Phenotype Information for B6-db (000697)

Type 2 diabetes phenotypes in male and female C57BL/6J mice with the leptin receptor mutation (B6-db; B6.BKS(D)-Lepr^db/J) include:

Severe obesity (Figure 1 and Table 2)
Transient hyperglycemia (Figure 2 and Table 1). B6-db/db glucose levels peak then decrease with time due to pancreatic islet cell hypertrophy. By contrast, BKS-db/db mice sustain high blood glucose throughout life.
Elevated serum total cholesterol, HDL cholesterol, triglycerides and glucose at 8 weeks of age; elevated serum total cholesterol, HDL cholesterol and glucose at 16 weeks of age (Table 3)
Glucose intolerance at 8 & 16 weeks (Figure 3)

Complete results, including spleen flow cytometry data, are available from the Mouse Phenome Database.

Figure 1 Body weight growth curve. Cohorts contained approximately 80 db/db and 40 db/+ mice per sex. Mice were fed a diet containing 6% fat (LabDiet^® 5K52 formulation).

Figure 2 Non-fasted glucose. Blood glucose levels of male and female mice between the ages of 4 and 16 weeks. Submandibular blood glucose measurements were obtained using a OneTouch Ultra 2 or UltraMini hand-held glucometer that was validated with a control glucose solution on each day of use. Values represent the mean and one standard deviation.

Figure 3 Glucose tolerance tests. Blood glucose levels during glucose tolerance tests (GTT) at 8 and 16 weeks of age. Following a 16 hour fast, an initial submandibular blood glucose reading was taken and mice were administered glucose by IP injection at 2g/kg body weight. Blood glucose was measured in 30 minute intervals. Any result exceeding the maximum reading of the meter was recorded as 600 mg/dL. Each data point represents the mean and one standard deviation of 10-20 mice.

Table 1 Distribution of homozygous (db/db) blood glucose values. The blood glucose values shown in Figure 2 were grouped into ranges to show the reversion to non-diabetic values as db/db mice age. Rows indicate the percentage of mice in the indicated ranges, with the exception of the final row that states the number of mice analyzed.

Glucose Range (mg/dL)	4 Weeks		6 Weeks		8 Weeks		10 Weeks		12 Weeks		14 Weeks		16 Weeks		18 Weeks		20 Weeks
	Males	Females	Males	Females	Males	Females	Males	Females	Males	Females	Males	Females	Males	Females	Males	Females	Males	Females
< 250	59%	58%	39%	43%	21%	37%	41%	34%	33%	57%	48%	63%	54%	59%	84%	74%	74%	91%
250 - 349	24%	30%	49%	40%	51%	39%	25%	40%	37%	25%	25%	26%	30%	29%	5%	17%	21%	0%
350 - 450	11%	13%	6%	13%	18%	18%	22%	13%	19%	9%	16%	3%	9%	4%	5%	4%	0%	4%
> 450	6%	0%	6%	5%	10%	7%	13%	13%	11%	9%	11%	8%	7%	9%	5%	4%	5%	4%
# Mice	80	80	80	80	80	90	79	77	79	76	56	76	56	56	19	23	19	23

Table 2 Body Composition. Mice were weighed and then analyzed using a Lunar PIXImus DEXA scanner. Calculations of body composition exclude the head. Values represent mean and one standard deviation of 10 non-fasted mice per age, sex and genotype. Results were analyzed separately by age and sex using two-way ANOVA with Sidak’s multiple comparisons test to identify values that differed significantly between genotypes, using GraphPad Prism version 6.07 for Windows (GraphPad Software).

