Background: Hypoglycemia-associated autonomic failure (HAAF) is a significant barrier to achieving optimal glucose levels in persons with diabetes. Our group and others have demonstrated that low leptin levels are concurrent with impaired hypoglycemic counter-regulation in two separate animal models of HAAF: six days of 60% caloric restriction (CR) in mice and 3 days of recurrent hypoglycemia (3dRH) in rats. In this study, we tested whether leptin treatment during CR or 3dRH could prevent the development of HAAF.

Methods: In experiment one, 3 groups of mice (two CR groups and one ad-lib fed control group) received either twice daily leptin (0.5-1μg/g, IP) or PBS. In experiment two, 3 groups of rats (two 3dRH and one control) received daily leptin or PBS injections (0.3-0 .7 mg/kg, IP). One day following the CR or 3dRH paradigms, all animals underwent a hypoglycemic ITT and levels of glucagon, leptin, epinephrine (rats), and corticosterone were assessed 60 min following insulin treatment.

Results: As expected, PBS treated CR mice and 3dRH rats had significantly reduced glucagon levels and epinephrine levels relative to controls (24 ± 5 vs. 95 ± 20 pmol/L and 57 ± 12 vs. 110 ± 9 ng/mL, respectively). In contrast, there was no differences in the glucagon levels of leptin treated CR mice and epinephrine levels of leptin treated 3dRH rats relative to their respective control groups. Leptin levels in both CR groups were reduced relative to controls (0.9 ± 0.3 and 0.2 ± 0.1 vs. 3.0 ± 0.5 ng/mL, respectively), while corticosterone was unchanged. Glucagon, corticosterone, and leptin levels were similar across groups in the 3dRH paradigm.

Discussion: Utilizing two separate animal models of HAAF, we established that leptin treatment can prevent the loss of hypoglycemic counter-regulation. Future studies investigating whether combining leptin treatment with insulin therapy could significantly reduce hypoglycemic complications in diabetes patients are warranted.


D. McDougal: None. M. DuVall: None. H.X. Sikaffy: None. R. Jariwala: None. C. Morrison: None. C.M. Hill: None.


American Diabetes Association (1-15-JF-37 to D.M.); National Institutes of Health (U54GM104940)

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