Redesign of insulin for use in implantable pumps

Nelson F. B. Phillips, PhD
Case Western Reserve University

Lay Abstract

The instability of insulin at body temperature poses a major barrier to the practical use of implantable insulin pumps, as envisioned within a "closed-loop" artificial endocrine pancreas. Indeed, implantable pumps are not currently approved by the US Food & Drug Administration because of the high rate of pump occlusion due to misfolding and aggregation of existing insulin formulations. Current formulations of insulin form glue-like deposits (called "fibrillation") that clog the pump tubing, leading to underdelivery. The fibrillation problem has remained intractable despite 20 years of research to find new additives or better tubing materials. In this application we propose to solve this problem by taking a new approach: structure-based re-design of the insulin molecule to make it resistant to misfolding and aggregation at body temperature.

Fibrillation-resistant insulin analogs would for the first time make possible the long-term use of an implantable insulin pump. Based on an understanding of the misfolding process, we will therefore synthesize novel insulin analogs designed to be highly active and ultra-stable. In particular, we seek analogs that can be stored for up to 3 months in the reservoir of an implantable pump without loss of biological activity or occlusion. We will test our novel analogs to ensure their activity to bind to the insulin receptor and to control the blood sugar of diabetic rats. Preliminary studies have shown that the stability of insulin can be dramatically improved without impairment of its biological activity. Thus, a first step towards the solution to this long-standing problem seems likely during this proposed funding period.

Whereas human insulin was once thought to be the best type of insulin to use in the treatment of Type I diabetes mellitus, we now know that human insulin can be improved. During the past decade the general use of "first-generation" insulin analogs (such as Humalog and Novolog) has proven to be safe and effective. Just as such "meal-time" analogs have enhanced the efficacy of conventional insulin therapy, we anticipate that a new generation of analogs will enable the long-term use of implantable pumps. This advance will be key to the success of an artificial endocrine pancreas. Novel ultra-stable insulin analogs would thus greatly benefit the long-term health and quality of life of patients with Type I diabetes mellitus. The impact of an implantable insulin pump with a three-month reservoir would be particularly dramatic for children and their families.

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Glucose metabolism in diabetic hearts

Xin Yu, ScD
Case Western Reserve University

Lay Abstract

Diabetes is a disease with wide prevalence in humans. There are 20.8 million children and adults in the United States, or 7% of the population, who have diabetes. Most people with diabetes have health problems that increase one's risk for heart disease and stroke. In fact, more than 65% of people with diabetes die from heart disease or stroke. With diabetes, heart attacks occur earlier in life and often result in death. However, the underlying basis for the development of diabetes associated heart disease is not fully understood. Evidence is emerging that it may be related to abnormal glucose utilization in heart, as diabetes is first and foremost a disorder in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar (glucose), starches and other food into energy needed for daily life. Hence, the objective of the proposed study is to delineate changes in glucose utilization and its impact on heart function in diabetes.

Our long-term goal is to elucidate the molecular mechanisms responsible for functional alterations in diabetic hearts, and to develop magnetic resonance imaging/spectroscopy techniques for noninvasive and sensitive detection of subtle changes in diabetic hearts before clinical symptoms develop. To achieve this goal, we seek to elucidate the energy-function relationship in diabetic hearts by developing state-of-the-art magnetic resonance imaging (MRI) and spectroscopy (MRS) methods. Specifically, we will characterize changes in heart muscle contraction using MRI. Changes in glucose utilization will be assessed by combining experimental nuclear magnetic resonance (NMR) spectroscopy with systems biology approach. Studies on isolated muscle cells will be performed to document changes in cell contractility. Protein analysis will be performed to seek the underlying molecular mechanisms responsible for heart dysfunction in diabetic hearts.

Further, the role of glucose transport and utilization in diabetic hearts will also be investigated in a mouse model with cardiac-specific overexpression of basal glucose transporter (GLUT1-TG). We anticipate that the proposed study will allow us to gain insights into the pathogenesis of diabetes associated heart disease. In addition, methods developed in this proposal will permit more sensitive and comprehensive quantification of cardiac phenotypes that directly reflect changes that occur at molecular levels.

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