Endocrine Abstracts

Background: ALMS1 is a 461kDa protein that, when mutated, causes Alström syndrome (AS). AS is a rare autosomal recessive disorder characterized by childhood obesity and early-onset insulin-resistant diabetes, amongst other features. Studies using primary human adipocytes revealed that ALMS1 is critical for insulin-regulated glucose transport. The predilection for insulin resistance and T2DM in AS children seems to reflect a hitherto uncharacterized role of ALMS1 in the insulin signaling pathway, rather than just being secondary to obesity.

Objective: We sought to characterize the effect of ALMS1 inactivation on insulin signaling and glucose transport in ALMS1-deprived primary human adipocytes.

Methods: In order to knock down ALMS1, we used human white visceral preadipocytes and used a lentiviral-mediated RNA-interference. To characterize the effect of this protein we performed q-PCR, western blot, immunofluorescence microscopy and protein identification by mass spectrometry. To evaluate the insulin-dependent glucose uptake, we used C57BL/6 transgenic mice, with anAlms f/f, adiponectin-cre +/−genotype.

Results: Our data demonstrate that in absence of insulin, ALMS1 is linked to αPKC, regulating the swelling and plasma membrane integration of GLUT4 secretory vesicles (GSVs). In response to insulin, ALMS1 is no longer bound to TBC1D4, concomitantly releasing αPKC and thereby allowing αPKC to activate the GSVvATPase, triggering GSVs membrane fusion. Subsequently, we demonstrated that in primary human adipocytes artificial release of αPKC from its ALMS1 binding site activated glucose absorption in absence of insulin.

Conclusion: These findings represent a novel exploitable pathway for drug development in order to treat hyperglycemia and glucose intolerance.