José Manuel Boavida

Background & Aims: Metabolic disorders such as dyslipidemia, metabolic dysfunction associated steatotic liver disease (MASLD), and diabetes are promoted by chronic proinflammatory and prooxidative states. Paraoxonase 1 (PON1), a liver derived HDL associated enzyme, plays an important antioxidant role by hydrolyzing oxidized lipids and protecting against oxidative stress induced damage. Genetic variation in PON1, particularly in promoter and coding regions, modulates enzyme expression and activity, thereby influencing susceptibility to metabolic and cardiovascular diseases. This study investigated the genetic determinants of serum paraoxonase (PONase) activity and their relationship with dysmetabolic phenotypes. Methods: A genome wide association study was conducted in 922 Portuguese individuals from the PREVADIAB2 cohort. Genetic variants and haplotypes related to PONase activity were analyzed, and associations with dysglycemia and liver fibrosis were evaluated in individuals aged over 55 years. Results: We identified two key PON1 variants as determinants of PONase activity: rs2057681 (in strong linkage disequilibrium with the non synonymous Q192R variant) and rs854572 (located in the promoter region). Analysis of rs854572; rs2057681 haplotypes revealed that specific combinations differentially modulate PONase activity and confer risk or protection for dysglycemia and liver fibrosis, depending on the rs2057681 genotype context. Notably, although PONase activity was strongly associated with PON1 variants, it did not directly correlate with dysmetabolic phenotypes, suggesting that genetic context and haplotype structure, rather than enzyme activity alone, shape disease susceptibility. Conclusions: These findings highlight the complex genetic architecture of PON1 and its role in metabolic disease risk, supporting the use of PON1 genetic information to uncover predisposition to dysmetabolic conditions. Our results provide insights into the interplay between PON1 genetics, enzyme function, and dysmetabolism, with implications for risk stratification in metabolic liver disease.

Aims/hypothesis: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. Methods: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. Results: In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10⁻⁷) and C-peptide release responses (rs2300757, p=6.86x10⁻⁵) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. Conclusions/interpretation: These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes. Graphical

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Diabetes Mellitus is a public health problem that is on the increase throughout the world, including in Portugal. This paper aims to identify the changing geographic pattern of this cause of death in Portugal and its association with sociomaterial deprivation. This is a transversal ecological study of the deaths by Diabetes Mellitus in Portuguese municipalities in three periods (1989-1993, 1999-2003 and 2006-2010). It uses a Bayesian hierarchical model in order to obtain a smooth standardized mortality ratio and the relative risk of death by Diabetes Mellitus associated to sociomaterial deprivation. In 1989-1993, the highest smooth standardized mortality ratio values were found in coastal urban municipalities (80% of municipalities with smooth standardized mortality ratio ≥ 161, of which 60% are urban); in 2006-2010, the opposite was found, with the highest smooth standardized mortality ratio values occurring in rural areas in southern inland regions (76.9% of municipalities with smooth standardized mortality ratio ≥ 161, of which 69.2% are rural), particularly the Alentejo. The relative risk of death by Diabetes Mellitus increases with vulnerability associated to social and economic conditions in the area of residence, and is significant in the last two periods (relative risk: 1.00; IC95%: 0.98-1.02). Diabetes Mellitus presents a geographic pattern marked by coastal-inland and urban-rural asymmetry. However, this has been altering over the last twenty years. 48% of the population reside in municipalities where the smooth standardized mortality ratio has increased in the last twenty years, particularly in the rural areas of inland Portugal. The highest smooth standardized mortality ratio are currently found in rural municipalities with the highest index of sociomaterial deprivation.

The dynamic response to insulin is highly potentiated after meal ingestion, and this meal-induced insulin sensitization (MIS) in healthy subjects is dependent on cholinergic mechanisms. The main objective of this study was to test the hypothesis that the reduced response to insulin observed in moderately overweight subjects, in comparison with control lean subjects, is due to MIS impairment and not to a reduction in the direct hypoglycemic action of insulin. Both lean and overweight male subjects were recruited. Insulin sensitivity (IS) was assessed by the rapid insulin sensitivity test (RIST) performed after a 24 h fast, as well as after a standardized meal. Fasting glucose disposal was similar between lean and overweight subjects. Following the meal, glucose disposal increased more extensively in lean than overweight subjects. The insulin profiles, in both fasted and fed states, were superimposable, suggesting that the absence of a factor other than insulin is responsible for the decreased postprandial insulin sensitivity observed in overweight subjects. Our data suggest that in overweight subjects, MIS contribution is decreased, which is responsible for the postprandial impaired IS observed and is suggested to be the cause, not effect, of mild adiposity.

Background/Aims: Chronic kidney disease (CKD) is a growing public health problem. However, data on risk factors and prevalence of CKD exist only in a small number of countries. Portugal has the highest incidence of end-stage renal disease (ESRD) among European countries, but there are huge disparities among countries. Whether these disparities reflect differences in risk factors, prevalence of CKD or other factors is currently unknown. Methods: We analyzed data from a nationally representative sample of 5,167 subjects, and estimated the prevalence of CKD and associated risk factors, and combined these prevalence estimates with available data on ESRD. Results: The prevalence of risk factors such as diabetes (11.7%), obesity (33.7%), and metabolic syndrome (41.5%) was similar to that in the US, but greater than in most European countries. The prevalence of CKD stages 3–5 was 6.1%, which is similar to that in other Western countries. The risk of ESRD was greater than in other European countries, but lower than in the US. Conclusion: The high incidence of ESRD among the Portuguese population is not due to a greater prevalence of CKD. A higher rate of progression associated with the high prevalence of risk factors may account for the high incidence of ESRD. The role of unmeasured factors needs to be evaluated in further studies.