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D L Coleman

Publications and source records attributed to D L Coleman.

At least 145 records · Page 8Linked to original sources
PubMed1981

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. III. Effect of H-2 haplotype and sex.

The expression of the mouse mutation, diabetes (db), was examined on eight different inbred genetic backgrounds. The influence of H-2 haplotype and sex was examined. Mice of both sexes in two diabetes (db) strains (C57BL/6J, 129/J) having the H-2b haplotype were resistant to the diabetogenic action of the mutant gene. On the contrary, two H-2d congenic diabetes stocks (C57BL/KsJ, DBA/2J) exhibited severe diabetes associated with beta-cell necrosis. However, diabetes resistance was not restricted to mice with H-2b haplotype since the congenic diabetes MA/J stock (H-2k) was also resistant. Similarly, diabetes susceptibility was not restricted to mice with the H-2d haplotype, since males, but generally not females, in the congenic CBA/Lt-db/db and C3HeB/FeJ-db/db stocks (both H-2k) also exhibited a severe diabetes. Males of the congenic SWR/J-db stock (H-2q) had a diabetes of intermediate severity. Female diabetes mice with H-2k and H-2q haplotypes exhibited a sustained hypertrophy and hyperplasia of beta-cells and were able to control hyperglycemia better than males. Thus, while the H-2b haplotype remains associated with resistance, and the H-2d haplotype with susceptibility to induction of genetic diabetes, the diabetes stocks with H-2k haplotype clearly illustrate the importance of non-H-2, but sex-associated, genetic modifiers.

Animals↗
PubMed1981

Inherited obesity-diabetes syndromes in the mouse.

Several different single-gene mutations are known to cause varying degrees of diabetes and obesity in mice. The severity of the diabetes produced depends on both the mutation itself and the interaction of the mutant gene with the inbred background. Establishing the nature of these gene-background interactions should aid us in our understanding of similar interactions that occur in human diabetes. The documentation of several different genes that produce similar, if not identical, diabetes-obesity syndromes suggests that lesions in many pathways can cause diabetes. An understanding of these defects in mice should help us to understand similar defects involved in the human disease. The developmental stages in each mutant are similar. The early symptoms include hyperphagia, hyperinsulinemia, and hypertrophy and hyperplasia of the beta cells of the islets of Langerhans. Hyperglycemia, obesity, and severe diabetes are secondary features that result from insulin resistance and the failure to sustain the secretion of massive amounts of insulin. All models appear to be able to utilize their food in a more efficient manner than normal. Even when restricted to 50% of that amount of food eaten by a normal mouse, mutants are able to maintain their weight and still remain obese. On fasting, the stored fat is utilized more efficiently. One cause of this efficiency in obese and diabetes mice is the ability to convert acetone (the end product of fatty-acid metabolism) to lactate which, in turn, can be converted to glucose, which can sustain continued lipolysis. The occurrence of increased efficiency in obesity and diabetes mutants lends credence to the thrifty-genotype hypothesis regarding the maintenance of the deleterious diabetes genes in human populations.

Alleles↗
PubMed1980

A new mutation (db3J) at the diabetes locus in strain 129/J mice. I. Physiological and histological characterization.

A spontaneous recessive mutation appearing in strain 129/J mice at the diabetes (db) locus on Chromosome 4 has been characterized. The new allele, designated db3J, produced hyperphagia and severe obesity. Mutants weighed in excess of 70 g by 6 months of age, compared to 22-28 g for lean littermates. Although the disease was similar to the mild hyperglycaemia-severe obesity syndrome exhibited by db gene presentation on the C57BL/6J inbred background, the syndrome in 129/J mice reduced lifespan, with mutants exhibiting sudden weight loss, hypoglycaemia, and a 67% mortality between 6 and 14 months of age. Mutant males, but not females, were transiently hyperglycaemic between 2 to 4 months of age, attaining a maximum mean blood sugar of 196 +/- 27 (SEM) mg/dl. Thereafter glucose levels declined to normoglycaemic values (80-100 mg/dl), and with increasing age, mutants of both sexes became hypoglycaemic (60 mg/dl at 9 months). Mutants of both sexes were extremely hyperinsulinaemic at the earlier ages, with mean plasma insulin at months 5 reflecting 30-fold elevations above normal for males and 18-fold for females. These levels diminished with age, the decline being more marked in males. Plasma glucagon levels were 3-fold elevated in the younger mutants of both sexes (86 pg/ml versus 28 pg/ml in normal mice), mean levels increasing to almost 5-fold above mean control vaues in the older age group (198 pg/ml versus 41 pg/ml in normal mice). Histopathological findings were limited to pancreas. Increasing necrosis of the exocrine, but not endocrine, pancreas was noted in aging mutants. Aldehyde fushsin staining of the mutant pancreas revealed hyperplastic islets filled with heavily granulated B-cells. B-cell hyperplasia was accompanied by a 30-fold increase over controls in pancreatic insulin content in the 8 month old mutants, whereas pancreatic glucagon content was only doubled. Morphometric analysis showed less than a 2-fold increase in the mean number of A-cells per islet. Thus, an interesting feature of expression of the diabetes gene in the 129/J strain is the persisting hyperglucagonaemia in the face of moderating hyperinsulinaemia.

