No abstract

The AMP (adenosine 5′-monophosphate)-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis that co-ordinates metabolic processes to ensure energy supply meets demand. At the cellular level, AMPK is activated by metabolic stresses that increase AMP or adenosine 5′-diphosphate (ADP) coupled with falling adenosine 5′-triphosphate (ATP) and acts to restore energy balance by choreographing a shift in metabolism in favour of energy-producing catabolic pathways while inhibiting non-essential anabolic processes. AMPK also regulates systemic energy balance and is activated by hormones and nutritional signals in the hypothalamus to control appetite and body weight. Failure to maintain energy balance plays an important role in chronic diseases such as obesity, type 2 diabetes and inflammatory disorders, which has prompted a major drive to develop pharmacological activators of AMPK. An array of small-molecule allosteric activators has now been developed, several of which can activate AMPK by direct allosteric activation, independently of Thr172 phosphorylation, which was previously regarded as indispensable for AMPK activity. In this review, we summarise the state-of-the-art regarding our understanding of the molecular mechanisms that govern direct allosteric activation of AMPK by adenylate nucleotides and small-molecule drugs.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700 000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer, including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a study indicating multiple levels of interaction between metallopeptidase inhibitor 1 (TIMP‐1) and the epidermal growth factor (EGF) signaling axis, which could explain how TIMP‐1 levels can affect the antitumor effects of EGFR inhibitors. We also reported an association between TIMP‐1‐mediated cell invasive behavior and KRAS status. To gain insight into the molecular mechanisms underlying the effects of TIMP‐1 in CRC, we examined by transcriptomics, proteomics, and kinase activity profiling a matched pair of isogenic human CRC isogenic DLD‐1 CRC cell clones, bearing either an hemizygous KRAS wild‐type allele or KRAS G13D mutant allele, exposed, or not, to TIMP‐1. Omics analysis of the two cell lines identified the receptor tyrosine kinase c‐Kit, a proto‐oncogene that can modulate cell proliferation and invasion in CRC, as a target for TIMP‐1. We found that exposure of DLD‐1 CRC cells to exogenously added TIMP‐1 promoted phosphorylation of c‐Kit, indicative of a stimulatory effect of TIMP‐1 on the c‐Kit signaling axis. In addition, TIMP‐1 inhibited c‐Kit shedding in CRC cells grown in the presence of exogenous TIMP‐1. Given the regulatory roles that c‐Kit plays in cell proliferation and migration, and the realization that c‐Kit is an important oncogene in CRC, it is likely that some of the biological effects of TIMP‐1 overexpression in CRC may be exerted through its effect on c‐Kit signaling.

In ONWARDS 1, a phase 3a, treat-to-target trial (NCT04460885) in insulin-naïve T2D randomized 1:1 to once-weekly icodec or once-daily glargine U100, time in, above and below range (TIR, TAR, TBR) and hypoglycemia duration were assessed with double-blinded CGM at pre-specified periods throughout the trial. TIR (70-180 mg/dL), TAR (>180 mg/dL), TBR (<70 and <54 mg/dL), median duration of hypoglycemia <70 mg/dL and the proportion of an episode spent <54 mg/dL were assessed at weeks (wks) 0-4, 22-26, 48-52, and 74-78. At wks 22-26, 48-52, and 74-78, mean TIR with icodec met the recommended target of >70%, and TIR and TAR were significantly improved with icodec vs glargine, with no significant difference between arms in TBR <54 mg/dL (table). There was a difference in favor of glargine in TBR <70 mg/dL at wks 48-52 and 74-78, but mean TBR <70 mg/dL and TBR <54 mg/dL were below recommended targets (4% and 1%, respectively) at all time periods for both arms. TIR, TBR and TAR did not differ significantly between arms at wks 0-4. Median duration of hypoglycemia <70 mg/dL and proportion of time <54 mg/dL were similar between arms at all time periods. In summary, TIR and TAR at wks 22-26, 48-52, and 74-78 were significantly improved with icodec vs glargine U100, with no significant difference in TBR <54 mg/dL and a similar duration of hypoglycemia <70 mg/dL between arms. Disclosure R. M. Bergenstal: Advisory Panel; Abbott Diabetes. Research Support; Abbott Diabetes. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc. Research Support; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Hygieia. Research Support; Insulet Corporation, Medtronic. Advisory Panel; Medtronic, Novo Nordisk. Research Support; Novo Nordisk. Consultant; Onduo LLC. Advisory Panel; Roche Diabetes Care. Research Support; Sanofi. Consultant; Sanofi. Research Support; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; Zealand Pharma A/S. S. K. Watt: Employee; Novo Nordisk. A. S. A. Matos: Employee; Novo Nordisk A/S. I. Lingvay: Advisory Panel; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Advisory Panel; Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc. Advisory Panel; Sanofi. Consultant; Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer. J. K. Mader: Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics. Research Support; A. Menarini Diagnostics, Abbott Diabetes. Advisory Panel; Abbott Diabetes. Speaker's Bureau; Abbott Diabetes. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Medtronic. Speaker's Bureau; Boehringer Ingelheim Inc., Becton, Dickinson and Company. Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Ypsomed AG, Viatris Inc., Servier Laboratories. Research Support; Dexcom, Inc., Profusa, Inc. Stock/Shareholder; Decide Clinical Software GmbH. Advisory Panel; Pharmasense, embecta. Speaker's Bureau; Medtrust. T. Nishida: Employee; Novo Nordisk Pharma Ltd. Stock/Shareholder; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Applied Therapeutics Inc. Research Support; Applied Therapeutics Inc. Advisory Panel; Boehringer Ingelheim Inc. Research Support; Boehringer Ingelheim Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company, Merck & Co., Inc., Novartis. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Oramed Pharmaceuticals. Research Support; Pfizer Inc. Advisory Panel; Sanofi. Research Support; Sanofi. Advisory Panel; Zealand Pharma A/S, Intarcia Therapeutics, Inc. Research Support; Intarcia Therapeutics, Inc. Advisory Panel; Hanmi Pharm. Co., Ltd. Funding Novo Nordisk A/S