SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid–stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to β cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.

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Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

Biochemical Journal ◽

10.1042/bj20140697 ◽

2015 ◽

Vol 468 (1) ◽

pp. 49-63 ◽

Cited By ~ 7

Author(s):

Jelena A. Stamenkovic ◽

Lotta E. Andersson ◽

Alice E. Adriaenssens ◽

Annika Bagge ◽

Vladimir V. Sharoyko ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Glucagon Secretion ◽

Nutrient Sensing ◽

Β Cells ◽

Mouse Pancreatic Islets ◽

Glucagon And Insulin ◽

Malate Aspartate Shuttle

Secretion of both glucagon and insulin is perturbed in Type 2 diabetes (T2D). In the present study, we identify a difference in mitochondrial shuttling between α- and β-cells that adjusts nutrient sensing and which potentially could be employed to specifically target secretion of either hormone.

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Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

Scientific Reports ◽

10.1038/s41598-021-94725-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Brenda Strutt ◽

Sandra Szlapinski ◽

Thineesha Gnaneswaran ◽

Sarah Donegan ◽

Jessica Hill ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Transporter ◽

Cell Mass ◽

Elevated Serum ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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Dextromethorphan stimulates insulin secretion from pancreatic β cells—a new role for an old drug?

Nature Reviews Endocrinology ◽

10.1038/nrendo.2015.49 ◽

2015 ◽

Vol 11 (5) ◽

pp. 253-253

Author(s):

Jennifer Sargent

Keyword(s):

Insulin Secretion ◽

Β Cells ◽

Pancreatic Β Cells

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PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Nature Communications ◽

10.1038/s41467-020-20632-z ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Daniela Nasteska ◽

Nicholas H. F. Fine ◽

Fiona B. Ashford ◽

Federica Cuozzo ◽

Katrina Viloria ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Metabolic Stress ◽

Human Islets ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Ionic Fluxes ◽

Transcriptomic Level ◽

Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0457 ◽

2020 ◽

Vol 33 (5) ◽

pp. 671-674

Author(s):

Tashunka Taylor-Miller ◽

Jayne Houghton ◽

Paul Munyard ◽

Yadlapalli Kumar ◽

Clinda Puvirajasinghe ◽

...

Keyword(s):

Insulin Secretion ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Β Cells ◽

Pancreatic Β Cells ◽

Newborn Period ◽

Case Presentation ◽

Male Baby ◽

Common Causes ◽

Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

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