Studies show difficulty in treating type 2 diabetes in youth and highlight unique aspects of the disease in young people
New research reveals that two diabetes medications do not prevent rapid progression of prediabetes or recent onset type 2 diabetes in young people with the disease, even though these are the only two medications approved for pediatric type 2 diabetes. More encouragingly, however, analyses comparing metabolic tests of adults in a companion study and the youth study participants are helping scientists understand how the disease differs with age, which may one day lead to better treatment approaches. Resistance to the glucose-lowering effects of insulin is often associated with overweight, obesity, or advancing age. At first the pancreas can compensate for this problem by simply secreting more insulin, but type 2 diabetes results if the pancreas gradually loses its ability to do so. Although long thought of as a disease of middle-aged and older adults, type 2 diabetes has been appearing in teenagers in small but increasing numbers in recent years. This trend is alarming for many reasons—for example, because the complications of the disease, which can be both debilitating and life threatening, are more likely to develop the longer someone has diabetes. Furthermore, the recent Treatment Options for Diabetes in Adolescents and Youth (TODAY) study found that type 2 diabetes was very difficult to treat when it occurred in younger people, and that the disease progressed much more rapidly than it did in those who develop it in middle age or later. TODAY compared metformin alone with metformin together with a lifestyle intervention, and with metformin plus another medication that was then commonly used to treat adults with diabetes; none of these approaches was found to be effective. One encouraging observation from that study was that participants who had been enrolled in the study earlier in the course of their disease fared better than those whose diabetes was already more advanced. This finding suggested that focusing on preventing disease progression in young people with prediabetes or recent onset type 2 diabetes might be beneficial.
Indeed, the idea for the Restoring Insulin Secretion (RISE) studies comes from earlier observations that use of the diabetes drug metformin and/or a long-acting form of insulin can improve the function of the insulin-producing beta cells of the pancreas in adults with prediabetes or recent-onset type 2 diabetes. The theory is that by taking some of the burden off the pancreas through early treatment—giving it a “rest”—it may be possible to slow or even reverse the progressive loss of its capacity to respond to glucose by secreting insulin. RISE is actually a group of three clinical trials testing this idea in different ways. Two trials are testing approaches to restoring insulin secretion in adults with prediabetes or recent-onset type 2 diabetes, and one studied younger participants, who were between 10 and 19 years of age at study enrollment. This RISE Pediatric Medication Study focused on preventing progression of the disease by utilizing the two drugs approved for treating type 2 diabetes in children, metformin and insulin. The RISE study randomly assigned the 91 participants to take metformin for 1 year, or to take a long-acting form of insulin for 3 months, followed by metformin for 9 months. (Insulin had not been tested in the TODAY study.) Unfortunately, neither approach was successful, as the disease progressed markedly in both groups over the course of the study, underlining the great importance of finding better approaches to preventing and treating type 2 diabetes in young people.
To try to understand the physiological reasons why type 2 diabetes is so much harder to treat when it develops at a young age, researchers also compared metabolic test results from participants in the pediatric RISE study with tests in adult participants in the other two RISE studies. Regardless of age, the RISE participants at entry into all three clinical trials had similar fasting blood glucose levels, and similar glucose levels 2 hours after ingesting a drink containing a standardized amount of sugar, referred to as an oral glucose tolerance test (OGTT). However, researchers examined the OGTT in greater detail, checking two measures of insulin levels before and after the glucose challenge and found a striking difference: at each time tested, the 10- to 19-year-old participants had markedly higher insulin levels than did the adults. This suggests that young people with prediabetes or early type 2 diabetes are different from older people with these conditions in that they retain a more robust capacity to produce insulin, but that this capacity is masked by a more severe degree of insulin resistance. Another analytic method supported these findings: researchers used an IV to increase blood glucose levels—holding them first at one level, and then at a higher level—and then measured how the participants’ pancreases and other tissues responded. Insulin levels rose significantly higher in the young RISE participants than in the adults, often beyond the amount of insulin that was needed or desirable. These results further confirm previous observations that puberty can aggravate insulin resistance, suggesting that improving insulin sensitivity may be a key therapeutic strategy; yet metformin—the only commonly used anti-diabetes drug that is known for improving insulin resistance—was ineffective for youth. These studies together underline the importance of finding new and better ways to treat and prevent type 2 diabetes in young people.
The RISE Consortium. Impact of insulin and metformin versus metformin alone on β-cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes. Diabetes Care. 41:1717-1725, doi: 10.2337/dc18-0787, 2018.
The RISE Consortium. Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: II. Observations using the oral glucose tolerance test. Diabetes Care. 41: 1707-1716, doi: 10.2337/dc18-0243, 2018.
The RISE Consortium. Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: I. Observations using the hyperglycemic clamp. Diabetes Care. 41:1696-1706, doi: 10.2337/dc18-0244, 2018.