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Enough vitamin D when young associated with lower risk of diabetes-related autoimmunity

Getting enough vitamin D during infancy and childhood is associated with a reduced risk of islet autoimmunity among children at increased genetic risk for type 1 diabetes, according to a study published this week in the journal Diabetes.

The study’s lead author, Jill Norris, MPH, PhD, of the Colorado School of Public Health, and her co-authors examined the association between vitamin D levels in the blood and islet autoimmunity. Islet autoimmunity, detected by antibodies that appear when the immune system attacks the islet cells in the pancreas that produce insulin, is a precursor to type 1 diabetes.

Professor Jill Norris, PhD, MPH, is lead author of the study.
Professor Jill Norris, PhD, MPH, is lead author of the study.

“For several years there has been controversy among scientists about whether vitamin D lowers the risk of developing of islet autoimmunity and type 1 diabetes,” said Dr. Norris.

Type 1 diabetes is a chronic autoimmune disease that is increasing by 3-5 percent annually worldwide. The disease is now the most common metabolic disorder in children under age 10. In younger children, the number of new cases is particularly high. And the risks seem to be greater at higher latitudes, further north from the equator.

Vitamin D represents a candidate protective factor for type 1 diabetes as it regulates the immune system and autoimmunity. Moreover, vitamin D status varies by latitude. But associations between vitamin D levels and islet autoimmunity have been inconsistent. This may be due to different study designs, population variation in vitamin D levels, or a failure to account for the combined effect of exposure and underlying genetic variation in the vitamin D pathway.

The findings are part of The Environmental Determinants of Diabetes in the Young (TEDDY) study, a large, multi-national study funded by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases.

TEDDY’s effort began in 2004 with children from six clinical centers: three in the U.S. (Barbara Davis Center for Childhood Diabetes at CU Anschutz, the Pacific Northwest Research Institute in Seattle, and Augusta University in Georgia) and three in Europe (Universities of Turku, Oulu, and Tampere in Finland, Helmholtz Zentrum München in Germany, and Lund University in Sweden). The aim of the study is to search for triggers and protective factors for type 1 diabetes in 8,676 children with elevated type 1 diabetes risk.

The TEDDY children were followed with blood samples drawn every three to six months from infancy, to determine the presence of islet autoimmunity, as well as levels of vitamin D.

The authors compared 376 children who developed islet autoimmunity with 1,041 children who did not.  The authors found that in children with a genetic variant in the vitamin D receptor gene, vitamin D levels in infancy and childhood were lower in those that went on to develop islet autoimmunity compared with those that did not develop autoimmunity.

This study is the first to show that higher childhood vitamin D levels are significantly associated with a decreased risk of IA.

“Since this association does not prove cause-and-effect, we look to future prospective studies to confirm whether a vitamin D intervention can help prevent type 1 diabetes,” Dr. Norris said.

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New oral diabetes drug shows promise

A University of Colorado Anschutz Medical Campus study finds sotagliflozin helps control glucose and reduces the need for insulin in patients with type 1 diabetes.

Principal results were published today in the New England Journal of Medicine of a global Phase 3 clinical trial in patients with type 1 diabetes treated with sotagliflozin. Sotagliflozin is an investigational new oral drug for patients with type 1 diabetes that has shown promise in improving glucose control without any increase in severe hypoglycemia or diabetic ketoacidosis compared to insulin alone.

Garg
Dr. Satish Garg

Among 1,402 trial participants given the drug, sotagliflozin showed clinically meaningful and statistically significant effects on glucose control. Concentrations of hemoglobin A1C, a measure of plasma glucose, were improved. Patients experienced a lower rate of confirmed severe hypoglycemia than observed in patients on placebo and also had weight loss.

According to lead investigator Satish Garg, MD, professor of medicine and pediatrics at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, no oral medication has ever been approved for the treatment of type 1 diabetes and sotagliflozin has the potential to become the first new treatment innovation in nearly a century since insulin.

Most patients do not achieve optimal glycemic control with insulin alone. A1C concentrations, hypertension and reduction in body weight are critical issues which significantly impact people living with type 1 diabetes.

“If approved by the FDA, sotagliflozin may be the first oral drug that helps patients with type 1 diabetes in improving their glucose control without any weight gain or increase and severe hypoglycemia,” Garg said. “If long-term use continues to show similar metabolic improvements in patients with type 1 diabetes, it is likely that the long-term complications of diabetes would be significantly reduced.”

Sotagliflozin would be used in conjunction with insulin. Trial participants taking the drug as an oral pill alongside traditional insulin treatments experienced significant improvements in glucose control, a drop in systolic and diastolic blood pressure and weight loss.

