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 firstdegree
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 alcohol consumption emerged among families
and controls.
The oxidative stress is a non-specific though certain component of pathogenesis at
numerous diseases states of aerobic organisms. Although molecular genetic
analysis has produced significant progress in T1D phenotype, much remains to be
learned about the molecular sequence of events leading from a generic familial
pro-oxidant background to a sporadic form of T1D (where oxidative damage
targets the insulin-secreting cells).
Keywords: Type 1 diabetes, family, diabetic nephropathy, inflammation, oxidative stress,
immunomodulatory mechanisms, sodium/hydrogen exchange, erythrocyte electron transfer,
lifestyle.
