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{
"created_at": "2024-04-18T18:19:31.857649Z",
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"answer": "The onset of diabetes in mice can occur as early as 3 to 4 weeks of age, with blood sugar concentrations often elevating between 5 and 8 weeks. However, in some cases, hyperglycemia can develop at approximately 20 weeks of age.",
"context": {
"0ffd1f4d-683e-4e44-a6b2-8d2d9849c45d": [
{
"document_id": "0ffd1f4d-683e-4e44-a6b2-8d2d9849c45d",
"text": "Diabetes incidence study. Mice were kept for 20-28 weeks and tested for diabetes monthly by blood glucose and weekly by urine assessment, with a positive indication being followed by twice-weekly blood testing.Mice were diagnosed as diabetic when the blood glucose concentration was over 260 mg/dl (14.4 mM) after 2-3 h of fasting for two sequential tests.Glucose and insulin tolerance tests were performed by injecting glucose (2 g/kg body weight) or insulin (1 U/kg body weight) intraperitoneally in mice fasted for 6-7 h.Tail vein blood was tested by a Contour glucometer.Assessments of plasma insulin, proinsulin and C-peptide levels were performed using commercial ELISA kits, according to the manufacturer's instructions (insulin, proinsulin and C-peptide mouse ELISA kits, R&D Systems Quantikine).Assays were performed with blinding, with mice coded by number until experimental end."
}
],
"1bf337a1-ffed-4199-a11f-c5a62df47980": [
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"document_id": "1bf337a1-ffed-4199-a11f-c5a62df47980",
"text": "\n\nSubsequently, genetic dissection of the diabetes-associated traits in the male BC1 progeny obtained from a cross between (normal B6 female ϫ diabetic TH male)F1 female and diabetic TH male mice (B6 cross) was carried out.Because of the sexual dimorphism, with respect to NIDDM onset, we used diabetic TH male mice as breeders to ensure the presence of a mutant allele(s) and targeted our genetic dissection using only male BC1 progeny.In male BC1 mice hyperglycemia developed at approximately 20 weeks of age and was sustained through a 30-week period studied.Based on these data, we measured plasma glucose levels three times in biweekly intervals (to minimize phenotyping error) between 20 and 26 weeks of age, and the mean of the three measurements was used for genetic analysis.Body weights were measured at 20 weeks.At the end of the study (26 weeks), plasma insulin levels and nasal-anal lengths were measured, and the five regional fat pads were dissected and weighed from a subset of 133 mice.In total, 206 male BC1 mice were collected, and individual mice were genotyped with 92 SSLP markers at approximately 20-cM intervals (covering ϳ96% of the genome)."
}
],
"20771d36-aa57-46ad-b3c6-80f5b038ba43": [
{
"document_id": "20771d36-aa57-46ad-b3c6-80f5b038ba43",
"text": "\n\nThe Diabetes (db) .Mouse (Chromosome 4).Diabetes (db), an autosomal recessive mutation, occurred in the C57BL/KsJ (BL/Ks) inbred strain and on this background is characterized by obesity, hyperphagia, and a severe diabetes with marked hyperglycaemia [7,22].Increased plasma insulin concentration is observed as early as 10 days of age [10].The concentration of insulin peaks at 6 to 10 times normal by 2 to 3 months of age then drops precipitously to near normal levels.Prior to the fall in plasma insulin concentration, the most consistent morphological feature of the islets of Langerhans appears to be hyperplasia and hypertrophy of the beta cells in an attempt to produce sufficient insulin to control blood glucose concentration at physiological levels.The drop in plasma insulin concentration is concomitant with islet atrophy and rapidly rising blood glucose concentrations that remain over 400 mg per 100 ml until death at 5 to 8 months [7].Compared with other obesity mutants the diabetic condition is more severe and the lifespan is markedly decreased."
