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H Markholst

Publications and source records attributed to H Markholst.

13 recordsLinked to original sources
PubMed1991

Diabetes segregates as a single locus in crosses between inbred BB rats prone or resistant to diabetes.

Diabetes-prone (DP) BB rats spontaneously develop insulin-dependent diabetes resembling type 1 diabetes mellitus in man. They also exhibit lifelong T cell deficiency. The segregation of both diabetes and lymphopenia was studied in crosses between this inbred line of rats and the related but nondiabetic and nonlymphopenic inbred diabetes-resistant (DR) BB rat line. Diabetes segregated as a single, autosomal recessive trait and was always accompanied by lymphopenia. Among the limited number of differences in the genomic DNA sequences of the two lines, DP and DR BB, one may account for the development of diabetes and lymphopenia in the DP BB rats. It may be possible to screen the genomic DNA for such differences to detect a marker for the phenotypes.

Aging↗
PubMed1991

Transplantation of purified islet cells in diabetic BB rats.

The ability to prepare purified islet Beta-cell aggregates was used to examine the survival of this cell type after allotransplantation in diabetic BB rats. The aggregates were intraportally implanted in numbers that were previously found to correct a streptozotocin-induced diabetic state in syngeneic or allogeneic Brown Norway recipients. When the grafts were prepared from RT1u/l donors, which shared the MHC-class I antigen with the BB recipients (RT1u/u), their implant sites became diffusely infiltrated by inflammatory cells and their metabolic function was completely lost within 5 weeks. MHC-class I incompatible islet Beta-cell allografts (RT1n/n) exhibited a longer survival, in particular when combined with other islet endocrine cells and/or when covered by a 5-week cyclosporin treatment. In the latter combination, 10 of 12 BB rat recipients remained normoglycaemic over the 10-week observation period, their liver implants presenting a comparable insulin reserve and similarly discrete mononuclear cell infiltration as streptozotocin-diabetic Brown Norway rats receiving this treatment. However, administration of cyclosporin to diabetic BB rats was associated with a morbidity that was not observed in drug-treated streptozotocin-diabetic Brown Norway animals or in untreated diabetic BB rats. It is concluded that MHC-incompatible islet Beta cells can induce a long-term normalization in diabetic BB rats provided that they are implanted under conditions which allow allograft acceptance. The standardized preparation of purified islet Beta-cell grafts can help assessing the conditions for successful transplantations in diabetes with an autoimmune origin.

Animals↗
PubMed1991

Leukocytosis at the onset of diabetes in crosses of inbred BB rats.

Inbred lymphopenic, diabetes-prone (DP) and non-lymphopenic, diabetes-resistant (DR) BB rats in a specific pathogen-free (SPF) colony were subjected to a cross-intercross breeding experiment which showed diabetes to segregate as a recessive trait. All DP rats, but none of the DR and F1 rats, developed diabetes. In contrast, about 25% of the F2 rats developed diabetes which made it possible to study these rats without maternal influence of diabetes. All rats were bled at regular intervals between 30 and 150 days of age, and the samples analyzed for numbers of leukocytes, lymphocytes, neutrophils, monocytes and eosinophils. Leukocyte numbers tended to increase with age until about 100 days, and to decline thereafter. Males had more leukocytes than females. Coinciding with the time of onset of overt diabetes, there was a large increase in eosinophils, along with smaller increases in neutrophils, monocytes and lymphocytes. These data in SPF DP and DR BB rats and their cross-intercross offspring demonstrate that the overt onset of diabetes is associated with a significant leukocytosis.

Aging↗
PubMed1990

Decreased levels of serum alpha-isoamylase prior to diabetes onset in BB rats.

The development of insulin-dependent diabetes mellitus (IDDM) includes a prodrome of autoimmunity against pancreatic beta cells. The period of subclinical islet cell disease with altered beta-cell function may be prolonged. We have determined the serum pancreatic alpha-isoamylase in both young diabetes-prone (DP) and newly diabetic BB rats to test whether changes in the pancreas prior to IDDM are reflected by this enzyme, shown to be regulated by insulin. A prospective analysis of inbred BB rats (n = 28) that later developed diabetes showed that the alpha-isoamylase at the time of onset was reduced by 19% (p less than 0.02) compared with levels observed 1 week earlier and by 30% (p less than 0.01) compared with levels 2 weeks before onset. Furthermore, when compared to age-matched diabetes-resistant (DR) BB rats in a cross-sectional study, the DP BB rats investigated in groups at 20, 30, 40, 50, 60, and 70 days of age had significantly lower (p less than 0.01) serum alpha-isoamylase already from 50 days of age, which is 2-6 weeks prior to the expected onset of diabetes. Finally, in 70-day-old cofostered DP and DR male rats with identical body weight and rates of growth, the serum alpha-isoamylase was decreased in the DP yet nondiabetic (n = 8) rats compared with the DR (n = 8) rats (p less than 0.05). Reduced levels of serum alpha-isoamylase, therefore, may reflect loss of beta cells or beta-cell function in the pancreas of diabetes-prone but not yet diabetic BB rats.

