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Leptin therapy reverses streptozotocin-induced diabetes by suppressing hepatic glucose
production and does not require parasympathetic innervation
H.C. Denroche1, E. Tudurí1, U.H. Neumann1, S.D. Covey2, T.J. Kieffer1;
1
Cellular and Physiological Sciences, 2Biochemistry and Molecular Biology, University of British
Columbia, Vancouver, Canada.
Background and aims: Leptin therapy is capable of normalizing fasting glucose levels in rodent
models of insulin-deficient diabetes, independent of increases in circulating insulin levels; yet the
mechanisms of this action remain unclear. Hepatic glucose production is a key diabetogenic pathway
that contributes to hyperglycemia in insulin-deficient diabetes, and can be down-regulated in part
through parasympathetic innervation. We hypothesized that leptin therapy reverses fasting
hyperglycemia in insulin-deficient diabetic rodents by suppressing hepatic glucose production,
possibly by enhancing parasympathetic tone to the liver.
Materials and methods: Blood glucose during a prolonged fast, and liver metabolic parameters were
assessed in streptozotocin (STZ)-treated C57Bl/6 male mice infused with leptin (STZ-leptin) or
vehicle (STZ-vehicle) continuously for 1 week via subcutaneous osmotic pump implants; non-diabetic
controls received buffer instead of STZ injection, and sham surgery instead of pump implantation.
Secondly, we used this same mode of leptin therapy in STZ-treated C57Bl/6 mice that received either
a subdiaphragmatic vagotomy or sham surgery to determine whether leptin therapy could lower blood
glucose in STZ-diabetic mice in the absence of hepatic vagal innervation.
Results: Ten μg/day leptin administration partially reduced 4 hour fasted blood glucose levels within
5 days of leptin therapy (15.3 ± 0.8 mmol/l STZ-leptin vs 24.4 ±1.1 mmol/l STZ-vehicle, P<0.0001)
but did not normalize blood glucose concentrations to non-diabetic levels (9.0 ± 0.5 mmol/l).
Interestingly, STZ-diabetic mice treated with leptin showed a robust and progressive fall in blood
glucose levels during a prolonged fast from 16.2 ± 2.9 mmol/l at 4 hours, to 4.6 ± 0.8 mmol/l by 15
hours fasting (P=0.004), a total decrease of 11.6 mmol/l. In contrast, during this same time frame nondiabetic and STZ-vehicle controls only showed a decrease of 2.2 ± 1.0 and 3.8 ± 2.3 mmol/l
respectively, suggesting that leptin therapy dramatically suppresses hepatic glucose production in this
model. Moreover, unlike controls, STZ-leptin treated mice were unable to raise plasma ketones during
prolonged fasting. Four-hour fasted STZ-leptin treated mice also displayed a ~55% reduction in
hepatic Glut2 expression compared to STZ-vehicle controls, and a severe depletion of hepatic
glycogen content (0.058 ± 0.007 mg/g tissue) compared to STZ-vehicle (4.7 ± 1.2 mg/g tissue,
P=0.003) and non-diabetic controls (4.4 ± 0.9 mg/g tissue, P=0.0004). We next examined whether the
glucose lowering effect of leptin may be mediated by vagal innervation, by determining whether
leptin therapy could lower blood glucose in STZ-diabetic mice with a subdiaphragmatic vagotomy.
Interestingly, loss of parasympathetic innervation did not block leptin action in this model, as
vagotomized mice had a more robust glucose lowering in response to leptin than sham operated
controls (4.7 ± 1.6 mmol/l vs 18.1 ± 1.5 mmol/l on day 3, P=0.0006).
Conclusion: Collectively, our data indicate that leptin therapy may lower blood glucose levels in
STZ-diabetic mice by suppressing hepatic glucose production, and that the glucose lowering action of
leptin in this model of insulin-deficient diabetes is independent of vagal innervation.
Supported by: Work funded by CIHR. HCD is supported by NSERC. TJK is supported by MSFHR.