},
{
"document_id": "20771d36-aa57-46ad-b3c6-80f5b038ba43",
"text": "\n\nThe animal models available for diabetes research (Table 1) are most often more like maturityonset diabetes in man.Obesity is a consistent factor and insulinopaenia is rare.However, the time of gene expression at about two weeks of age is within the time period of juvenile expression.The severity and clinical course of the diabetes produced depends on the interaction of the mutant gene with the inbred background rather than the action of the gene itself.Thus on one inbred background a well-compensated, maturity onset type diabetes, compatible with near normal life is observed whereas on another inbred background the syndrome presents as a juvenile-type diabetes with insulinopaenia, islet cell degeneration, marked hyperglycaemia, some ketosis and a much shortened lifespan.Unfortunately, vascular, retinal and the other complications of diabetes are not seen consistently in these rodent syndromes.It seems that the severely diabetic animal either does not live long enough to develop these complications or that rodents are particularly resistant to those complications that commonly afflict human diabetics.Several comprehensive bibliographies and excellent reviews of the various studies carried out with each of these syndromes in animals have been published [2,3,19,30,31,32].This presentation will be restricted primarily to the research undertaken by my colleagues and myself with the two mouse mutations; diabetes (db), and obese (ob).Both mutations have been extensively studied by numerous investigators in attempts to define the primary lesion causing the syndrome.As yet, the primary defect remains illusive, although several possibilities are becoming increasingly plausible in the light of current research.Although the metabolic abnormalities associated with both obese and diabetes have many similarities with regard to the overall progression of the obesity-diabetes state, the documentation of two single genes on separate chromosomes makes it unlikely that the two syndromes are caused by the same primary lesion.However, the marked similarity between the two mutants when maintained on the same genetic background implies that the defects may occur in the same metabolic pathway."
},
{
"document_id": "20771d36-aa57-46ad-b3c6-80f5b038ba43",
"text": "\n\nDiabetes-obesity syndromes in rodents"
}
],
"29e232a4-a580-411d-83a3-7ff6a4e8f0ad": [
{
"document_id": "29e232a4-a580-411d-83a3-7ff6a4e8f0ad",
"text": "\n\nDiabetes-related clinical traits for 275 B6XBTBR-ob/ ob F2 male mice at 10 weeks of age."
}
],
"43d5140a-ad39-438e-8ba6-76dd3c7c42bc": [
{
"document_id": "43d5140a-ad39-438e-8ba6-76dd3c7c42bc",
"text": "However, in other contexts, B6 mice are more likely\nthan D2 to spontaneously develop diabetic syndromes,\nAging Clin Exp Res\n\nindicating that risk factors exist on both genetic backgrounds [29]. QTL mapping studies indicate that these\nmurine metabolic traits have a complex genetic architecture that is not dominated by any single allele [29–31],\nmuch like humans [32, 33]. Prior work identified candidate genes on Chr 13 that might\nunderlie diabetes-related traits, including RASA1, Nnt, and\nPSK1. RASA1 show strong sequence differences between\nB6 and D2 strains [34]. Rasche et al."
}
],
"52990c69-609c-448e-9f2c-36e1655ca6db": [
{
"document_id": "52990c69-609c-448e-9f2c-36e1655ca6db",
"text":"In total, about\n360 male mice (10 for each strain) were fed with either a regular\nchow diet (CD) or a high-fat diet (HFD) to induce obesity and\nassociated metabolic stress. At 20 weeks of age, a test meal\nbolus was administered orally, and postprandial BAs and blood\nglucose levels were analyzed at three different time points (before\nand 30 or 60 min after gavage). Nine weeks later, the mice were\nsacrificed 4 h after feeding, a time point in which the main metabolic adaptive processes in response to BA-mediated food intake\nare captured."
