Key result
In a mouse model of type 1 diabetes, insulin treatment restored impaired cardiac parasympathetic responsiveness and GIRK1 expression via an SREBP-1-dependent mechanism.
Why the study?
Does insulin regulation via SREBP-1 improve parasympathetic responsiveness and GIRK1 expression in a mouse model of diabetic autonomic neuropathy?
Does insulin regulation via SREBP-1 improve parasympathetic responsiveness and GIRK1 expression in a mouse model of diabetic autonomic neuropathy?
Insulin regulates cardiac parasympathetic responsiveness and GIRK1 expression via an SREBP-1-dependent mechanism, which may be impaired in diabetic autonomic neuropathy.
Does not yet change clinical practice in diabetic autonomic neuropathy; leaves open translation of SREBP-1 mechanism to humans.
RATIONALE: Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, I(KAch), via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor. OBJECTIVE: We describe a unique SREBP-1-dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN. METHODS AND RESULTS: Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2(Akita) type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the duration of bradycardia, a 52+/-8% decrease in atrial expression of GIRK1 (P<0.01), and a 31.3+/-2.1% decrease in SREBP-1 (P<0.05). Whole-cell patch-clamp studies of atrial myocytes from Akita mice exhibited a markedly decreased carbamylcholine stimulation of I(KAch) with a peak value of -181+/-31 pA/pF compared with -451+/-62 pA/pF (P<0.01) in cells from wild-type mice. Western blot analysis of extracts of Akita mice demonstrated that insulin treatment increased the expression of GIRK1, SREBP-1, and I(KAch) activity in atrial myocytes from these mice to levels in wild-type mice. Insulin treatment of cultured atrial myocytes stimulated GIRK1 expression 2.68+/-0.12-fold (P<0.01), which was reversed by overexpression of dominant negative SREBP-1. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired I(KAch) to levels in cells from wild-type mice. CONCLUSIONS: These results support a unique molecular mechanism for insulin regulation of GIRK1 expression and parasympathetic response via SREBP-1, which might play a role in the pathogenesis of DAN in response to insulin deficiency in the diabetic heart.
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Park et al. (2009) studied Diabetic autonomic neuropathy. Insulin treatment and SREBP-1 adenoviral expression vs. Wild-type mice and untreated Akita mice was evaluated on Cardiac parasympathetic responsiveness (I(KAch) activity and GIRK1 expression) (p=<0.01). In a mouse model of type 1 diabetes, insulin treatment restored impaired cardiac parasympathetic responsiveness and GIRK1 expression via an SREBP-1-dependent mechanism.
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