Looking back—What have we already learned?

• The Restoring Insulin Secretion (RISE) Adult Medication Study (NCT01779362) asked the question of whether beta-cell function can be preserved or improved during 12 months of pharmacologic intervention, and maintained for 3 months following the withdrawal of therapy, in youth and adults with dysglycemia.
• 91 pediatric patients were enrolled along with 267 obese adults to medication and 88 obese adults allocated to surgery (laparoscopic banding).
• RISE found that in individuals with impaired glucose tolerance (IGT) or recently diagnosed T2D, youth were more insulin resistant and secreted more insulin than adults.
• In adults, there were no consistent benefits after medication withdrawal, while in youth insulin resistance and beta-cell dysfunction were unresponsive to interventions.

Alpha-cell function

• Lower circulating levels of glucagon in youth vs. adults with IGT or early T2D indicate that alpha-cell dysfunction does not explain insulin resistance or beta-responsiveness in youth: beta-responsiveness may contribute to suppression of glucagon levels in youth.
• In RISE, interventions aimed at reducing insulin resistance (metformin), reversing glucose toxicity (glargine before metformin), stimulate insulin secretion (liraglutide), and induce weight loss (surgery) all failed to induce any durable improvements in beta-cell function over 12 months (medications) or 24 months (surgery).
• Gastric banding and liraglutide treatment each lowered fasting glucagon and acute glucagon responses: weight loss may be a shared mechanism for this effect.

Proinsulin and the beta-cell

• Insulin sensitivity is 50% lower in youth compared to adults, despite similar body mass index.
• The beta-cell is more sensitive to changes in glucose in youth vs. adults with IGT.
• Compared to adults, youth with IGT and T2D are more insulin resistant and secrete more insulin than adults.
• Beta-cells in youth with IGT are more responsive to glucose than adults with IGT, with no differences in those with T2D.
• Beta-cell function in youth declines over time despite 12 months of treatment with metformin or glargine followed by metformin, while matched adult treatment arms show stable beta-cell function.
• Adults show modest benefits in beta-cell function with gastric banding and while on liraglutide plus metformin.