The purpose of this review is to examine the current scientific literature regarding the interplay between the exocrine and endocrine pancreas, specifically the role of the exocrine pancreas in the pathogenesis of canine diabetes mellitus. β-cell death caused by exocrine pancreatic inflammation is thought to be an under-recognised contributor to diabetes mellitus in dogs, with up to 30% of canine diabetic patients with concurrent evidence of pancreatitis at post-mortem examination. Current diagnostics for pancreatitis are imprecise, and treatments for both diseases individually have their own limitations: diabetes through daily insulin injections, which has both welfare and financial implications for the stakeholders, and pancreatitis through treatment of clinical signs, such as analgesia and anti-emetics, rather than targeted treatment of the underlying cause. This review will consider the evidence for exocrine pancreatic inflammation making an active contribution to pancreatic β-cell loss and insulin-deficiency diabetes in the dog and explore current and potential future diagnostic and treatment avenues to improve outcomes for these patients.

Beta-casomorphins (BCMs) are the bio-active peptides having opioid properties which are formed by the proteolytic digestion of β-caseins in milk. BCM-7 forms when A1 milk is digested in the small intestine due to a histidine at the 67th position in β-casein, unlike A2 milk, which has proline at this position and produces BCM-9. BCM-7 has further degraded into BCM-5 by the dipeptidyl peptidase-IV (DPP-IV) enzyme in the intestine. The opioid-like activity of BCM-7 is responsible for eliciting signaling pathways which enable a wide range of physiological effects. The aim of our study was to find out the differential role of BCMs (BCM-7, BCM-9 and BCM-5) on pancreatic β-cell proliferation, insulin secretion, and opioid peptide binding receptors from β-cells (RIN-5F cell line) in normal (5.5 mM) and high glucose (27.5 mM) concentrations. Our results showed that BCM-7/9/5 did not affect β-cell viability, proliferation, and insulin secretion at normal glucose level. However, at higher glucose concentration, BCMs significantly protected β-cells from glucotoxicity but did not affect the insulin secretion. Interestingly, in the presence of Mu-opioid peptide receptor antagonist CTOP, BCMs did not protect β-cells from glucotoxicity. The results suggest that BCMs protect β-cells from glucotoxicity via non-opioid mediated pathways because BCMs did not modulate the gene expression of the mu, kappa and delta opioid peptide receptors.

Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.

In type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete proinflammatory cytokines that initiate cell death in insulin producing islet β-cells. Protein kinase C δ (PKCδ) plays a role in mediating cytokine-induced β-cell death; however, the exact mechanisms are not well understood. To address this, we used an inducible β-cell specific PKCδ KO mouse as well as a small peptide inhibitor of PKCδ. We identified a role for PKCδ in mediating cytokine-induced β-cell death and have shown that inhibiting PKCδ protects pancreatic β-cells from cytokine-induced apoptosis in both mouse and human islets. We determined that cytokines induced nuclear translocation and activity of PKCδ and that caspase-3 cleavage of PKCδ may be required for cytokine-mediated islet apoptosis. Further, cytokine activated PKCδ increases activity both of proapoptotic Bax with acute treatment and C-Jun N-terminal kinase with prolonged treatment. Overall, our results suggest that PKCδ mediates cytokine-induced apoptosis via nuclear translocation, cleavage by caspase-3, and upregulation of proapoptotic signaling in pancreatic β-cells. Combined with the protective effects of PKCδ inhibition with δV1-1, the results of this study will aid in the development of novel therapies to prevent or delay β-cell death and preserve β-cell function in T1D.

Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin-secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of pre-existing β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions.

OBJECTIVE: Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with β-cell loss in diabetes, the mechanism by which TNF induces β-cell demise remains unclear.
METHODS: Here, we dissected the contribution of RIPK1 scaffold versus kinase functions to β-cell death regulation using mice lacking RIPK1 specifically in β-cells (Ripk1β-KO mice) or expressing a kinase-dead version of RIPK1 (Ripk1D138N mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, Ripk1β-KO mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents.
RESULTS: Inhibition of RIPK1 kinase activity (Ripk1D138N mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in β-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. Ex vivo, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition.
CONCLUSIONS: Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.

OBJECTIVE: Growth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo.
METHODS: Pancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were analyzed by unbiased quantitative stereology in comparison to wild-type controls (WT, n = 12) at 3 and 7-8.5 months of age. In vivo secretion capacity for insulin and glucose tolerance were assessed by intravenous glucose tolerance tests (ivGTTs) in GHR-KO (n = 3) and WT (n = 3) pigs of the respective age groups.
RESULTS: Unbiased quantitative stereological analyses revealed a significant reduction in total β-cell volume (83% and 73% reduction in young and adult GHR-KO vs. age-matched WT pigs; p < 0.0001) and volume density of β-cells in the pancreas of GHR-KO pigs (42% and 39% reduction in young and adult GHR-KO pigs; p = 0.0018). GHR-KO pigs displayed a significant, age-dependent increase in the proportion of isolated β-cells in the pancreas (28% in young and 97% in adult GHR-KO vs. age-matched WT pigs; p = 0.0009). Despite reduced insulin secretion in ivGTTs, GHR-KO pigs maintained normal glucose tolerance.
CONCLUSIONS: GH insensitivity in GHR-KO pigs leads to decreased β-cell volume and volume proportion of β-cells in the pancreas, causing a reduced insulin secretion capacity. The increased proportion of isolated β-cells in the pancreas of GHR-KO pigs highlights the dependency on GH stimulation for proper β-cell maturation. Preserved glucose tolerance accomplished with decreased insulin secretion indicates enhanced sensitivity for insulin in GH insensitivity.

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.NEW & NOTEWORTHY β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.

The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.

Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β-cell apoptosis rates are relatively low in diabetes. Instead, β-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to β-cell failure. The underlying mechanisms driving β-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing β-cell dedifferentiation in T2D. This review explores the proposed drivers of β-cell dedifferentiation leading to β-cell failure, and discusses current interventions capable of reversing this process, thus restoring β-cell identity and function.