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Abnormal Glucagon Responses Emerge Early within 2 years of diagnosis in Type 1 Diabetes. Diab Care

NEW YORK (Reuters Health) – Youth with type 1 diabetes show abnormal plasma glucagon responses to mixed meal tolerance tests within two years after diagnosis, according to researchers from the Diabetes Research in Children Network (DirecNet).

”Our findings demonstrate that dysregulation in glucagon secretion is seen early in the course of disease, being demonstrated in some of our subjects within the first year after diagnosis,” said Dr. Jennifer Sherr from Yale University School of Medicine in New Haven, Connecticut.

”These data provide compelling evidence for the use of adjunctive therapies that suppress glucagon secretion in youth regardless of disease duration,” she told Reuters Health by email.

In many patients with type 1 diabetes, exaggerated alpha-cell responses to amino acid stimulation, manifested by higher glucagon levels, may contribute to postprandial hyperglycemia.

Dr. Sherr and colleagues compared the magnitudes of glucagon responses to a standard mixed-meal tolerance test in 25 youth with type 1 diabetes and 20 non-diabetic, age- and sex-matched children.

During the first year after diagnosis, children with diabetes had significantly lower fasting and peak stimulated plasma C-peptide levels than did non-diabetic children, but only one type 1 diabetic had a peak stimulated C-peptide value below 0.2 mmol/L.

By the end of the second year, though, seven of the 25 diabetic children had peak stimulated C-peptide values below 0.2 mmol/L, the researchers reported in Diabetes Care, online April 2.

Fasting plasma glucagon levels did not differ between diabetic and non-diabetic children during years 1 and 2. In contrast, peak increases in glucagon levels after the mixed meal were significantly higher in diabetic children than in their non-diabetic peers.

All but two diabetic children had clinically relevant increases in plasma glucagon by year 2, compared with 40% of control subjects. The rise in total glucagon secretion paralleled the increasing duration of type 1 diabetes.

”More than 40 years ago, Unger et al. suggested that diabetes was a bihormonal disease characterized by too little insulin and too much glucagon,” the authors explain. ”Interest in this question faded during the early intensive treatment era when attention turned to impaired glucagon responses to hypoglycemia.”

”These observations provide a compelling rationale for further studies on the benefits of agents like pramlintide and GLP-1 agonists that can suppress abnormal glucagon responses to feeding in the treatment of youth with type 1 diabetes,” they conclude.

”Importantly, the degree of dysregulated glucagon secretion in these youth with type 1 diabetes approximates the glucagon secretion seen in healthy, young adults in response to insulin-induced hypoglycemia,” Dr. Sherr said.

”While treatment of type 1 diabetes has largely been limited to insulin therapy, further exploration of and application of adjunctive therapies may prove to be as important in the management of type 1 diabetes in both the adult and pediatric populations,” she said.

Glucagon and alpha cells have been major subjects of research in the laboratory of Dr. Hongju Wu from Tulane University in New Orleans, Louisiana.

Dr. Wu, who was not involved in the new work, explained that glucagon and insulin are mutually suppressive, leading to exaggerated glucagon secretion in type 1 diabetes.

”The lack of insulin in type 1 diabetes has always been thought to be the major reason for too much glucagon,” she told Reuters Health by email. ”In our recent animal studies, we also observed more glucagon-producing cells in experimental type 1 diabetes, which may contribute to the exaggerated glucagon secretion.”

”The importance of glucagon in diabetes management has not been emphasized enough,” Dr. Wu said. ”I hope this study can promote physicians to take glucagon into more consideration in their practice.”

Diabetes Care 2014 May

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