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M A Permutt

Publications and source records attributed to M A Permutt.

At least 109 records · Page 6Linked to original sources
PubMed1991

Coordinate reduction of rat pancreatic islet glucokinase and proinsulin mRNA by exercise training.

Exercise training results not only in enhanced insulin sensitivity but also in a reduction in insulin secretion. In this study, we examined the effects of exercise training on the expression of genes potentially related to insulin synthesis and glucose-stimulated insulin release by measuring pancreatic islet proinsulin, glucose-transporter (GLUT2), and glucokinase mRNAs. Female Wistar rats were subjected to 100 min of running at 25 m.min-1 up a 15% incline for 90 min/day for 6 days/wk for 3 wk. Pancreatic mRNA was evaluated by Northern- and dot-blot analysis with [32P]cRNA probes. We found no change in the pancreatic content of GLUT2 mRNA but found marked decreases in the content of proinsulin mRNA (78%, P less than 0.005) and glucokinase mRNA (65%, P less than 0.001). These results suggest that exercise modulates both islet glucose metabolism and insulin synthesis at the level of gene expression. Furthermore, there was a significant correlation between the decreases in glucokinase and proinsulin mRNA concentrations (r = 0.95, P less than 0.001), suggesting that expression of these genes is regulated in parallel.

Animals↗
PubMed1990

Glucose transporter protein content and glucose transport capacity in rat skeletal muscles.

The relationships among fiber type, glucose transporter (GLUT-4) protein content, and glucose transport activity stimulated maximally with insulin and/or contractile activity were studied by use of the rat epitrochlearis (15% type I-20% type II2a-65% type IIb), soleus (84-16-0%), extensor digitorum longus (EDL, 3-57-40%), and flexor digitorum brevis (FDB, 7-92-1%) muscles. Insulin-stimulated 2-deoxy-D-glucose (2-DG) uptake was greatest in the soleus, followed (in order) by the FDB, EDL, and epitrochlearis. On the other hand, contractile activity induced the greatest increase in 2-DG uptake in the FDB, followed by the EDL, soleus, and epitrochlearis. The effects of insulin and contractile activity on 2-DG uptake were additive in all the muscle preparations, with the relative rates being FDB greater than soleus greater than EDL greater than epitrochlearis. Quantitation of the GLUT-4 protein content with the antiserum R820 showed the following pattern: FDB greater than soleus greater than EDL greater than epitrochlearis. Linear regression analysis showed that whereas a relatively low and nonsignificant correlation existed between GLUT-4 protein content and 2-DG uptake stimulated by insulin alone, significant correlations existed between GLUT-4 protein content and 2-DG uptake stimulated either by contractions alone (r = 0.950) or by insulin and contractions in combination (r = 0.992). These results suggest that the differences in maximally stimulated glucose transport activity among the three fiber types may be related to differences in their content of GLUT-4 protein.

Actins↗
PubMed1990

Glucose transporter levels in spontaneously obese (db/db) insulin-resistant mice.

In the present study we examined mRNA and protein levels for the muscle/adipose tissue glucose transporter (GLUT-4) in various tissues of spontaneously obese mice (C57BL/KsJ, db/db) and their lean littermates (db/+). Obese (db/db) mice were studied at 5 wk of age, when they were rapidly gaining weight and were severely insulin resistant, evidenced by hyperglycemia (plasma glucose 683 +/- 60 vs. 169 +/- 4 mg/dl in db/+, P less than 0.05) and hyperinsulinemia (plasma insulin 14.9 +/- 0.53 vs. 1.52 +/- 0.08 ng/ml in db/+, P less than 0.05). The GLUT-4 mRNA was reduced in quadriceps muscle (67.5 +/- 8.5%, P = 0.02), but unaltered in adipose tissue (120 +/- 19%, NS), heart (95.7 +/- 6.1%, NS), or diaphragm (75.2 +/- 12.1%, NS) in obese (db/db) mice relative to levels in lean littermates. The GLUT-4 protein, measured by quantitative immunoblot analysis using two different GLUT-4 specific antibodies, was not different in five insulin-sensitive tissues including diaphragm, heart, red and white quadriceps muscle, and adipose tissue of obese (db/db) mice compared with tissue levels in lean littermates; these findings were consistent when measured relative to tissue DNA levels as an index of cell number. These data suggest that the marked defect in glucose utilization previously described in skeletal muscle of these young obese mice is not due to a decrease in the level of the major muscle glucose transporter. An alternate step in insulin-dependent activation of the glucose transport process is probably involved.

