Type 2 diabetes in adults with sickle cell disease: can we dive deeper?

Sickle cell disease (SCD) is a group of hereditary blood disorders caused by the inheritance of two mutated haemoglobin (Hb) β alleles, of which at least one is the β^s allele. Individuals who are homozygous for the β^s allele have sickle cell anaemia (SCA), the most common form of SCD. The second most common form of SCD is HbSC, caused by the inheritance of one β^s allele and one β^c allele. Other heterozygous forms of SCD include HbSβ⁰-thalassaemia, HbSβ⁺-thalassaemia, and several less common genotypes (Kato et al, 2018).

SCD is characterized by elevated rates of haemolysis, which causes increased protein turnover, resulting in hypermetabolism (Badaloo et al, 1989). For this reason, individuals with SCD were historically considered to be at low risk of developing type 2 diabetes (T2D) (Ballas, 2018). However, the intriguing findings of Zhou et al (2019) revealed that the prevalence of T2D in SCD patients in the US is now comparable to the prevalence of T2D among the general African-American population. Furthermore, age, hypertension and dyslipidaemia were all positively associated with T2D among SCD patients (Zhou et al, 2019). These remarkable findings provide crucial information for clinicians about the importance of screening for T2D in aging patients with SCD, particularly in those with hypertension or dyslipidaemia (Zhou et al, 2019).

One of the strengths of the study reported by Zhou et al (2019) was the large number of subjects with SCD included in the analyses. A total of 7070 adults with SCA, HbSC, HbSβ-thalassaemia or “other SCD” were all included in the SCD group (Zhou et al, 2019). However, it is well recognized that the different SCD genotypes vary widely in disease severity, and in the number and nature of SCD complications. For example, the most severe forms of SCD are SCA and HbSβ⁰-thalassaemia, as these genotypes have the highest concentrations of intracellular HbS, resulting in increased haemoglobin polymerization and erythrocyte sickling, the primary pathological mechanisms of SCD (Chang et al, 2018). These two genotypes are characterized by more frequent vaso-occlusive crises (VOC), severe anaemia and acute chest syndrome (ACS) (Ballas, 2018). On the other hand, HbSC is commonly considered to be a milder form of SCD, due to lower levels of intracellular HbS. HbSC patients generally have milder anaemia, less frequent VOC, and lower mortality than SCA patients (Kato et al, 2018). However, HbSC patients tend to have an increased risk of developing proliferative retinopathy and otological disorders (Lionnet et al, 2012). Furthermore, recent data from the US showed that the median age of survival was 58 years for individuals with SCA, and 66 years for people with HbSC (Elmariah et al, 2014). Finally, HbSβ⁺-thalassaemia is generally considered to be less severe than SCA, HbSC, and HbSβ⁰-thalassaemia (Chang et al, 2018). In light of the findings of Zhou et al (2019), which showed that SCD subjects with T2D were older and had lower rates of VOC and ACS compared to those without T2D, and the fact that life expectancy and risk of VOC and ACS vary between the SCD genotypes, it would be pertinent to determine whether the prevalence of T2D differs among the different genotypes included in SCD population studied by Zhou et al (2019).

Lipid profile and anthropometrics, two factors that are associated with T2D pathogenesis, also differ between SCA and HbSC disease. A recent study (Lalanne-Mistrih et al, 2018) showed that SCA and HbSC subjects had distinct lipid profiles that also differed from the general population. Notably, SCA subjects had higher triglyceride levels, which were associated with ACS, while non-high density lipoprotein-cholesterol levels were associated with osteonecrosis in HbSC subjects (Lalanne-Mistrih et al, 2018). Furthermore, obesity has been shown to be on the rise in people with SCD, particularly in those with HbSC (Ballas, 2018). Interestingly, the results of Lalanne-Mistrih et al (2018) revealed that mean body mass index (BMI) was significantly lower in the SCA compared to the HbSC subjects. However, there was an over-representation of individuals with a normal BMI combined with abdominal obesity in the SCA group (Lalanne-Mistrih et al, 2018). Current estimates indicate that 60% of the SCD population in the US has SCA, and 30% has HbSC disease (Hassell, 2010). As Zhou et al (2019) found an association between dyslipidaemia and T2D in individuals with SCD, and there was a higher percentage of overweight/obesity in the SCD with T2D group, it would be interesting to perform additional analyses to determine the percentage of subjects with SCA, HbSC, and other SCD genotypes in the two study groups (SCD with and without T2D). These analyses could indicate whether the differences in lipid profile, anthropometrics, disease severity, and mortality between the common forms of SCD could modify T2D risk.

Another factor that modulates the severity of SCD is the inheritance of alpha-thalassaemia. Alpha-thalassaemia reduces intracellular haemoglobin concentrations, thereby decreasing haemoglobin polymerization and reducing haemolysis (Chang et al, 2018). The clinical effects of alpha-thalassaemia are generally beneficial, including reduced occurrence of stroke, pulmonary hypertension, glomerulopathy and priapism. On the other hand, alpha-thalassaemia appears to increase the risk of VOC and osteonecrosis in SCA (Connes et al, 2016). As an estimated 30% of SCD patients carry one or more alpha-thalassaemia deletions it is possible that alpha-thalassaemia could be a confounding factor in the study conducted by Zhou and colleagues (Chang et al, 2018). The results of Zhou et al (2019) showed that SCD patients with T2D had an increased risk of nephropathy and stroke. Given that alpha-thalassaemia reduces the risk of stroke and glomerulopathy, it would be interesting to determine whether the SCD patients who did not have T2D were more likely to have alpha-thalassaemia.

In conclusion, the population of aging adults with SCD and T2D in the US appears to be expanding. Therefore, in order to provide adequate patient care, there is an urgent need to develop a better understanding of which SCD patients have the highest risk of developing T2D. Determining whether certain SCD genotypes are predisposed to developing T2D would facilitate early diabetes diagnosis and treatment, which is the most effective way to improve patient outcomes.

Author contributions

SS, EN and PC wrote the paper.