Rediscovery of the Second β-Cell Hormone: Co-replacement With Pramlintide and Insulin in Type 1 Diabetes.

Abstract

Insulin is always deficient relative to need in diabetes. Injected insulin is essential to replace the complete lack of insulin in type 1 diabetes and to supplement endogenous insulin for many people with type 2 diabetes. Unfortunately, despite advances in insulin formulation and delivery and the effects of other glucose-lowering therapies instead of or in combination with insulin, the goals of therapy are seldom completely met. People using insulin (especially prandial insulin) are at risk for hypoglycemia and weight gain, and their postprandial glucose levels are rarely well controlled. Surprisingly, an obvious contributor to this dilemma has received little attention—a concurrent deficiency of the hormone amylin in all people with diabetes. Amylin was isolated and characterized three decades ago (1,2), about 70 years after insulin therapy became available, and “co-replacement therapy” with insulin and amylin was soon proposed for type 1 diabetes (3). Delay in characterization of amylin was partly due to its tendency to self-aggregate and cling to glass or plastic surfaces. In some species, notably cats and humans, amylin aggregates as “amyloid” in the endocrine pancreas and may contribute to injury of β-cells (4). Studies have been further hampered by difficulties in assaying amylin levels in blood, where significant proportions are modified and likely inactive (5). Even so, much has been learned about amylin’s distribution, regulation, and physiologic functions in animal and human studies (6). It is a 37–amino acid peptide that is produced in the pancreatic β-cell and secreted in parallel with insulin, and thus it is lacking in type 1 diabetes (6,7). Although present in other parts of the body, amylin is released into the blood only by β-cells. The actions of secreted amylin are mediated through parts of the brain that are outside the blood-brain barrier, and effects elsewhere depend on …