2.

Transcriptional Regulation of Insulin

Gene Expression
Isabella Artner and Roland Stein

Summary. The insulin gene is expressed exclusively in the beta cells of the
islet of Langerhans. The release of this polypeptide hormone into the blood-
stream, principally in response to elevated glucose levels, is essential for
controlling carbohydrate metabolism in peripheral tissues. A fundamental
cause of diabetes, a disease that affects millions of people and is a major cause
of morbidity and mortality, is the inability of beta cells to produce sufficient
amounts of insulin, resulting in hyperglycemia. A large effort is underway to
identify and characterize the transcriptional regulators of genes, like insulin,
that are important in islet beta cell function. It is hoped that this knowledge
will provide information into how beta cell function is disrupted in type 2
diabetic individuals, and to provide a foundation for cell-based therapies that
may be effective in diabetes treatment. Many of the cis-acting sequences,
essential in directing both selective and glucose-inducible transcription
within the 5′-flanking region of the insulin gene, have been defined and
several of the key trans-activators isolated, including PAX-6, PDX-1, MafA,
and BETA2/NeuroD1. In addition, the inactivation of genes encoding these
regulatory proteins in mice has established that most play a role in islet cell
differentiation during pancreas development. In this review, the regulatory
role of the islet-enriched transcription factors of the insulin gene will be dis-
cussed, with a focus on their role in adult beta cell function.

Introduction
Insulin is a powerful regulator of metabolism. This hormone, which is pro-
duced by the beta cells of the endocrine pancreas, increases the storage of
glucose, fatty acids, and amino acids by its actions on liver, adipose tissue,

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical

Center, 723 Light Hall, Nashville, TN 37232, USA

13
14 I. Artner and R. Stein

and muscle. The endocrine pancreas is comprised of discrete cellular islands

(termed the islets of Langerhans), which are dispersed throughout the larger
mass of the exocrine pancreas. The islets of rodents are mainly composed of
beta cells, but at their periphery contain four other endocrine cell types,
alpha, delta, epsilon, and pancreatic polypeptide (PP) that synthesize the
hormones glucagon, somatostatin, ghrelin, and PP, respectively.
The primary regulator of insulin expression in pancreatic beta cells is the
concentration of blood glucose. The phosphorylation of glucose by glucoki-
nase, which exhibits a high Km for glucose, appears to function as the glucose
sensor by adjusting the metabolic flux through glycolysis to the extracellular
glucose concentration [1]. Glucose metabolism in beta cells generates intra-
cellular signals which stimulate insulin secretion, insulin mRNA translation,
and insulin gene transcription (reviewed in [2]).
Diabetes mellitus, the primary human disease affecting the endocrine pan-
creas, results either from the autoimmune destruction of beta cells (type 1
diabetes) or from defects in the production of insulin and/or sensing of this
hormone by peripheral tissues (type 2 diabetes). Because of reduced insulin
action, blood glucose levels remain elevated and cause early morbidity and
mortality. Despite insulin’s availability and advances in bioengineering that
have led to improved technologies for insulin administration, the available
systems incompletely mimic the beta cell’s ability to sense and reduce circu-
lating glucose levels sufficiently to prevent the severe complications associ-
ated with the disease, which predominately targets the kidney, vasculature,
and eye.
Type 2 is the most common form of diabetes mellitus and largely afflicts
middle-aged individuals. Genetic studies suggest a major genetic component,
but few susceptibility genes have been identified [3], except in maturity
onset diabetes of the young (MODY). MODY, an autosomal dominant
form of type 2 diabetes, is characterized by early-onset (usually <25 years)
with a primary defect in insulin secretion [4]. There are six identified genetic
loci associated with MODY. Although the first locus discovered was for
the gene encoding glucokinase [5], it is striking that all of the other character-
ized ones represent transcription factors involved in the regulation of
essential target genes expressed in pancreatic beta cells, and include Hepato-
cyte Nuclear Factor 1alpha (HNF), HNF1beta, HNF4alpha, PDX-1, and
BETA2/NeuroD1 (reviewed in [6]). Notably, BETA2 [7] and PDX-1 [8] are
direct regulators of insulin transcription. These findings illustrate how the
identification and characterization of transcriptional regulators of islet-
enriched products, like insulin, provide insight into the disease process. This
chapter focuses on how such islet-enriched transcriptional regulators of the
insulin gene impact islet beta cell function (see [2,9] for recent pertinent
reviews).