 5) (H); β-cell rate sensitivity (β-RS) ) (I); enhancer factor ratios at 120 minutes (J) and 180 minutes (K); fasting insulin clearance (L), oral glucose tolerance test (OGTT) (M), and percent reduction from fasting to OGTT ( N); Oral Glucose Insulin Sensitivity (OGIS) Index (O) in obese youth at baseline (week 0) and after a low n–6:n–3 PUFA ratio diet (week 12)
.
Row and column representation
.
Error bars and shaded areas indicate SEM
.
Panels A and B were modified with permission from ref
.
[24].
Use the paired Wilcoxon signed-rank test to test for differences between groups
.
p-values ​​below 0.
10 are reported
.

Figure 2 Correlation between changes in oral glucose insulin sensitivity (OGIS) index and changes in insulin clearance during oral glucose tolerance test (OGTT) (A); changes in liver fat fraction (HFF%) and changes in insulin clearance during OGTT Correlations between changes (B) or changes in OGIS index (C); and between changes in beta-cell glucose sensitivity and changes in insulin clearance during OGTT (D)
.
Change was calculated as the difference between measurements before and after a 12-week low n–6:n–3 PUFA ratio diet
.
Correlation was tested with Pearson correlation
.
The area between the dashed lines represents the 95% confidence interval for the line of best fit
.

Figure 3 Plasma insulin (A) and glucose (B) in response to a 75 g oral glucose tolerance test (OGTT) at baseline (week 0) and after a low n–6:n–3 PUFA ratio diet (week 12) Concentrations, subjects' post-load insulin clearance increased significantly (>25% of baseline) or changed slightly (25%)
.
Data are reported as mean SEM
.

Table 1 Glucose tolerance and insulin metabolism in study participants stratified according to diet-induced changes in post-load insulin clearance at enrollment and after the 12-week intervention
.

Conclusion
.
We demonstrate that a 12-week diet with a low n–6:n–3 PUFA ratio improves hyperinsulinemia by increasing fasting and postprandial insulin clearance in obese youth, independent of weight loss, glucose concentration, and insulin secretion
.

Original source: Tricò D, Galderisi A, Van Name MA, et al.
A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinemia by restoring insulin clearance in obese youth .
Diabetes Obes Metab 2022 Mar 17