Alleles↗
PubMed1980

Genetic control of serine dehydratase and phosphoenolpyruvate carboxykinase in mice.

Inbred strains of mice were found to differ with regard to their endogenous activities of the liver enzyme serine dehydratase (SD) and phosphoenolpyruvate carboxykinase (PEPCK). The strain distribution patterns for the activity of each enzyme were identical. On feeding of high-protein diets or on fasting, the activities of both enzymes were induced in a concordant fashion which suggested the control of both enzymes by a single gene. Genetic analysis established that the induction of both enzymes on feeding of high-protein diets was controlled by a single gene (Sdr-1), whereas the induction of SD, but not of PEPCK, in fasting was controlled by different single gene (Sdr-2). The lack of segregation of the backcross generations with respect to PEPCK activities obtained on fasting precluded the establishment of any association of the response of PEPCK to fasting with either the Sdr-1 or Sdr-2 locus. The strain of mice (BALB/cJ) that had the ability to maximally induce both gluconeogenic enzymes under both dietary treatments failed to survive a fast as long as those strains with less ability to induce. This suggests that the ability to induce key enzymes in gluconeogenesis when food is unavailable is of little consequence with regard to their ability to produce essential nutrients necessary for survival.

Animals↗
PubMed1980

Acetone metabolism in mice: increased activity in mice heterozygous for obesity genes.

Mice were found to convert acetone to lactate at appreciable rates. The conversion of acetone to gluconeogenic precursors could provide additional glycolytic intermediates that would allow the more complete utilization of lipid stores and increase survival time during starvation. In mice that were starved for 3 days or were provided with acetone in the drinking water the acetone-metabolizing pathway was induced to levels severalfold normal. Mice heterozygous for obesity-producing mutations, either obese (ob/+) or diabetes (db/+), showed induction of the activity of this pathway to a significantly higher degree than did homozygous normal (+/+) mice of the same strain. This more effective conversion of acetone to lactate exhibited by heterozygous mice could account for their prolonged survival on a starvation regimen compared to that of normal homozygotes. The rate-limiting step in the pathway appears to be the conversion of acetone to a hydroxylated derivative. The enzyme system effecting this conversion is an NADPH-requiring microsomal oxygenase found in the liver.

Acetone↗
PubMed1980

Temporal relationship of tissue somatostatin-like immunoreactivity to metabolic changes in genetically obese and diabetic mice.

Somatostatin-like immunoreactivity (SRIF-LI) content in 2 N acetic acid extracts of hypothalamus, gastric antrum, and pancreas was measured in genetically obese (C57BL/6J ob/ob and db/db) and diabetic (C57BL/KsJ db/db and ob/ob) mice and normal littermate controls from 5 to 24 wk to determine the relationship of previously reported changes to the development of metabolic abnormalities. Hypothalamic SRIF-L concentration was similar in control, diabetic, and obese mice at all ages and increased progressively with age in all groups. Gastric antrum SRIF-LI was similar in all groups of mice at all ages. Obese mice gained weight progressively and showed moderate hyperglycemia and marked hyperinsulinemia from 5 wk of age. Pancreatic SRIF-LI content in obese (C57BL/6J) animals was similar to that in lean littermate controls, but pancreatic SRIF-LI concentration (expressed by weight or protein content) was decreased until 8 (6J ob/ob) and 10 (6J db/db) wk. Diabetic (C57BL/KsJ) mice showed a similar metabolic pattern until 10 wk with no change in pancreatic SRIF-LI content or concentration. Thereafter a progressive fall in serum insulin and a marked rise in serum glucose was associated with increasing pancreatic SRIF-LI content and concentration. These studies suggest that the genetically hyperphagic syndromes are unassociated with any change in hypothalamic or gastric SRIF-LI; that pancreatic SRIF-LI increases occur in response to, rather than as the cause of, relative hypoinsulinemia; and that the genetic background of the mice (KsJ or 6J) rather than the mutant gene (db or ob) determines the defect in carbohydrate metabolism and the pancreatic SRIF-LI response.

