Tu, Y. H. et al. An evolutionarily conserved gene family encodes proton-selective ion channels.

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

Denisovans are members of a hominin group only known from fragmentary fossils genomically studied from a single site, Denisova Cave 1-3 in Siberia, and from their genetic legacy through gene flow into several low-altitude East Asian populations 4,5 and high-altitude modern Tibetans 6 . The lack of morphologically informative Denisovan fossils impedes our ability to connect geographically and temporally dispersed Asian fossil hominins and understand their relation to these recent populations in a coherent manner, including the Denisovan-inherited human adaptation to the high-altitude Tibetan Plateau 7,8 . Here we report a Denisovan mandible, identified by ancient protein analysis 9,10 , found in Baishiya Karst Cave, Xiahe County, Gansu Province (China), on the Tibetan Plateau. We determine the mandible to be at least 160 thousand years old through U-series dating of an adhering carbonate matrix. It is the first direct evidence of this hominin group outside the Altai Mountains, and provides unique insights into Denisovan mandibular and dental morphology. Our results indicate that archaic hominins occupied the Tibetan Plateau in the Middle Pleistocene and successfully adapted to high-altitude hypoxia environments much earlier than the regional arrival of modern Homo sapiens.

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