Alpha-cells and therapy of diabetes: Inhibition, antagonism or death?

Klempel, Natalie; Thomas, Keith; Conlon, J. Michael; Flatt, Peter; Irwin, Nigel

doi:10.1016/j.peptides.2022.170877

Cited by 5 publications

(2 citation statements)

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“…Moreover, alpha cells are innately more resistant to oxidative stress and induction of apoptosis than beta cells ( Eizirik et al 2023 ). Indeed, there is a suggestion that alpha cells could represent a viable direct target for diabetes therapies ( Klempel et al 2022 ). Notably, in the current study female mouse islets were composed of more alpha cells than males, with no obvious difference in turnover rates.…”

Section: Discussionmentioning

confidence: 99%

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice

Tanday,

Coulter-Parkhill,

Moffett

et al. 2023

Journal of Endocrinology

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The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received 5 daily doses of STZ (50 mg/kg, i.p) or 10 daily doses of HC (70 mg/kg, i.p), with parameters assessed on day 11. STZ-induced hyperglycaemia was evident in both sexes, alongside impaired glucose tolerance and reduced insulin concentrations. HC also had similar metabolic effects in male and female mice resulting in classical increases of circulating insulin indicative of insulin resistance. Control male mice had larger pancreatic islets than females and displayed a greater reduction of islet and beta-cell area in response to STZ insult. In addition, female STZ mice had lower levels of beta-cell apoptosis than male counterparts. Following HC administration, female mouse islets contained a greater proportion of alpha-cells when compared to males. All HC mice presented with relatively comparable increases in beta- and alpha-cell turnover rates, with female mice being slightly more susceptible to HC-induced beta-cell apoptosis. Interestingly, healthy control female mice had inherently increased alpha- to beta-cell transdifferentiation rates, which was decreased by HC treatment. The number of glucagon-positive alpha-cells altering their lineage to insulin-positive beta-cells was increased in male, but not female, STZ mice. Taken together, although there was no obvious sex-specific alteration of metabolic profile in STZ or HC mice, subtle differences in pancreatic islet morphology emphasises the impact of sex hormones on islets and importance of taking care when interpreting observations between males and females.

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Section: Discussionmentioning

confidence: 99%

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice

Tanday,

Coulter-Parkhill,

Moffett

et al. 2023

Journal of Endocrinology

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“…The identification of small molecules that modulate α-cell function constitutes a distinct strategy that may lead to useful candidate compounds. Potent and safe new drugs that specifically reduce glucagon secretion from α-cells without impacting other cells in the body could represent a major advance for both new-onset as well as established T1D ( 10 ). Based on results from the late Roger Unger and others, suppressing glucagon secretion can improve glucose control and reduce the need for insulin injections in rodent models ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Small molecule glucagon release inhibitors with activity in human islets

et al. 2023

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PurposeType 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. ResultsHere, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. ConclusionGiven the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity in vitro.

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Regulated and adaptive in vivo insulin secretion from islets only containing β-cells

Perez-Frances,

Bru-Tari,

Cohrs

et al. 2024

Nat Metab

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Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing ‘non-β-cells’ (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.

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Alpha-cells and therapy of diabetes: Inhibition, antagonism or death?

Cited by 5 publications

References 84 publications

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice

Small molecule glucagon release inhibitors with activity in human islets

Regulated and adaptive in vivo insulin secretion from islets only containing β-cells

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