}
],
"770beab7-59a4-4bbe-94a5-79a965ab696a": [
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"document_id": "770beab7-59a4-4bbe-94a5-79a965ab696a",
"text": "\n\nBB rats usually develop diabetes just after puberty and have similar incidence in males and females.Around 90% of rats develop diabetes between 8 and 16 weeks of age.The diabetic phenotype is quite severe, and the rats require insulin therapy for survival.Although the animals have insulitis with the presence of T cells, B cells, macrophages and NK cells, the animals are lymphopenic with a severe reduction in CD4 + T cells and a near absence of CD8 + T cells (Mordes et al., 2004).Lymphopenia is not a characteristic of type 1 diabetes in humans or NOD mice (Mordes et al., 2004) and is seen to be a disadvantage in using the BB as a model of type 1 diabetes in humans.Also, in contrast to NOD mice, the insulitis is not preceded by peri-insulitis.However, the model has been valuable in elucidating more about the genetics of type 1 diabetes (Wallis et al., 2009), and it has been suggested that it may be the preferable small animal model for islet transplantation tolerance induction (Mordes et al., 2004).In addition, BB rats have been used in intervention studies (Hartoft-Nielsen et al., 2009;Holmberg et al., 2011) and studies of diabetic neuropathy (Zhang et al., 2007)."
}
],
"77daf125-3e88-41fe-92fd-71a9ce9c6671": [
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"document_id": "77daf125-3e88-41fe-92fd-71a9ce9c6671",
"text": "\n\nAgeing likewise affects metabolic parameters in rodents.Analogous to what occurs in humans, the body weight of the C57BL/6J mouse, the most commonly used mouse strain for metabolic studies, increases with age, peaking at ~9 months 133 , and older C57BL/6J mice (22 months) have reduced lean mass and increased fat mass compared with young 3-month-old mice 134 .In both rats and mice, fasting glucose levels are mostly stable throughout life, but whereas glucose tolerance generally worsens with age in rats, mice are less affected [135][136][137][138][139][140] .In fact, 2-year-old male C57BL/6J mice were significantly more glucose tolerant than their 5-month-old counterparts 138 .Consistent with these findings, glucosestimulated insulin release from the pancreas decreases with age in rats, but not in mice 137,138 ."
}
],
"b1a1282d-421f-494a-b9df-5c3c9e1e2540": [
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "All mice h o m o z y g o u s for t h e d i a b e t e s\ngene (db/db) b e c o m e diabetic, t h e first d i s t i n g u i s h i n g\nf e a t u r e being a m a r k e d t e n d e n c y to o b e s i t y w i t h large\nf a t d e p o s i t i o n s o b s e r v e d in t h e a x i l l a r y a n d i n g u i n a l\nregions a t a b o u t 3 t o 4 weeks of age."
},
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "In many of these diabetic mice\nblood sugar concentration tends to increase gradually\nbetween 5 and 12 weeks of age, after which it may rise\nsharply to over 500 rag/100 ml of blood almost overnight. The diabetic condition, thus, appears to develop\nin two phases, an early one when there is some regulation of blood sugar concentration, and a later stage\ncharacterized by a marked increase in hyperglycemia\nand a complete loss of metabolic control. A few exceptional diabetics, usually females, exhibit\na pattern similar to that shown in Fig. 3. Although\n16\n240\n\nD.L. COLEMANand K.P."
},
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "Results\nAll mice homozygous for the trait, diabetes (db),\ndevelop an abnormal and characteristic deposition of\nfat beginning at 3 to 4 weeks of age, making their early\nidentification possible. The difference in size and\nappearance of litter-mate 6-week old mice, one normal\nand one diabetic, is shown in Fig. 1. Weight increases\n\nFig. 1. C57BL/Ks-db litter-mates a t 6 weeks."
},
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "of age; m o r e o f t e n this e l e v a t i o n occurs b e t w e e n 5\na n d 8 weeks. I n older d i a b e t i c mice b l o o d sugar\nc o n c e n t r a t i o n s g r e a t e r t h a n 600 m g / 1 0 0 m l are n o t\n\nu n c o m m o n ."
