Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Abstract

■ AbstractBACKGROUND: Unlike other strains, spontaneously type 1 non-obese diabetic (NOD) mice experience transient hyperinsulinemia after weaning. The same applies for NOD/SCID mice, which lack functional lymphocytes, and unlike NOD mice, do not develop insulitis and diabetes like NOD mice. AIMS: Given that β-cell stimulation is a natural feature of gestation, we hypothesized that glucose homeostasis is disturbed in gestate pre-diabetic NOD and non-diabetic NOD/SCID mice, which may accelerate the onset of diabetes and increase diabetes prevalence. METHODS: During gestation and postpartum, mice were analyzed under basal feed conditions, and following glucose injection (1 g/kg, i.p.) after overnight fast, using glucose tolerance test (GTT). Glycemia, corticosteronemia, blood and pancreatic insulin, glucagon levels, islet size, and islet morphology were evaluated. Glycemia and mortality were assessed after successive gestations in NOD mice mated for the first time at 2 different ages. RESULTS: 1. Basal glucagonemia rose markedly in first-gestation fed NOD mice. 2. β-cell hyperactivity was present earlier in first-gestation non-diabetic fasted NOD and NOD/SCID mice than in age-matched C57BL/6 mice, assessed by increased insulin/glucose ratio after GTT. 3. Overnight fasting increased corticosteronemia rapidly and sharply in pre-diabetic gestate NOD and NOD/SCID mice. 4. Islet size increased in non-diabetic gestate NOD mice compared with C57BL/6 mice. 5. Successive gestations accelerated diabetes onset, and contributed to increased mortality in NOD mice. CONCLUSIONS: First-gestation prediabetic NOD and non-diabetic NOD/SCID mice exhibited β-cell hyperactivity and deregulation of glucagon and/or corticosterone secretion. This amplified normally occurring insulin resistance, further exhausted maternal β-cells, and accelerated diabetes in NOD mice.

HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression1

“…8). We found that the level of insulin expression was statistically indistinguishable between NOD.HLA-B*39:06 Hom .β2m KO mice and their Ins2 Het and Ins2 KO counterparts, with an average concentration of 0.8 ng/ml, consistent with previous reports for other mouse strains (44). This supports the notion that the changes in disease onset are due to diminished immunological tolerance to insulin (30, 31) and not to an inherently decreased ability to produce insulin.…”

HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression

“…9). We found that the level of insulin expression was statistically indistinguishable between NOD.HLA-B*39:06 Hom .β2m KO mice and their Ins2 Het and Ins2 KO counterparts, with an average concentration of 0.8 ng/ml, consistent with previous reports for other mouse strains (37, 47). This supports the notion that the changes in disease onset are solely due to diminished T cell tolerance to insulin associated with Ins2 ablation (28–30, 32), and not also influenced by an inherently decreased ability to produce insulin.…”

Loss of HGF/c-Met Signaling in Pancreatic β-Cells Leads to Incomplete Maternal β-Cell Adaptation and Gestational Diabetes Mellitus

“…Steroid hormones have been shown to counteract the mitogenic, prosurvival, and functional effects of PRL/PL in β-cells in vitro ( 31 , 32 , 50 ), suggesting that upregulation of steroid hormones at the end of pregnancy could be responsible for the increase in β-cell death and normalization of β-cell mass and function. In our studies, we have found that the absence of HGF/c-Met signaling in β-cells leads to increased β-cell death at GD15, when β-cell death is not altered in wild-type mice, suggesting enhanced sensitivity to mild increases in steroid hormone levels that could occur at this gestational day ( 51 , 52 ). Indeed, PancMet KO β-cells are more sensitive than wild-type cells to death induced by low doses of dexamethasone, and HGF protects human β-cells from dexamethasone-induced cell death in vitro, further reinforcing the possibility that c-Met deficiency might enhance the susceptibility of β-cells to the negative effects of mild hormonal changes ( 51 , 52 ).…”