By integrating systematic views of the transcription, translation machinery at single-cell level, we intend to gain insights into the molecular changes in diabetes and in aging and provide the research community with useful database resources.
Category: Current nPOD Projects
Mechanisms Involved in Expansion of Beta Cells in Pregnancy
Pregnancy is associated with a marked increase in the number of pancreatic beta cells in response to the increased insulin demand. In rats and mice the growth of the beta cell mass is primarily due to proliferation of the existing beta cells resulting in enlargement of the islets of Langerhans. However, in a study of […]
Aging Beta Cell
Type 2 diabetes (T2D) increases with age with the majority of patients being above the fifth decade of life. These data underline the importance of studying how aging contributes to the reduced beta cell mass and dysfunctional insulin secretion found in T2D. However, the specific contribution of beta cell aging and senescence to diabetes has […]
Target confirmation in human pancreas
Type 1 Diabetes (T1D) is caused by autoimmune-induced beta-cell destruction and successful beta-cell regeneration offers a potential cure to the disease. We have identified a beta-cell regenerative target that leads to the restoration of beta-cell mass in mouse models of beta-cell deficiency. We seek to confirm the observed cellular phenotype in human pancreatic samples.
Characterizing T-Cell Populations in Diabetes
This study seeks to understand the immune cells important for beta cell loss by studying the function and type of cells present in lymphoid tissue.
Mass Spectrometry Based Digital Histology nPOD (Berlin BCRT)
The individual heterogeneities of Type 1 diabetic pancreas could hinder a successful investigation and classification of the underlying mechanisms in diabetic disorders. This indicates the necessity of in situ analysis of tissue sections by novel imaging mass spectrometry technology, which enables the spatial investigation of protein profiles from an examined tissue section, thus allowing to […]
Preventive Insulin Therapy for Type 2 Diabetes (Addendum: Pancreatic beta cell heterogeneity; Addendum: Heterogeneity of human beta cells)
Two major pathophysiologic abnormalities underlie most cases of type 2 diabetes (T2D): insulin resistance and defects in pancreatic beta-cell function. These defects are initially compensated by an increase in insulin secretion and in the number of insulin secreting cells. However, with time, beta cell dysfunction and T2D develops, requiring intervention therapies. Eventually, there is significant […]
Hormonal regulation of adipose tissue macrophage functions in diabetes
Our research is focused on the understanding of hormonal control of adipose tissue macrophage (ATM) function. ATMs play key roles in diabetes development: when they adopt an inflammatory activation state, they inhibit insulin signaling, cause systemic insulin resistance, exacerbate autoimmunity and pancreatic beta cell destruction. On the contrary, when ATMs undergo a so-called alternative activation, […]
Regulation of Beta Cell Secretory Pathway Calcium Homeostasis in Type 1 Diabetes
Calcium plays a vital role in many processes that govern beta cell function, including the production, maturation, and regulated secretion of insulin. The fidelity of these processes depends on the maintenance of calcium subcompartments and their respective transmembrane gradients, which are organized at both the cellular and organelle level. Then endoplasmic reticulum, Golgi apparatus, and […]
The sensory innervation of the pancreatic islet in health and diabetes
The role the nervous system plays in modulating islet inflammation and diabetes pathogenesis has barely been examined. Recent papers suggest that changes in sensory innervation initiate autoimmune diabetes in mice, which is in line with the notion that sensory neurons contribute to inflammation in several chronic disorders. Thus, the local interactions between the immune system […]
Analysis of normal pancreas from PNET patients with and without diabetes
Spontaneous recovery from established type 1 diabetes (T1D) is so rare that only one well-documented case has ever been described in an adult, and in that case recovery resulted from an insulin-secreting tumor, not regeneration of the patient’s normal beta-cells. Therefore, when we saw a 50 year old man at UCSF with T1D who got […]
Hybrid peptides as target antigens for pathogenic T cells in human T1D patients
We have recently discovered a new form of beta-cell autoantigen, which is recognized by CD4 T cells, and is formed through a novel post-translational modification of beta-cell peptides that involves the fusion between insulin peptide fragments and peptides of other secretory granule proteins. The hybrid insulin peptides (HIPs) are highly antigenic for autoreactive and pathogenic […]
Transcriptome analysis of highly purified islet cell populations
Therapies focused on sustaining or promoting endogenous insulin production for individuals at risk for or with T1D will require a thorough understanding of the gene expression patterns in islet α, β, and δ cells from control subjects and from individuals with T1D. Toward that end, we have developed methods to essentially purify α, β, and δ cells from human pancreata by […]
Development of a platform for ex-vivo functional and 3D morphological assessment of islet physiology in nPOD human pancreata, also in response to viral infections associated with type 1 diabetes pathogenesis
Impairment and destruction of beta cells by an autoimmune attack leads to the onset of hyperglycemia in type 1 diabetes (T1D). However, knowledge on changes in islet cell physiology leading to dysfunction, failure and death of the cells is incomplete. This is partially due to technical limitations which do not allow the study of islet […]
Uncovering pathological factors and mechanisms leading to β-cell death in type 1 diabetes
We hypothesize that β-cell toxicity in T1D can be induced via different pathways by distinct pathological ligands (AGEs, S100-proteins, amyloidogenic amylin) of the receptor for advanced glycation endproducts (RAGE) that become upregulated in the diabetic pancreas. We also hypothesize that C-peptide (+) T1D subjects may be more susceptible to amylin-induced β-cell toxicity. Amylin is co-produced /co-secreted with […]
Differentially expressed genes in inflamed human islets
The downregulation of cyclin D3 due to infiltration is causally related to beta cell dysfunction and beta cell-apoptosis in beta cells from NOD mice. We would like to confirm whether this is true in human beta cells. In order to validate cyclin D3 as a target for T1D therapy in humans, we need to evaluate the […]