Building a Bridge Between Clinical and Basic Research: The Phenotypic Elements of Familial Predisposition to Type 1 Diabetes

Abstract

Familial aggregation has been shown for type 1 diabetes (T1D) although the nature of the factors (environment and/or genetics) responsible remains unclear. Familial clustering of diabetic nephropathy as well as of increased cardiovascular morbidity and early mortality has also been observed. This review describes the nearly 20 years history of our investigation in parallel with contemporary literature. The story is presented from the early years' strong focus on possible markers of T1D nephropathy (urinary albumin, urinary enzymes, erythrocyte Na/Li countertransport, and erythrocyte Na/H exchange) to the last clinical investigations to determine relevant biological markers of familial predisposition to T1D. Our studies of case-families recruited unaffected first-degree relatives of sporadic T1D cases and population-based controls. Unlike multiple-case families, these families are those less likely to carry a strong genetic predisposition. Participants were both interviewed and provided biological material for a detailed functional characterisation of their biochemical phenotype. These studies have initially excluded that the erythrocyte Na/H exchange could be a marker of diabetic nephropathy. On the contrary, NHE activity was significantly higher in T1D family members independently of the presence of renal disease. Basic science knowledge of NHE and its functional implications have also been reviewed. Unexpectedly, we found evidence of increased oxidative stress in nondiabetic normotensive relatives of T1D patients, apart from soluble markers of autoimmunity and despite seemingly intact antioxidant defences. Markers of oxidation were associated with markers of inflammation and we concluded that the familial increase in NHE activity could be ascribed to the direct stimulatory effect of oxidative stress. Relatives showed also immunological hallmarks and cardiovascular abnormalities that were related to indices of oxidative stress and metabolic syndrome. Other peculiarities emerged from measuring the erythrocytes redox system that exports electrons across the cell membrane to external oxidants as a function of cytoplasmic electron donor concentration. This electron transfer might reflect the functional state of membrane proton pumps that modulate intracellular redox levels. The transport system contributed to oxidation in T1D families, whereas in healthy people it protected from oxidation. Furthermore, dietary intake of vitamin C and sporting activities modulated erythrocyte electron transfer efficiency. The contribution of environmental factors was investigated using the European Prospective Investigation of Cancer and Nutrition questionnaires that provided evidence of common unhealthy dietary behaviours, which could even predispose to the development of diabetes and cardiovascular complications, in subjects living in Pisa. However, lifestyle of T1D relatives was indistinguishable from those of controls, except for the higher daily intake of niacin and the lower physical activity levels. No difference in smoking or...

Trace Elements, Magnesium, and the Efficacy of Antioxidant Systems in Children with Type 1 Diabetes Mellitus and in Their Siblings

“…Data from Reis et al [52] showed that in comparison with healthy individuals, patients with T1DM exhibited an increase in ROS generation, while plasma antioxidant status remained unaltered. Matteucci et al [53] demonstrated a disturbed antioxidant status in first-degree relatives of patients with T1DM, which may have been caused by a general pro-oxidative background resulting from an impaired erythrocyte redox system. In the present study, TaS in the siblings of patients with T1DM was significantly lower than in the controls, and the amount was comparable to that of patients with diabetes.…”

Electron Pathways through Erythrocyte Plasma Membrane in Human Physiology and Pathology: Potential Redox Biomarker?

“…In contrast, hydrogen peroxide suppresses NHE1 promoter activity and increases cell sensitivity to death triggers. These findings have important clinical implications on account of the observed erythrocyte NHE hyperactivity in relation to chronic states of oxidative stress in humans (Matteucci and Giampietro, 2000a; Matteucci and Giampietro, 2001; Matteucci and Giampietro, 2006; Matteucci and Giampietro, 2007a and b). Indeed, RBC NHE activity has been noted as being significantly higher in type 1 diabetes (T1D) family members, independently of the presence of renal disease.…”

“…RBC vfcy has been further characterized in healthy subjects and T1D families with regard to: (a) the rate of electron transport in relation with body mass and metabolic efficiency, and (b) the modulating effects of diet and lifestyle on erythrocyte electron transfer system (Matteucci and Giampietro, 2006; Matteucci and Giampietro, 2007a). Among healthy controls, individuals with BMI ≤25 kg/m 2 had lower RBC vfcy in comparison with subjects who were overweight or obese.…”

NMR-Based Metabolomics and Its Application in Drug Metabolism and Cancer Research

“…Such molecular information of cellular metabolism plays an important role in our understanding of the development and progression of cancer. Cancer can be influenced by many factors, such as diet, environment, and lifestyle [64]. Among all of the "omics" approaches, only metabolomics technology has provided a suitable tool in investigations of pathwayspecific metabolic alterations in the development and progression of cancer and could possibly be employed in the clinical diagnosis of cancer [59].…”