Downregulation of FKBPL influences metabolic and vascular function in experimental model of diabetes
- Publisher:
- Springer Verlag
- Publication Type:
- Conference Proceeding
- Citation:
- Diabetologia, 2018, 61, (Suppl 1), pp. 1-620
- Issue Date:
- 2018-10-01
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| Filename | Description | Size | |||
|---|---|---|---|---|---|
| 2018_Article_54thEASDAnnualMeetingOfTheEuro.pdf | 49.11 MB |
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Background and aims: There are currently over 400 million people
living with diabetes in the world. Cardiovascular disease (CVD) is the
leading cause of death globally and people with diabetes have a three-fold
higher incidence of CVD. The underlying mechanisms implicated in the
development of CVD in association with diabetes are linked to aberrant
angiogenesis and endothelial dysfunction. FKBPL is a novel antiangiogenic protein which has a critical role in physiological and pathological angiogenesis. While Fkbpl homozygous knockout mice resulted
in embryonic lethality, Fkbpl+/− embryos were viable and developed
normally but showed signs of early vascular dysfunction and leakiness.
Based on these findings, we now investigate the effect of FKBPL downregulation on metabolic and vascular function in a streptozotocin (STZ)-
induced diabetic mouse model.
Materials and methods: Both wild-type (WT, C57BL/6N) Fkbpl+/+ and
Fkbpl+/− mice were randomized between 10 and 12 weeks of age to either
STZ treatment (5 consecutive STZ injections at 50 mg/kg/day) or vehicle
control treatment with citrate buffer. Metabolic parameters were measured weekly. Insulin tolerance (ITT) and echocardiography tests were
performed at 12 weeks of diabetes. Following 13 weeks of diabetes,
organs were excised for immunofluorescent ex-vivo analysis.
Comparisons were analyzed using one-way ANOVA.
Results: Blood glucose levels were higher in Fkbpl+/− diabetic mice
compared to Fkbpl+/+ diabetic controls during a period of 8 to 12 weeks
of diabetes (p < 0.05, n ≥ 6). Glycated haemoglobin (HbA1c) was higher
in both non-diabetic and diabetic Fkbpl+/− mice compared to Fkbpl+/+
controls (non-diabetic, 31 ± 0.9 mmol/mol vs. 27.25 ± 0.8 mmol/mol, p <
0.05, n ≥ 6; diabetic, 88.7 ± 3.1 mmol/mol vs. 69.8 ± 3.5 mmol/mol, p <
0.001, n ≥ 6). Notably, Fkbpl+/− non-diabetic mice gained more weight
compared to Fkbpl+/+ non-diabetic controls on a normal diet (10.92 ±
0.51 g vs. 7.05 ± 1.02 g, p < 0.05, n ≥ 6). However, no differences in
blood glucose levels were observed between these two groups of mice.
The results of ITT at 12 weeks of diabetes showed a trend towards higher
blood glucose levels in diabetic Fkbpl+/− mice compared to Fkbpl+/+
diabetic controls (at 0 min, 33.3 ± 0 mmol/l vs. 29.12 ± 0.56 mmol/l,
p < 0.05; at 120 min, 20.3 ± 3.02 mmol/l vs. 15.6 ± 1.61 mmol/l, p =
0.09, n ≥ 6). This was associated with significant cardiac diastolic dysfunction, as indicated by reduced E/A ratio in both Fkbpl+/+ and Fkbpl+/−
diabetic mice compared to their respective controls (p < 0.001, n ≥ 6),
whilst E/A tended to be elevated in the non-diabetic Fkbpl+/− mice compared to Fkbpl+/+ controls (p = 0.08, n ≥ 6). Immunofluorescence staining
of the hearts showed lower FKBPL protein expression in Fkbpl+/+ diabetic mice compared to non-diabetic controls (mean fluorescence intensity: 0.12 ± 0.03 vs. 1 ± 0.17, p < 0.01, n ≥ 4). Cardiac protein expression
of intercellular adhesion molecule 1 (ICAM-1), a marker of endothelial
dysfunction, was higher in diabetic animals as well as in Fkbpl+/− nondiabetic mice compared to Fkbpl+/+ controls (mean fluorescence intensity: 1.37 ± 0.13 vs. 1 ± 0.04, p < 0.01, n ≥ 4).
Conclusion: Our results suggest that FKBPL may play a key regulatory
role in fat and glucose metabolism as well as irregular cardiac angiogenesis associated with diabetes. As such, FKBPL could be explored as a
potential therapeutic target for prevention of cardiovascular complications of diabetes
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