Pathophysiology of type 2 diabetes in sub-Saharan AfricansGoedecke, Julia H.; Mendham, Amy E.
doi: 10.1007/s00125-022-05795-2pmid: 36166072
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.Graphical abstract[graphic not available: see fulltext]
Reassessing the evidence: prandial state dictates glycaemic responses to exercise in individuals with type 1 diabetes to a greater extent than intensityYardley, Jane E.
doi: 10.1007/s00125-022-05781-8pmid: 35978179
Recent guidelines suggest that adding anaerobic (high intensity or resistance) activity to an exercise session can prevent blood glucose declines that occur during aerobic exercise in individuals with type 1 diabetes. This theory evolved from earlier study data showing that sustained, anaerobic activity (high intensity cycling) increases blood glucose levels in these participants. However, studies involving protocols where anaerobic (high intensity interval) and aerobic exercise are combined have extremely variable glycaemic outcomes, as do resistance exercise studies. Scrutinising earlier studies will reveal that, in addition to high intensity activity (intervals or weight lifting), these protocols had another common feature: participants were performing exercise after an overnight fast. Based on these findings, and data from recent exercise studies, it can be argued that participant prandial state may be a more dominant factor than exercise intensity where glycaemic changes in individuals with type 1 diabetes are concerned. As such, a reassessment of study outcomes and an update to exercise recommendations for those with type 1 diabetes may be warranted.Graphical abstract[graphic not available: see fulltext]
Disruption of retinal inflammation and the development of diabetic retinopathy in mice by a CD40-derived peptide or mutation of CD40 in Müller cellsPortillo, Jose-Andres C.; Yu, Jin-Sang; Vos, Sarah; Bapputty, Reena; Lopez Corcino, Yalitza; Hubal, Alyssa; Daw, Jad; Arora, Sahil; Sun, Wenyu; Lu, Zheng-Rong; Subauste, Carlos S.
doi: 10.1007/s00125-022-05775-6pmid: 35920844
Aims/hypothesisCD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by purinergic receptor (P2X7)-dependent production of proinflammatory cytokines in myeloid cells. In the diabetic retina, CD40 and P2X7 upregulate a broad range of inflammatory molecules that promote development of diabetic retinopathy. The molecular event downstream of CD40 that activates the PLCγ1–ATP–P2X7–proinflammatory cytokine cascade and promotes development of diabetic retinopathy is unknown. We hypothesise that disruption of the CD40-driven molecular events that trigger this cascade prevents/treats diabetic retinopathy in mice.MethodsB6 and transgenic mice with Müller cell-restricted expression of wild-type (WT) CD40 or CD40 with mutations in TNF receptor-associated factor (TRAF) binding sites were made diabetic using streptozotocin. Leucostasis was assessed using FITC-conjugated concanavalin A. Histopathology was examined in the retinal vasculature. Expression of inflammatory molecules and phospho-Tyr783 PLCγ1 (p-PLCγ1) were assessed using real-time PCR, immunoblot and/or immunohistochemistry. Release of ATP and cytokines were measured by ATP bioluminescence and ELISA, respectively.ResultsHuman Müller cells with CD40 ΔT2,3 (lacks TRAF2,3 binding sites) were unable to phosphorylate PLCγ1 and release ATP in response to CD40 ligation, and could not induce TNF-α/IL-1β secretion in bystander myeloid cells. CD40–TRAF signalling acted via Src to induce PLCγ1 phosphorylation. Diabetic mice in which WT CD40 in Müller cells was replaced by CD40 ΔT2,3 failed to exhibit phosphorylation of PLCγ1 in these cells and upregulate P2X7 and TNF-α in microglia/macrophages. P2x7 (also known as P2rx7), Tnf-α (also known as Tnf), Il-1β (also known as Il1b), Nos2, Icam-1 (also known as Icam1) and Ccl2 mRNA were not increased in these mice and the mice did not develop retinal leucostasis and capillary degeneration. Diabetic B6 mice treated intravitreally with a cell-permeable peptide that disrupts CD40–TRAF2,3 signalling did not exhibit either upregulation of P2X7 and inflammatory molecules in the retina or leucostasis.Conclusions/interpretationCD40–TRAF2,3 signalling activated the CD40–PLCγ1–ATP–P2X7–proinflammatory cytokine pathway. Src functioned as a link between CD40–TRAF2,3 and PLCγ1. Replacing WT CD40 with CD40 ΔT2,3 impaired activation of PLCγ1 in Müller cells, upregulation of P2X7 in microglia/macrophages, upregulation of a broad range of inflammatory molecules in the diabetic retina and the development of diabetic retinopathy. Administration of a peptide that disrupts CD40–TRAF2,3 signalling reduced retinal expression of inflammatory molecules and reduced leucostasis in diabetic mice, supporting the therapeutic potential of pharmacological inhibition of CD40–TRAF2,3 in diabetic retinopathy.Graphical abstract[graphic not available: see fulltext]
Associations between parental type 2 diabetes risk and offspring birthweight and placental weight: a survival analysis using the Walker cohortSánchez-Soriano, Carlos; Pearson, Ewan R.; Reynolds, Rebecca M.
