A5080665608- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Diabetes and associated disorders
- Diet, Metabolism, and Disease
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Gut microbiota and health
- RNA and protein synthesis mechanisms
- Fungal and yeast genetics research
- Cancer, Hypoxia, and Metabolism
- Diabetes Management and Research
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Maternal Mental Health During Pregnancy and Postpartum
- Erythrocyte Function and Pathophysiology
- Birth, Development, and Health
- Tryptophan and brain disorders
- Receptor Mechanisms and Signaling
- Yeasts and Rust Fungi Studies
- RNA modifications and cancer
- Plant Disease Resistance and Genetics
- Lipid metabolism and biosynthesis
- Adipokines, Inflammation, and Metabolic Diseases
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
University of Illinois Chicago
2017-2024
University of Illinois Urbana-Champaign
2021-2022
University of Chicago
2006-2016
Northwestern University
2016
Pacific Northwest Diabetes Research Institute
2001-2006
University of Washington
2001-2006
The University of Texas Southwestern Medical Center
1998
University of Aberdeen
1991-1994
OBJECTIVE Conditional gene targeting has been extensively used for in vivo analysis of function β-cell biology. The objective this study was to examine whether mouse transgenic Cre lines, mediate β-cell– or pancreas-specific recombination, also drive expression the brain. RESEARCH DESIGN AND METHODS Transgenic lines driven by Ins1, Ins2, and Pdx1 promoters were bred R26R reporter strains. activity assessed β-galactosidase yellow fluorescent protein pancreas Endogenous monitored using...
Chronic exposure to elevated levels of fatty acids impairs pancreatic beta cell function, a phenomenon thought contribute the progressive deterioration insulin secretion in type 2 diabetes. We have previously demonstrated that prolonged isolated islets palmitate inhibits preproinsulin mRNA presence high glucose concentrations. However, whether this occurs via transcriptional or post-transcriptional mechanisms has not been determined. In addition, nature lipid metabolites involved inhibition...
Endocrine cells are continually regulating the balance between hormone biosynthesis, secretion, and intracellular degradation to ensure that cellular stores maintained at optimal levels. In pancreatic β-cells, insulin in β-granules mostly upheld by efficiently up-regulating proinsulin biosynthesis translational level rapidly replenish lost via exocytosis. Under normal circumstances, of plays a relatively minor janitorial role retiring aged β-granules, apparently crinophagy. However, this...
G protein-coupled receptors have been well described to contribute the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing receptor, free acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and rodents, its expression altered during resistance. Thus, we explored role FFAR2 regulating GSIS. First, assessing phenotype wild-type Ffar2(-/-) mice vivo, observed no differences with regard glucose homeostasis on normal or high-fat diet, a...
Pregnancy presents a unique physiological challenge that requires changes coordinated by placentally and non–placentally derived hormones to prepare the mother for metabolic stress presented fetal development ensure appropriate nutrient allocation between fetus. Of particular importance is maintenance of normal glucose metabolism during pregnancy. Here, we describe in pregnancy highlight new insights into these adaptations have emerged over past decade using novel methodologies, specifically...
Abstract Liver cancer (LC) is the fourth leading cause of death from malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in LC compared healthy liver tissue. Using combination vitro and vivo tools, we examined role HKDC1 development progression. Importantly, ablation stops progression via its action at mitochondria by promoting metabolic reprogramming shift glucose flux away TCA cycle. leads mitochondrial...
Insulin secretory dysfunction of the pancreatic β-cell in type-2 diabetes is thought to be due defective nutrient sensing and/or deficiencies mechanism insulin exocytosis. Previous studies have indicated that GTP-binding protein, Rab3A, plays a mechanistic role Here, we report Rab3A<sup>−/−</sup> mice develop fasting hyperglycemia and upon glucose challenge show significant intolerance coupled ablated first-phase release consequential insufficient secretion <i>in vivo</i>, without...
Proinsulin biosynthesis is regulated in response to nutrients, most notably glucose. In the short term (≤2h) this due increases translation of pre-existing mRNA. However, prolonging glucose stimulation (24 h) also preproinsulin mRNA levels. It has been proposed that secreted insulin from pancreatic β-cell regulates its own synthesis through a positive autocrine feedback mechanism. Here comparative contributions and levels on proinsulin were examined isolated islets. Also, role upon four...
