New Insights from the Restoring Insulin Secretion (RISE) Study—Differences between Adults and Youth with Prediabetes and Type 2 Diabetes

Sharon Edelstein, ScM; Thomas A. Buchanan, MD; Kristina Utzschneider, MD; Kristen J. Nadeau, MD, MS

ADA 2020 - Oral session

3 minute listen
8 minute read

Key messages

  • Predictors of glycemia deterioration were identified in adults: insulin sensitivity and first phase beta-cell responses.
  • Predictors of glycemia deterioration identified in youth include glycemia and all beta-cell responses measures.

Key messages

  • Predictors of glycemia deterioration were identified in adults: insulin sensitivity and first phase beta-cell responses.
  • Predictors of glycemia deterioration identified in youth include glycemia and all beta-cell responses measures.

Background

What do we already know about this topic?

  • The increase in the prevalence of obesity has contributed to the increased incidence of prediabetes and type 2 diabetes mellitus (T2D) among youth and adults.
  • Progressive decline in beta-cell function is now well recognized in children and adults to be pivotal in the progression from normal to abnormal glucose tolerance.
  • Given the increased recognition of the critical role of the beta-cell in the pathogenesis of T2D, efforts have begun to shift to prevention of the loss of insulin secretion among individuals at high risk for T2D or early stages of the disease.

From RISE…

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.

Conclusions

  • Youth with IGT/T2D are more insulin resistant, have higher insulin secretion, and lower insulin clearance, more rapid beta-cell deterioration, and poorer response to interventions vs. adults.
  • Insulin sensitivity and first phase beta-cell responses are predictors of glycemia deterioration in adults.
  • Glycemia and all beta-cell responses measures are predictors of glycemia deterioration in youth.
  • Glucagon does not explain differences in beta-cell function in youth vs. adults.
  • Gastric banding increased insulin sensitivity and clearance, preserved beta-cell function, and improved glycemia for over 2 years in adults.

Conclusions

  • Youth with IGT/T2D are more insulin resistant, have higher insulin secretion, and lower insulin clearance, more rapid beta-cell deterioration, and poorer response to interventions vs. adults.
  • Insulin sensitivity and first phase beta-cell responses are predictors of glycemia deterioration in adults.
  • Glycemia and all beta-cell responses measures are predictors of glycemia deterioration in youth.
  • Glucagon does not explain differences in beta-cell function in youth vs. adults.
  • Gastric banding increased insulin sensitivity and clearance, preserved beta-cell function, and improved glycemia for over 2 years in adults.

This is a highlights summary of an oral session given at the ADA 2020 - 80th Scientific Sessions and presented by:

Sharon Edelstein, ScM
Dept. of Epidemiology & Biostatistics, George Washington University, Washington, DC, USA

Thomas A. Buchanan, MD
Dept. of Physiology and Biophysics and Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA

Kristina Utzschneider, MD
Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA

Kristen J. Nadeau, MD, MS
Section of Pediatric Endocrinology, Dept. of Pediatrics, University of Colorado - School of Medicine, Aurora, CO, USA

The content is produced by Infomedica, the official reporting partner of ADA 2020 Virtual Meeting. The summary text was drafted by Patrick Moore, PhD, and reviewed by Marco Gallo, MD, an independent external expert, and approved by Dana M. Dabelea, MD, PhD, the scientific editor of the program.

The presenting authors of the original session had no part in the creation of this conference highlights summary.

In addition, an expert commentary on the topic has been provided by:

Dana M. Dabelea, MD, PhD
University of Colorado
Director of the LEAD Center and Conrad M. Riley Endowed Professor
Denver, CO, USA

Dana M. Dabelea, MD, PhD
University of Colorado
Director of the LEAD Center and Conrad M. Riley Endowed Professor
Denver, CO, USA

Dr. Dabelea is a Professor of Epidemiology and Pediatrics and the Director of the Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center at the University of Colorado Anschutz Medical Campus (AMC).

Her main research interest is understanding how early life behaviors, environmental exposures and other risk factors operating during fetal or early post-natal life, influence the development of obesity, diabetes  and cardiovascular outcomes throughout the lifecourse (developmental origins of health and disease). Her experience includes epidemiological studies with community-based and clinic-based sampling, longitudinal follow-up, and extensive sample collection and storage.

As the Director of the LEAD Center and lead investigator on over $18 million NIH and CDC grants, she oversees large, longitudinal, cohort studies spanning the entire lifecourse, from pregnancy through old age. Among others, she serves as national Co-Chair of the Steering Committee for the multi-center SEARCH for Diabetes in Youth Study. SEARCH is a landmark US population-based study conducting both surveillance and observational research in the field of pediatric type 1 and type 2 diabetes. Dr. Dabelea is also part of the Diabetes Prevention Program Outcomes Study (DPPOS), another landmark US diabetes study in older adults, which has provided the evidence base for diabetes prevention efforts, and is now studying diabetes-and aging-related outcomes and comorbidities.

Finally, Dr. Dabelea is also Principal Investigator of Healthy Start, a Colorado pre-birth cohort study following over 1400 mother –child dyads from before birth through childhood and adolescence, to understand the developmental origins of several chronic pediatric diseases. With Healthy Start, Dr. Dabelea leads a multi-disciplinary team of investigators, as part of the NIH-assembled ECHO consortium (Environmental influences on Childhood Health Outcomes). These studies, several ancillary studies supported by these cohorts, as well as other studies conducted by LEAD investigators under Dr. Dabelea’s direction, provide an exceptionally rich resource for training and mentoring students, junior faculty, residents and fellows in clinical diabetes research, lifecourse research, maternal and child health research, and chronic disease epidemiology.



Diabetes
Integrated Physiology/Obesity


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