Molecular modulation of medical nutrition therapy in obese patients with type 2 diabetes mellitus

The number of adults with diabetes has reached a global prevalence of approximately 9.3%, 463 million in 2019. According to the International Diabetes Federation, this prevalence is projected to rise sharply by 51%, affecting 700 million adults worldwide by 2045. Dysregulation of peroxisome proliferator-activated receptors (PPARs) and its’ coactivator PPAR gamma co-activator-1-alpha (PPARGC1A) in fatty acid oxidation (FAO) and increased inflammation are among the main factors leading to the pathogenesis of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease (CVD) and metabolic syndrome. Medical nutrition therapy (MNT) has become one of the primary clinical guidelines in diabetes management, and sustained weight loss via MNT of merely 3% to 5% has the ability to produce clinical health improvements such as reductions in CVD risk factors and glycaemic control. We hypothesised that weight loss would modulate molecular changes that underlie favourable clinical health improvement. The obese patients with T2DM were randomised to either energyrestricted isocaloric MNT or conventional dietetic therapy (CDT) arms for endpoint interventions. Clinical phenotypes, the PPARs pathway target genes expressions and deoxyribonucleic acid (DNA) methylation promoter region of PPARGC1A were measured at baseline and endpoint intervention from peripheral blood mononuclear cells (PBMC). The lean non-diabetic participants were recruited as baseline characteristics of the PPARs target genes. Genotyping of single nucleotide polymorphism (SNP) of Pro12Ala and Gly482Ser from the PPAR gamma (PPARG) and PPARGC1A as well as Leu162Val polymorphism in PPAR alpha (PPARA) were conducted from PBMC of the T2DM with obesity patients. Genotyping of SNPs serves to assess the association of SNPs with clinical phenotypes. The PBMC was used as a surrogate for metabolic tissues, and bariatric patients were recruited to validate study findings by elucidating whether transcriptional regulation of PPARs pathway in PBMC was associated with skeletal muscle, visceral fat (VF) and subcutaneous fat (SF). Our results showed that, firstly, the MNT arm demonstrated a significant reduction in weight and other clinical phenotypes associated with the improvement of CVD risk factors and glycaemic control (p<0.05), irrespective of SNPs variants; whereas the CDT arm did not demonstrate significant changes in pre-and post-intervention except diastolic pressure reduction. However, T2DM patients in the CDT arm with 12Ala carriers displayed a significant reduction in body composition and glycaemic level, indicating the predisposition effect of SNPs on conventional dietary responses (p<0.05), but there is no association found between MNT arm and SNPs (p>0.05). The MNT arm had achieved over 80% adherence to the dietary regime, a substantial improvement compared to previously reported 16.4% adherence. Secondly, The FAO and anti-inflammatory pathway’s gene expression of T2DM obese patients were down-regulated than lean non-T2DM. However, at the endpoint, these genes were upregulated in the MNT arm and significantly associated with the improvement of clinical phenotypes (p<0.05). Thirdly, the transcriptional upregulation of PPARs target gene was inversely associated with DNA methylation in the PPARGC1A promoter region (p<0.05) in both arms, but no transcriptional association was associated with the SNPs (p>0.05) in both arms. Fourthly, both the PBMC’s PPARs pathway transcriptional regulation and DNA methylation profile in promoter regions were well associated with the skeletal muscle of the bariatric patients (p<0.05), indicating the feasibility of PBMC as a prospective diagnostic tool, at least as a surrogate for skeletal muscle. In conclusion, the reduction of DNA methylation profile in PPARGC1A promoter region up-regulates gene expression of PPARs target gene in obese T2DM at pre-and post-intervention, contributing to clinical improvements. Our study indicates that epigenetic demonstrates superiority over genetic predisposition. Since epigenetic modification is inheritable but reversible, current discoveries provide mechanistic insight to improve diagnosis, therapy and prevention to T2DM, obesity and CVD management.

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