Glucose Homeostasis in the Nonobese Diabetic Mouse at the Prediabetic Stage¹

Abstract

Because few data were available on glucose homeostasis at the early prediabetic stage in the nonobese diabetic (NOD) mouse, we investigated glycemia, insulinemia, and pancreatic insulin content under basal conditions in both sexes of 4-, 6-, and 8-week-old fed NOD mice, compared with sex-and age-matched fed C57BL/6 mice. We also investigated glucose tolerance in both sexes of fasting 8-week-old NOD and C57BL/6 mice. The main results obtained under basal fed conditions, when comparing both strains, were lower glycemia and higher insulinemia in NOD females at all ages investigated and in NOD males (particularly at 6 weeks of age). Glucose tolerance tests showed that: 1) the blood glucose response to 1 g/kg ip glucose was less sustained in both sexes of 8-week-old NOD mice than in their control counterparts; 2) the blood insulin response to glucose (1 g/kg ip) appeared earlier in both sexes of NOD mice than in sex-matched C57BL/6 mice; 3) an unusual sexual dimorphism existed in NOD mice, compared with controls, with females secreting, in response to glucose, twice as much insulin as males; 4) dose-response studies (1-6 g/kg glucose) confirmed the lower increase in blood glucose levels in both sexes of NOD mice and their unusual sexual dimorphism in insulin secretion; and 5) glucose tolerance tests in 4-to 8-week-old NOD mice showed that although the sexual dimorphism in insulin secretion was not observed in 4-week-old mice, it was particularly striking at 6 weeks of age. Taken together, these results suggest that ␤-cell hyperactivity exists in the NOD mouse at the early prediabetic stage, especially in NOD females. (Endocrinology 139: [1115][1116][1117][1118][1119][1120][1121][1122][1123][1124] 1998) I NSULIN-DEPENDENT diabetes mellitus (IDDM), or type 1 diabetes, has a long prodromic phase in both humans (in whom the detection of autoantibodies precedes diabetes onset by years) and spontaneous models of the disease, such as the nonobese diabetic (NOD) mouse (in which insulitis precedes hyperglycemia by weeks or months) (1, 2). In firstdegree relatives of IDDM patients, with regard to glucose homeostasis, data vary from normal to subnormal or, even more surprisingly, to excessive insulin and C-peptide secretion in response to glucose and/or arginine (1-8). In line with the possible existence of hyperactive ␤-cells at the prediabetic stage in humans, the following have been observed: 1) increased levels of insulin and proinsulin under basal fasting conditions in nondiabetic identical twins of IDDM patients (5, 6); and 2) increased levels of proinsulin under basal conditions and after glucose stimulation in first-degree relatives or newly diagnosed patients (3, 9 -14). In spontaneous experimental models of IDDM, most data dealing with glucose homeostasis at the prediabetic stage demonstrated a lower insulin response to glucose in both BB rats (15-21) and NOD mice (22)(23)(24)(25)(26). However, in the BB rat in particular, the existence of hyperactive ␤-cells at the prediabetic stage can be suggested on the...

Contribution of Different Mechanisms to Pancreatic Beta-cell Hyper-secretion in Non-obese Diabetic (NOD) Mice during Pre-diabetes

“…Blood glucose levels 20 -60 min after intravenous glucose infusions were significantly lower in 6-week-old NOD mice compared with the control (Fig. 1A), which suggested an excessive insulin release, as has been previously proposed (3,26). The Ca 2ϩ clearance and glucosestimulated calcium oscillations of individual NOD beta-cells were not significantly different from those of Balb/c cells (Figs.…”

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Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

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“…Blood was collected in a capillary tube by retro orbital bleeding as described previously [45] from the STZ/HFD-32 fed mice at the end of study before sacrifice. In the case of the ob/ob mice, weekly blood samples were collected from the tail, and blood glucose levels were measured immediately using an Accu-Check Performa blood glucose meter.…”