Hyperglycemia, impaired glucose tolerance and elevated glycated hemoglobin levels in a long-lived mouse stock

Abstract

We have previously demonstrated that two wild-derived stocks of mice, Idaho and Majuro, are significantly longer-lived than mice of a control stock (DC) generated as a four-way cross of commonly used laboratory strains of mice. This study provides independent confirmation of this earlier finding, as well as examining serum glucose, insulin, leptin, glycated hemoglobin (GHb), cataract severity, and glucose tolerance levels in each of the stocks. Both the mean (+20%) and maximum (+13%) life span of the Idaho mice were significantly increased relative to the DC stock, while in the Majuro mice only maximum (+15%) life span was significantly increased. In addition, Majuro mice were hyperglycemic in both the fed and fasted states compared both to laboratory-derived and Idaho stocks, had significantly elevated GHb levels and cataract scores, and were glucose intolerant although serum insulin levels did not differ between stocks. Body weight and body mass index (BMI)-corrected leptin levels were also dramatically (1.5-3-fold) higher in the Majuro mice. The longevity of Id mice was not accompanied by changes in serum glucose and insulin levels, or glucose tolerance compared to DC controls, although GHb levels were significantly lower in the Idaho mice. Taken together, these findings suggest that neither a reduction of blood glucose levels nor an increase in glucose tolerance is necessary for life span extension in mice.

Fig. 1

Weight (top panel) and body mass index (BMI, body panel) as a function of age in wild-derived (Idaho, Majuro) mouse stocks and in a genetically heterogeneous laboratory stock (DC) of mice. Each point represents the mean (±SEM) of each stock. For body weight N=40, 40, and 41 mice at 1 month for the DC, Idaho, and Majuro mice, respectively; due to natural deaths sample sizes decreased with time such that N=7, 21, and 13 at 30 months. For BMI, N=39, 40, and 38 at 6 months and N=24, 31, and 27 at 24 months.

Fig. 2

Kaplan–Meier survival curves for DC, Idaho, and Majuro mice before (left panel) and after (right panel) the removal of individuals that died a natural death before the age of 800 days. Each point represents a single mouse. Statistical significance was calculated by log-rank test, and individual marks on each plot indicate mice that were still alive on 27 October 2004 (censored observations; N=6 Idaho, 2 Majuro).

Fig. 3

Mean (±SEM) non-fasting serum glucose levels in 6-month-old DC, Idaho, and Majuro mice. Three sets of values are given for each stock; i.e. prior to removing any individuals based upon age at death (all mice), as well as after removing those individuals that died after or before 800 days of age. Numbers in boxes indicate sample sizes. (*) indicates a significance difference for Majuro versus DC and Idaho mice at p<0.01 for each comparison.

Fig. 4

Mean (±SEM) glycated hemoglobin (GHb) levels in 6 and 14-month-old DC, Idaho, and Majuro mice. Different letters indicate significance differences among stocks at p≤0.05 for all.

Fig. 5

Mean (±SEM) cataract scores in 18 and 24-month-old DC, Idaho, and Majuro mice. (*) indicates a significance difference between stocks at p≤0.05 for all.

Fig. 6

Serum glucose levels 0–180 min after an intraperitoneal glucose challenge (2 mg/g body weight) in DC, Idaho, and Majuro mice at 2–4 (top panel), 10–14 (middle panel), and 17–21 (bottom panel) months of age. Each point indicates the mean (±SEM) for each stock and time after injection. N=9, 10, and 10 (2–4-month-old); 7, 7, and 3 (10–14-month-old); and 5, 5, and 5 at 0, 15, 45, and 90 min and 3, 2, and 3 at 180 min (17–21-month-old) mice for the DC, Idaho, and Majuro stocks respectively.

Fig. 7

Serum insulin levels 0–60 min after an intraperitoneal glucose challenge (2 mg/g body weight) in DC, Idaho, and Majuro mice. Other details as in Fig. 6 except that N=5, 5, and 4 mice for the old HET3, Idaho, and Majuro stocks, respectively.

Fig. 8

Basal circulating serum leptin levels (inset), and leptin levels relative to weight (light bars) or BMI (dark bars) in 6-month old fed DC, Idaho, and Majuro mice. Each bar represents the mean±SEM for each stock. N=27, 25, and 27 for the DC, Idaho, and Majuro mice respectively. Different letters above bars indicate a significant difference among stocks at p≤0.05. * indicates a significant difference at p≤0.05.