A5063385172- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Diabetes and associated disorders
- Genetics, Aging, and Longevity in Model Organisms
- Genetic Mapping and Diversity in Plants and Animals
- Regulation of Appetite and Obesity
- Metabolism, Diabetes, and Cancer
- Circadian rhythm and melatonin
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Adipokines, Inflammation, and Metabolic Diseases
- Birth, Development, and Health
- Animal Genetics and Reproduction
- Epigenetics and DNA Methylation
- Calcium signaling and nucleotide metabolism
- Muscle Physiology and Disorders
- Peroxisome Proliferator-Activated Receptors
- PI3K/AKT/mTOR signaling in cancer
- Adenosine and Purinergic Signaling
- Transgenic Plants and Applications
- Chronic Kidney Disease and Diabetes
- Genetics and Physical Performance
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Phagocytosis and Immune Regulation
- Electrolyte and hormonal disorders
Jackson Laboratory
2013-2024
L'Alliance Boviteq
2019
University of Arizona
2019
The T lymphocytes mediating autoimmune destruction of pancreatic beta cells in the nonobese diabetic (NOD) mouse model insulin-dependent diabetes mellitus (IDDM) may be generated due to functional defects hematopoietically derived antigen-presenting (APC). However, it has not been clear which particular subpopulations APC (B lymphocytes, macrophages, and dendritic cells) contribute development activation diabetogenic NOD mice. In current study we utilized a functionally inactivated...
The C57BL/6J (B6/J) male mouse represents a standard for diet‐induced obesity (DIO) and is unique in expressing loss‐of‐function nicotinamide nucleotide transhydrogenase ( Nnt ) gene. This mutation was associated with marked reduction glucose‐stimulated insulin secretion from B6/J islets vitro moderately impaired glucose clearance vivo . To assess the contribution of this mutation, we compared DIO responsiveness ‐mutant males to wild‐type C57BL/6NJ (B6/NJ) over 14‐week period feeding...
Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake intestinal absorption of glucose. In context mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm 7 months age until their death. extended median survival male 14%. increased 9% for 90th percentile survival, with parallel effects seen each 3 test...
In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan 19% (p < 0.0001, log-rank test) and 11% = 0.007) when fed at 14.4 ppm starting 16 20 months, respectively. 90th percentile lifespans were 7% 0.004, Wang-Allison 5% 0.17). Body weights reduced about 20% after 17aE2 diets. Four other interventions tested in males females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone,...
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or combination rapamycin acarbose started at 9 16 months age (RaAc9, RaAc16). In male mice, Rapa Aca led to a longer than either two prior cohorts mice treated with only, suggesting that this drug was more potent its components used alone. females, receiving both drugs...
Obesity, a major risk factor for type II diabetes, is becoming more prevalent in Western populations consuming high calorie diets while expending less energy both at the workplace and home. Most human obesity, probably most diabetes as well, reflects polygenic rather than monogenic inheritance. We have genetically dissected mouse model of obesity-driven by outcrossing obese, diabetes-prone, NZO (New Zealand Obese)/HlLt strain to relatively lean NON (Nonobese Nondiabetic)/Lt strain, then...
Insulin-dependent diabetes mellitus (IDDM) in NOD/Lt mice represents a complex polygenic disease. NOR/Lt is recombinant congenic strain (RCS) which limited regions of the genome have been replaced by from C57BL/KsJ strain. NOR are insulitis resistant and free despite genetic identity with NOD at numerous chromosomal containing previously described insulin-dependent (Idd) genes, including strongly diabetogenic H2g7 major histocompatibility (MHC) haplotype. The present study revealed...
Chromosome locations of non–major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD other inbred strains congenic for the MHC haplotype (H2g7). At least nine non-MHC IDDM susceptibility (Idd) were previously identified at first backcross (BC1) after outcross C57BL/10.H2g7 (B10.H2g7). We investigated whether same set Idd loci segregated with NON.H2g7 mice. Since outcrosses and B10.H2g7 performed...
Abstract To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead different survival outcomes, we compared three dosing regimens. Initiation Rapa 42 ppm increased significantly both male and female mice. Exposure for a 3‐month period led significant longevity benefit males only. Protocols which each month treatment was followed by without exposure were also effective sexes, though this approach less than continuous Interpretation...
Abstract In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, Nrf2 activator astaxanthin (Asta) extended median male lifespan 12% ( p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, 8% 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec 544 48 ppm, stated as mean SE n ) of independent diet preparations. Both were started 12 months age. The 90th percentile for both treatments in absolute value 6% males, but neither significant Wang–Allison...