The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that for glucose-stimulated insulin secretion and diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, acetoacetate were investigated as candidate stimulus-coupling glucose-induced rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed...
Insulin is stored in pancreatic β‐cells β‐granules. Whenever insulin secreted response to a nutrient secretagogue, there complementary increase proinsulin biosynthesis replenish intracellular stores. This specific regulation of predominately regulated at the translational level. Recently, highly conserved cis ‐element 5′‐untranslated region (UTR) preproinsulin mRNA, named ppIGE, has been identified that required for biosynthesis. ppIGE also found 5′‐UTR certain other translationally...
Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute release is characteristic reduced control in prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase and improve control. To determine physiological role cAMP-dependent protein kinase (PKA), a mouse model was developed to PKA activity specifically pancreatic β-cells. In response sustained hyperglycemia, potentiated both release. contrast, bolus enhanced alone....
Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response patients with type 2 diabetes compared healthy human controls. The aim of this study was to determine mechanistic causes underlying reduced efficacy GLP-1R ligands.Using primary mouse islets line MIN6, outcomes downstream were analyzed: Insulin secretion; phosphorylation cAMP-response...
Background & aimsNormal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to metabolic changes by unclear mechanisms. This study aimed understand mechanistic underpinnings GM—maternal metabolism interaction.MethodsThe GM and plasma metabolome CD1, NIH-Swiss, C57 mice were analyzed with use 16S rRNA sequencing untargeted liquid chromatography–mass spectrometry throughout gestation. Pharmacologic genetic knockout mouse models used identify role indoleamine...
Glucose regulates proinsulin biosynthesis via stimulation of the translation preproinsulin mRNA in pancreatic beta-cells. However, mechanism by which this occurs has remained unclear. Using recombinant adenoviruses that express with defined alterations, untranslated regions (UTRs) were examined for elements specifically control rat islets. These studies revealed 5'-UTR was necessary glucose translation, whereas 3'-UTR appeared to suppress translation. together 5'- and 3'-UTRs acted...
Insulin receptor substrate 2 (IRS-2) plays a critical role in pancreatic β-cells. Increased IRS-2 expression promotes β-cell growth and survival, whereas decreased levels lead to apoptosis. It was found that turnover rat islet β-cells rapid, with mRNA protein half-lives of ∼90 min ∼2 h, respectively. However, this countered by specific glucose-regulated mediated at the transcriptional level. Glucose (≥6 mm) increased dose-dependent manner, reaching maximum 4-fold increase 5–6-fold ≥12 mm...
Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity improve metabolic health. This study aimed determine overall physiological consequences activation adipose tissue. Mice expressing an activated catalytic subunit (Adipoq-caPKA mice) showed increased activity subcutaneous, epididymal, mesenteric white (WAT) depots brown...
The regulation of proinsulin biosynthesis in pancreatic β-cells is vital for maintaining optimal insulin stores glucose-induced release. majority nutrient fuels that induce release also stimulate biosynthesis, but since exocytosis and synthesis involve different cellular mechanisms, a point divergence the respective metabolic stimulus–response coupling pathways must exist. A parallel examination secretion was undertaken same β-cells. In MIN6 cells, shared requirement glycolysis to generate...
We have tested the clones used in European Yeast Chromosome III Sequencing Programme for possible artefacts that might been introduced during cloning or passage through Escherichia coli. Southern analysis was performed to compare BamHI, EcoRI, HindIII and PstI restriction pattern each clone with of corresponding locus on chromosome parental yeast strain. In addition, further enzymes were maps most map predicted by nucleotide sequence (Oliver et al., 1992). Only four 506 6-bp sites not...
Results from epidemiological and prospective studies indicate a close association between periodontitis diabetes. However the mechanisms by which periodontal pathogens influence development of prediabetes/diabetes are not clear. We previously reported that oral administration pathogen, Porphyromonas gingivalis (Pg) to WT mice results in insulin resistance, hyperinsulinemia, glucose intolerance Pg translocates pancreas. In current study, we determined specific localization relation mouse...
Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability dissipate energy and improve systemic insulin sensitivity glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads an increase oxygen consumption induction thermogenic gene program that includes uncoupling protein 1 (Ucp1) fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase 3 (GSK3) as negative regulator basal β-adrenergically...