Pathophysiology of type 2 diabetes in sub-Saharan Africans

Abstract

Sub-Saharan Africa (SSA) is the region with the highest projected rates of increase in type 2 diabetes (129% by 2045), which will exacerbate the already high prevalence of type 2 diabetes complications and comorbidities in SSA. In addition, SSA is grappling with poverty-related health problems and infectious diseases and is also undergoing the most rapid rates of urbanisation globally. These socioenvironmental and lifestyle factors may interact with genetic factors to alter the pathophysiological sequence leading to type 2 diabetes in sub-Saharan African populations. Indeed, current evidence from SSA and the diaspora suggests that the pathophysiology of type 2 diabetes in Black Africans is different from that in their European counterparts. Studies from the diaspora suggest that insulin clearance is the primary defect underlying the development of type 2 diabetes. We propose that, among Black Africans from SSA, hyperinsulinaemia due to a combination of both increased insulin secretion and reduced hepatic insulin clearance is the primary defect, which promotes obesity and insulin resistance, exacerbating the hyperinsulinaemia and eventually leading to beta cell failure and type 2 diabetes. Nonetheless, the current understanding of the pathogenesis of type 2 diabetes and the clinical guidelines for preventing and managing the disease are largely based on studies including participants of predominately White European ancestry. In this review, we summarise the existing knowledge base and data from the only non-pharmacological intervention that explores the pathophysiology of type 2 diabetes in SSA. We also highlight factors that may influence the pathogenesis of type 2 diabetes in SSA, such as social determinants, infectious diseases and genetic and epigenetic influences.

Keywords: Beta cell function; Epigenetics; Ethnicity; Genetics; Hyperinsulinaemia; Infectious diseases; Insulin resistance; Insulin sensitivity; Obesity; Review; Social determinants.

Fig. 1

(a) Conventional paradigm of type 2 diabetes showing that insulin resistance is the primary abnormality, which is accompanied by a compensatory increase in insulin secretion, coupled with a decrease in insulin clearance to maintain normoglycaemia, until beta cell exhaustion ensues and hyperglycaemia develops. This conventional paradigm posits that increasing obesity leads to adipocyte hypertrophy, oxidative stress, fibrosis and macrophage recruitment and the release of adipokines and inflammatory mediators. This increased inflammatory state, together with reduced adipocyte adipogenic capacity, leads to adipocyte lipolysis and the overflow of excess NEFAs to visceral adipose tissue (VAT) and other ectopic sites (e.g. liver, muscle and pancreas). The increased inflammation and ectopic fat accumulation results in reduced hepatic and peripheral insulin sensitivity [12]. This model is based on studies including predominately populations of European descent. (b) Comparison of the conventional model of the pathogenesis of type 2 diabetes with findings from studies of Black Africans from SSA. These findings relate to studies in predominately Black African women and show that, compared with White Europeans, Black Africans have a higher prevalence of obesity but present with a phenotype of low levels of VAT and high levels of abdominal and gluteo-femoral subcutaneous adipose tissue (SAT). Notably, Black Africans have lower insulin sensitivity and present with hyperinsulinaemia, characterised by high insulin secretion and reduced hepatic insulin clearance. While little is known about pancreatic fat content, levels of intramyocellular lipids (IMCL) do not differ by ethnicity, but hepatic fat content is lower in Black Africans, which corresponds to lower de novo lipogenesis and lower circulating VLDL-TG concentrations. Lower hepatic fat accumulation is associated with higher hepatic insulin sensitivity and lower hepatic glucose output, and accordingly the prevalence of IFG is relatively low compared with that in White Europeans. The characteristics of gluteal SAT shown in the figure are amplified by obesity. While higher inflammation levels are observed in SAT of Black Africans, this is not associated with insulin sensitivity as in White Europeans. Dotted lines indicate an inverse relationship; red crosses identify characteristics that are lower in Black Africans; red arrows emphasise a stronger relationship in Black Africans; – indicates no differences compared with White Europeans; ? indicates uncertainty. T2D, type 2 diabetes; VLDL-TG, VLDL-triacylglycerol. This figure is available as part of a downloadable slideset

Fig. 2

Comparison of receiver operating characteristic (ROC) curves of basal insulin secretion and clearance to predict dysglycaemia in middle-aged Black South African women 1.5 years later (Mtintsilana and Goedecke et al, unpublished). This figure is available as part of a downloadable slideset