We used mouse genetics to model how polygenic thresholds for the transition from impaired glucose tolerance (IGT) NIDDM are reached. NON/Lt and NZO/Hl inbred strains selected IGT obesity, respectively. Their Fl male progeny consistently developed NIDDM. Genetic analysis of F2 males both cross directions identified an NON-derived diabetogenic locus, Nidd 1, on chromosome (Chr) 4 near leptin receptor. This locus was associated with reduced plasma insulin, increased non-fasted blood glucose,...
Numerous studies suggest that rapamycin treatment promotes insulin resistance, implying could have negative effects on patients with, or at risk for, type 2 diabetes (T2D). New evidence, however, indicates produces some benefits to energy metabolism, even in the context of T2D. Here, we survey 5 mouse models T2D (KK, KK-Ay, NONcNZO10, BKS-db/db, TALLYHO) quantify well-recognized markers glucose homeostasis within a wide range environments. Interestingly, dietary did not exacerbate impaired...
Abstract Neural communication between the brain and adipose tissues regulates energy expenditure metabolism through modulation of tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, aging), total subcutaneous white (scWAT) innervation is decreased (‘adipose neuropathy’). With advanced age in C57BL/6J mouse, small fiber peripheral nerve endings die back, resulting reduced contact with adipose‐resident blood vessels other cells. This...
Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions to trigger disease. Here, we combine variable numbers of known quantitative trait loci (QTL) for obesity contributed by New Zealand Obese (NZO/HlLt) Nonobese Nondiabetic (NON/Lt) strains in the form 10 interval-directed recombinant congenic (RCS), with NON/Lt as background strain, dissect involved. All RCS gain significantly more weight than NON parental but none are obese parental,...
This review compares two novel polygenic mouse models of type 2 diabetes (T2D), TALLYHO/JngJ and NONcNZO10/LtJ, contrasts both with the well-known C57BLKS/J-Lepr(db) (db/db) monogenic diabesity model. We posit that new are more representative "garden variety" obesity underlying human T2D in terms their polygenetic rather than etiology. Moreover, clinical phenotypes these less extreme, for example, moderated development coupled extreme endocrine disturbances. The progressive produces a...
Abstract Ubiquitously expressed CD38 and T cell-expressed ADP-ribosyltransferase 2 (ART2) are ectoenzymes competing for NAD substrate. exerts pleiotropic actions in hemopoietic nonhemopoietic compartments via effects on calcium mobilization. ART2 is an naive CD4+ CD8+ cells. ART2-catalyzed ADP-ribosylation of the P2X7 purinoreceptor elicits apoptosis. Transfer a genetically disrupted allele into autoimmune diabetes-prone NOD/Lt background accelerated diabetes onset both sexes, whereas...
Interleukin (IL)-1β and IL-18 are two cytokines associated with the immunopathogenesis of diabetes in NOD mice. Both these cleaved by caspase-1 to their biologically active forms. IL-1 is a proinflammatory cytokine linked β-cell damage, stimulates production interferon (IFN)γ synergy IL-12. To examine effects produced deficiency on development NOD/Lt mice, disrupted Casp1 gene was introduced speed congenic technique. Casp1−/− bone marrow-derived macrophages stimulated lipopolysaccharide no...
Abstract Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination with metformin ameliorates rapamycin while maintaining its benefits. From 12 to 30 weeks age, NcZ10 males were fed control diet or diets supplemented rapamycin, metformin, both. alone reduced weight gain, adiposity, HOMA‐IR, inflammation, prevented hyperinsulinemia pre‐steatotic hepatic...
Although thiazolidinediones suppress hyperglycemia in diabetic (NON × NZO)F1 males, these mice exhibit unusual sensitivity to drug-induced exacerbation of an underlying hepatosteatosis only rarely experienced human patients. To establish the pharmacogenetic basis for this sensitivity, a panel recombinant congenic strains (RCSs) with varying degrees obesity and diabetes was generated by fixing selected NZO HlLt alleles on diabetes- hepatosteatosis-resistant NON/Lt background. Four new were...
Although P2rx7 has been proposed as a type 1 diabetes (T1D) susceptibility gene in NOD mice, its potential pathogenic role not directly determined. To test this possibility, we generated new stock deficient P2X(7) receptors. T1D development was altered by ablation. Previous studies found CD38 knockout (KO) mice developed accelerated partly because of loss CD4(+) invariant NKT (iNKT) cells and Foxp3(+) regulatory T (Tregs). These immunoregulatory cell populations are highly sensitive to...
While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it not tested polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with (14 ppm encapsulated diet) and monitored for the development As expected, accelerated onset severity hyperglycemia. However, nephropathy ameliorated, as both glomerulonephritis IgG deposition subendothelial tuft were markedly reduced. Insulin production secretion...