Hepatic Insulin Clearance: A Novel Therapeutic Target in Type 2 Diabetes
Abstract
Type 2 diabetes (T2D) reached epidemic proportions around the world and ~10% of the U.S. population suffers from this disease. The defining feature of T2D is abnormally high levels of glucose in the blood, which leads to significant morbidity (blindness, kidney disease, limb amputation) and mortality (heart attack, stroke). The physiological defect underlying T2D is the insufficient metabolic action of insulin, a key hormone regulating glucose homeostasis. In patients with T2D, impaired insulin action is the consequence of two principal mechanisms: insufficient insulin secretion by the pancreas and abnormal insulin response in target tissues (muscle, liver, adipose), which is referred to as insulin resistance. Because of the dual etiology of T2D, most previous research focused on how to improve insulin secretion and how to decrease insulin resistance. As a result, antidiabetic drugs in the clinic today target one of these processes. Although insulin resistance is a key component of T2D, not all insulin-resistant individuals suffer from the disease. These healthy individuals manage to overcome reduced tissue insulin sensitivity by raising insulin concentration in the blood through a process called hyperinsulinemic compensation. It is well established that hyperinsulinemic compensation is the result of two processes: increased pancreatic insulin secretion and reduced removal of the hormone from the circulation, referred to as insulin clearance. While the regulation of insulin secretion has been extensively studied, the process of insulin clearance has received relatively little attention. Importantly, it remains unknown whether naturally occurring variation in insulin clearance affects the risk for T2D and whether the manipulation of insulin clearance offers therapeutic benefits similar to that of insulin secretion. Thus, our overall objective is to fill this knowledge gap by investigating the therapeutic potential of targeting insulin clearance. In preliminary studies, we used genetic approaches in the mouse to identify a novel determinant of insulin clearance. In the present proposal, we will use this gene to manipulate insulin clearance in prediabetic and diabetic mouse models to assess the impact on disease progression. We anticipate that the proposed studies will provide novel insights into the molecular determinants of insulin clearance and the pathogenesis of T2D. Importantly, our results may identify targeting insulin clearance as a novel therapeutic paradigm in T2D and pave the way for novel therapeutic approaches in the prevention and treatment of this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210643
Entities
People
- Miklos Peterfy
Organizations
- United States Army
- Western University of Health Sciences