},
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "I n older mice with blood sugar concentrations over 250 rag/100 ml, injections of up t o 100 units /\n100 g were completely ineffective in reducing blood sugar\nto normal levels. Continued treatment of young diabetic\nmice with daily injections of insulin, although controlling Mood sugar concentrations initially, did not prevent or delay either the obesity or the uncontrollable\nhigh blood sugar concentrations, which usually develop\nat about 6 to 8 weeks of age."
},
{
"document_id": "b1a1282d-421f-494a-b9df-5c3c9e1e2540",
"text": "Although the early onset of diabetes in db mice\ncoincides with t h a t in juvenile diabetes in man, the\nsymptoms of obesity and elevated serum insulin are\nmore suggestive of the pattern of development observed in the maturity-onset type of diabetes. As yet,\nnone of the lesions associated with advanced diabetes\nin humans such as retinopathies, cardiovascular and\nkidney lesions have been observed, possibly because\nof the early onset of the diabetes and the relatively\nrapid deterioration and death of these mice."
}
],
"c24330f7-9f82-404a-86d5-a16d814bb754": [
{
"document_id": "c24330f7-9f82-404a-86d5-a16d814bb754",
"text": "\n\nTo screen for genes that show correlation with different phenotypic outcome in diabetic mouse models, we used the cross-sectional design and performed microarray analysis on 24-wk-old STZ-treated and db/db mice with established renal pathology.In parallel with the functional genomics characterization, each individual mouse underwent a detailed renal phenotype analysis.Mice that were treated with low doses of STZ developed diabetes and moderately severe albuminuria (twice the control).In mice with C57B6/J background, the mesangial changes were mild or absent.Mice with 129SvJ genetic background developed significant glomerular changes.However, these were not significantly different from the agematched controls (K.Sharma, K. Susztak, and E.P. Bo ¨ttinger, unpublished observations).The db/db mice became insulin resistant and developed diabetes at approximately 8 wk of age.Albuminuria was detected as early as 3 to 4 wk after the development of hyperglycemia.The glomerular histology was characterized by severe diffuse mesangial expansion, as previously reported (49)."
},
{
"document_id": "c24330f7-9f82-404a-86d5-a16d814bb754",
"text": "Renal lesions in diabetic mouse models\n\nDb/db mice, which have a recessive mutation in the hypothalamic leptin receptor, develop obesity at 4 wk of age and type 2 diabetes at approximately 8 wk of age.In C57BL/6J background, the diabetes and the obesity are usually less severe than in the C57BL/KsJ background (44).Kidneys are generally enlarged in this mouse strain, and structural glomerular changes (e.g., diffuse glomerulosclerosis, GBM thickening) occur without evidence of tubulointerstitial disease (40).Glomerular lesions of the KK mice are characterized by diffuse and nodular mesangial sclerosis without evidence of tubular disease (45).The lack of reliable mouse models prompted the National Institute of Diabetes and Digestive and Kidney Diseases to fund a consortium for the development and phenotyping of new diabetic mouse models that would resemble closely human DNP."
}
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"document_id": "c802cb60-1a15-4962-8e6d-f06608c00a54",
"text":"In total, about\n360 male mice (10 for each strain) were fed with either a regular\nchow diet (CD) or a high-fat diet (HFD) to induce obesity and\nassociated metabolic stress. At 20 weeks of age, a test meal\nbolus was administered orally, and postprandial BAs and blood\nglucose levels were analyzed at three different time points (before\nand 30 or 60 min after gavage). Nine weeks later, the mice were\nsacrificed 4 h after feeding, a time point in which the main metabolic adaptive processes in response to BA-mediated food intake\nare captured."
}
],
"ed1a5572-124a-4824-8b9c-5a540e5d6092": [
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"document_id": "ed1a5572-124a-4824-8b9c-5a540e5d6092",
"text": "Assessment of Diabetes\n\nMice were monitored for the development of diabetes as described previously (Wicker et al. 1994)."
}
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