Adipose Tissue↗
PubMed1990

Effects of altered glucose homeostasis on glucose transporter expression in skeletal muscle of the rat.

Previous studies have suggested that alteration in the expression of the insulin-regulatable glucose transporter of muscle (GLUT-4 protein) may be an important determinant of insulin action. In the present studies, we have examined GLUT-4 mRNA and protein concentrations in muscle after variations in the metabolic status of the intact animal (i.e., 7 d streptozotocin-induced diabetes, 7 d insulin-induced hypoglycemia, and 3 d fasting). These changes in glucose homeostasis were associated with the following changes in GLUT-4 gene products: a decrease of approximately 30% in both mRNA and protein with diabetes; a 50% increase in mRNA and a 2.4-fold increase in protein with insulin injection; and normal mRNA in spite of a 2.7-fold increase in protein with fasting. Fasted diabetics exhibited an increase of 50% in GLUT-4 mRNA and a 2.4-fold increase in protein relative to fed diabetics. In diabetic and insulin-injected groups, the changes in GLUT-4 protein were similar to changes in mRNA, but in fasting, GLUT-4 protein increased without a concomitant change in mRNA. Overall there was no correlation between muscle concentrations of GLUT-4 protein and mRNA. Muscle GLUT-4 protein concentration tended to correlate with plasma glucose (r = -0.57, P less than 0.001), but not with plasma insulin. These results indicate that (a) chronic changes in glucose homeostasis are associated with changes in expression of GLUT-4 protein in muscle; (b) GLUT-4 protein increased in fasted soleus muscle without change in mRNA, thereby differing from fasted adipocytes in which both GLUT-4 products diminish; and (c) no simple relationship exists between total muscle GLUT-4 protein content and whole-body insulin sensitivity.

Animals↗
PubMed1990

Polymorphisms of GLUT2 and GLUT4 genes. Use in evaluation of genetic susceptibility to NIDDM in blacks.

The liver/islet (GLUT2) and muscle/adipose tissue (GLUT4) glucose-transporter gene products, membrane proteins that facilitate glucose uptake into cells, are important molecules for normal carbohydrate metabolism. Recent isolation of the genes encoding these proteins provides a means to assess the role of possible defects that might contribute to impaired glucose-stimulated insulin secretion or impaired insulin-mediated glucose uptake, both prominent phenotypic features of non-insulin-dependent diabetes (NIDDM). A GLUT2 cDNA clone was isolated from a human liver cDNA library to search for polymorphisms at this locus in American Blacks. Three highly polymorphic sites were identified, one of which (EcoRI-Hae III) appears to be due to an insertion and/or deletion of 200 base pairs of DNA. Significant linkage disequilibrium between these sites over approximately 30 kilobases of genomic DNA suggested that these polymorphisms could be in linkage disequilibrium with mutations at this locus if they exist. A GLUT4 cDNA clone was also utilized to search for polymorphisms at this locus, but only one previously described polymorphism was observed. GLUT2 and GLUT4 cDNA probes were used to evaluate DNA polymorphisms in genomic DNA from American Blacks with NIDDM. The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these loci did not differ from the frequencies in nondiabetic subjects. Because no associations with NIDDM were found, it appears unlikely that mutations at these loci contribute in a major way to the genetic susceptibility to NIDDM observed in American Blacks.

Alleles↗
PubMed1990

Genetics of NIDDM.

