The Capacity to Secrete Insulin Is Dose-Dependent to Extremely High Glucose Concentrations: A Key Role for Adenylyl Cyclase

Insulin secretion is widely thought to be maximally stimulated in glucose concentrations of 16.7-to-30 mM (300-to-540 mg/dL). However, insulin secretion is seldom tested in hyperglycemia exceeding these levels despite the Guinness World Record being 147.6 mM (2656 mg/dL). We investigated how islets respond to 1-h exposure to glucose approaching this record. Insulin secretion from human islets at 12 mM glucose intervals dose-dependently increased until at least 72 mM glucose. Murine islets in 84 mM glucose secreted nearly double the insulin as in 24 mM (p < 0.001). Intracellular calcium was maximally stimulated in 24 mM glucose despite a further doubling of insulin secretion in higher glucose, implying that insulin secretion above 24 mM occurs through amplifying pathway(s). Increased osmolarity of 425-mOsm had no effect on insulin secretion (1-h exposure) or viability (48-h exposure) in murine islets. Murine islets in 24 mM glucose treated with a glucokinase activator secreted as much insulin as islets in 84 mM glucose, indicating that glycolytic capacity exists above 24 mM. Using an incretin mimetic and an adenylyl cyclase activator in 24 mM glucose enhanced insulin secretion above that observed in 84 mM glucose while adenylyl cyclase inhibitor reduced stimulatory effects. These results highlight the underestimated ability of islets to secrete insulin proportionally to extreme hyperglycemia through adenylyl cyclase activity.

The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes

<b>Objective</b> <p>Despite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis. </p> <p><b>Research design and methods</b></p> <p>SimpliciT1 was a Phase 1b/2 adaptive study. Phase 2 activities were conducted in 2 parts. Part 1 randomized 20 participants using continuous glucose monitors (CGM) and continuous subcutaneous insulin infusion (CSII). Part 2 randomized 85 participants on multiple daily injections of insulin or CSII. In both Part 1 and 2, participants were randomized to TTP399 800 mg or matched placebo (fully blinded) and treated for 12-weeks. The primary endpoint was the change in HbA1c from baseline to week 12.</p> <p><b>Results</b></p> <p>The difference in the change in HbA1c from baseline to week 12 between TTP399 and placebo was -0.7% (95% CI -1.3, -0.07) in Part 1 and -0.21 (95% CI -0.39, -0.04) in Part 2. Despite a greater decrease in HbA1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in Part 2. In both Part 1 and Part 2, plasma beta-hydroxybutrate and urinary ketones were lower during treatment with TTP399 than placebo. </p> <p><b>Conclusions</b></p> <p>TTP399 lowers HbA1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.</p>

The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes

<b>Objective</b> <p>Despite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis. </p> <p><b>Research design and methods</b></p> <p>SimpliciT1 was a Phase 1b/2 adaptive study. Phase 2 activities were conducted in 2 parts. Part 1 randomized 20 participants using continuous glucose monitors (CGM) and continuous subcutaneous insulin infusion (CSII). Part 2 randomized 85 participants on multiple daily injections of insulin or CSII. In both Part 1 and 2, participants were randomized to TTP399 800 mg or matched placebo (fully blinded) and treated for 12-weeks. The primary endpoint was the change in HbA1c from baseline to week 12.</p> <p><b>Results</b></p> <p>The difference in the change in HbA1c from baseline to week 12 between TTP399 and placebo was -0.7% (95% CI -1.3, -0.07) in Part 1 and -0.21 (95% CI -0.39, -0.04) in Part 2. Despite a greater decrease in HbA1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in Part 2. In both Part 1 and Part 2, plasma beta-hydroxybutrate and urinary ketones were lower during treatment with TTP399 than placebo. </p> <p><b>Conclusions</b></p> <p>TTP399 lowers HbA1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.</p>