Aging↗
PubMed1990

Lack of systematically found insulin autoantibodies in spontaneously diabetic BB rats.

Insulin autoantibodies (IAAs) occur in newly diagnosed human insulin-dependent diabetes mellitus (IDDM) patients, but their presence in BB rats is controversial, possibly due to assay differences or variability in the animals studied. To resolve this controversy, IAAs were measured in well-characterized inbred BB rats both in radioligand assays with 125I-labeled rat insulin I or II, respectively, and in an enzyme-linked immunosorbent assay (ELISA) with rat insulin as antigen. In prospective studies, a total of 57 serums from 16 diabetes-prone (DP) BB rats were obtained during an interval ranging from 15 wk to the last week before onset and at onset of diabetes. At comparable ages, 21 serums were obtained from 8 DP BB rats not developing diabetes, and 70 matched serums were obtained from 19 diabetes-resistant (DR) BB rats. Levels of antibody binding increased slightly with increasing age in DP and matched DR rats. Two rats were positive at onset of IDDM in all assays but not in earlier samples. Otherwise, only few isolated serums from both types of rats regardless of diabetes had increased binding in one of the assays. In a cross-sectional study, the insulin-binding levels in 150-day-old DP rats (n = 20) that had not yet developed diabetes did not correlate with insulitis present in 3 of 20 rats and did not differ from 150-day-old DR BB rats (n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

Insulitis and diabetes are preceded by a decrease in beta cell volume in diabetes-prone BB rats.

Immunocytochemistry combined with morphometry was used to test the hypothesis that insulitis and diabetes are preceded by quantitative changes in the pancreas of diabetes-prone BB (DPBB) rats. Diabetes-resistant BB (DRBB) rats of the w-subline served as controls. In the first part of the study rats aged 15, 30, 45, and 60 days were studied. At 60 days preceding both insulitis and onset of diabetes, the DPBB rats demonstrated lower volumes of the entire pancreas, the parenchyma, the endocrine pancreas, and beta, A, and D cells. Body weights of the DPBB rats were lower than the DRBB rats from 15 days of age on. In the second part of the study, DP and DRBB rats were coreared by a foster mother to obtain weight-matched animals. Morphometric analysis at 70 days of age revealed a reduction in both the beta cell volume density and volume whereas no differences were seen in other pancreatic parameters. These results indicate that the appearance of insulitis and the later onset of insulin-dependent diabetes are preceded by a reduction in beta cell volume.

Animals↗
PubMed1989

Derivation of non-lymphopenic BB rats with an intercross breeding.

Previous studies have suggested that the development of diabetes in the BB rats does not require the expression of T lymphopenia. In order to derive non-lymphopenic diabetic rats and define the relationship between the T cell abnormalities, MHC genotype, and diabetes, we performed a cross between BB/H and diabetes resistant BB/control followed by an intercross of the F1. In the F2, the overall incidence of diabetes and lymphopenia was 30% and 27%, respectively. Lymphopenia was strongly associated with diabetes (p less than 0.001) and was seen in 76% of the diabetic F2's. However, 6 of the diabetic were non-lymphopenic (24%) and 3 of the non-diabetics were lymphopenic (5%). In the non-lymphopenic diabetic animals, all T cell levels were within the normal range, but diabetes occurred at an earlier age than their lymphopenic littermates (p less than 0.001). In contrast to the strong association between the inheritance of lymphopenia and diabetes, no relationship between diabetes and Class I MHC restriction fragment length polymorphisms was found. We conclude: 1) Diabetes and lymphopenia are strongly associated inherited abnormalities in the BB rat and are not associated with Class I RFLP defined genotypes within the RTIu haplotype, 2) Animals in whom diabetes occurs in the absence of lymphopenia can be derived using this breeding approach 3) In our non-lymphopenic rats, diabetes occurred at an earlier age possibly reflecting the restoration of quantitative or qualitative T cell defects found in lymphopenic BB rats.

Animals↗
PubMed1989

Increased levels of circulating immune complexes are not associated with diabetes in BB rats.

