This chapter will concentrate on the monogenic disorders of the beta cell that account for 1–2% of diabetes. They are discrete disorders, which are a significant cause of diabetes in their own right. Correct molecular diagnosis is important to predict clinical course, explain other associated clinical features, enable genetic counseling, diagnose family members, and most importantly guide appropriate treatment. In addition to this clinical importance, the discovery and study of monogenic disorders has given further insight into the physiology and pathophysiology of the beta cell.
In normal health the pancreatic beta cell is a finely tuned system that ensures appropriate insulin release in order to maintain homeostasis of blood glucose within a narrow physiologic range. Problems with the beta cell can result in diabetes, or more rarely, oversecretion of insulin and hypoglycemia. The most common disease resulting from beta-cell dysfunction in humans is type 2 diabetes (T2DM). This is a complex polygenic disorder that is likely to represent a heterogeneous spread of defects.
MONOGENIC BETA-CELL DISORDERS IN KEY ASPECTS OF BETA-CELL FUNCTION
To understand the pathophysiology of the beta cell in monogenic diabetes it is important to outline the process whereby the beta cell senses glucose and translates this into an appropriate release of insulin. Figure 28.1 shows a schematic representation of the beta cell and the legend describes the process of glucose-insulin secretion coupling. The sites of monogenic defects (indicated on the figure) that cause diabetes or hypoglycemia are as follows:
- GLUT2: GLUT2 mutations cause Fanconi–Bickel syndrome. The phenotype is predominantly due to defects in hepatic GLUT2 causing glycogen storage disease, rather than pancreatic GLUT2. This will not be discussed in this chapter.
- GCK: Loss of function mutations in GCK cause a rise in fasting glucose with maintained homeostasis, referred to as glucokinase—maturity onset diabetes of the young (GCK-MODY).
- Glycolysis: Defects in glycolysis are described in transcription factor MODY (TF-MODY) due to mutations in Hepatocyte nuclear factor (HNF)-1 alpha (HNF1A) and HNF4A.
- Mitochondria: Mitochondrial defects are described in: maternally inherited diabetes and deafness (MIDD).
- KATP channel: Mutations in SUR1 and Kir6.2 (components of The KATP channel) cause both permanent and temporary neonatal diabetes and have been shown to cause hyperinsulinemia of Infancy.
- Endoplasmic reticulum: Wolfram syndrome (WFS-1) and Wolcott–Rallison syndrome (EIF2AK3) genes encode proteins that localize to the endoplasmic reticulum.
- Insulin: Insulin gene mutations causing mutant insulin, which misfold and cannot be secreted resulting in neonatal diabetes.
CLINICAL CATEGORIES OF MONOGENIC ?-CELL DISORDERS
This chapter will discuss the three most important clinical categories of monogenic disorders of the beta cell: (1) Maturity-onset diabetes of the young, (2) Neonatal diabetes, and (3) Diabetes with marked extrapancreatic features (see Figure 28.2).