Tipping the balance:Haemoglobinopathies and the risk ofdiabetes

AIM: To establish a link between the risk of diabetes with haemoglobinopathies by examining available evidence of the effects of iron and blood glucose homeostasis from molecular to epidemiological perspectives.METHODS: A systematic literature search was performed using electronic literature databases using various search terms. The International Diabetes Federation World Atlas was used to generate a list of populations with high rates of diabetes. Pub Med, Scopus and Google Scholar were used to identify which of these populations also had a reported prevalence of haemoglobin abnormalities.RESULTS: Abnormalities in iron homeostasis leads to increases in reactive oxygen species in the blood. This promotes oxidative stress which contributes to peripheral resistance to insulin in two ways:(1) reduced insulin/insulin receptor interaction; and(2) β-cell dysfunction. Hepcidin is crucial in terms of maintaining appropriate amounts of iron in the body and is in turn affected by haemoglobinopathies. Hepcidin also has other metabolic effects in places such as the liver but so far the extent of these is not well understood. It does however directly control the levels of serum ferritin. High serum ferritin is found in obese patients and those with diabetes and a meta-analysis of the various studies shows that high serum ferritin does indeed increase diabetes risk.CONCLUSION: From an epidemiological standpoint, it is plausible that the well-documented protective effects of haemoglobinopathies with regard to malaria may have also offered other evolutionary advantages. By contributing to peripheral insulin resistance, haemoglobinopathies may have helped to sculpt the so-called "thrifty genotype", which hypothetically is advantageous in times of famine. The prevalence data however is not extensive enough to provide concrete associations between diabetes and haemoglobinopathies- more precise studies are required.

Acid–base Homeostasis and Implications to the Phenotypic Behaviors of Cancer

Acid–base homeostasis is a fundamental property of living cells,and its persistent disruption in human cells can lead to a wide range of diseases.In this study,we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas(TCGA)database.Built on our previous study,we quantitatively estimated the average production rate of OHby cytosolic Fenton reactions,which continuously disrupt the intracellular pH(pHi)homeostasis.Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms(RMs)are induced to produce net protons(H+)at comparable rates of Fenton reactions to keep the pHi stable.We then discovered that a number of wellknown phenotypes of cancers,including increased growth rate,metastasis rate,and local immune cell composition,can be naturally explained in terms of the Fenton reaction level and the induced RMs.This study strongly suggests the possibility to have a unified framework for studies of cancerinducing stressors,adaptive metabolic reprogramming,and cancerous behaviors.In addition,strong evidence is provided to demonstrate that a popular view that Na+/H+exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.