Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks
Publication date: 3 December 2019Source: Cell Reports, Volume 29, Issue 10Author(s): Benjamin D. Stein, Diego Calzolari, Kristina Hellberg, Ying S. Hu, Lin He, Chien-Min Hung, Erin Q. Toyama, Debbie S. Ross, Björn F. Lillemeier, Lewis C. Cantley, John R. Yates, Reuben J. ShawSummaryMetformin is the front-line treatment for type 2 diabetes worldwide. It acts via effects on glucose and lipid metabolism in metabolic tissues, leading to enhanced insulin sensitivity. Despite significant effort, the molecular basis for metformin response remains poorly understood, with a limited number of specific biochemical pathways studied to date. To broaden our understanding of hepatic metformin response, we combine phospho-protein enrichment in tissue from genetically engineered mice with a quantitative proteomics platform to enable the discovery and quantification of basophilic kinase substrates in vivo. We define proteins whose binding to 14-3-3 are acutely regulated by metformin treatment and/or loss of the serine/threonine kinase, LKB1. Inducible binding of 250 proteins following metformin treatment is observed, 44% of which proteins bind in a manner requiring LKB1. Beyond AMPK, metformin activates protein kinase D and MAPKAPK2 in an LKB1-independent manner, revealing additional kinases that may mediate aspects of metformin response. Deeper analysis uncovered substrates of AMPK in endocytosis and calcium homeostasis.Graphical Abstract
TYPE 2 diabetes is a common condition yet many people in the UK will not realise they have it because the symptoms do not necessarily make you feel unwell. Symptoms are caused by consistently high blood sugar levels, and, overtime, this can affect different parts of the body, including the shoulder.
This study aimed to design a simple surrogate marker (i.e., predictor) of the minimal model glucose effectiveness (SG), namely calculated SG (CSG), from a short insulin-modified intravenous glucose tolerance test (IM-IVGTT), and then to apply it to study women with previous gestational diabetes mellitus (pGDM). METHODS: CSG was designed using the stepwise model selection approach on a population of subjects (n=181) ranging from normal tolerance to type 2 diabetes mellitus (T2DM). CSG was then tested on a population of women with pGDM (n=57). Each subject underwent a 3-hour IM-IVGTT; women with pGDM were observed early ...
We reported a significant increase of ghrelin epsilon-cells in the pancreas and basal serum after Sleeve gastrectomy versus the control groups. The epsilon cellular increment was related to neogenesis, as the neurogenin-3 marker revealed. The Roux-en Y Gastric Bypass showed neither epsilon cell increase nor basal serum changes in ghrelin release. As a conclusion, we reported that the severe suppression of the fundus gastric produced the recovery of ghrelin released by the epsilon cells, which was indicative of an ontogenic embryonic pancreatic function. PMID: 31951010 [PubMed - as supplied by publisher]
TYPE 2 diabetes symptoms tend to develop gradually so many people in the UK will be living with the condition without realising it. Symptoms arise as a result of consistently high blood sugar levels and there are a number of signs in your mouth that can indicate uncontrolled blood sugar levels.
Contributors : Simon Dankel ; Regine Asen ; Laurence Dyer ; Divya PriyankaSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensObesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, and discovered a novel role for the adipocyte-expressed neutral amino acid transpo...
Contributors : Simon Dankel ; Regine AsenSeries Type : Expression profiling by high throughput sequencingOrganism : Danio rerioObesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, and discovered a novel role for the adipocyte-expressed neutral amino acid transporter SLC7A10/ASC-1 in the regulati...
We describe evidence for substance use as a risk factor for new-onset diabetes, prevalence of use in people with diabetes, evidence linking substance use with diabetes-related health outcomes, and evidence on the management of these co-occurring conditions.
ConclusionSilent myocardial ischemia is highly prevalent at about one in four asymptomatic diabetic patients. An increased CIMT can be a surrogate marker of higher coronary risk amongst these asymptomatic diabetics.