Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes

Abstract

A common feature in the pathophysiology of different types of diabetes is the reduction of β cell mass and/or impairment of β cell function. Diagnosis and treatment of type 1 and type 2 diabetes is currently hampered by a lack of reliable techniques to restore β cell survival, to improve insulin secretion, and to quantify β cell mass in patients. Current new approaches may allow us to precisely and specifically visualize β cells in vivo and provide viable therapeutic strategies to preserve, recover, and regenerate β cells. In this review, we discuss recent protective approaches for β cells and the advantages and limitations of current imaging probes in the field. Type 1 and Type 2 Diabetes (T1D and T2D) as a β Cell Pathology T1D and T2D, although arising from different etiologies, are each associated with physical and/or functional loss of insulin-secreting β cells [1-3]. T1D is described as a heterogeneous inflammatory disease characterized by infiltration of the pancreatic islets with a number of autoimmune cells (CD4+ and CD8+ T cells, macrophages, dendritic cells, and B cells) [4]. Recent evidence suggests that progression of islet infiltrates promotes β cell dysfunction (reduced first-phase insulin response) and later β cell elimination, which ultimately results in the onset of diabetes. Interestingly, it is now clear that residual β cell mass can be found several years after diagnosis. Thus, a desired strategy for T1D treatment should suppress β cell autoimmunity, along with protection and restoration of the remaining β cell mass. Currently, there are no clinically approved interventional therapies for treating the underlying autoimmunity and boosting β cell survival in T1D. T2D, however, is characterized by insulin resistance following progressive decline in β cell function and accumulation of islet amyloid polypeptide (IAPP, or amylin) in the pancreatic islets [2,5]. The pathology is far more complex, as a recent study on newly diagnosed diabetic subjects postulates a reclassification into five distinct clusters based on the metabolic profile and risk of complications; three of the different cluster are currently considered T2D [6]. The treatment of T2D is mainly limited to metformin monotherapy as the initial strategy to improve insulin sensitivity. When the patient cannot control glycemia by lifestyle and metformin, a pharmacology approach to increase β cell resistance and function will be required, as an alternative to chronic exogenous insulin injections. Highlights Pancreatic β cell failure is characteristic to both T1D and T2D. The JAK-STAT pathway is a promising target to prevent autoimmune β cell destruction. Several strategies are currently being tested to improve insulin production in T2D: preventing β cell death/dysfunction, enhancing β cell proliferation, ameliorating β cell dedifferentiation, and inducing transdifferentiation into β like cells. Imaging and diagnostic tools are required to improve the efficacy of current therapeutic strategies aimed at restoring β cell function. Nanotechnology...

Rheb1 promotes glucose-stimulated insulin secretion in human and mouse β-cells by upregulating GLUT expression

“…Impaired insulin secretion from β-cells is one of the major causes of diabetes [1,38]. At the initial stage of the disease, β-cell proliferation and activities are increased to meet the augmented insulin demands [39,40].…”

“…Rheb1 promotes β-cell proliferation. Impaired glucose homeostasis may result from reduced β-cell mass or impaired insulin secretion [1]. To elucidate the mechanism by which Rheb1 deficiency in -cells impairs glucose homeostasis, we quantified the βcell area in the Rheb1 βKO mice and the loxp control mice.…”

“…Reduced β-cell mass and/or impaired β-cell function are considered primary causes leading to the development of all types of diabetes [1][2][3][4]. In rodents and humans, dysregulation of neogenesis, apoptosis, proliferation, dedifferentiation and/or transdifferentiation may lead to reduced β-cell mass [5].…”

A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes

“…This is of particular relevance since the effectiveness of currently available treatments for T2D are limited in time and likely impacted by the continuous deterioration of beta cell function over the course of the disease 51 . Novel treatment strategies to delay disease progression by restoring and durably preserving beta cell function are needed 52,53 . Anti-diabetic medications offering blood glucose control by improving peripheral insulin sensitivity such as metformin, or by increasing insulin secretion such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated bene ts in beta cell adaptation to high-fat diet-induced insulin resistance in hIAPP transgenic rodents and short-term improvements in human islet graft function in diabetic mouse recipients 34,[54][55][56] .…”

Distinctive Clinical and Pathologic Features of Immature Teratomas Arising from Induced Pluripotent Stem Cell Injection in a Patient with type 2 Diabetes: A Case Report

“…Type 2 diabetes (T2DM) accounts for 85-95% of all cases and is characterized by insulin resistance in insulin-responsive tissues and impaired insulin secretion by pancreatic β-cells [2]. The majority of patients need to inject insulin for their lifetime to control blood sugar, which always results from serious complications caused by irreversible pancreatic β-cell damage [3]. In recent years, an increasing number of experts have begun to use regenerative medicine to treat irreversible pancreatic damage to β-cells in pancreatic islets using human pluripotent stem cells (iPSCs) [4].…”