Citations

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

Abstract Abstract SCI-3 The processes that lead to the susceptibility of post-mitotic tissues to diseases of aging are poorly understood, but mitochondria are considered a key regulator. SIRT3 is mitochondrial sirtuin, a member a family of NAD+-dependent deacetylases. We have previously shown that increased levels of NAD+ in mitochondria promote cell survival in a SIRT3-dependent manner, but how this protection is mediated is unknown. Here we show that mitochondrial NAD+ levels decline dramatically with age and that SIRT3 is a critical component and regulator of the mitochondrial transition pore (MTP). Mice lacking SIRT3 exhibit hyperacetylation of the MTP with age, and as a result, develop multiple defects in post-mitotic tissues as they age, including mitochondrial defects, susceptibility to cardiac failure, and learning and memory deficits. In a mouse model of Alzheimer's disease (AD), SIRT3 knockout mice show striking phenotypes including small size, kyphosis, and a markedly reduced lifespan. Similar to mice, human brain samples show that acetylation of the MTP increases with age and with AD. These findings indicate that declining NAD levels with age lead to memory deficits and accelerate age-related diseases in post-mitotic tissues due to a decline in SIRT3 activity and unscheduled opening of the MTP. Disclosures: Sinclair: GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.