Age & Sex	Genotype	Body Weight (g)	Bone Mineral Density (g/cm²)	Bone Mineral Content (g)	Bone Area (cm²)	Lean Tissue (g)	Fat Tissue (g)	Percent Fat Tissue
8 Week Males	db/db	40.4 ± 3.2^a	0.047 ± 0.002	0.44 ± 0.07	9.4 ± 1.2	17.3 ± 2.0^a	21.7 ± 2.4^a	55.6 ± 4.0^a
8 Week Males	db/+	28.8 ± 1.5^a	0.053 ± 0.002	0.46 ± 0.03	8.8 ± 0.5	21.2 ± 1.3^a	6.2 ± 0.8^a	22.5 ± 2.3^a
8 Week Females	db/db	36.0 ± 2.6^a	0.044 ± 0.001	0.34 ± 0.03	7.7 ± 0.6	15.5 ± 1.1	19.9 ± 1.6^a	56.1 ± 1.9^a
8 Week Females	db/+	23.0 ± 1.2^a	0.050 ± 0.002	0.39 ± 0.03	7.8 ± 0.8	15.5 ± 0.9	6.5 ± 0.8^a	29.6 ± 2.8^a
16 Week Males	db/db	54.4 ± 3.1^a	0.050 ± 0.001	0.53 ± 0.05	10.6 ± 1.0	20.2 ± 1.7^b	32.5 ± 3.2^a	61.7 ± 3.3^a
16 Week Males	db/+	34.1 ± 2.9^a	0.060 ± 0.003	0.58 ± 0.03	9.6 ± 0.5	23.9 ± 1.4^b	9.4 ± 2.0^a	27.9 ± 3.9^a
16 Week Females	db/db	55.3 ± 2.7^a	0.050 ± 0.002	0.49 ± 0.08	9.8 ± 1.4	19.3 ± 1.1	33.9 ± 3.0^a	63.7 ± 2.0^a
16 Week Females	db/+	29.1 ± 2.1^a	0.058 ± 0.001	0.50 ± 0.04	8.6 ± 0.6	17.8 ± 0.9	10.8 ± 1.8^a	37.5 ± 3.9^a
^a P ≤ 0.0001 ^b P ≤ 0.001

Table 3 Clinical chemistry. All values were measured from serum collected from submandibular blood except HbA1c, which was measured from submandibular whole blood. Values represent mean and one standard deviation of 10-20 non-fasted mice per age and diet group. Results were obtained using a Beckman Coulter AU680 chemistry analyzer. Results were analyzed separately by age and sex using two-way ANOVA with Sidak’s multiple comparisons test to identify values that differed significantly by genotype, using GraphPad Prism version 6.07 for Windows (GraphPad Software).

Age & Sex	Genotype	Total Cholesterol (mg/dL)	HDL Cholesterol (mg/dL)	LDL Cholesterol (mg/dL)	Triglycerides (mg/dL)	Free Fatty Acids (mEq/L)	Glucose (mg/DL)	HbA1c (NGSP %)
8 Week Males	db/db	218 ± 62^a	139 ± 41^b	8.7 ± 2.1	200 ± 66^b	1.2 ± 0.4	399 ± 122^a	7.8 ± 0.8
8 Week Males	db/+	125 ± 18^a	92 ± 14^b	4.4 ± 1.4	150 ± 38^b	1.2 ± 0.4	207 ± 41^a	5.7 ± 0.3
8 Week Females	db/db	216 ± 33^a	137 ± 19^a	8.3 ± 1.4	203 ± 48^a	1.3 ± 0.4	310 ± 108^a	7.4 ± 0.8
8 Week Females	db/+	109 ± 10^a	82 ± 9^a	5.5 ± 1.3	138 ± 32^a	1.3 ± 0.3	192 ± 22^a	5.4 ± 0.4
16 Week Males	db/db	291 ± 75^a	174 ± 27^a	20.0 ± 12.4	131 ± 27	1.4 ± 0.4	273 ± 82^a	10.7 ± 1.7
16 Week Males	db/+	123 ± 36^a	95 ± 26^a	3.3 ± 1.3	139 ± 34	1.5 ± 0.4	184 ± 49^a	6.2 ± 0.7
16 Week Females	db/db	282 ± 92^a	166 ± 39^b	18.3 ± 8.4	167 ± 80	2.0 ± 0.9	370 ± 197^a	8.5 ± 1.9
16 Week Females	db/+	110 ± 15^a	86 ± 9^b	6.5 ± 1.9	113 ± 26	1.6 ± 0.3	183 ± 39^a	6.2 ± 0.7
^a P ≤ 0.0001 ^b P ≤ 0.01

Phenotype Information for B6-db (000697)

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