This brief review discusses the current level of understanding of the role of genetic defects in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) and the use of molecular-genetic methods for this study. Evidence for genetic susceptibility is strong, and defects in both insulin production and action are suspect. With restriction-fragment-length polymorphisms and genomic sequencing, various candidate loci are being evaluated. Evidence that multiple genes are involved is only circumstantial. If NIDDM is genetically heterogeneous and also influenced by environmental components, population associations and linkage analyses in families may not be as easily interpreted as for diseases involving single major gene defects.

Diabetes Mellitus, Type 2↗
PubMed1990

Insulin gene in diabetes. Analysis through RFLP.

Insulin deficiency is a prominent feature of non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus that could result from defects in the insulin gene. Cloning of this gene has permitted molecular-genetic studies including the definition of multiple-DNA-sequence polymorphisms detected with restriction endonucleases, or restriction-fragment-length polymorphisms (RFLPs), and the mapping of the insulin gene to the short arm of chromosome 11 adjacent to the insulinlike growth factor II (IGF-II) and tyrosine hydroxylase genes. The combined RFLPs for the insulin, IGF-II, and tyrosine hydroxylase genes make this a highly informative locus for genetic studies of the insulin gene in diabetes. Early studies of an RFLP consisting of variable-number tandem repeats (VNTR) of DNA near the insulin gene suggested an association of certain alleles with approximately 170 copies of the repeat unit with NIDDM. Although subsequent studies in NIDDM did not confirm this association, an association of different alleles defined by approximately 40 copies of the repeat unit in this VNTR region with IDDM has been demonstrated in multiple studies. This VNTR region and the multiple other RFLPs for this region have been used in linkage analysis to study the segregation of insulin genes in families. These studies have failed to demonstrate a major significant role for insulin-gene defects in NIDDM, maturity-onset diabetes of the young, or IDDM in American Blacks and Whites and under various models of inheritance. Several pedigrees with diabetes and defects of the insulin gene have been described, however, and a minor role for this gene in NIDDM cannot be eliminated from available studies. Similarly, the association studies of the insulin gene and IDDM suggest a minor modifying role undetectable in pedigree studies. The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis.

Chromosomes, Human, Pair 11↗
PubMed1990

Polymorphisms of HepG2/erythrocyte glucose-transporter gene. Linkage relationships and implications for genetic analysis of NIDDM.

To assess the contribution of the HepG2/erythrocyte glucose-transporter (HepG2 GT) gene to the inherited susceptibility to non-insulin-dependent diabetes mellitus (NIDDM), cDNA and genomic probes were used to search for restriction-endonuclease polymorphisms at this locus. Analysis of DNA from 16 unrelated Black American individuals with 19 enzymes and as many as six different probes, defined four polymorphisms over a 45-kilobase region. Nucleotide diversity (pi = 0.006) was low relative to that at other loci, with an average of 1 in 1700 base pairs different between two chromosomes at this locus. The observed combined heterozygosity for these four sites was 0.69, which indicates that the markers at this locus could be useful for linkage analysis in families. Linkage-disequilibrium values between the four polymorphisms were evaluated by pairwise analysis and extended haplotypes. Calculating pairwise associations by the disequilibrium statistic delta or by another measure of disequilibrium, D' (the maximum likelihood of disequilibrium, which is less dependent on frequency), significant linkage disequilibrium could not be demonstrated. However, the frequencies of the observed extended haplotypes were shown to differ (chi 2 = 9.1, df = 2, P less than 0.025) from predicted frequencies if the sites were in linkage equilibrium in Blacks. The frequencies of these four polymorphisms were determined in Black nondiabetic (n = 44) and NIDDM (n = 63) subjects. Neither the allelic nor genotypic frequencies of the polymorphisms differed between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Black People↗
PubMed1989

A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.

