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Metformin Alone or Combined with Insulin Does Not Improve or Preserve Beta-Cell Function in Youth with Impaired Glucose Tolerance or Newly Diagnosed Type 2 Diabetes
 
Restoring Insulin Secretion (RISE) Pediatric Medication Study shows that youth have markedly reduced insulin sensitivity and respond differently to medications
 
 According to recent research, the insulin resistance and pancreatic beta-cell (β-cell) dysfunction associated with type 2 diabetes (T2D) was unresponsive to treatment with metformin alone or metformin combined with insulin glargine in youth with impaired glucose tolerance (IGT), which is an element of prediabetes, or early T2D. Additionally, youth with IGT and T2D, compared to adults, are more insulin resistant, and thus their insulin is less effective in lowering blood glucose levels in their bodies.
 
These findings from the Restoring Insulin Secretion (RISE)program’s Pediatric Medication Study were presented today 
 
T2D is increasing in prevalence in youth and adults in the U.S., and increases the risk of early morbidity and mortality, as well as long-term complications. T2D and its precursor, prediabetes, are characterized by insulin resistance and beta-cell dysfunction in youth and adults, and prediabetes includes IGT.
 
However, research has suggested that T2D in youth might represent a more severe and rapidly progressive condition than in adults.
Given the increased recognition of the critical role of pancreatic β-cell function (β-cells store and release insulin in the body) in the pathogenesis of T2D, research efforts have begun to focus on prevention of the loss of insulin secretion among individuals at high risk for T2D or in early stages of the disease. The RISE program consists of three randomized, multi-center studies across the U.S. The trials focus on youth and adults to assess the impact of different interventions at the stage of IGT or shortly after the diagnosis of T2D to determine if the β-cell decline observed in IGT and early T2D could be halted or reversed.
 
Baseline data comparing youth and adults as well as results of one of the RISE studies, the RISE Pediatric Medication Study, will be featured in three articles published online simultaneously with today’s Symposium and in the August 2018 issue of Diabetes Care.
Baseline data for the trial was obtained from two adult arms of the study and was compared to youth. Both age groups had IGT and recently diagnosed T2D. The assessments used two different evaluation methods: the hyperglycemic clamp and the oral glucose tolerance test (OGTT).
 
These two tests were both performed in 66 youth, ages 10-19 (80.3 percent with IGT) and 355 adults (70.7 percent with IGT). The results from both tests showed that youth have markedly lower insulin sensitivity compared to adults. In response, the insulin release by the pancreas in youth was much higher than in adults. However, the increased β-cell responsiveness in youth was still not enough to maintain normal glucose levels, indicating impaired β-cell function.
 
In the “Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp,” article, the RISE researchers compared insulin sensitivity and β-cell responses in youth versus adults with IGT or recently diagnosed T2D using a hyperglycemic clamp. During a hyperglycemic clamp, researchers raise a subject’s glucose concentration above optimal level by administering an intravenous infusion of glucose. The desired high blood glucose concentration is maintained by adjusting the glucose infusion amount. This test enables researchers to then assess how well the pancreas can secrete insulin in response to glucose and how well the body responds to the insulin it secretes. Following a 10-hour overnight fast, a two-step hyperglycemic clamp was performed on each patient.
The youth had lower insulin sensitivity, hyper-responsive β-cells and reduced insulin clearance compared with adults. Insulin sensitivity in youth was 46 percent lower than in the comparably overweight, dysglycemic adults. The RISE researchers note that it remains to be determined if age-related differences contribute to declining β-cell function and/or impact responses to glucose-lowering interventions.
 
In the article, “Metabolic Contrasts Between Youth and Adults with Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: II. Observations Using the Oral Glucose Tolerance Test,” the RISE Consortium performed a 3-hour OGTT. During the OGTT, participants had a baseline, fasting blood draw and then consumed a beverage containing glucose. Blood draws were then conducted at multiple time points over three hours to measure blood glucose and insulin concentrations.
 
The results from the OGTT showed that the balance between insulin sensitivity and β-cell responses differs between youth and adults with IGT or recently diagnosed T2D. The findings are compatible with those observed with the hyperglycemic clamp and suggest that youth with every meal are having to release larger amounts of insulin to try and regulate their glucose metabolism.
Because metformin and insulin each have been shown to improve β-cell function in adults with IGT or recent-onset T2D, RISE researchers conducted the RISE Pediatric Medication Study in youth with IGT or recently diagnosed T2D. The study tested the effect of three months of insulin glargine titrated to lower glucose to well within the normal range (target fasting 4.4 – 5.0 mmol/L or 80 – 90 mg/dL), followed by metformin for nine months, versus 12 months of metformin alone. Between 2013 and 2016, a total of 91 youth between the ages of 10 and 19 years of age, and with a BMI of ≥85th percentile for their age and sex, participated in the study. Of the group, 60 percent of the youth had IGT and 40 percent had been diagnosed with T2D for a duration of less than six months.
 
The study results, detailed in the article, “Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes,”  revealed the insulin resistance and β-cell dysfunction seen in these youth with IGT or early T2D was unresponsive to both treatment regimens. No significant differences were observed between the treatment groups at baseline, 12 months, or 15 months in β-cell function, BMI percentile, HbA1c, fasting glucose, or oral glucose tolerance test 2-h glucose results. Additionally, three months after withdrawal of the intervention, the youths’ β-cells were even less responsive than when they started the study, indicating disease progression. Thus, the intervention did not appear to have any lasting benefit.
 
“These findings contrast with prior reports in adults, showing an improvement in β-cell function after 12 months of treatment with metformin or after insulin treatment, either for diabetes prevention or treatment,” said Kristen Nadeau, MD, MS, Professor of Pediatric Endocrinology at the University of Colorado Anschutz Medical Campus. “Early treatment of youth with IGT or type 2 diabetes may require other glucose-lowering medications alone or in combination to combat insulin resistance and arrest the progressive loss of β-cell function in youth. Additionally, the results of our study call for further studies to better understand the physiology of youth-onset type 2 diabetes and to identify new, safe and effective treatment options for youth with IGT or type 2 diabetes.”
 
“Early β-cell failure creates permanent dependence on insulin, and thus, youth may be at higher risk of future diabetes complications,” said senior author Steven E. Kahn, MB, ChB, professor and Leonard L. Wright and Marjorie C. Wright Chair in the Division of Metabolism, Endocrinology and Nutrition, and Director of the Diabetes Research Center at the VA Puget Sound Health Care System and University of Washington School of Medicine in Seattle. “It is imperative that we create future research opportunities to allow us to better understand and prevent the underlying causes of rapid β-cell failure in youth, and to identify new treatment approaches for youth with IGT or type 2 diabetes.”
 
the results are published in Diab Care
 
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