Pharmakologie, Toxikologie und Klinische Pharmazie

Research Topic: Diabetology

Key words:
beta-cell physiology, type-2 diabetes mellitus, ion channels as drug targets, signalling pathways, beta-cell apoptosis, knock-out mouse models

Research 1:

KATP channel

Research 2:

Regulation of glucose metabolism in beta-cells from SUR1 knock-out mice

Research 3:

Oxidative stress

Research 4:

Ca2+ regulated K+ channels: Significance for beta-cell function and apoptosis

Research 5:

The AMP-activated protein kinase and beta-cell function

Research 6:

Bile acids and beta-cell function

Research 7:

Microelectrode Arrays (MEAs)

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Research 1

KATP channel regulation of beta-cells

The KATP channel of pancreatic beta-cells plays a predominant role in insulin secretion because it links beta-cell metabolism to electrical activity that triggers Ca2+ influx and finally exocytosis. It is known that KATP channel activity is regulated by ATP and ADP. KATP channels are the drug targets for oral antidiabetic drugs like sulfonylureas or glinides.

Meanwhile it became clear that the regulation of beta-cell KATP channels is very complex. However, to understand the mechanisms responsible for KATP channel regulation will markedly contribute to comprehend the pathophysiology of type-2 diabetes mellitus. Our group publishes important papers in this field:

article

Cooperating groups in this project:

Research 2

Regulation of glucose metabolism in beta-cells from SUR1 knock-out mice

In SUR1 knockout (KO) mice the beta-cell specific sulfonylurea binding subunit 1 (SUR1) of the KATP channel has been genetically deleted.

Surprisingly adult animals are almost normoglycemic. Thus, this mouse model is an ideal candidate in search of KATP channel independent mechanisms that regulate glucose homeostasis. This research field may disclose new drug targets to influence glucose homeostasis in malfunctioning beta-cells.

Cooperating groups in this project:

Research 3

Oxidative stress

Type-2 diabetes mellitus (T2DM) is characterized by a loss of beta-cell function and a loss of beta-cell mass. Persistent overstimulation of beta-cells by fuels leads to the accumulation of reactive oxygen species (ROS). ROS are critically involved in the toxic effect of lipids and glucose (glucolipotoxicity) in T2DM. The worldwide dramatic increase of type-2 diabetic patients underlines the importance to find strategies to delay the onset or even prevent the disease. This project intends to provide strategies to protect beta-cells against oxidative stress and thus the loss of function and induction of apoptosis.

This paper has been awarded with the Phoenix Wissenschaftspreis 2010

Cooperating groups in this project:

Research 4

Ca2+ regulated K+ channels: Significance for beta-cell function and apoptosis

For a long period of time the KATP channel has been considered to be the most important channel for beta-cell function. From the experiments with mice lacking functional KATP channels we learned that other K+ channels must be involved in the regulation of glucose homeostasis. Good candidates are Ca2+-regulated K+ channels. These channels may not only play a role in the regulation of beta-cell function but also in the control in beta-cell mass. Both parameters mass and function are disturbed in type-2 diabetes. The enormous increase of patients with type-2 diabetes mellitus requires an intensive search for new drug targets to intervene as early as possible during the development of the disease. In this project we examine the link between the activity of two different Ca2+-dependent K+ channels (BK and SK4) and beta-cell function and survival. For this purpose we will also use BK and SK4 knock-out mice.

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Cooperating groups in this project:

Research 5

The AMP-activated protein kinase and beta-cell function

The AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of metabolism in many cells. It is stimulated by AMP and antidiabetic drugs like metformin and glitazones and inhibited by ATP. The beta-cell KATP channels which are essential for insulin secretion are regulated by nucleotides. However, KATP channels do not sense the bulk cellular ATP concentration. Enzymes like the adenylate kinase and the creatine kinase are involved in the regulation of the nucleotide concentrations in the direct vicinity of the KATP channels. This project will clarify the role of the AMPK for the regulation of KATP channels and thus insulin secretion. Moreover, the study should show whether metformin and glitazones directly affect beta-cells.

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Research 6

Bile acids and beta-cell function

During the last decade it became clear that bile acids are important signalling molecules besides their well known role in lipid metabolism. It is known that bile acids can activate membrane-bound and nuclear receptors. This project is the first study that evaluates the effects of bile acids on beta-cell function and apoptosis.

Cooperating groups in this project:

Research 7:

Microelectrode Arrays (MEAs)

Insulin secretion is tightly coupled to the electrical activity of beta-cells. At glucose concentrations stimulatory for insulin secretion, electrical activity is oscillating with bursts of action potentials and hyperpolarized interburst phases. Electrical activity can be measured by intracellular microelectrodes (Fig. 2 Aa & Ba), a time- and animal-consuming procedure that is inappropriate to test substances with a high throughput. The MEAs allow to record electrical activity (Fig. 2 Ab &Bb) with up to 60 extracellular electrodes simultaneously. The project intends to adapt the method to facilitate testing of possible antidiabetic drugs and provide concentration-response curves of distinct drugs in a reasonable period of time.

Figure 1 Figure 2

Cooperating groups in this project: