Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: An open-label, non-randomised controlled study

OBJECTIVE: One year of comprehensive continuous care intervention (CCI) through nutritional ketosis improves glycosylated haemoglobin(HbA1c), body weight and liver enzymes among patients with type 2 diabetes (T2D). Here, we report the effect of the CCI on surrogate scores of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. METHODS: This was a non-randomised longitudinal study, including adults with T2D who were self-enrolled to the CCI (n=262) or to receive usual care (UC, n=87) during 1 year. An NAFLD liver fat score (N-LFS) >-0.640 defined the presence of fatty liver. An NAFLD fibrosis score (NFS) of >0.675 identified subjects with advanced fibrosis. Changes in N-LFS and NFS at 1 year were the main endpoints. RESULTS: At baseline, NAFLD was present in 95% of patients in the CCI and 90% of patients in the UC. At 1 year, weight loss of ≥5% was achieved in 79% of patients in the CCI versus 19% of patients in UC (p<0.001). N-LFS mean score was reduced in the CCI group (-1.95±0.22, p<0.001), whereas it was not changed in the UC (0.47±0.41, p=0.26) (CCI vs UC, p<0.001). NFS was reduced in the CCI group (-0.65±0.06, p<0.001) compared with UC (0.26±0.11, p=0.02) (p<0.001 between two groups). In the CCI group, the percentage of individuals with a low probability of advanced fibrosis increased from 18% at baseline to 33% at 1 year (p<0.001). CONCLUSIONS: One year of a digitally supported CCI significantly improved surrogates of NAFLD and advanced fibrosis in patients with T2D

Type 2 diabetes prevention focused on normalization of glycemia: A two-year pilot study

The purpose of this study is to assess the effects of an alternative approach to type 2 diabetes prevention. Ninety-six patients with prediabetes (age 52 (10) years; 80% female; BMI 39.2 (7.1) kg/

Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans

The increased expression of PNPLA3148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10-8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers

Role of FADS1 in Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is a rapidly advancing liver disease with very limited treatment options available. One of the main hallmark of NAFLD is lipid profile deregulation, where lack of LCPUFA such as DHA, EPA and AA are often reported in the NAFLD liver samples. The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of PUFA to generate long chain LCPUFA. FADS polymorphisms are often linked to reduced LC-PUFA levels as well as decreased delta-5 enzyme activity in serum and erythrocyte profiles. Our study investigated the association of six GWAS-identified FADS cluster polymorphisms with liver lipid profiles. This study revealed the association between FADS polymorphisms with decreased FADS1 expression and increased hepatic fat content. Those individuals with minor alleles had higher lipid content and reduced FADS1 expression. We also showed that the FADS polymorphisms also altered the liver lipid profiles pattern, where those with minor alleles were associated with increased ratios of saturated to unsaturated phospholipids. We further investigated the molecular mechanism on how FADS1 deregulation facilitate lipid accumulation using both in-vitro and in-vivo models. Downregulating FADS1 increases the susceptibility of hepatocytes to lipid accumulation where else overexpressing FADS1 plays a protective role against lipid accumulation in hepatocytes. Triglyceride and lipid droplets levels were significantly higher in FADS1 null mice when compared to the wild type mice. We showed that fatty acid oxidation, lipogenesis and triglyceride synthesis and storage pathways were altered in the FADS1 deficient condition. Both PPARα and FGF21 mRNA and protein expressions were significantly decreased in the FADS1 knockdown cells and FADS1 null mice. Furthermore, the FGF21 promoter binding activity was significantly reduced in the FADS1 knockdown cells, suggesting a reduced transcriptional activation of the FGF21 gene. Overexpressing FADS1 and treating FADS1 knockdown cells with DHA reduced triglycerides level. DHA treatment also significantly alleviated fatty acid oxidation and lipogenesis pathways. Likewise, DHA treatment also affected the PPARα-FGF21 axis by elevating the expressions of PPARα and FGF21 as well as increasing the FGF21 promoter binding activity. Collectively, these results suggest that deregulation in FADS1 alters the lipid composition in the liver by reducing the amount of important LCPUFAs and altering the PPARα-FGF21 axis

Reversing Type 2 Diabetes: A Narrative Review of the Evidence

Background: Type 2 diabetes (T2D) has long been identified as an incurable chronic disease based on traditional means of treatment. Research now exists that suggests reversal is possible through other means that have only recently been embraced in the guidelines. This narrative review examines the evidence for T2D reversal using each of the three methods, including advantages and limitations for each. Methods: A literature search was performed, and a total of 99 original articles containing information pertaining to diabetes reversal or remission were included. Results: Evidence exists that T2D reversal is achievable using bariatric surgery, low-calorie diets (LCD), or carbohydrate restriction (LC). Bariatric surgery has been recommended for the treatment of T2D since 2016 by an international diabetes consensus group. Both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) now recommend a LC eating pattern and support the short-term use of LCD for weight loss. However, only T2D treatment, not reversal, is discussed in their guidelines. Conclusion: Given the state of evidence for T2D reversal, healthcare providers need to be educated on reversal options so they can actively engage in counseling patients who may desire this approach to their disease

Reply to "Utility of Unrefined Carbohydrates in Type 2 Diabetes. Comment on Reversing Type 2 Diabetes: A Narrative Review of the Evidence, Nutrients, 2019, 11, 766"

We appreciate the interest and comments from Joshi et al. [1] regarding our recent paper [2]. Here are our specific comments to concerns that they raised