M. Sperling
Aug 25, 2009
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Pediatric Diabetes
Abstract
A major goal of diabetes research is to find ways to preserve and enhance residual insulin secretory capacity that children with diabetes still possess at initial diagnosis. Residual insulin capacity, measured as prevailing C-peptide concentration, manifests as the honeymoon phase in type 1 diabetes; as the ability to use minimal or no insulin, or oral agents or no medications at all in type 2 diabetes after recovery from ‘‘glucose toxicity’’; and the restoration of endogenous insulin secretion by sulfonylurea in selected forms of monogenic diabetes. This enhanced residual insulin secretion is expected to maintain better metabolic control with lower extremes in the ranges of glycemia and ultimately fewer complications. However, attaining the goal of predictably preserving residual insulin secretion has proved elusive. Early reports of enhanced preservation for up to one year by intensive intravenous insulin therapy delivered via an artificial pancreas could not be replicated (1,2). Attempts to prevent clinical type 1 diabetes mellitus in those deemed at high risk have not succeeded when testing with parenteral, oral or nasal insulin or by the use of nicotinamide or by avoidance of cow’s milk in newborn feeding (3,4). Two recent studies, one in humans (5) and one in a mouse model of genetic diabetes (6), provide new hope and impetus for intensive therapy at the onset of clinical disease. The human study, one of a series undertaken by type 1 diabetes TrialNet, an international collaborative clinical trials network, tested the effects of a monoclonal antibody against CD20 (Rituximab), an essential costimulatory molecule necessary for B cell development and survival (5). Rituximab depletes B lymphocytes from the circulation and has been successfully used against autoimmune diseases such as rheumatoid arthritis. Participants with newly diagnosed T1DM of less than 2 to 4 weeks after clinical onset, were randomized to receive 4 weekly infusions of the moloclonal antibody or placebo. The primary outcome measure was the area under the curve (AUC) of C-peptide during the 2 hours after a mixed meal tolerance test; secondary measures included dose of insulin needed and hemoglobin A1c levels. In all of these measures, Rituximab was superior to placebo in helping to achieve lower hemoglobin A1c and lower doses of exogenous insulin while retaining higher C-peptide secretion. Side effects, to date, have been mild to minimal in this study. Thus, partial preservation of β cell function was achieved for approximately 1 year despite only 4 injections of Rituximab. Moreover, T1DM is generally considered to be a T-lymphocyte mediated disease, and B-lymphocytes are generally considered to play only a permissive role in T-cell function. Hence, a relatively new area of research for preserving β cell function has been opened (5). Due caution is needed, however, because chronic use in older subjects with autoimmune diseases such as SLE or rheumatoid arthritis, have been associated with severe side effects, especially progressive multi-focal leucoencephalopathy (PML). The study in mice describes a model of human neonatal diabetes mellitus (NDM) (7) by expressing mutant KATP channels in the pancreatic islets from birth, or at various periods after birth, by making the induction of expression dependant on exposure to tamoxifen (6). Thereby, the expression can be limited to pancreatic β cells as well as time of appearance. Such models also permit study of the impact of the mutation on insulin secretion in response to glucose or sulfonylurea, impact of the mutation on islet insulin content and architecture, and impact of preventing hyperglycemia (8, 9). Germ line expression limited to β cells led to severe diabetes, growth retardation and progressive loss of insulin content such that islets could not respond to sulfonylurea as well as glucose. Similarly, delayed expression in adult mice also led to diabetes mellitus with loss of insulin content in the β cells. However, insulin content and the ability to respond to sulfonylurea, but not glucose, remained normal if hyperglycemia was prevented, either by islet transplantation under the kidney capsule, or administration of a sulfonylurea before, but not after, the induction of expression (6). This is a remarkable model of glucose toxicity that argues strongly for avoiding hyperglycemia (6–9). Clearly, this is not a model of autoimmune diabetes mellitus as commonly seen in pediatric practice. However, the principle of avoiding hyperglycemia in order to retain normal insulin content and ability to respond to the appropriate stimuli has relevance not only to type 1 diabetes, but also to the increasing prevalence of type 2