Glucose Supply and Insulin Demand Dynamics of Antidiabetic Agents

Abstract

Alpha-glucosidase inhibitors, metformin, and TZDs demonstrate a greater effect on glucose supply, while secretagogues, basal insulin, and bolus insulin demonstrate a greater effect on insulin demand. Because T2DM cardiovascular outcome trials have not demonstrated macrovascular benefit with more aggressive blood glucose reduction when using conventional algorithms that predominantly focus on insulin demand, it would appear logical to consider a model that incorporates both the extent of blood glucose lowering (hemoglobin A1c) and the means by which the blood glucose was reduced (SD ratio) when considering macrovascular outcomes.

Characterization of Cardiovascular Outcomes in a Type 2 Diabetes Glucose Supply and Insulin Demand Model

“…To help explain this situation, where long-term, cardiovascular outcome trials have resulted in counterintuitive outcomes, we presented data in this issue of Journal of Diabetes Science and Technology, for a pharmacokinetic/ pharmacodynamic model that characterizes the effect of conventional antidiabetic therapies on the glucose supply [carbohydrate intake and intestinal absorption (carbohydrate exposure, CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), and insulin resistance (IR)], and insulin demand [peripheral insulin exposure (PIE) and peripheral glucose uptake (PGU)] dynamic. 4 Moreover, it is our hypothesis that the mechanism used to attain blood glucose reduction may be as important, or possibly of greater importance, than the extent of blood glucose reduction. To determine if pharmacotherapeutic strategies that favor the glucose supply or insulin demand dynamic are associated with cardiovascular benefit, we retrospectively identified patients with five years of eligibility prior to experiencing an initial event, matched them to patients not experiencing an event, and assessed the impact of the glucose supply:insulin demand (SD) ratio in conjunction with measured glucose control (HbA1c).…”

“…The amylinomimetic, pramlintide: (1) increases satiety, diminishes caloric intake, and reduces weight; [32][33][34][35][36][37][38] (2) has no evidence for diminished intestinal absorption; (3) delays gastric emptying; [39][40][41][42][43] (4) decreases glucagon secretion; [44][45][46] (5) reduces postprandial oxidative stress; 47 (6) has no apparent effect on PGU; 48 and (7) diminishes insulin requirements. 34 It would appear pramlintide would have the most profound effect on CE (decrease), HGU (decrease), GNG (decrease), and IR (decrease), while having modest to negligible effects on PGU and PIE.…”

“…4 Most importantly, the literature used to identify the effect of each antidiabetic agent on each target was often from a small number of sources, unavailable, or conducted in patients at various stages of their disease progression. Similarly, determining the dose-response relationship for antidiabetic agents (alone and in combination with other agents) on the respective targets was often not possible because of a small literature base and the predominance of singledose, monotherapy studies.…”

“…4 Moreover, it is our hypothesis that the mechanism used to attain blood glucose reduction may be as important, or possibly of greater importance, than the extent of blood glucose reduction. To determine if pharmacotherapeutic strategies that favor the glucose supply or insulin demand dynamic are associated with cardiovascular benefit, we retrospectively identified patients with five years of eligibility prior to experiencing an initial event, matched them to patients not experiencing an event, and assessed the impact of the glucose supply:insulin demand (SD) ratio in conjunction with measured glucose control (HbA1c).…”

1-Deoxynojirimycin: Occurrence, Extraction, Chemistry, Oral Pharmacokinetics, Biological Activities and In Silico Target Fishing

“…The pharmacokinetic of DNJ after oral administration has been studies by some researchers [17,18,19]. Moreover, DNJ has many biological activities, including antihyperglycemic [20,21,22,23,24,25], anti-obesity [26,27,28,29,30], and anti-viral [31] have also been reported [32,33,34,35].…”