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

Abstract

Insulin resistance and β-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 β-cell function has provided a uniform tool to measure β-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.

Impact of Sex and Obesity on Echocardiographic Parameters in Children and Adolescents

“…Further support comes from recent adult data. The protective effect of female sex on CV health is lost in presence of additional comorbidities and stresses (such as type 2 diabetes, hypertension, hypercholesterinaemia, sedentary lifestyle, mental stress) [ 26 – 28 ].…”

Insulin sensitivity and kinetics in African American and White people with obesity: Insights from different study protocols

“…Plasma insulin concentration after the insulin infusion initially (from 25 min until about 60 min) tended to be slightly greater in the AA group than in the NHW group and was not different between the two groups afterward (Figure 3F). Hepatic insulin delivery was greater in the AA group than in the NHW group during the first 10 minutes of the IVGTT (35 [8] vs. 21 [2] nmol, p < 0.05) and was not different between the two groups after the insulin infusion (Figure 3G). Plasma insulin clearance during the first 10 minutes after intravenous glucose injection (Figure 3E) and during the entire 120-minute IVGTT (not shown) was markedly lower in the AA group than in the NHW group.…”

“…Insulin resistance and hyperinsulinemia are major independent risk factors for developing type 2 diabetes in people with obesity (1‐3). It has been proposed that African American (AA), compared with non‐Hispanic White (NHW), men and women with obesity have an increased risk for developing type 2 diabetes because they are more insulin resistant and because they have both an increased β‐cell response to glucose and markedly (~50%) impaired hepatic insulin clearance (4‐7).…”

Insulin Clearance in Obesity and Type 2 Diabetes

“…Furthermore, studies on fibroblasts demonstrated that the ability of insulin to bind, internalize, and regulate its own receptor is not altered in T2D [ 133 ]. This is not unexpected because T2D is primarily due to severe β-cell dysfunction whereas insulin sensitivity is no worse than in people with obesity without T2D [ 1 , 3 ].…”

“…Compared with healthy lean people, people with obesity have increased basal and postprandial plasma insulin concentrations [ 1 , 2 , 3 ]. People with obesity and type 2 diabetes (T2D) have lower postprandial insulin than those without T2D, and the relative insulin insufficiency is responsible for the marked hyperglycemia in people with T2D [ 1 , 2 , 3 ]. The prevailing thought is that the increase in plasma insulin in people with obesity is a compensatory response to obesity-associated insulin resistance.…”