New Potential Adjuncts to Treatment of Children With Type 1 Diabetes Mellitus

Abstract

Insulin administration is the primary therapy for type 1 diabetes mellitus (T1DM). Current available insulin therapies do not successfully enable children with T1DM to reach glycemic goals without side effects such as hypoglycemia and weight gain. Pramlintide is a synthetic analog of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon and is indicated for use in patients with type 1 and type 2 diabetes. Recent studies in adult patients have examined the role of glucagon-like peptide 1 (GLP-1) and agents that bind to its receptor in type 1 diabetes. It is hypothesized that a major component of the glycemic effect is attributable to the known action of GLP-1 to delay gastric emptying and to inhibit glucagon secretion. Further studies with the use of amylin analogs and long-acting GLP-1 agonists as congeners with insulin in T1DM are indicated in children. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of these newer pharmacologic agents as adjunctive therapy in T1DM in children and adolescents. Current standards of care recommend intensive diabetes management and lowering hemoglobin A1c (HbA1c) to as close to normal as possible. However, 87 years after the discovery of insulin, physicians and patients still struggle for optimal diabetes control because of limitations of insulin therapy.The Diabetes Control and Complication Trial demonstrated the direct relationship between glycemic control as predicted by HbA1c and onset and prevention of microvascular complications (1,2). Studies show a strong correlation between HbA1c and plasma glucose levels both at fasting and over postprandial periods (3,4). Studies also suggest that postprandial hyperglycemia is an important risk factor for the development of macrovascular disease (5,6). Increased glycemic variability seems to correspond with elevated markers of oxidative stress and inflammation associated with cardiovascular disease (7). Thus, reductions in postprandial glycemic variability may be an important step in lowering complications related to diabetes (8). However, as insulin doses are pushed in an attempt to normalize blood glucose after meals, risk of hypoglycemia and excessive weight gain occur.This failure to achieve and maintain euglycemia in majority of children with T1DM provides an impetus to seek newer adjunctive therapies that are both safe and effective. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of newer pharmacologic agents as adjunctive therapy in T1DM in children.Pathophysiology of type 1 diabetes and rationale for adjunctive therapy. The postprandial glucose profile is determined by several factors: the rate and extent of glucose absorption, secretory patterns of various hormones (insulin, glucagon, amylin, and incretin hormon...

GLP-1-Analoga in der Therapie des Diabetes mellitus Typ 1

“…Die generell niedrige Exenatid-Dosis wurde aufgrund des pädiatrischen Klientels gewählt. Bei einem Teilnehmer trat eine anhaltende Hypoglykämie auf [9].…”

“…Sie zeigen alle einen vielversprechenden therapeutischen Effekt von GLP-1-Analoga bei Typ-1-Diabetes [2,3,6,9,12], jedoch wird die methodische Beurteilung der eingeschlossenen Literatur nicht näher beschrieben. Auch sind in nur drei der fünf Reviews die Ein-und Ausschlusskriterien definiert, so dass die Ergebnisse insgesamt kritisch zu betrachten sind [2,3,12].…”

“…Dabei können die verzögerte Magenentleerung und die Reduktion der Glukagonspiegel als gesicherte Effekte angesehen werden [3]. Die positive Auswirkung von GLP-1-Analoga auf den Blutglukosespiegel bei Typ-1-Diabetes scheint dabei unabhängig von der Betazell-Restfunktion zu sein [4,5,7,9,13].…”

Treatment of Type 2 Diabetes in Youth

“…Despite the goal of withdrawing insulin therapy after its initial introduction, only 28% of patients were able to come off insulin, and of those, 60% required reinitiation of insulin because of poor control (28). It should be noted that the use of insulin for optimal blood glucose control is accompanied by excessive weight gain and the risk of hypoglycemia (32). Adherence rates to multiple daily injections of insulin have been lower than other hypoglycemic agents in studies involving adults and children (33), and, thus, while insulin can be effective, its drawbacks necessitate consideration of alternative or adjunctive therapy options.…”

The evolving place of incretin-based therapies in type 2 diabetes

“…First preclinical studies suggest that theoretically such a combination therapy may be feasible in the future [106]. Besides the positive effect on the beta cells, GLP-1 may also influence glycaemic parameters in a favourable way by slowing gastric emptying and affecting glucagon secretion in type 1 diabetes [107]. A small mechanistic study in type 1 diabetic individuals showed that an intravenous GLP-1 infusion reduced fasting hyperglycemia in the morning, which was provoked by omitting the basal insulin injection at night [108].…”