A5043761987- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Adipose Tissue and Metabolism
- Cellular Mechanics and Interactions
- Diabetes and associated disorders
- Pancreatic and Hepatic Oncology Research
- Microtubule and mitosis dynamics
- Genetic Syndromes and Imprinting
- RNA regulation and disease
- Genetic Mapping and Diversity in Plants and Animals
- Calcium signaling and nucleotide metabolism
- RNA Research and Splicing
- Diet, Metabolism, and Disease
- Adipokines, Inflammation, and Metabolic Diseases
- Glycosylation and Glycoproteins Research
- Plant biochemistry and biosynthesis
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Nutrition, Genetics, and Disease
University of Wisconsin–Madison
2012-2023
Genetic susceptibility to type 2 diabetes is primarily due β-cell dysfunction. However, a genetic study directly interrogate function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on Western-style diet, and measured insulin secretion in response variety of secretagogues. Insulin DO ranged >1,000-fold even though none the were diabetic. The secretory each secretagogue had unique architecture; some loci specific for one...
We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from trans-Golgi network (TGN) vacuole. Whole-body KO mice, when made obese with leptin(ob) mutation (ob/ob), developed diabetes. β Cells these mice had severe deficiency of secretory granules (SGs) and insulin. Interestingly, single secretagogue challenge failed consistently elicit an insulin dysfunction. However,...
Dense-core vesicle (DCV) exocytosis is a SNARE (soluble N-ethylmaleimide–sensitive fusion attachment protein receptor)-dependent anterograde trafficking pathway that requires multiple proteins for regulation. Several C2 domain–containing are known to regulate Ca2+-dependent DCV in neuroendocrine cells. In this study, we identified others by screening all (∼139) human RNA interference 40 genes were identified, including several encoding with roles (CAPS [calcium-dependent activator secretion...
CIP4, a member of the F-BAR family proteins, plays important roles in variety cellular events by regulating both membrane and actin dynamics. In many cell types CIP4 functions vesicle formation, endocytosis tubulation. However, recent data indicate that is also involved protrusion some types, including cancer cells (lamellipodia invadopodia) neurons (ribbed lamellipodia veils). neurons, localizes specifically to extending protrusions limit neurite outgrowth early development. The mechanism...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: (1) 8 mM glucose; (2) glucose plus amino acids; (3) glucose, acids, 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 glucose. These stimuli interrogate...
Insulin secretion from pancreatic β cells is essential for glucose homeostasis. An insufficient response to the demand insulin results in diabetes. We previously showed that cell-specific deletion of Zfp148 (β-Zfp148KO) improves tolerance and mice. Here, we performed Ca2+ imaging islets β‑Zfp148KO control mice fed both a chow Western-style diet. β-Zfp148KO demonstrated improved sensitivity sustained oscillations elevated levels. also exhibited amino acid-induced influx under low conditions,...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: (1) 8 mM glucose; (2) glucose plus amino acids; (3) glucose, acids, 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 glucose. These stimuli interrogate...
Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly low-density lipoprotein cholesterol (LDL-C) in genome-wide association studies. However, validation studies mice and cell lines have produced variable results regarding directionality of effect on LDL-C. This, together fact that several genes, has raised question whether is causal gene this locus. Using whole exome sequencing members an Amish population, we identified coding...
G6PC2 is predominantly expressed in pancreatic islet β-cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing action glucokinase, thereby regulating fasting blood (FBG). Prior studies have shown G6pc2 promoter alone unable confer sustained islet-specific gene expression mice, suggesting existence distal enhancers regulate expression. Using information from both mice and humans knowledge single nucleotide...
Introduction & Objective: High-risk single-nucleotide polymorphisms (SNPs) account for only ~20% of type 2 diabetes heritability, implying islet genes greatly influence one another to alter risk. Correlative analysis does not reveal conditional dependencies between key players regulating function whereas machine learning (ML) may do so. Methods: Using data from 374 genetically diverse mice, we derived models predicting protein abundance with gradient-boosted decision tree algorithms....
Abstract Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: 1) 8 mM glucose; 2) glucose plus amino acids; 3) glucose, acids, 10 nM GIP; and 4) 2 glucose. These stimuli interrogate β-cell function, α-cell signaling, incretin...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: 1) 8 mM glucose; 2) glucose plus amino acids; 3) glucose, acids, 10 nM GIP; and 4) 2 glucose. These stimuli interrogate β-cell function, α-cell signaling, incretin responses....
<p><i>G6PC2</i> is predominantly expressed in pancreatic islet beta cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing action glucokinase, thereby regulating fasting blood (FBG). Prior studies have shown <i>G6pc2</i> promoter alone unable confer sustained islet-specific gene expression mice, suggesting existence distal enhancers regulate expression. Using information from...
<p><i>G6PC2</i> is predominantly expressed in pancreatic islet beta cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing action glucokinase, thereby regulating fasting blood (FBG). Prior studies have shown <i>G6pc2</i> promoter alone unable confer sustained islet-specific gene expression mice, suggesting existence distal enhancers regulate expression. Using information from...
ABSTRACT Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: 1) 8 mM glucose; 2) glucose plus amino acids; 3) glucose, acids, 10 nM GIP; and 4) 2 glucose. These stimuli interrogate β-cell function, α-cell signaling, incretin...