Fig. 3

Schematic diagram indicating the changes in response to a 12 week combined aerobic and resistance exercise training intervention in Black South African women with obesity. The exercise intervention resulted in an increase in insulin sensitivity (S_I) but no change in acute insulin response to glucose (AIRg), with a corresponding increase in the disposition index (DI), an estimate of beta cell function [49]. Ectopic lipid content, measured in the liver, pancreas and skeletal muscle (intramyocellular lipids [IMCL] and extramyocellular lipids [EMCL]), did not change in response to the intervention, but functional changes in skeletal muscle and adipose tissue were evident. Exercise training resulted in content-driven improvements in mitochondrial function that were associated with changes in lipid intermediates [57]. With an increase in body weight, skeletal muscle triacylglycerol subspecies and lipid intermediates (ceramides and sphingomyelins) were increased in the control group. However, the changes in skeletal muscle lipid metabolism in both the exercise group and the control group did not correspond to changes in IMCL or EMCL. Exercise training resulted in a small but significant decrease in body weight and gynoid fat mass (% of total fat mass), with a greater reliance on fat oxidation at baseline promoting the reduction in gynoid fat mass [98]. Using a transcriptome approach, we showed that exercise training resulted in a change in the expression of 58 genes in the gluteal SAT, and these differed from the 74 genes whose expression was changed in abdominal SAT [34]. Within the gluteal SAT, these genes were mainly related to immune and inflammatory responses and lipid metabolism, whereas in the abdominal SAT these genes were related to muscle-associated processes [34]. Commensurate with these findings, we reported a higher inflammatory gene expression profile (TNF-α, IL-10, MIF and NF-κB mRNA) in the gluteal (and not abdominal) SAT following exercise training, which may reflect tissue remodelling related to the decrease in gynoid fat mass [56]. Gluteal SAT was the depot that showed the most consistent reductions in H₂O₂ emissions, as a marker of reactive oxygen species (ROS) production [33]. These results further support the systemic adaptations, which show a decrease in circulating thiobarbituric acid reactive substances (TBARS), a by-product of lipid peroxidation by ROS, with a simultaneous increase in circulating catalase, a reflection of antioxidant enzyme activity [56]. Although exercise training did not change abdominal fat content, abdominal SAT mitochondrial respiration and coupling increased and alterations in the fatty acid profile were observed [33, 99]. These findings show changes in the functional capacity of abdominal SAT and highlight major depot-specific differences that reflect the heterogeneous capacity of SAT to adapt to behavioural changes such as exercise training, which indirectly influence signalling pathways that regulate fat distribution and insulin dynamics. Finally, we showed a decrease in estimated stearoyl-CoA desaturase (SCD1) activity, a marker of de novo lipogenesis, which was associated with lower liver fat levels [99]. Arrows indicate changes; – indicates no change in response to the intervention. DAG, diacylglycerol; MIF, macrophage migration inhibitory factor; mtDNA, mitochondrial DNA; MUFA, monounsaturated fatty acid; PC, phosphatidylcholine; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; SGMS1, sphingomyelin synthase 1; SGMS2, sphingomyelin synthase 2; SM, sphingomyelin; TAG, triacylglycerol; TCA, tricarboxylic acid. This figure is available as part of a downloadable slideset

Fig. 4

Proposed model of the pathogenesis of type 2 diabetes in sub-Saharan African populations. Pathogenesis is characterised by hyperinsulinaemia due to reduced insulin clearance and hypersecretion of insulin, which is probably driven by a genetic predisposition and lifestyle factors, in particular the consumption of a hypercaloric, high-carbohydrate (CHO) diet. Hyperinsulinaemia reduces skeletal muscle insulin sensitivity, creating a negative feedback loop, exacerbating hyperinsulinaemia and obesity and eventually leading to beta cell failure and the development of type 2 diabetes. Black African women present with a phenotype of low VAT and high gluteo-femoral SAT, which is probably genetically determined. The large gluteo-femoral SAT depot acts as a reservoir for excess fatty acids, but eventually the adipogenic capacity is exceeded, and changes within the gluteo-femoral SAT result in an increase in lipolysis and release of NEFAs, which may further stimulate beta cell function. The excess NEFAs are redistributed to the abdominal region and ectopic sites (liver and muscle). The increase in VAT and/or liver fat from a lower baseline and the greater sensitivity to the effects of these depots exacerbate the insulin-resistant state. Insulin resistance within skeletal muscle is not characterised by increased intramyocellular lipids, but rather by changes in lipid intermediates and subspecies. These changes are associated with decreased mitochondrial content and oxidative capacity and changes in insulin signalling pathways. The pathophysiology of type 2 diabetes in Black African men differs from that in women. Compared with women with the same level of body fatness, men have lower insulin sensitivity, insulin secretion and beta cell function, and show a stronger relationship of total and central adiposity with type 2 diabetes risk. Men with type 2 diabetes often present with a phenotype of low BMI (<25 kg/m²) and low insulin secretion and beta cell failure. Exposure to infectious disease may further influence the pathogenesis of type 2 diabetes and further impact the risk for type 2 diabetes. Solid lines represent the direction of relationships and thicker lines represent stronger relationships; dotted orange lines show attenuated relationships. ASAT, abdominal subcutaneous adipose tissue; GSAT, gluteo-femoral subcutaneous adipose tissue; T2D, type 2 diabetes. This figure is available as part of a downloadable slideset