Increased levels of circulating immune complexes (IC) have been described in insulin-dependent diabetic (IDD) patients at the time of diagnosis. The aim of the present study was to test whether the spontaneously diabetic BB rat had changes in IC levels at different ages prior to and at onset of IDDM as compared with diabetes resistant BB rats and normal Wistar Furth rats. The IC levels were related to serum IgG concentration as well as to total peripheral blood lymphocyte counts. Three groups of rats with 12 animals in each were followed: Diabetes-prone, lymphopenic (DP) BB rats with an expected high incidence of diabetes, diabetes-resistant (DR) BB rats from the non-diabetic w-subline, and Wistar Furth rats. Blood samples collected on 12, 22, 29, 43, 71, and 99 days of age were analyzed for IC, detected in a solid phase C1q assay, serum IgG levels, and peripheral blood lymphocytes. Diabetes developed in 8/12 (66%) DP BB rats between 70 and 93 days of age while none of the DR BB rats developed diabetes. The levels of IC tended to increase with age in all three groups of rats and did not differ between DP BB and Wistar rats whereas DR BB rats had significantly higher levels (p less than 0.05-0.01) at all ages. The profile of serum IgG was similar in all rats showing a high level at 12 days of age and a nadir at day 29 followed by an increase from day 43 until the end of the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Reduced pancreatic insulin is associated with retarded growth of the pancreas in young prediabetic BB rats.

The beta-cell function in the perfused pancreas, the total pancreatic insulin content, and the weights of pancreas, kidney, spleen, and total body fat were compared at the age of 30 and 45 days in diabetes-prone and body weight-matched diabetes-resistant male BB rats. These inbred rats had an incidence rate of diabetes at 90 days of age of 80 and 0%, respectively. At day 30, the pancreatic insulin content was reduced in the diabetes-prone (n = 10) rats to 15 micrograms (range 7.7-31.8) compared with 32 micrograms (range 23.3-52.9) in the diabetes-resistant (n = 10) rats (p less than 0.01). Although the kinetics of insulin release in response to glucose was maintained, the amount of insulin released in the diabetes-prone rats was decreased (p less than 0.05) including the first peak (p less than 0.05). The weight of the spleen was less (p less than 0.05); whereas the weights of the pancreas, kidney, and total body fat did not differ from those observed in the diabetes-resistant control rats. At 45 days of age, the weight of the pancreas in the diabetes-prone rats (n = 8) was reduced to 159 mg (range 100-190) from 202 mg (range 185-214) (p less than 0.01). The body weight and body fat were identical to those observed in the diabetes-resistant controls (n = 8) and their kidney (p less than 0.05) and spleen (p less than 0.01) were larger. The insulin content was reduced to the same magnitude as the reduction of pancreatic weight.

Adipose Tissue↗
PubMed1988

Interleukin-1 potentiates glucose stimulated insulin release in the isolated perfused pancreas.

The acute effects of recombinant human interleukin-1 beta (rIL-1) on basal and glucose-stimulated insulin release were investigated in the isolated perfused pancreas. At a concentration of 20 micrograms/l rIL-1 had no effect on basal insulin release, but increased the total amount of insulin released during first and second phase insulin release in response to 20 mmol/l D-glucose in the rat pancreas (P less than 0.05). In addition, 26 micrograms/l of rIL-1 potentiated insulin release in response to square wave infusions of stimulatory concentrations of glucose (11 mmol/l) in the porcine pancreas. We hypothesize that IL-1 in the systemic circulation may affect B cell function in vivo.

Animals↗
PubMed1986

Insulin release and pancreatic insulin is reduced in young prediabetic BB rats.

The pancreases of approximately 50 days old diabetes-prone BB/Hagedorn (BB/H) and of the genetically closely related, but non-diabetic BB w-subline (control BB) rats were perfused to determine the capacity of D-glucose to release insulin before the expected development of diabetes. The BB/H rats were from a colony with 82-84% incidence of insulin-dependent diabetes mellitus (IDDM) by 140 days of age. The total amount of insulin released from the BB/H rat pancreas during stimulation with 20 mmol/1 mmol/ D-glucose was reduced by nearly 50% (P less than 0.01). The initial peak of insulin release was similar between the two groups of animals, whereas the amount of insulin released during the second peak accounted for the diminished release (P less than 0.01). The extractable pancreatic insulin was 30% (P less than 0.05) less in the BB/H rats. Total insulin release expressed relative to the pancreatic insulin content, was therefore not different between the two groups. It is concluded that about 20-40 days before the mean age of clinical onset of IDDM in BB/H rats, the capacity to release insulin in response to D-glucose is reduced along with a diminished pancreatic insulin content. This abnormality seems to be preceded only by islet cell surface antibodies but not by insulitis.

Animals↗