Beta cells in type 1 diabetes: mass and function; sleeping or dead?

Oram, Richard A.; Sims, Emily K.; Evans‐Molina, Carmella

doi:10.1007/s00125-019-4822-4

Cited by 116 publications

(94 citation statements)

References 79 publications

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“…Our results suggest that the natural evolution of the β cell-specific CD8 + T cell response during the prediabetic period in young children becomes increasingly dominated by end-stage cytolytic effector cells which are capable of directly mediating β cell destruction. These data fit with observations that at clinical diagnosis β cell destruction is already well advanced [84]. Of interest, previous studies of the DIPP cohort have reported that the HLA-A*24 allele is associated with accelerated disease progression from seroconversion to clinical disease [26].…”

Section: Discussionsupporting

confidence: 88%

Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Yeo

Pujol‐Autonell

Baptista

et al. 2019

Clinical and Experimental Immunology

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Summary In type 1 diabetes (T1D), autoreactive cytotoxic CD8+ T cells are implicated in the destruction of insulin‐producing β cells. The HLA‐B*3906 and HLA‐A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8+ T cells that recognize peptides presented by these class I molecules on pancreatic β cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)‐specific and insulin B (InsB)‐specific CD8+ T cells in HLA‐B*3906+ children newly diagnosed with T1D and in high‐risk HLA‐A*2402+ children before the appearance of disease‐specific autoantibodies and before diagnosis of T1D. Antigen‐specific CD8+ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA‐B*3906+ children with T1D, we observed an increase in PPI5–12‐specific transitional memory CD8+ T cells compared to non‐diabetic, age‐ and HLA‐matched subjects. Furthermore, PPI5–12‐specific CD8+ T cells in HLA‐B*3906+ children with T1D showed a significantly more antigen‐experienced phenotype compared to polyclonal CD8+ T cells. In longitudinal samples from high‐risk HLA‐A*2402+ children, the percentage of terminal effector cells within the InsB15–24‐specific CD8+ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA‐B*3906‐restricted autoreactive CD8+ T cells in T1D. Collectively, our results provide evidence that β cell‐reactive CD8+ T cells restricted by disease‐associated HLA class I molecules display an antigen‐experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.

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Section: Discussionsupporting

confidence: 88%

Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Yeo

Pujol‐Autonell

Baptista

et al. 2019

Clinical and Experimental Immunology

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“…With the identification of persistent proinsulin processing in individuals with undetectable C-peptide, it is intriguing to ask whether other β cell populations are dysfunctional enough to be considered merely dormant (18). How the surviving β cells managed to elude autoimmune destruction and whether these other groups of dormant β cells could be rejuvenated remain important questions (19).…”

Section: Discussionmentioning

confidence: 99%

Residual β cell function and monogenic variants in long-duration type 1 diabetes patients

Keenan

Shah

et al. 2019

Journal of Clinical Investigation

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BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between β cell function and pathology and clinical characteristics. METHODS. Individuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and β cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/ arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort. RESULTS. Of the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with HLA-/AAband HLA + /AAb-Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as "likely pathogenic" (rare exome variant ensemble learner [REVEL] >0.75). CONCLUSION. All Medalists retained insulin-positive β cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to β cell function, and many with HLA + diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.

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“…Together, this suggests that β‐cell loss could be overestimated in T2D and rather it is changes in β‐cell phenotype and function which are more important in the diseases pathogenesis (Marselli et al., 2014). In a similar fashion, β‐cell loss in T1D may also be linked to an increase in dysfunctional β‐cells (Oram, Sims, & Evans‐Molina, 2019). For example, β‐cell dedifferentiation is another mechanism linked to β‐cell failure (Talchai, Xuan, Lin, Sussel, & Accili, 2012).…”

Section: Effect Of Exercise On β‐Cell Massmentioning

confidence: 96%

The benefits of physical exercise for the health of the pancreatic β‐cell: a review of the evidence

Curran

Drayson

Zoppi

et al. 2020

Experimental Physiology

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Physical exercise is a core therapy for type 1 and type 2 diabetes. Whilst the benefits of exercise for different physiological systems are recognised, the effect of exercise specifically on the pancreatic -cell is not well described. Here we review the effects of physical exercise on -cell health.We show that exercise improves -cell mass and function. The improved function manifests primarily through the increased insulin content of the -cell and its increased ability to secrete insulin in response to a glucose stimulus. We review the evidence relating to glucose sensing, insulin signalling, -cell proliferation and -cell apoptosis in humans and animal models with acute exercise and following exercise training programmes. Some of the mechanisms through which these benefits manifest are discussed. K E Y W O R D S

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Beta cells in type 1 diabetes: mass and function; sleeping or dead?

Cited by 116 publications

References 79 publications

Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Residual β cell function and monogenic variants in long-duration type 1 diabetes patients

The benefits of physical exercise for the health of the pancreatic β‐cell: a review of the evidence

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