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Non‐alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose‐lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose‐lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose‐lowering agents on NAFLD and may represent the key to NAFLD treatment. [ABSTRACT FROM AUTHOR]

Background: Anti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans. Methods: Fifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda). Results: Glucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m²) and found that those with higher BMI had a greater increase in bCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below themedian (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066). Conclusions: Our pilot study demonstrates that six-month treatment with anti- PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI. [ABSTRACT FROM AUTHOR]

Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]

The article offers information on the incretin effect (IE) and its role in regulating β cell functional response and insulin secretion dynamics. Topics include the impact of IE reduction in type 2 diabetes, a study using surgical removal of β cell mass as a model for diabetes development, and findings suggesting that preexisting defects in β cell response to incretins predict the risk of developing impairments in glucose tolerance after β cell mass reduction.