α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Doliba, Nicolai M.; Rozo, Andrea V.; Roman, Jeffrey; Qin, Wei; Traum, Daniel; Gao, Long; Liu, Jinping; Manduchi, Elisabetta; Liu, Chengyang; Golson, Maria L.; Vahedi, Golnaz; Naji, Ali; Matschinsky, Franz M.; Atkinson, Mark A.; Powers, Alvin C.; Briššová, Marcela; Kaestner, Klaus H.; Stoffers, Doris A.

doi:10.1172/jci156243

Cited by 35 publications

(29 citation statements)

References 61 publications

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“…That GABA reinforces the inhibitory communication from beta to alpha cells suggests the islet GABA system as a target to treat diabetes. Dysregulation of alpha cell glucagon secretion in low glucose contributes to diabetic hyperglycemia and is observed in T2D, T1D and pre-T1D autoantibody positive individuals ( 136 , 137 ). Coincidentally, islets from donors with T2D and T1D are also observed to be depleted of GABA ( 12 ).…”

Section: Effect Of Gaba On Glucagon Secretionmentioning

confidence: 99%

The role of GABA in islet function

et al. 2022

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Gamma aminobutyric acid (GABA) is a non-proteinogenic amino acid and neurotransmitter that is produced in the islet at levels as high as in the brain. GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD), of which the 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes. Originally described to be released via synaptic-like microvesicles or from insulin secretory vesicles, beta cells are now understood to release substantial quantities of GABA directly from the cytosol via volume-regulated anion channels (VRAC). Once released, GABA influences the activity of multiple islet cell types through ionotropic GABAA receptors and metabotropic GABAB receptors. GABA also interfaces with cellular metabolism and ATP production via the GABA shunt pathway. Beta cells become depleted of GABA in type 1 diabetes (in remaining beta cells) and type 2 diabetes, suggesting that loss or reduction of islet GABA correlates with diabetes pathogenesis and may contribute to dysfunction of alpha, beta, and delta cells in diabetic individuals. While the function of GABA in the nervous system is well-understood, the description of the islet GABA system is clouded by differing reports describing multiple secretion pathways and effector functions. This review will discuss and attempt to unify the major experimental results from over 40 years of literature characterizing the role of GABA in the islet.

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Section: Effect Of Gaba On Glucagon Secretionmentioning

confidence: 99%

The role of GABA in islet function

et al. 2022

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“…For example, impaired glucagon secretion among diabetic patients has been identified for decades [34,35]. This result is supported by recent experiments performed on islets isolated from diabetic patients showing both a decreased expression of key alpha cellsenriched transcription factors, and a loss of glucose-regulated glucagon secretion [36,37]. A limited number of studies also suggest an alteration of delta cells function in type 1 diabetes [38,39].…”

Section: Introductionmentioning

confidence: 80%

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Burghgrave

Lourenço

Berthault

et al. 2022

Cells

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Type 1 diabetes (T1D) is an auto-immune disease characterized by the progressive destruction of insulin-producing pancreatic beta cells. While beta cells are the target of the immune attack, the other islet endocrine cells, namely the alpha and delta cells, can also be affected by the inflammatory milieu. Here, using a flow cytometry-based strategy, we compared the impact of IFNγ, one of the main cytokines involved in T1D, on the three endocrine cell subsets isolated from C57BL/6 mouse islets. RNA-seq analyses revealed that alpha and delta cells exposed in vitro to IFNγ display a transcriptomic profile very similar to that of beta cells, with an increased expression of inflammation key genes such as MHC class I molecules, the CXCL10 chemokine and the programmed death-ligand 1 (PD-L1), three hallmarks of IFNγ signaling. Interestingly, at low IFNγ concentration, we observed two beta cell populations (responders and non-responders) based on PD-L1 protein expression. Our data indicate that this differential sensitivity relies on the location of the cells within the islet rather than on the existence of two different beta cells subsets. The same findings were corroborated by the in vivo analysis of pancreatic islets from the non-obese diabetic mouse model of T1D, showing more intense PD-L1 staining on endocrine cells close to immune infiltrate. Collectively, our work demonstrates that alpha and delta cells are as sensitive as beta cells to IFNγ, and suggests a gradual diffusion of the cytokine into an islet. These observations provide novel insights into the in situ inflammatory processes occurring in T1D progression.

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“…The observation implies that those children who later present with type 1 diabetes may have variable glucose metabolism in their early years. Although reasons behind this remain speculative, previous studies have shown alterations also in glucagon-producing alpha cells in preclinical type 1 diabetes ( 25 ). It remains possible that alpha cell dysfunction is presently lost prior to decreasing insulin secretion leading to hypoglycemia in future progressors.…”

Section: Discussionmentioning

confidence: 99%

Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups

Helminen

Pokka²,

Aspholm³

et al. 2022

Front. Endocrinol.

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BackgroundAnatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes.MethodsThe Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated.ResultsWe observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups.ConclusionWe report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones.

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α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Cited by 35 publications

References 61 publications

The role of GABA in islet function

The role of GABA in islet function

Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups

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