Metabolism on-line - the virtual tutorial room

 

copyright © 2008 - 2015 David A Bender

 

An unusual cause of diabetes - how the pancreas senses a rise in blood glucose

 

Key points from this exercise:

If an enzyme has a Km that is significantly lower than the normal range of substrate concentration in the cell then it will act at a more or less constant rate regardless of changes in the availability of substrate.

If an enzyme has a Km that is similar to, or higher than, the normal range of substrate concentration in the cell, it will show increasing activity as the concentration of substrate increases.

In the liver, the low Km isoenzyme, hexokinase, always acts at a constant rate, since it is saturated at all normal concentrations of glucose in the liver. Its role is to provide a constant entry of glucose into glycolysis to meet the liver's metabolic needs.

In the liver and pancreas, the high Km isoenzyme, glucokinase, permits increased metabolism of glucose when the plasma concentration rises above the normal fasting level. In the liver this provides the first step in the control of blood glucose concentration, trapping glucose in the liver as glucose 6-phosphate, which cannot cross the cell membrane, and leading to increased synthesis of glycogen and fatty acids.

In the pancreas, glucokinase acts as the sensor of increased blood glucose, leading to increased formation and metabolism of glucose 6-phosphate. Metabolism of this glucose leads to an increase in ATP formation, which leads to closure of a potassium channel, depolarisation of the cell membrane and opening of a voltage-gated calcium channel. The increased intracellular calcium stimulates fusion of insulin secretory granules with the cell membrane and exocytosis - the secretion of insulin.

More about MODY

Altogether 11 types of MODY have been described, due to mutations in different genes (see http://omim.org/entry/606391 for these different types of MODY).

MODY 2, due to glucokinase deficiency, is characterised by moderate hyperglycaemia, but is not associated with the adverse effects of poor glycaemic control seen in other types of diabetes, and generally no treatment is required. More on MODY due to glucokinase deficiency at http://www.diabetesgenes.org/content/glucokinase and http://omim.org/entry/125851.

The following paper on mutations in glucokinase and MODY may be of interest. Note that when the paper was published MODY was considered to be a variant of type 2 diabetes, since patients were still able to secrete some insulin, but not enough to maintain normal glycaemia in response to a glucose load. MODY is now considered to be a separate type of diabetes, distinct from either type 1 or type 2.

Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6.
Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships.
Gidh-Jain M, Takeda J, Xu LZ, Lange AJ, Vionnet N, Stoffel M, Froguel P, Velho G, Sun F, Cohen D, et al.

Abstract
The glycolytic enzyme glucokinase plays an important role in the regulation of insulin secretion and recent studies have shown that mutations in the human glucokinase gene are a common cause of an autosomal dominant form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) that has an onset often during childhood. The majority of the mutations that have been identified are missense mutations that result in the synthesis of a glucokinase molecule with an altered amino acid sequence. To characterize the effect of these mutations on the catalytic properties of human beta-cell glucokinase, we have expressed native and mutant forms of this protein in Escherichia coli. All of the missense mutations show changes in enzyme activity including a decrease in Vmax and/or increase in Km for glucose. Using a model for the three-dimensional structure of human glucokinase based on the crystal structure of the related enzyme yeast hexokinase B, the mutations map primarily to two regions of the protein. One group of mutations is located in the active site cleft separating the two domains of the enzyme as well as in surface loops leading into this cleft. These mutations usually result in large reductions in enzyme activity. The second group of mutations is located far from the active site in a region that is predicted to undergo a substrate-induced conformational change that results in closure of the active site cleft. These mutations show a small approximately 2-fold reduction in Vmax and a 5- to 10-fold increase in Km for glucose. The characterization of mutations in glucokinase that are associated with a distinct and readily recognizable form of NIDDM has led to the identification of key amino acids involved in glucokinase catalysis and localized functionally important regions of the glucokinase molecule.

link to the abstract and free full text by clicking here

and a more recent review

Rev Endocr Metab Disord. 2010 Sep;11(3):179-83.
Mutations in pancreatic ß-cell glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus.
Hussain K.

Abstract

Glucokinase is a key enzyme involved in regulating insulin secretion from the pancreatic ß-cell. The unique role of glucokinase in human glucose physiology is illustrated by the fact that genetic mutations in glucokinase can either cause hyperglycaemia or hypoglycaemia. Heterozygous inactivating mutations in glucokinase cause maturity-onset diabetes of the young (MODY), homozygous inactivating in glucokinase mutations result in permanent neonatal diabetes whereas heterozygous activating glucokinase mutations cause hyperinsulinaemic hypoglycaemia.

link to the abstract and full text by clicking here

 

End of this exercise