A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

Abstract

Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. MethodsThe presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption-ionisation-time of flight (MALDI-TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. Diabetologia (2012) 55:3262-3272 DOI 10.1007/s00125-012-2716 Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2716-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Results Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from nondiabetic isolated islets. Conclusions/interpretation We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

“…It has, however, been thought that proglucagon is processed to glucagon in a-cells due to cell-specific expression of the processing enzymes prohormone convertase 2. However, as recently demonstrated by Marchetti et al in human islets, GLP-1 may also be expressed in a-cells (29). It has also been shown that under certain conditions, such as high glucose, GLP-1 production is increased in a-cells due to a specific overexpression of prohormone convertase 1/3 (30).…”

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…Moreover, recent studies on glucose-dependent insulinotrophic polypeptide (GIP) and GLP1 have pointed out that both hormones are synthesized and secreted from islet α-cells under conditions of cellular stress imposed by β cytotoxic attack or increased insulin demand (Fujita et al 2010, Donath & Burcekin 2013, Moffett et al 2014. Increased expression of PC1/3 relative to PC2 in islet α-cells directs proglucagon processing away from glucagon towards GLP1 in these conditions (Wideman et al 2007, Marchetti et al 2012. As GLP1 and GLP2 are produced by the same convertase in equimolar amount (Janssen et al 2013), it is likely to hypothesize that GLP2 pancreatic expression also changes in stress conditions, such as derangements of islet cell function associated with prolonged consumption of HFD.…”

Status of Bone Mineral Density in Children with Type 1 Diabetes Mellitus and Its Related Factors

“…In addition to influencing the pathophysiology on bone diseases caused by diabetes, bone density disorder in type 1 DM is also influenced by genetic factors (11). Also, increasing risk of fractures has been reported in diabetic patients treated with insulin drugs than non-insulin drugs (12). Considering importance of osteoporosis in the individual's activity and increased risk of pathological fractures in the future, determining prevalence and risk factors of the problem in children with type 1 DM and necessary treatments for its reduction is essential (13).…”