A Journey in Diabetes: From Clinical Physiology to Novel Therapeutics: The 2020 Banting Medal for Scientific Achievement Lecture

Insulin resistance and beta-cell dysfunction are the core pathophysiological mechanisms of all hyperglycemic syndromes. Advances in in vivo investigative techniques have made it possible to quantify insulin resistance in multiple sites (skeletal and myocardial muscle, subcutaneous and visceral fat depots, liver, kidney, vascular tissues, brain and intestine), to clarify its consequences for tissue substrate selection, and to establish its relation to tissue perfusion. Physiological modeling of beta-cell function has provided a uniform tool to measure beta-cell glucose sensitivity and potentiation in response to a variety of secretory stimuli, thereby allowing us to establish feedbacks with insulin resistance, to delineate the biphasic time course of conversion to diabetes, to gauge incretin effects, and to identify primary insulin hypersecretion. As insulin resistance also characterizes several of the comorbidities of diabetes (e.g., obesity, hypertension, dyslipidemia), with shared genetic and acquired influences, the concept is put forward that diabetes is a systemic disease from the outset, actually from the prediabetic stage. In fact, early multifactorial therapy, particularly with newer antihyperglycemic agents, has shown that the burden of micro- and macrovascular complications can be favorably modified despite the rising pressure imposed by protracted obesity.

Automated summary

Insulin resistance and beta-cell dysfunction are the core pathophysiological mechanisms of all hyperglycemic syndromes, with implications for various comorbidities of diabetes. Early multifactorial therapy has shown promising results in improving micro- and macrovascular complications despite the challenges posed by prolonged obesity.