Animals↗
PubMed1979

Obesity genes: beneficial effects in heterozygous mice.

The mouse mutant genes obese (ob) and diabetes (db) cause similar obesity-diabetes states in homozygotes. These obesity syndromes are characterized by a more efficient conversion of food to lipid and, once stored, a slower rate of catabolism on fasting. Heterozygous mice, either ob/+ or db/+, survived a prolonged fast significantly longer than normal homozygotes (+/+); this suggests that the heterozygotes exhibited increased metabolic efficiency, a feature normally associated with both homozygous mutants. The existence of this thriftiness trait, if manifested by heterozygous carriers in wild populations, would lend credence to the thrifty gene concept of diabetes. Beneficial effects of normally deleterious genes may have played a role in the development of diabetes-susceptible human populations, as well as having provided the survival advantage that has allowed both the development and successful establishment of species in desert and other less affluent regions.

Animals↗
PubMed1979

Ultrastructural and morphometric studies of delta cells in pancreatic islets from C57BL/Ks diabetes mice.

An ultrastructural and immunocytochemical study was undertaken to elucidate the temporal and quantitative aspects of the changes occurring in the delta cells in the pancreatic islets of C57BL/KsJ db/db (diabetes) mice. Electron microscopy revealed that prior to the major topographical redistribution of delta cells from their peripheral location to the islet interior, long delta cell filopodial extensions penetrated into the islet, greatly increasing the area of surface contact between delta cells and hypersecretory beta cells. Coincident with delta cells redistribution in islets of 8 to 10 week diabetes mice, the mean number of delta cells per islet had increased significantly. In contrast, their volume density had decreased, indicating incomplete compensation for beta cell hyperplasia which had commenced approximately 4 weeks earlier. In the 14 week mutants, numbers of delta cells per islet and islet volume reached maximum values while delta cell volume density had been restored to a control level. Delta cell volume density exhibited a 2-fold increase in the mutants at 20 weeks that coincided with massive beta cell necrosis. However, a decline in the number of delta cells per islet (173.6 +/- 20.9 at 14 weeks versus 91.2 +/- 20 weeks) suggests that islet degeneration in terminal stages of the syndrome also includes some loss of these cells.

Animals↗
PubMed1979

Endocrine pancreatic cells of postnatal "diabetes" (db) mice in cell culture.

Ultrastructural characteristics as well as secretory and biosynthetic behavior of monolayer pancreatic cell cultures established from 4-day-old C57BL/KsJ misty diabetic (m db/m db) mice have been studied in comparison to normal littermate controls. Hypersecretion of glucagon by alpha-cells from BL/Ks misty diabetic mice after 2 days in vitro was found to precede any hyperfunction of the insulin-secreting beta-cells. The increased level of glucagon-release in BL/Ks cell cultures from diabetic mice was accompanied by a greatly enhanced level of incorporation of [3H]tryptophan into glucagon-like molecules whose specific radioactivity was up to 15-fold higher than that observed in cultures from genetic controls. The finding of an alpha-cell dysfunction in cultures established from preweaning diabetic BL/Ks mice suggests that glucagon could play an early role in shaping the events that culminate in the expression of frank diabetes in this inbred strain.

Animals↗
PubMed1978

Pharmacokinetic model for salicyclate in cerebrospinal fluid, blood, organs, and tissues.

The developed pharmacokinetic model, an extension of the Bischoff--Dedrick model, simultaneously predicts the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs, and tissues. The model, which is entirely different from conventional compartment models, is derived from basic considerations of drug distribution with biochemical and physiological meaning. The dog was studied at three different dosages of salicylate: therapeutic, moderate intoxication, and severe intoxication. The predicted kinetics of salicylate in cerebrospinal fluid, blood, plasma, liver, muscle, and adipose tissue by the model agreed well with the experimental data. The effectiveness of hemoperfusion treatment for the severely intoxicated dog by albumin-coated activated carbon and its effect on the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs and tissues were studied. The model was also applied to predict the kinetic changes of salicylate in the body during and after the extracorporeal treatment. The predicted results also agreed with the experimental data.

Adipose Tissue↗