Insulin binds to a receptor on the cell surface, thereby triggering a biological response within the target cell. Mutations in the insulin receptor gene can render the cell resistant to the biological action of insulin. We have studied a family in which two sisters have a genetic form of insulin-resistant diabetes mellitus. The technique of homozygosity mapping has been used to demonstrate that the mutation causing diabetes in this consanguineous family is genetically linked to the insulin receptor gene. The two insulin-resistant sisters are homozygous for a mutation encoding substitution of valine for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. Transfection of mutant insulin receptor cDNA into NIH3T3 cells demonstrated that the Val382 mutation impaired post-translational processing and retarded transport of the insulin receptor to the plasma membrane. Thus, the mutation causes insulin resistance by decreasing the number of insulin receptors on the surface of the patients' cells.

Cells, Cultured↗
PubMed1989

Genetic analysis of obesity-induced diabetes associated with a limited capacity to synthesize insulin in C57BL/KS mice: evidence for polygenic control.

Expression of obesity-induced diabetes associated with the diabetes or db mutation in mice varies in inbred strains. This study utilized a genetic analysis to evaluate the number of genes responsible for the difference in diabetes responses between mice of the susceptible C57BL/KsJ (BL/Ks) and resistant 129/J inbred strains. BL/Ks (db/+) males and 129/J (+/+) females were bred to generate F1 hybrids, and the F1 females (db/+ and +/+, distinguished by progeny testing) were backcrossed to BL/Ks (db/+) males. A total of 252 backcrossed males were obtained, of which 31 were db/db and obese. While the plasma glucose of all the fed backcrossed mice was greater than 22 mmol/l, the expression of diabetes varied considerably, as measured by fasting plasma glucose, fed plasma insulin, and pancreatic insulin and proinsulin mRNA content. That proinsulin mRNA content was a good indicator of diabetes severity and islet dysfunction was seen in the inverse correlation between proinsulin mRNA content and fasting plasma glucose (r = 0.69, p less than 0.001), and a direct correlation between proinsulin mRNA and plasma insulin (r = 0.86, p less than 0.001), and pancreatic insulin content (r = 0.61, p less than 0.01). If a single gene were responsible for severe islet dysfunction, one-half of the backcrossed mice would develop low proinsulin mRNA levels like the BL/Ks parent, and one-half would be resistant to islet destruction. Statistical evaluation (SKUMIX) of the distribution of these parameters in backcrossed mice rejected with a high degree of probability a bimodal distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice.

To assess genetic factors determining sensitivity to streptozotocin-induced diabetes in inbred strains of mice, a genetic analysis of streptozotocin-sensitive C57BL/6J and streptozotocin-resistant C3H/HeJ mice was performed. One week after a single dose of streptozotocin (200 mg/kg body weight), differences in plasma glucose concentration were marked between male mice of the C57BL/6J and C3H/HeJ strains (p less than 0.001). To determine the number of genes responsible for the difference, F1 male progeny of a cross between parental strains were produced, and found to be streptozotocin resistant like C3H/HeJ parents. F1 mice were, therefore, backcrossed with streptozotocin-sensitive C57BL/6J mice (Backcross: F1 female female X C57BL/6J male male). The plasma glucoses of backcrossed male mice (n = 41) following streptozotocin treatment appeared to segregate into two populations, half like the C57BL/6J parent, and half like the F1 parent. Statistical analysis of the data revealed that the data fit a model with two distributions better than one with a single distribution, suggesting a single major gene responsible for the difference in streptozotocin susceptibility. This hypothesis was also supported by the observation that streptozotocin sensitivity in 12 recombinant inbred strains of C57BL/6J and C3H/HeJ mice appeared to segregate into two classes. Resistance to streptozotocin induced diabetes in F1 mice suggested that the expression of this gene is recessive, although X-chromosome linked inheritance could not be excluded. Efforts to map the streptozotocin-sensitivity gene revealed lack of right linkage to several loci including the H-2 locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1989

Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA.

Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-Km, low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. We isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus.

Animals↗
PubMed1989

Proinsulin mRNA levels in fasting and fed ADX rats: evidence for an indirect effect of glucocorticoids.