doi: 10.1007/s00125-022-05776-5pmid: 35951032
Aims/hypothesisLow birthweight (BW) is associated with the development of type 2 diabetes. Genome-wide analyses have identified a strong genetic component to this association, with many BW-associated loci also involved in glucose metabolism. We hypothesised that offspring BW and placental weight (PW) are correlated with parental type 2 diabetes risk, reflecting the inheritance of diabetes risk alleles that also influence fetal growth.MethodsThe Walker cohort, a collection of birth records from Dundee, Scotland, from the 1950s and the 1960s was used to test this hypothesis by linking BW and PW measurements to parental health outcomes. Using data from SCI-Diabetes and the national death registry, we obtained health records for over 20,000 Walker parents. We performed Fine–Gray survival analyses of parental type 2 diabetes risk with competing risk of death, and Cox regression analyses of risk of death, independently in the maternal and paternal datasets, modelled by offspring BW and PW.ResultsWe found significant associations between increased paternal type 2 diabetes risk and reduced offspring BW (subdistribution hazard ratio [SHR] 0.92 [95% CI 0.87, 0.98]) and PW (SHR 0.87 [95% CI 0.81, 0.94]). The association of maternal type 2 diabetes risk with offspring BW or PW was not significant. Lower offspring BW was also associated with increased risk of death in both mothers (HR 0.91 [95% CI 0.89, 0.94]) and fathers (HR 0.95 [95% CI 0.92, 0.98]), and higher offspring PW was associated with increased maternal mortality risk (HR 1.08 [95% CI 1.04, 1.13]) when adjusted for BW.Conclusions/interpretationWe identified associations between offspring BW and reduced paternal type 2 diabetes risk, most likely resulting from the independent effects of common type 2 diabetes susceptibility alleles on fetal growth, as described by the fetal insulin hypothesis. Moreover, we identified novel associations between offspring PW and reduced paternal type 2 diabetes risk, a relationship that might also be caused by the inheritance of diabetes predisposition variants. We found differing associations between offspring BW and PW and parental risk of death. These results provide novel epidemiological support for the use of offspring BW and PW as predictors for future risk of type 2 diabetes and death in mothers and fathers.Graphical abstract[graphic not available: see fulltext]
Infections in the first year of life and development of beta cell autoimmunity and clinical type 1 diabetes in high-risk individuals: the TRIGR cohortKordonouri, Olga; Cuthbertson, David; Belteky, Malin; Aschemeier-Fuchs, Bärbel; White, Neil H.; Cummings, Elisabeth; Knip, Mikael; Ludvigsson, Johnny
doi: 10.1007/s00125-022-05786-3pmid: 36083343
Aims/hypothesisAccumulated data suggest that infections in early life contribute to the development of type 1 diabetes. Using data from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), we set out to assess whether children who later developed diabetes-related autoantibodies and/or clinical type 1 diabetes had different exposure to infections early in life compared with those who did not.MethodsA cohort of 2159 children with an affected first-degree relative and HLA-conferred susceptibility to type 1 diabetes were recruited between 2002 and 2007 and followed until 2017. Infections were registered prospectively. The relationship between infections in the first year of life and the development of autoantibodies or clinical type 1 diabetes was analysed using univariable and multivariable Cox regression models. As this study was exploratory, no adjustment was made for multiple comparisons.ResultsAdjusting for HLA, sex, breastfeeding duration and birth order, those who had seven or more infections during their first year of life were more likely to develop at least one positive type 1 diabetes-related autoantibody (p=0.028, HR 9.166 [95% CI 1.277, 65.81]) compared with those who had no infections. Those who had their first viral infection aged between 6 and 12 months were less likely to develop at least one positive type 1 diabetes-related antibody (p=0.043, HR 0.828 [95% CI 0.690, 0.994]) or multiple antibodies (p=0.0351, HR 0.664 [95% CI 0.453, 0.972]). Those who had ever had an unspecified bacterial infection were more likely to develop at least one positive type 1 diabetes-related autoantibody (p=0.013, HR 1.412 [95% CI 1.075, 1.854]), to develop multiple antibodies (p=0.037, HR 1.652 [95% CI 1.030, 2.649]) and to develop clinical type 1 diabetes (p=0.011, HR 2.066 [95% CI 1.182, 3.613]).Conclusions/interpretationWe found weak support for the assumption that viral infections early in life may initiate the autoimmune process or later development of type 1 diabetes. In contrast, certain bacterial infections appeared to increase the risk of both multiple autoantibodies and clinical type 1 diabetes.Graphical abstract[graphic not available: see fulltext]
Normal and disordered gastric emptying in diabetes: recent insights into (patho)physiology, management and impact on glycaemic controlJalleh, Ryan J.; Jones, Karen L.; Rayner, Christopher K.; Marathe, Chinmay S.; Wu, Tongzhi; Horowitz, Michael
doi: 10.1007/s00125-022-05796-1pmid: 36194250
Gastric emptying is a major determinant of postprandial blood glucose, accounting for ~35% of variance in peak glucose in both healthy individuals and those with type 2 diabetes. Gastric emptying is frequently disordered in individuals with diabetes (both abnormally delayed and accelerated). Delayed gastric emptying, i.e. diabetic gastroparesis, may be linked to upper gastrointestinal symptoms for which current treatment remains suboptimal; pharmacological acceleration of delayed emptying is only weakly associated with symptom improvement. Accordingly, the relationship between symptoms and delayed gastric emptying is not simply ‘cause and effect’. In insulin-treated patients, disordered gastric emptying, even when not associated with gastrointestinal symptoms, can cause a mismatch between the onset of insulin action and the availability of absorbed carbohydrate, leading to suboptimal glycaemic control. In patients with type 2 diabetes, interventions that slow gastric emptying, e.g. glucagon-like peptide-1 receptor agonists, reduce postprandial blood glucose. This review focuses on recent insights into the impact of gastric emptying on postprandial blood glucose, effects of diabetes therapy on gastric emptying and the management of disordered gastric emptying in diabetes. In view of the broad relevance of gastric emptying to diabetes management, it is important that future clinical trials evaluating novel therapies that may affect gastric emptying should quantify the latter with an appropriate technique, such as scintigraphy or a stable isotope breath test.Graphical abstract[graphic not available: see fulltext]