Sotagliflozin is a unique dual inhibitor that works by inhibiting two sodium-glucose transporters: SGLT1 and SGLT2. Each modulates glucose levels. SGLT1 regulates the uptake of glucose in the gut while SGLT2 regulates the re-uptake of glucose in the kidney, according to the authors.

“Sotagliflozin added to insulin therapy can potentially help patients with type 1 diabetes improve their glucose control and hopefully manage the disease with fewer complications,” Garg said. “This would not be a replacement for insulin; it is an adjunctive therapy. However, because it works in the gut and the kidneys, it doesn’t require insulin to have an effect.”

The inTandem3 study was a double-blind, placebo controlled and randomized Phase 3 trial including adults with type 1 diabetes at 133 sites worldwide. In conjunction with this publication, the data were announced today at the 53rd Annual Meeting of the European Association Study for Diabetes in Lisbon, Portugal.

The 24-week trial evaluated the safety and efficacy of sotagliflozin at 400mg per day in randomized patients treated with any insulin regimen – pumps or injections. Eligible patients included men and nonpregnant women aged 18 and older, and they were required to self-monitor blood glucose.

The study met its primary endpoint with statistical significance, demonstrating the superiority of sotagliflozin 400 mg compared to placebo in the proportion of patients with A1C less than seven percent at week 24, no episode of severe hypoglycemia and no episode of diabetic ketoacidosis after randomization.

The outcome on every secondary endpoint favored sotagliflozin over placebo, achieving statistical significance for all four secondary endpoints, including change from baseline in A1C, body weight, systolic blood pressure in patients with baseline SBP less than or equal to 130 mm Hg and bolus insulin dose. Sotagliflozin significantly reduced A1C compared to placebo after 24 weeks of treatment.

“As is known with sodium glucose cotransporter 2 (SGLT2) inhibitors, patients experienced more episodes of diabetic ketoacidosis in the trial,” Garg said.

Diarrhea and genital mycotic infection also affected participants more than placebo, but less than one percent discontinued the study due to these effects.

“Sotagliflozin may reduce the bad effects of insulin and the dose patients need,” Garg said. “Patients in our study had lower weights, no severe hypoglycemia and better blood pressure.”

Garg is a faculty member at the University of Colorado School of Medicine at the Anschutz Medical Campus and is editor in-chief of Diabetes Technology and Therapeutics Journal.

Garg and his colleagues are working to publish more results on other inTendem1 and 2 phase 3 clinical trials in type 1 diabetes, including data on continuous glucose monitoring in future publications.

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Type 2 diabetes diagnosis in youth leads to increased health complications

A new report published this month in the Journal of the American Medical Association points to a significantly higher burden of diabetes-related complications in adolescents and young adults with type 2 diabetes compared to type 1 diabetes, with greater health complications in minority youth.

The study, from researchers involved with the nationwide SEARCH for Diabetes in Youth Study, looked at five health complications and co-morbidities of diabetes, including: retinopathy (eye disease), diabetic kidney disease, peripheral neuropathy (altered sensation in the feet), arterial stiffness and high blood pressure.

The researchers studied 1,746 adolescents and young adults with type 1 diabetes and 272 with type 2 diabetes. Their findings showed that, after less than eight years following a diagnosis, approximately one-third of teenagers and young adults with type 1 diabetes and almost 75 percent of those with type 2 diabetes had at least one health complication or comorbidity. Additionally, any adjustment for differences in age, sex, race/ethnicity, and levels of glucose control over time, did not remove the excess prevalence among those with type 2 diabetes.

“The high burden of early complications in youth with diabetes requires additional research to clarify the underlying causes and to identify effective intervention strategies,” said Dr. Dana Dabelea, lead author and co-chair of the national SEARCH Study and professor of epidemiology at the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus. “It is extremely useful to have these estimates of the presence of complications in adolescents and young adults who are being treated with current therapies, especially because the complications are frequent. We need to make sure each risk factor is under the best control possible to reduce future problems.”

The SEARCH for Diabetes in Youth Study has been monitoring the burden of diabetes in youth with onset less than 20 years of age since 2000. Five U.S. clinical centers and principal investigators participated, including: Seattle Children’s Hospital, (Dr. Catherine Pihoker); Kaiser Permanente Southern California, (Dr. Jean Lawrence); Colorado School of Public Health (Dr. Dana Dabelea); Cincinnati Children’s Hospital, (Dr. Larry Dolan); and the Universities of North and South Carolina Schools of Public Health, (Dr. Elizabeth Mayer-Davis, SEARCH co-chair). The central laboratory is at the Northwest Lipid Research Laboratory, (Dr. Santica Marcovina) and the Coordinating Center is at the Wake Forest School of Medicine (Dr. Ralph D’Agostino and Dr. Lynne Wagenknecht, co-directors).

SEARCH is funded by the National Institutes of Health and the Centers for Disease Control and Prevention.

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