To determine whether glucocorticoids are required to maintain pancreatic proinsulin mRNA levels during dietary manipulation, rats were adrenalectomized (ADX) or sham operated (SO) and subsequently fasted or pair fed for 2 days. Proinsulin mRNA concentrations were 54 +/- 8% lower (P less than 0.05) in fed ADX rats and 47 +/- 10% lower (P less than 0.01) in fasted ADX rats relative to values in fed and fasted SO rats, respectively. When ADX rats were fasted for 24 h and either refed 20% sucrose for 30 h or injected with dexamethasone (DEX) 0.125 mg/kg ip every 12 h for three doses, circulating plasma glucose levels were restored and pancreatic proinsulin mRNA concentrations rose 3.3 and 2.7-fold, respectively (each P less than 0.05). Plasma glucose and proinsulin mRNA levels (n = 40) were correlated (r = 0.58, P less than 0.0001). We conclude that the regulation of proinsulin mRNA concentration does not absolutely require endogenous glucocorticoids, since either adequate sucrose intake in ADX rats or physiological glucocorticoid responses in fasted rats suffice to restore pancreatic mRNA concentrations. It appears that glucocorticoid stimulation of pancreatic proinsulin mRNA levels is mediated indirectly through its regulation of glucose metabolism.

Adrenalectomy↗
PubMed1989

Proinsulin I and II gene expression in inbred mouse strains.

Mice and rats express two nonidentical insulins from a pair of unlinked genes. We have applied a nuclease protection assay, which can sensitively quantify each of the mouse insulin mRNAs, to the resolution of the following questions concerning their expression. First, it has not been established whether alterations in expression of one or both of these genes cause differing total insulin biosynthetic capacity noted between several inbred mouse strains. These studies showed that the relative abundance of mRNAs encoding mouse insulins I and II was identical in four separate mouse strains. In spontaneously obese, hyperinsulinemic (db/db)C57BL/KsJ mice, both proinsulin I and proinsulin II mRNAs were increased relative to the levels in normal (+/db) C57BL/KsJ mice, but again the ratio of the two mRNAs did not differ. The ratio was nearly identical to that for the orthologous mRNAs in rats, indicating that the mechanisms which regulate insulin mRNAs in rodents are conserved in both genes in several mouse strains and between rodent species. This finding suggests that differences between mouse strains in insulin biosynthetic capacity result from differences in the glucose sensing/signalling mechanism at a point before coordinate gene transcription. Second, low levels of insulin synthesis have been suggested as an explanation for relatively high levels of insulin in several nonpancreatic tissues. We showed that the ribonuclease protection assay, sufficiently sensitive to measure 1/2000th the amount of insulin mRNA present in pancreas, was unable to detect insulin mRNA in salivary gland. This result indicates that the high levels of radioimmunoassayable insulin detected in salivary glands are not the result of insulin synthesis in situ.

Animals↗
PubMed1988

Molecular-genetic analysis and assessment of insulin action and pancreatic beta-cell function.

Although the hereditary nature of non-insulin-dependent diabetes mellitus (NIDDM) is well recognized, the nature of the predisposing defect remains elusive. Individuals with a history of gestational diabetes had shown a reduced insulin-sensitivity index (S1) in the absence of fasting hyperglycemia. To determine whether this finding could result from an inherited defect of the insulin receptor, an NIDDM pedigree was ascertained through a former gestational-diabetic proband. The proband, her siblings, and her first cousins were clinically characterized for insulin sensitivity with the minimal-model-based S1 from a modified glucose tolerance test. Islet function was characterized by the incremental insulin response to 5 g i.v. arginine at baseline and at a plasma glucose level of 500-600 mg/dl. Genetic studies included linkage analyses for the insulin gene and the insulin-receptor gene with DNA polymorphisms (restriction-fragment-length polymorphisms, RFLPs) previously described. The pattern of inheritance in this large pedigree appeared to follow autosomal-dominant transmission. No defect in islet function was found, but as a group, third-generation family members had an S1 that was significantly lower than that of weight-matched control individuals, suggesting an inherited defect in insulin action. Genetic studies showed no sharing of insulin gene, insulin-receptor-gene alleles among the diabetic individuals, or insulin-receptor alleles among third-generation individuals with insulin insensitivity. The genetic analyses thus suggest that this pedigree has an inherited defect that is not linked to the insulin gene or the insulin-receptor gene. The diminished S1 may nonetheless suggest an inherited defect in insulin action.

