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Type 2 diabetes (T2D) has become a global epidemic. Although several drugs are available to manage T2D, problems associated with person-to-person variability in drug efficacy and potential side-effects remain unresolved. Owing to the emerging role of the gut microbiome in obesity and T2D, the interaction between gut microbes and anti-diabetic drugs and its influence on drugs' functions remains of immediate research interest. On one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence drug metabolism and effects. Hence, understanding this bi-directional drug-microbiome interaction and how it influences the clinical outcomes of antidiabetic drugs can pave the way to develop next-generation strategies to ameliorate diabetes. This review presents evidences demonstrating the putative interactions between anti-diabetic drugs and the gut microbiome, and discusses the potential of microbiome modulators to manipulate drug-microbiome interactions and the drug metabolism., Graphical abstract Unlabelled Image, Highlights • Gut microbes interact with medications used to treat T2D, that at least partially mediates potential benefits of these drugs. • Anti-diabetic drugs impact gut microbiome and its metabolic activity and vice-versa. • Understanding the dynamics of drug-microbiome cross-talk would offer better therapeutic outcomes for diabetes.

Background Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. Methods Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11–13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. Findings GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p, Highlights • Children exposed to gestational diabetes (GDM) had lower cortical excitability, measured as higher resting motor thresholds. • The GDM group also exhibited smaller LTD-like neuroplastic responses to repetitive brain stimulation. • These were associated with lower salivary cortisol and with maternal diabetes severity, especially insulin resistance. Our results suggest that gestational diabetes, even when detected and treated as per clinical guidelines, has subtle effects on important neurophysiological processes persisting into early adolescence, including neuroplasticity and possibly cortisol secretion. The extent of these effects is related to the severity of maternal diabetes, particularly insulin resistance, during mid pregnancy. These results may aid in understanding how insulin resistance and hyperglycemia affect the developing brain. Further, our results indicate that earlier detection and pharmacologic treatment of gestational diabetes may attenuate or prevent these changes to neurodevelopment, and that maternal metformin treatment does not influence these aspects of development.

Background The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation. Methods The impact of the KLB rs17618244 variant on histological liver damage was surveyed in a retrospective cohort of 1111 adult patients with MAFLD. Subgroup analysis was performed according to the presence of obesity (BMI>35; n = 708). Immortalized HSCs (LX-2) were transfected with the KLB wild type (LX-2_KLBwt), or with the mutant one carrying the rs17618244 (LX-2_KLBmut). Findings At ordinal regression analysis the KLB rs17618244 variant was associated with hepatic fibrosis (OR 1.23, 95% C.I.1.004–1.51; p = 0.04), but not with steatosis, inflammation and ballooning. By stratifying patients according to the presence of obesity, the KLB A allele was further associated with lobular inflammation (OR 1.32, 95% C.I.1.02–1.72; p = 0.03) and cirrhosis (OR 2.51, 95% C.I.1.23–5.05; p = 0.01) Moreover, hepatic KLB expression correlated with that of fibrogenic genes. LX-2_KLBmut cells showed reduced KLB protein levels paralleled by an induction of pro-fibrogenic genes and enhanced proliferative rate. Interpretation The KLB rs17618244 variant is associated with hepatic fibrosis, inflammation and cirrhosis mainly in obese patients with MAFLD and HSCs which carry this mutation are highly proliferative and acquire a myofibroblast-like phenotype. Funding Ricerca Finalizzata Ministero della Salute GR-2019–12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Ca Granda (PD and ALF), Ricerca Finalizzata Ministero della Salute RF-2013–02,358,319 (ALF), and Ricerca Corrente and 5 × 1000 Ministero della Salute (AA).

Background Type 2 diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, whether the association is causal remains unestablished. Research Design and Methods We performed a Mendelian Randomization (MR) analysis in 11,502 participants aged 40 and above, from a well-defined community in Shanghai during 2011–2013, to explore the causal association between T2D and decreased estimated GFR (eGFR) and increased urinary albumin-to-creatinine ratio (uACR). We genotyped 34 established T2D common variants in East Asians, and created a T2D-genetic risk score (GRS). We defined decreased eGFR as eGFR, Highlights • A MR study was conducted to explore the causal association between T2D and decreased renal function. • Weighted T2D genetic risk score (GRS) was used as the instrumental variable (IV). • A higher T2D_GRS was associated with higher risk of decreased glomerular filtration rate (GFR). • T2D estimated by the IV may causally associate with risk of decreased renal function in the MR analysis. Epidemiological and clinical studies show that type 2 diabetes (T2D) is a risk factor for dysregulation of kidney function and albuminuria, intensive diabetes treatment was associated with better renal outcomes, suggesting a possible causal link between T2D and renal outcomes. Recently, the Mendelian Randomization (MR) approach using genetic variants as the instrumental variable has been widely used for assessing causality in population studies, because the genetic alleles are allocated randomly during gamete formation and are inherited independent of potential confounding factors and represented as a life-long exposure, which could oppose the bias such as confounding or reverse causation, or short-term intervention. We found that in 11,502 community dwelling Chinese adults, a genetic risk score representing the susceptibility to T2D but not other metabolic traits was significantly associated with decreased renal function, in dependent of obesity, lipids and high blood pressure. These findings for the first time provided novel evidence for a causal relationship between genetically determined T2D and decreased kidney function by using MR.