Changes in beta cell function occur in prediabetes and early disease in the Lepr db mouse model of diabetes

Abstract

Aims/hypothesis Type 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease. Methods The Lepr db mouse (age 13-18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells. Results We identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule-granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose. Conclusions/interpretation Beta cell function is altered in prediabetes and there are further changes in the progression to early disease.

Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling‐dependent manner

“…Type 2 diabetes mellitus (T2DM) is the predominant form of diabetes and is characterized by insulin resistance and pancreatic β‐cell failure, which lead to abnormally high blood glucose levels (hyperglycaemia) . Impaired function of β‐cells, which are responsible for the production and secretion of insulin, is a critical contributing factor for the progression from prediabetes to diabetes . The loss of responding β‐cells in pancreatic islets has been found in genetically diabetic (db/db) mice .…”

“…1,2 Impaired function of β-cells, which are responsible for the production and secretion of insulin, is a critical contributing factor for the progression from prediabetes to diabetes. 3,4 The loss of responding β-cells in pancreatic islets has been found in genetically diabetic (db/db) mice. 5 Although previous studies have reported that the β-cell-specific transcription factors pancreatic duodenal homeobox 1 (PDX-1) and v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) play key roles in the maintenance of β-cell function and the production of insulin, 6,7 the precise molecular mechanisms underlying β-cell function and insulin expression remain largely unknown, thus greatly limiting the development of effective therapeutic strategies against T2DM.…”

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

“…This drop is coincident with the increase in AUC of the GTT (Figure 4.1D) and demonstrates very clearly that altered beta-cell function is strongly associated with loss of glucose homeostasis. The new findings are consistent with my previous chapter (chapter 3), where animals with overt disease and compromised GTTs were studied ). The results now show that at stage 2 the beta-cells are still competent to secrete and that a high potassium stimulus can elicit insulin secretion.…”

“…The rarity of sequential/ mutigranular exocytosis in pancreatic beta-cells under normal condition is believed to play an important physiological role in prolonged regulation of blood glucose concentration whereby massive secretion is prevented. However, when stimulated with muscarinic agonist carbachol or glucagon like peptide 1 (GLP-1) in addition to glucose, compound exocytosis of the insulin-containing granules becomes quantitatively significant (3)(4) times increase) which suggests an important role of this type of exocytosis in essential conditions where insulin demand is very high (Kwan and Gaisano 2005;Hoppa, Jones et al 2012).…”

“…To determine if insulin content in single cells was changing, immunofluorescence of insulin was performed in isolated islets. This identified an increase in cellular insulin storage at stage 1 and a decrease at stages [2][3][4]n=13 WT, 13 db/db mice).…”