Islets from human donors with higher but not lower hemoglobin A1c levels respond to gastrin treatment in vitro

Abstract

Gastrin is a peptide hormone, which in combination with other factors such as TGFα, EGF or GLP-1, is capable of increasing beta cell mass and lowering blood glucose levels in adult diabetic mice. In humans, administration of a bolus of gastrin alone induces insulin secretion suggesting that gastrin may target islet cells. However, whether gastrin alone is sufficient to exert an effect on isolated human islets has been controversial and the mechanism remained poorly understood. Therefore, in this study we started to examine the effects of gastrin alone on cultured adult human islets. Treatment of isolated human islets with gastrin I for 48 h resulted in increased expression of insulin, glucagon and somatostatin transcripts. These increases were significantly correlated with the levels of donor hemoglobin A1 c (HbA 1c ) but not BMI or age. In addition, gastrin treatment resulted in increased expression of PDX1 , NKX6 . 1 , NKX2 . 2 , MNX1 and HHEX in islets from donors with HbA 1c greater than 42 mmol/mol. The addition of YM022, an antagonist of the gastrin receptor cholecystokinin B receptor (CCKBR), together with gastrin eliminated these effects, verifying that the effects of gastrin are mediated through CCKBR.CCKBR is expressed in somatostatin-expressing delta cells in islets from all donors. However, in the islets from donors with higher HbA 1c (greater than 42 mmol/mol [6.0%]), cells triple-positive for CCKBR, somatostatin and insulin were detected, suggesting a de-differentiation or trans-differentiation of endocrine cells. Our results demonstrate a direct effect of gastrin on human islets from prediabetic or diabetic individuals that is mediated through CCKBR + cells. Further, our data imply that gastrin may be a potential treatment for diabetic patients.

Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

“…Our regimen of induction of Haplo-MC is undergoing a phase 1 clinical trial for treatment of sickle cell disease, and initial results are promising, with much reduced toxicity (NCT03249831). This trial does not use GE, but GE has been used in patients ( 68 , 69 ), and it has been shown that islets from human donors with higher but not lower hemoglobin A1c levels respond to gastrin treatment in vitro ( 48 ). We will further evaluate GE’s effect on human islet cells using freshly isolated human islets or live pancreas slice assay as recently reported by Speier and coworkers ( 70 ).…”

“…Gastrin is also expressed by α and β cells in the islets of diabetic rodents and humans ( 47 ). Gastrin in combination with other factors such as transforming growth factor alpha, EGF, or glucagon-like peptide-1 is capable of increasing β cell mass and lowering blood glucose levels in adult diabetic mice ( 48 ). Gastrin exerts its effect on transcription, at least in part, through gastrin receptor cholecystokinin B receptor (CCKBR) ( 48 , 49 ).…”

“…Gastrin in combination with other factors such as transforming growth factor alpha, EGF, or glucagon-like peptide-1 is capable of increasing β cell mass and lowering blood glucose levels in adult diabetic mice ( 48 ). Gastrin exerts its effect on transcription, at least in part, through gastrin receptor cholecystokinin B receptor (CCKBR) ( 48 , 49 ). CCKBR is expressed in both somatostatin-expressing δ cells and glucagon-producing α cells in islets ( 48 , 50 , 51 ).…”

“…Gastrin exerts its effect on transcription, at least in part, through gastrin receptor cholecystokinin B receptor (CCKBR) ( 48 , 49 ). CCKBR is expressed in both somatostatin-expressing δ cells and glucagon-producing α cells in islets ( 48 , 50 , 51 ).…”

Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment

“…Gastrin may also contribute to β-cell mass through maintaining β-cell identity under diabetic conditions. For example, gastrin treatment of islets from DM patients resulted in increased expression of insulin (INS), PDX-1, MAFA, NKX homeobox 1 (NKX6.1), NK2 homeobox 2 (NKX2.2), monitor neuron and pancreas homeobox 1 (MNX1), and common β-cell markers [ 89 ]. Islets from patients with higher HbA1C, signifying higher average blood glucose level in the prior 3 months, experienced a more profound increase in these β-cell transcription factors compared with those with lower HbA1C [ 89 ].…”