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. 2011 May;60(5):1414-23.
doi: 10.2337/db10-0958. Epub 2011 Apr 4.

Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling

Heather C Denroche  1 , Jasna Levi, Rhonda D Wideman, Roveena M Sequeira, Frank K Huynh, Scott D Covey, Timothy J Kieffer
Affiliations

Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling

Heather C Denroche et al. Diabetes. 2011 May.

Abstract

Objective: Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes.

Research design and methods: After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted.

Results: Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes.

Conclusions: These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.

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Figures

FIG. 1.
FIG. 1.
Leptin therapy reverses hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice. Four-hour fasted parameters in STZ-leptin–treated (black), STZ-saline (white), and nondiabetic (gray) mice are shown. Mice received subcutaneous 14-day osmotic pump implants containing a 10 μg/day dose of leptin or saline on day 0. A: Plasma leptin levels on day 7 and day 14 after pump implantation (n = 5). Day 7 samples were collected from the saphenous vein. Leptin was undetectable in plasma samples from STZ-saline mice. B: Blood glucose (n = 5). C: β-Hydroxybutyrate levels on day 14 (n ≥4). D: Body weight (n = 5). B and D: Statistical analyses were performed by one-way ANOVA multiple comparison procedure with Holm-Sidak post hoc testing (Sigma Stat, SYSTAT Software, Inc.). *P < 0.01 STZ-leptin vs. STZ-saline mice; †P < 0.01 STZ-leptin vs. nondiabetic mice; ‡P < 0.01 STZ-saline vs. nondiabetic mice. Data are expressed as means ± SEM.
FIG. 2.
FIG. 2.
The effects of leptin on hyperglycemia in mice with STZ-induced diabetes are acute. Four-hour fasted blood glucose in STZ-leptin (black) and STZ-saline (white) mice (n = 7) is shown. C57BL/6J mice given STZ on day −5 were subsequently treated with 5 μg/day leptin or saline via subcutaneous 14-day osmotic pumps implanted on day 0. Pumps were removed on day 14 after blood glucose measurement. STZ-saline mice were killed on day 19 because of deteriorating body condition. The STZ-leptin group received a 7-day osmotic pump implant delivering 24 μg/day leptin on day 24. Statistical analyses were performed with one-way ANOVA multiple comparison procedure with Holm-Sidak post hoc testing. Data are expressed as means ± SEM.
FIG. 3.
FIG. 3.
Leptin improves postprandial glucose metabolism in mice with STZ-induced diabetes. A and B: Random-fed blood glucose on day 13 and i.p. glucose tolerance on day 9 in STZ-leptin (black), STZ-saline (white), and nondiabetic (gray) mice are shown. A: All but one STZ-saline mouse had a blood glucose concentration above the limit of detection and was assigned a value of 33.3 mmol/L (n = 5). B: Mice received an i.p. injection of 1.5 g/kg glucose at time 0 (n ≥4). C: Area under the curve values for the IPGTT. Data are expressed as means ± SEM.
FIG. 4.
FIG. 4.
Leptin reduces plasma lipid levels in mice with STZ-induced diabetes. Four-hour fasted plasma triglycerides (A), cholesterol (B), and free fatty acids (C) in STZ-leptin (black), STZ-saline (white), and nondiabetic (gray) mice on day 14 (n ≥ 4) are shown. Data are expressed as means ± SEM.
FIG. 5.
FIG. 5.
Leptin reduces plasma glucagon and growth hormone levels and enhances insulin action in mice with STZ-induced diabetes. Four-hour fasted plasma glucagon (A), growth hormone (B), and corticosterone (C) on day 14 (n ≥4) are shown. D: Four-hour fasted plasma insulin (day 7) and random-fed plasma insulin (day 13) were measured in samples collected from the saphenous vein. Fasted insulin was undetectable in all but one mouse in both the STZ-leptin and STZ-saline groups (n ≥4), whereas random-fed insulin was detectable in most STZ-induced mice tested (n ≥3). The limit of detection (0.025 ng/mL) is shown as a broken line. E: Insulin tolerance test (day 4; n = 5). All but one mouse in both the STZ-leptin and nondiabetic groups had to be rescued with exogenous glucose at 10 min after insulin injection. Statistical analyses were performed using Student t test on 10-min values. F: Glucose uptake measured in soleus muscle collected 20 min after intravenous injection of 2-deoxy-D-[14C]glucose with and without insulin (n = 3–5). Glucose uptake was normalized to tissue weight. STZ-leptin (black), STZ-saline (white), and nondiabetic (gray) are shown. *P < 0.05 STZ-leptin vs. STZ-saline mice; †P < 0.05 STZ-leptin vs. nondiabetic mice; ‡P < 0.05 STZ-saline vs. nondiabetic mice. Data are expressed as means ± SEM.
FIG. 6.
FIG. 6.
The long form of the leptin receptor is truncated in livers of Leprflox/flox Albcre mice. A: Schematic representation of Leprflox and LeprΔ17 alleles. B: RNA was extracted from livers of Leprflox/flox Albcre mice and Leprflox/flox controls for use as a template for generating cDNA (RT+). Reactions lacking reverse transcriptase were set up as negative controls (RT−). The cDNA generated was PCR amplified using primers indicated in A. These primers generate a 343 base pair amplicon for the Leprflox transcript and a 267 base pair amplicon for the LeprΔ17 transcript. Arrows on the left denote the migration of molecular weight markers.
FIG. 7.
FIG. 7.
Leptin relieves the symptoms of STZ-induced diabetes in Leprflox/flox Albcre mice. Four-hour fasted parameters in Leprflox/flox Albcre and Leprflox/flox mice that were STZ administered on day −4, and received subcutaneous 14-day osmotic pumps delivering 10 μg/day leptin or saline on day 0, are shown. A: Plasma leptin (n ≥4). B: Blood glucose (n ≥4). C: Plasma β-hydroxybutyrate (n ≥4). D: Body weight (n ≥4). E: Plasma insulin (n ≥4). Only two STZ-leptin–treated Leprflox/flox Albcre mice had detectable levels of insulin. F: Insulin tolerance test on day 11 (n ≥3). Area under the curve values are shown in the inset. A, C, and E: Pre-STZ (gray), STZ-saline (white), and STZ-leptin (black). B, D, and F: Leprflox/flox Albcre mice given STZ-leptin (▼) or STZ-saline (▽). Leprflox/flox controls given STZ-leptin (●) or STZ-saline (○) are shown. B and D: Statistical analyses were performed using one-way ANOVA multiple comparison procedure with Holm-Sidak post hoc testing on values. *P < 0.0001 Leprflox/flox Albcre STZ-leptin vs. STZ-saline mice; #P < 0.0001 Leprflox/flox STZ-leptin vs. STZ-saline mice. Data are expressed as means ± SEM.
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