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Nature 546, 248 - 253 (7657)
Published online: 2017-06-08; | doi:10.1038/nature22394

Article: Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

  1. #70189
    Date:
    2017-06-24 04:33:04 AM
    Majid Ali said:

    Mechanisms of Insulin Regulation and Two Dimensions of Insulin Dysregulation

    Zhang et al. report the cryo-electron microscopy structure of the activated glucagon-like peptide 1 receptor (GLP-1R) and provide a structural framework for understanding activation of class B G protein-coupled receptor (ref. 1). GLP-1, a hormone released from the gut, acts on its receptor (GLP-1R) to play important roles in insulin homeostasis. Specifically, it stimulates glucose-dependent insulin secretion, decreases glucagon secretion, and inhibits gastric motility and appetite.

    The work of Zhang and colleagues is important for physicians who treat diabetes because class B G protein-coupled receptors (GPCRs) are important therapeutic targets. Beyond that, this work invites all physicians to a deeper study of the inner mechanisms of insulin homeostasis, a subject that is seldom duly considered in clinical medicine. Specifically, insulin dysregulation has two distinct dimensions: (1) the first dimension of pathophysiology of hyperinsulinism which predates Type 2 diabetes (T2D) and is not accompanied by glycemic abnormalities detectable by the laboratory tests in current use; and (2) the dimension of T2D accompanied by hyperglycemia and its biochemical consequences. This author has long recognized the need for a shift of clinical focus from glycemic status to insulin homeostasis for detecting and optimally managing adverse metabolic, proinflammatory, endothelial, developmental, and neurologic effects of hyperinsulinism (ref. 2-6).

    Recently, the author and his colleagues reported hyperinsulinism prevalence of 75.1% in 684 patients from a general population in New York metropolitan area (ref. 7). The insulin database of this study permitted us to explore the following aspects of insulin homeostasis and insulin dysregulation: (1) pathogenesis of insulin resistance; (2) stratification of hyperinsulinism for optimal clinical use; (3) study of responses to carbohydrates and non-carbohydrate challenges in insulin-based care of hyperinsulinism and T2D (ref. 8); (4) hyperinsulinism-to-T2D progression; (5) proinflammatory and immune-dysregulating roles of insulin dysregulation; (6) the central role of mitochondrial dysfunction in insulin dysregulation; (7) hyperinsulinism as an energetic response to chronic cellular injury; and (8) the profound therapeutic significance of insulin serving as the ?minister of metabolism and energy? to ?King Oxygen? of the human body (ref.4,9,10).

    Zhang et al. observe that both class A and B GPCRs types (receptors) converge topologically in the cytoplasmic side, and this structural similarity near the G protein coupling sites reflects a convergence of activation pathways. It enables receptors of his large family to bind and be activated by very diverse ligands, but signal intracellularly via a small common repertoire of G proteins. Clinicians may not be expected to find in these advances in the basic science of insulin regulation any new light shed on the clinical aspects of insulin homeostasis noted above. Still, this new work with cryo-EM technology may serve us as a reminder, albeit indirect, that not paying full attention to adverse effects of undetected and unmanaged hyperinsulinism, the first dimension of insulin dysregulation, leaves much to be desired. Of course, this first dimension of insulin dysregulation, unless corrected, progresses to the second dimension of T2D.

    References

    1. Zhang Y, Sun B, Feng D, et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature. 2017;546:248-253.
    2. Ali M. Epidemic of Dysoxygenosis and the Metabolic Syndrome. In: The Principles and Practice of Integrative Medicine. Volume 5. Pp 246-256. Canary 21 Press. New York. 2005.
    3. Ali M. Dysox Model of Diabetes and De-Diabetization Potential. Townsend Letter-The examiner of Alternative Medicine. 2007; 286:137-145.
    4. Ali M. Oxygen, Insulin Toxicity, Inflammation, and the Clinical Benefits of Chelation. Part I. Townsend Letter-The examiner of Alternative Medicine. 2009;315:105-109. October, 2009.
    5. Ali M. Dr. Ali?s Plan . Ai M. Dr. Ali?s Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.
    6. Ali M. Importance of Subtyping Diabetes Type 2 Into Diabetes Type 2A and Diabetes Type 2B. Townsend Letter-The Examiner of Alternative Medicine. 2014; 369:56-58.
    7. Ali M. Fayemi AO, Shifting Focus From Glycemic Statsus to Insulin Homeostasis. Ali M, Fayemi AO, Ali O, Dasoju S, Chaudhary D, Hameedi S, Amin J, Ali K, and Svoboda B. Shifting focus from glycemic status to insulin homeostasis for stemming global tides of hyperinsulinism and Type 2 diabetes. Townsend Letter – The examiner of Alternative Medicine. 2017;402:91-96.
    8. Ali M. Dasoju S, Karim N, Amin J, Chaudary D. Study of Responses to Carbohydrates and Non-carbohydrate Challenges In Insulin-Based Care of Metabolic Disorders. Townsend Letter-The Examiner of Alternative Medicine. 2016; 391:48-51.
    9. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004;253:64-65.
    10. Ali M. Oxygen and Aging. (Ist ed.) New York, Canary 21 Press. Aging Healthfully Book 2000.

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