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. 2011 Feb;152(2):394-404.
doi: 10.1210/en.2010-0890. Epub 2010 Dec 15.

Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia

Jonathan P German  1 , Joshua P Thaler, Brent E Wisse, Shinsuke Oh-I, David A Sarruf, Miles E Matsen, Jonathan D Fischer, Gerald J Taborsky Jr, Michael W Schwartz, Gregory J Morton
Affiliations

Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia

Jonathan P German et al. Endocrinology. 2011 Feb.

Abstract

The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

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Figures

Fig. 1.
Fig. 1.
CNS leptin normalizes blood glucose levels in uDM. Plasma insulin (A), plasma leptin (B), mean daily food intake (C), and blood glucose levels (D) in nondiabetic controls (veh-veh) or in STZ-induced diabetic animals receiving either icv veh and fed ad libitum (STZ-veh-AL) or PF (STZ-veh-PF), or leptin (1 μg/d) delivered either sc (STZ-leptin-sc) or directly into the brain (STZ-leptin) (n = 7–9 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh; #, P < 0.05 vs. STZ-veh-PF. lep, Leptin.
Fig. 2.
Fig. 2.
Glucose-lowering effect of CNS leptin is not explained by glycosuria or recovery of β-cells. Urinary glucose (A) and daily water intake (B) and plasma insulin (C) and blood glucose profiles (D) during an ip glucose tolerance test (2 g/kg · body weight), in nondiabetic controls or in STZ-induced diabetic animals receiving either icv veh and fed ad libitum or PF, or icv leptin (n = 7–9 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh; #, P < 0.05 vs. STZ-veh-PF. lep, Leptin.
Fig. 3.
Fig. 3.
CNS leptin suppresses HGP and increases Rg in uDM. Ra (A) and Rd (B) determined from [3-3H]glucose tracer studies and Rg determined from 2[14C]DG studies in red gastrocnemius muscle and brain (C), BAT and heart (D) in nondiabetic controls or in STZ-induced diabetic animals receiving icv veh and PF or icv leptin (n = 5–6 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh; #, P < 0.05 vs. STZ-veh-PF. lep, Leptin.
Fig. 4.
Fig. 4.
CNS leptin infusion normalizes hepatic gluconeogenic gene expression in uDM. Hepatic expression of G6Pase (A) and Pepck (B) using real-time PCR, Igfbp-2 (C), liver triglyceride (D), and liver glycogen content (E) in nondiabetic controls or STZ-induced diabetic animals receiving either icv veh and fed ad libitum or PF or icv leptin (n = 7–9 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh; #, P < 0.05 vs. STZ-veh-PF. lep, Leptin.
Fig. 5.
Fig. 5.
CNS leptin suppresses HGP and increases glucose utilization in uDM during a hyperglycemic clamp. Basal and glucose-stimulated plasma insulin (A) and C-peptide levels (B) and arterial glucose levels (C) and glucose infusion rate (D) required to maintain blood glucose levels at approximately 210 mg/dl during the hyperglycemic clamp, endogenous (Endo) Ra (E), percentage suppression of HGP (F), Rd (G), percentage increase in glucose utilization (H), and Rg in red gastrocnemius muscle and brain (I) BAT and heart (J) in STZ-induced diabetic animals receiving icv leptin or in nondiabetic controls receiving icv veh (n = 5 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh. lep, Leptin.
Fig. 6.
Fig. 6.
CNS leptin normalizes plasma glucagon and corticosterone levels in uDM. Plasma glucagon (A), plasma corticosterone (B), norepinephrine (NE) (C), epinephrine (EPI) (D), NEFAs (E), and total ketone bodies (acetoacetate and β-hydroxybutyrate) (F) in STZ-induced diabetic animals receiving either icv veh and fed ad libitum or PF, icv leptin or icv veh in nondiabetic controls (n = 7–9 per group). Data represent mean ± sem; *, P < 0.05 vs. veh-veh; #, P < 0.05 vs. STZ-veh-PF. lep, Leptin.
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