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    • Although GLP has greater insulin releasing effects at pharma

    2021-10-18

    Although GLP-1 has greater insulin-releasing effects at pharmacological concentrations [10], it is apparent that the higher circulating concentrations of GIP combined with more pronounced increase in secretion following feeding make GIP the major physiological incretin [7], [11]. The peptide exerts pleiotropic actions on beta 2×Taq PCR Master Mix(with dye) ranging from the stimulation of insulin biosynthesis and secretion to the enhancement of beta cell proliferation and protection against apoptosis induced by cytotoxic attack [7]. Interestingly GIP also has direct beneficial extra-pancreatic actions including positive effects on bone formation that may be physiologically important following feeding [12]. Recent studies on cellular biology of GIP and GLP-1 have indicated that both hormones are synthesised and secreted from islet alpha cells under conditions of cellular stress imposed by beta cytotoxic attack or increased insulin demand such as observed in pregnancy [13], [14], [15]. Thus it is commonly believed that increased expression of PC1/3 relative to PC2 in islet alpha cells directs proglucagon processing away from glucagon towards GLP-1 in these situations [16], [17], [18]. In contrast, both pro-convertase enzymes can process proGIP to biologically active forms GIP(1–42) or GIP(1–30) [19]. This local incretin system within the islets makes a physiological sense given that intestinal-derived incretins are rapidly degraded in the circulation such that their circulating half-lives are less than 10min and that >95% circulate as inactive GIP(3–42) and GLP-1(9–36) [6], [7]. The physiological significance of islet derived incretin peptides has been highlighted also by recent studies in GLP-1 and GIP receptor knock-out mice which indicate the importance of GLP-1 in the expansion of beta cell mass in pregnancy and involvement of both GLP-1 and particularly GIP in islet compensation to cellular stress and hydrocortisone-induced insulin resistance [14], [20]. Given that the fat component of the diet is particularly a strong stimulus to GIP release from intestinal K-cells which serves to promote both glucose-induced insulin secretion and fat storage [7], GIP has been proposed to play a prominent role in obesity and underlying derangements of islet cell function and glucose metabolism associated with prolonged consumption of high fat diet. The present work with GIPRKO mice highlights the key role of GIP in islet compensation association with high fat feeding and suggests that defects in GIP action, such as observed in type 2 diabetes, contribute to the process of eventual beta cell demise.
    Materials and methods
    Results
    Discussion The present study has evaluated islet adaptations to prolonged feeding of high fat diet which was initiated at the time of weaning in C57BL/6 mice. Consistent with previous findings [22], high fat fed mice exhibited increased adiposity as evidenced by measurement of body fat stores by DXA scanning. In contrast to other strains of mice, such as Swiss NIH [23], high fat fed C57BL/6 mice did not exhibit non-fasting hyperglycaemia. Their insulin resistance was modest and compensated by substantial elevation of circulating insulin and small decrease of glucagon, giving rise to a significantly lower circulating glucose/insulin molar ratio compared with mice fed normal laboratory chow. Such strain differences in responses to high fat diets have been noted in mice previously, indicating the important role of genetic factors in metabolic regulation [24]. As expected, the hyperinsulinaemia in high fat fed C57BL/6 mice was driven by a marked elevation of plasma GIP, pancreatic insulin stores, an increase in total islet numbers and a relative increase in the proportion of large (>25,000μm2) as opposed to small (<10,000μm2) sized islets in the pancreas. Within populations of individual islets, total cellular area was increased, reflecting enhancement of both beta and alpha cell areas. Notably pancreatic stores of glucagon but not GLP-1 were suppressed by high fat feeding. In fact, the major product of proglucagon processing in alpha cells was switched from glucagon to GLP-1, consistent with the activation of PC1/3 under these conditions [17]. Interestingly circulating GLP-1 concentrations were unchanged. This was associated with an increase of both beta cell proliferation and apoptosis but the overall effect was in favour of more than 2-fold increase of beta cell mass. These effects indicate a key role of beta cell replication in the expansion of islet size but further studies are needed to determine whether neogenesis or cellular reprogramming underlies the observed increase of islet numbers [25], [26].