SGLT-2 Inhibitors: Is There a Role in Type 1 Diabetes Mellitus Management?

OBJECTIVE: The purpose of this review is to identify and evaluate disease management of patients with type 1 diabetes mellitus (T1DM) who were treated with a sodium-glucose cotransporter 2 (SGLT-2) inhibitor as an adjunct to insulin therapy. DATA SOURCES: A PubMed (1969 to March 2017) and Ovid (1946 to March 2017) search was performed for articles published utilizing the following MESH terms: canagliflozin, empagliflozin, dapagliflozin, type 1 diabetes mellitus, insulin dependent diabetes, insulin, sodium-glucose transporter 2. There were no limitations placed on publication type. STUDY SELECTION AND DATA EXTRACTION: All English-language articles were evaluated for association of SGLT-2 inhibitors and type 1 diabetes. Further studies were identified by review of pertinent manuscript bibliographies. DATA SYNTHESIS: All 3 SGLT-2 inhibitors, when combined with insulin, resulted in an overall reduction of hemoglobin A1C (up to 0.49%), lower total daily insulin doses, and a reduction in weight (up to 2.7 kg). The combination therapy of insulin and SGLT-2 inhibitors also resulted in a lower incidence of hypoglycemia. Study duration varied from 2 to 18 weeks. CONCLUSION: A review of the identified literature indicated that there is a potential role for the combination of SGLT-2 inhibitors with insulin in T1DM for improving glycemic control without increasing the risk of hypoglycemia. The short duration and small sample sizes limit the ability to fully evaluate the incidences of diabetic ketoacidosis and urogenital infections. The risks associated with this combination of medications require further evaluation.

Central regulation of photosensitive membrane turnover in the lateral eye of Limulus, II: octopamine acts via adenylate cyclase/cAMP-dependent protein kinase to prime the retina for transient rhabdom shedding.

Why photoreceptors turn over a portion of their photoreceptive membrane daily is not clear; however, failure to do so properly leads to retinal degeneration in vertebrates and invertebrates. Little is known about the molecular mechanisms that regulate shedding and renewal of photoreceptive membrane. Photoreceptive cells in the lateral eye of the horseshoe crab Limulus turn over their photoreceptive membrane (rhabdom) in brief, synchronous burst in response to dawn each morning. Transient rhabdom shedding (TRS), the first phase of rhabdom turnover in Limulus, is triggered by dawn, but requires a minimum of 3-5 h of overnight priming from the central circadian clock (Chamberlain & Barlow, 1984). We determined previously that the clock primes the lateral eye for TRS using the neurotransmitter octopamine (OA) (Khadilkar et al., 2002), and report here that OA primes the eye for TRS through a G(s)-coupled, adenylate cyclase (AC)/cyclic adenosine 3',5'-monophosphate (cAMP)/cAMP-dependent protein kinase (PKA) signaling cascade. Long-term intraretinol injections (6-7 h @ 1.4 microl/min) of the AC activator forskolin, or the cAMP analogs Sp-cAMP[s] and 8-Br-cAmp primed the retina for TRS in eyes disconnected from the circadian clock, and/or in intact eyes during the day when the clock is quiescent. This suggests that OA primes the eye for TRS by stimulating an AC-mediated rise in intracellular cAMP concentration ([cAMP]i). Co-injection of SQ 22,536, an AC inhibitor, or the PKA inhibitors H-89 and PKI (14-22) with OA effectively antagonized octopaminergic priming by reducing the number of photoreceptors primed for TRS and the amount of rhabdom shed by those photoreceptors compared with eyes treated with OA alone. Our data suggest that OA primes the lateral eye for TRS in part through long-term phosphorylation of a PKA substrate.