Adult↗
PubMed1988

Insulin gene in familial NIDDM. Lack of linkage in Utah Mormon pedigrees.

Although non-insulin-dependent diabetes mellitus (NIDDM) is well recognized to be an inherited disease, the genetic lesion responsible remains to be determined. Several pedigrees have been reported in which defects of the insulin gene result in glucose intolerance or diabetes in affected members, but the role of insulin gene mutations in NIDDM is unknown. To evaluate this role, we ascertained 23 Caucasian pedigrees for a diabetic individual with at least one diabetic family member, sampled the unaffected individuals by a 75-g glucose tolerance test, and prepared leukocyte DNA on all family members. Included in the pedigrees ascertained were those with both predominantly lean and predominantly obese diabetic members and four pedigrees included as insulin-dependent diabetic individual. Insulin gene involvement was evaluated via previously described restriction-fragment-length polymorphisms (RFLPs) for the insulin gene and the nearby c-Ha-Ras oncogene (HRAS). Combination of these RFLPs resulted in the ability to trace the insulin alleles in all pedigrees studied. Analysis of individual pedigrees for sharing of insulin alleles was possible in 12 pedigrees, and lack of linkage was demonstrated in 6 of them. Neither linkage nor lack of linkage could be proved in the remaining pedigrees. Analysis of the pooled pedigree data failed to demonstrate linkage under several models, including autosomal-dominant and -recessive inheritance with different sporadic frequencies of diabetes and different prevalence figures. These results show that mutations of the insulin gene and the immediately surrounding area, including regulatory regions of the insulin gene, are unlikely to account for a significant subset of NIDDM in Caucasian individuals.

Diabetes Mellitus, Type 2↗
PubMed1988

Genetic analysis of glucose tolerance in inbred mouse strains. Evidence for polygenic control.

To determine genetic factors involved in diabetes susceptibility in inbred strains of mice, we initially evaluated differences in fed plasma glucose and insulin concentrations among six strains (AKR/J, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, and SWR/J). There was considerable variation in fed plasma glucose concentration, with C3H/HeJ mice the most glucose tolerant (174 +/- 7 mg/dl) and C57BL/6J mice the least glucose tolerant (252 +/- 7 mg/dl, P less than .0001 vs. C3H/HeJ mice). Glycosylated hemoglobin of C57BL/6J mice (4.0 +/- 0.06%) was also higher than that of C3H/HeJ mice (3.52 +/- 0.06%, P less than .0001). The fed plasma insulin concentration did not differ between these two strains. Glucose tolerance was further evaluated in overnight-fasted C3H/HeJ and C57BL/6J mice by an intraperitoneal glucose tolerance test (IPGTT). Although fasting plasma glucose did not differ, the most remarkable difference in plasma glucose during IPGTT between C57BL/6J and C3H/HeJ mice was noted at 30 min (489 +/- 29 vs. 227 +/- 20 mg/dl, P less than .001). To determine the number of genes involved in the phenotypic difference in glucose tolerance, C57BL/6J males were crossed with C3H/HeJ females (F1, C3H/HeJ X C57BL/6J), and the F1 hybrid females were backcrossed with C57BL/6J males (backcrossed, F1 X C57BL/6J). Plasma glucose after 30 min on IPGTT was 219 +/- 8 (n = 21), 456 +/- 18 (n = 23), and 292 +/- 13 (n = 23) mg/dl for C3H/HeJ, C57BL/6J, and F1 mice, respectively (P less than .001 for all comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