COMMENTARY

Study Highlights Aggressive Nature of Type 2 Diabetes in Youth

Steven E. Kahn, MBChB;  Mark Harmel, MPH

Disclosures

October 16, 2018

Editorial Collaboration

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The Restoring Insulin Secretion (RISE) studies[1] have been designed to advance our understanding of the pathophysiology of type 2 diabetes and impaired glucose tolerance (prediabetes) in youth and adults, and to look at the impact of interventions that are meant to improve beta-cell function in these two groups.

Beta cells appear to fail more rapidly in youth than in adults.

This study has been supported in large part by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. As mentioned, the goal was to assess approaches that address beta-cell dysfunction. In both youth and adults, the loss of the ability of beta cells to adequately secrete insulin results in the development of impaired glucose tolerance and, ultimately, type 2 diabetes. Previous studies[2] have also suggested that the disease may be more aggressive in youth, primarily because the beta cells appear to fail more rapidly in youth than in adults.

Baseline data were obtained from 355 adults (aged ≥ 20 years) and 66 youth (aged 10-19 years).[3] Using very sophisticated measures, the RISE consortium definitively demonstrated that the insulin-sensitive tissues, responsible primarily for glucose uptake and regulating glucose metabolism by clearing it from the bloodstream, are more resistant to insulin's action in youth than in adults. Using both the hyperglycemic clamp and data from oral glucose tolerance tests, we found that youth insulin sensitivity is 50% that observed in adults.

In the natural history of the disease in youth, the beta cells are hyperresponsive and progressively deteriorate more rapidly than beta cells in adults. Thus, when youth develop diabetes, the disease will progress more rapidly and require much more intervention.

RISE Treatment Protocols

In the RISE Pediatric Medication Study,[4] 91 youth were randomly assigned to receive either metformin alone for 12 months or glargine—a basal insulin used to lower the fasting glucose to 80-90 mg/dL—for 3 months followed by metformin up to 2000 mg/day for 9 months. After 12 months of therapy in both groups, treatment was withdrawn for 3 months to see whether any potential effect was retained beyond treatment withdrawal.

Despite the interventions, the participants' beta-cell function continued to decline; the beta cells were more dysfunctional 15 months after treatment initiation than they had been at the time the participants entered the study. Likewise, we also saw the hemoglobin A1c increase from a baseline of 5.7% to an average of 6% in both treatment groups.

Results from two more RISE protocols will be announced within the next year. The RISE adult surgery study compares 24 months of metformin versus lap band surgery at 24 months' follow-up. We hope the results will be available in October 2018. The second protocol, the adult medication study, will compare metformin alone, glargine for 3 months followed by metformin for 9 months, liraglutide plus metformin for 12 months, and placebo. In this study, the placebo arm and metformin arms are blinded, so it's a partially blinded trial. From these studies, we hope to learn whether we can slow progression with either the surgical approach or one of the medication regimens.

All three studies include metformin, and the adult and pediatric medication trials include glargine followed by metformin. We will be able to learn whether the impact in youth differs from the impact in adults. We hope to announce the results of the adult medication study in June 2019. We believe that we will learn a great deal more that will inform us about impaired glucose tolerance in youth, type 2 diabetes in youth and adults, and the effects of these interventions, and thus gain a better idea of how best to treat these people.

One might be disappointed that we were not able to exert a dramatic effect on outcomes in the youth. However, let me make two points. First, we did not have a placebo arm in the pediatric medication study specifically because we included participants who had early-onset type 2 diabetes, and it would be unethical to treat the children with a placebo. It is possible that the rate of progression would have been greater in a placebo arm than we observed in the two treatment groups.

Second, although one might be disappointed because we were not able to slow progression or bring about improvement, what we have learned from this study is incredibly informative regarding the aggressive nature of this disease in youth. The fact that metformin and insulin are the two approved treatments for type 2 diabetes in children but did not seem to slow disease progression does not mean that we should not be using them. We should not leave these children untreated. If we did, I believe that the progression of their disease would be much more rapid. We need to continue to use them aggressively. Down the road, we hope to identify alternative therapies that will better slow disease progression.

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