Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease, defined by insulin resistance and insufficient insulin secretion to maintain normoglycemia. Amyloidogenic aggregates are a hallmark of T2DM patients; they are cytotoxic for the insulin producing β-cells, and cause inflammasome-dependent secretion of IL-1β. To avoid the associated β-cell loss and inflammation in advanced stage T2DM, we developed a novel monoclonal therapy targeting the major component of aggregates, islet amyloid polypeptide (IAPP). The here described monoclonal antibody (mAb) m81, specific for oligomeric and fibrils, but not for soluble free IAPP, is able to prevent oligomer growth and aggregate formation in vitro, and blocks islet inflammation and disease progression in vivo. Collectively, our data show that blocking fibril formation and prevention of new amyloidogenic aggregates by monoclonal antibody therapy may be a potential therapy for T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, characterized by chronic inflammation of pancreatic islets, impaired insulin secretion, and the presence of amyloidogenic aggregates [1,2]
50% of patients are diagnosed on time, and are able to slow the development of T2DM-associated organ damage with available conventional anti-diabetic drugs and ameliorated diabetes care
Besides insulin resistance [8,9], which leads to more insulin demand and higher blood-glucose levels, we focused on the presence of amyloidogenic aggregates in the pancreatic islets which are mainly composed of accumulated islet amyloid polypeptide (IAPP), known as amylin [1,10,11]
Summary
Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, characterized by chronic inflammation of pancreatic islets, impaired insulin secretion, and the presence of amyloidogenic aggregates [1,2]. Numbers of T2DM patients are rising worldwide, reaching pandemic proportions; according to the International Diabetes Federation (IDF), 9% of adults aged 20–79 years—an astonishing 463 million people—are living with diabetes. If the current trends continue, a projection to the year 2045 estimates 700 million adults living with diabetes. Apart from the clear evidence that good lifestyle habits— comprising healthy diet [3] and moderate physical activity [4]—could decrease this high count, there is currently no available curative or preventive drug against T2DM. 50% of patients are diagnosed on time, and are able to slow the development of T2DM-associated organ damage with available conventional anti-diabetic drugs and ameliorated diabetes care. Symptomatic treatment alone does not stop the progression of T2DM to islet damage and other related irreversible complications [5]
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