Susceptibility to db gene and streptozotocin-induced diabetes in C57BL mice: control by gender-associated, MHC-unlinked traits

Leiter, Edward H.; Le, Phuoc; Coleman, D L

doi:10.1007/bf00345448

Cited by 35 publications

(23 citation statements)

References 38 publications

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“…The animals used in the initial mouse experiments were all male C57BL/6J SOD2 +/+ or C57BL/6J SOD2 +/− . Previous studies revealed that C57BL/6J female mice were resistant to induction of diabetes by STZ injection (Leiter et al, 1987). The mice were genotyped and assigned to one of 4 groups, SOD2 +/+ nondiabetic control (C), SOD2 +/+ diabetic (D), SOD2 +/− C, SOD2 +/− D. Monthly 6 h fasting tail blood glucose measurements confirmed the onset and maintenance of diabetes.…”

Section: Sod2 +/+ and Sod2 +/− Stz-treated Micementioning

confidence: 99%

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

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Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O 2 •− ) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2 +/− mice results in increased levels of O 2 •− , activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2 +/− C57BL/6J mice and their SOD2 +/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.

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Section: Sod2 +/+ and Sod2 +/− Stz-treated Micementioning

confidence: 99%

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

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“…B6 and BKS share genetic identity at ϳ88% of markers tested. Differences include MHC haplotypes, but this has been excluded as the explanation (18). Diabetes pathogenesis in BKS-Lepr db-1J mice was particularly responsive to dietary carbohydrate (19).…”

Section: C57blks/j and Nod/lt: Two Paradigm Diabetes-permissive Inbrementioning

confidence: 99%

Mouse Models and the Genetics of Diabetes

Leiter

Lee

2005

Diabetes

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In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic ␤-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating ␤-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to ␤-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct. Diabetes 54 (Suppl. 2):S151-S158, 2005 T he complex of genes in the HLA locus (IDDM1) contributing the major component of human susceptibility to autoimmune type 1 diabetes clearly provides a starting point for comparison for overlap with major susceptibility contributors to classic type 2 diabetes. Indications of humoral immunity against pancreatic ␤-cell autoantigens in 10 -30% of patients deemed clinically to have type 2 diabetes led to the concept that these patients exhibit latent autoimmune diabetes in adults (LADA), or "type 1.5" diabetes (1). Many LADA patients exhibit decreased frequency of the highest risk HLA class I and class II alleles and increased frequency of HLA alleles conferring strong protection against juvenile-onset type 1 diabetes (1). Although most type 2 diabetes cases clearly are not autoimmune in causation, and thus, specific HLA alleles are not identified as major type 2 diabetes susceptibility contributors, the LADA cases raise the possibility that a subset of non-HLA susceptibility may be shared. Under such circumstances, the absence of the high-risk HLA alleles results in a more slowly progressive disease that only presents in adulthood when pathophysiological stresses on ␤-cells, including obesity and insulin resistance shared in common with patients with classic type 2 diabetes, become prevalent.Polymorphisms in the upstream regulatory region of the insulin gene currently represent the strongest non-HLA locus linked to human type 1 diabetes susceptibility (IDDM2) (2). The pathogenic mechanism has not been associated with insulin processing, secretion, or action, but rather with the ability to express intrathymically and elicit T-cell tolerance to this major type 1 diabetes autoantigen (3,4). Alleles associated with resistance to type 1 diabetes, on the other hand, have been associated with polycystic ovarian syndrome (5), an insulin resistance syndrome that often leads to type 2 diabetes. Because type 2 diabetes often culminates in insulin deficiency attributed to ␤-cell failure associated with chron...

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“…An additional study (Study 2) was performed to confirm whether RII␤ Ϫ/Ϫ mice showed improved insulin sensitivity and glucose responsiveness as compared with wild-type mice. In addition, because of the sex dimorphism in obesity and diabetes often seen among mice (21,22), we examined males and females separately. Body weights and adiposities were recorded for diabetogenic diet-fed mice, and IPGTT and insulin sensitivity tests were performed.…”

Section: Diabetogenic Phenotypes Of Rii␤mentioning

confidence: 99%

Mutation of the RIIβ Subunit of Protein Kinase A Prevents Diet-Induced Insulin Resistance and Dyslipidemia in Mice

et al. 2001

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The mechanisms by which obesity contributes to diabetic phenotypes remain unclear. We evaluated the role of protein kinase A (PKA) signaling events in mediating diabetes associated with obesity. PKA comprises two regulatory subunits and two catalytic subunits and is activated by cAMP. The RII␤ regulatory subunit is abundantly expressed in adipose tissue and brain. Knockout mice lacking this subunit are lean and display remarkable resistance to diet-induced obesity. We investigated whether these mice were also resistant to diet-induced diabetes and whether this effect was dependent on reduced adiposity. Mice were fed a high-fat, high-carbohydrate diet and weight gain and diabetes phenotypes were examined. RII␤ ؊/؊ mice displayed decreased body weights, reduced insulin levels, improved insulin sensitivity, and improved total-body glucose disposal as compared with wild-type controls. Plasma levels of VLDL and LDL cholesterol were also reduced in high fat-fed RII␤ ؊/؊ mice compared with wild-type mice. Taken together, these data demonstrate that loss of RII␤ protects mice from diet-induced obesity, insulin resistance, and dyslipidemia. Diabetes 50:2555-2562, 2001 R ecent reports indicate that obesity is rapidly increasing in industrialized nations. More than 35% of American adults are now considered overweight or obese (1), and obesity is an important contributing factor to the development of type 2 diabetes (2-4). Dyslipidemia is often observed in association with obesity and diabetes and is a significant contributor to the increased mortality observed in diabetic patients (5,6). Characteristics of type 2 diabetes include impaired glucose disposal, diminished insulin production, and increased hepatic glucose output. The mechanisms by which obesity contributes to these phenotypes remain unclear (7).Signaling via protein kinase A (PKA) plays an important role in regulating metabolism and body weight (8). PKA is activated by cAMP and comprises two regulatory and two catalytic subunits (8). Four regulatory isoforms (RI␣, RI␤, RII␣, and RII␤) and two catalytic isoforms (C␣ and C␤) are expressed in the mouse, and each is encoded by a separate gene. The RII␤ subunit is expressed principally in three tissues known to regulate energy homeostasis: brown adipose tissue, white adipose tissue, and brain (8,9). Recent studies suggest that the induction of PKA in certain tissues may decrease obesity. For example, activation of the adipose-specific ␤-adrenergic receptor (10), which signals via PKA, decreases obesity in both genetically obese (ob/ob) (11,12) and diet-induced obese mice (13), suggesting that signaling mechanisms through this pathway are important in preventing obesity.Studies in mice lacking a specific PKA subunit, RII␤, have revealed an unexpected role for this protein in regulating energy balance (9). RII␤ knockout mice (RII␤ Ϫ/Ϫ ) remain remarkably lean even when challenged with a high-fat diet (9). These animals have increased metabolic activity, manifested by increases in body temperature, uncoupling protein 1 ...

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Susceptibility to db gene and streptozotocin-induced diabetes in C57BL mice: control by gender-associated, MHC-unlinked traits

Cited by 35 publications

References 38 publications

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Mouse Models and the Genetics of Diabetes

Mutation of the RIIβ Subunit of Protein Kinase A Prevents Diet-Induced Insulin Resistance and Dyslipidemia in Mice

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