BC21D Carbohydrate Metabolism Rachael Irving Biochemistry

β cell Dysfunction and Diabetes Insulin resistance lead to the increase need for insulin biosynthesis. Increased demand leads to exhaustion of the β cells and ultimate failure. The β cells may also become desensitized due to elevations in glucose. Increased glucose levels have been associated with reduction in the expression of the insulin and the gene (PDX-1) responsible for regulation of β cell replication.

Model of Pancreatic β Cell

β cells and compensatory response. In response to insulin resistance and decreased insulin sensitivity β cells must demonstrate compensatory hyperplasia. If the β cells do not overproduce to compensate for the stress of insulin resistance then excess glucose will stay in the circulation and this will lead to diabetes.

Impaired Glucose Tolerance If the β cells can somewhat compensate for elevated glucose by producing some insulin, that causes some level of glucose reduction, a condition results which is called impaired glucose tolerance (a touch of sugar).

Model of Pancreatic β Cell

Mechanism leading up to inherited diabetes Glucose is transported into the cell by a specific protein(GLUT-2)on the cell surface. Glucokinase catalyzes the transfer of phosphate from ATP to glucose to form glucose- 6- phosphate. Glucokinase functions as the glucose sensor of the β cells.

Mechanism leading up to inherited diabetes The generation of ATP by glycolysis and the krebs cycle leads to inhibition and closure of the ATP sensitive potassium channels. The generation also leads to opening of the voltage dependent calcium channels. Insulin secretory granules fuse with the plasma membrane and insulin is released.

Mechanism leading up to inherited diabetes If any of the genes encoding glucokinase is defective then there will be a reduction in β cell glucokinase activity, decreased glucose phosphorylation in the β cell and glucose stimulated insulin release at any blood glucose level. Mutation in the genes that are involved in transcription of insulin can lead to diabetes.

Inherited Diabetes ( Maturity Onset Diabetes of the Young-MODY) MODY 1 Patients with mutations in the gene that encode HNF-4  (MODY1) which is located on chromosome 20q12-q13.1, have altered glucose metabolism in the liver and impaired insulin secretion in the β cells. In most patients the diabetes occurs at post-pubertal age.

MODY 2 More than 130 forms of mutations have been identified in the glucokinase gene, which is situated on chromosome 7p13-15 and which is commonly called MODY2. It is the most well characterized subtype of MODY. Glucokinase is mostly expressed in the pancreatic β cells and in the liver and acts as a glucose sensor to fine tune insulin secretion and blood glucose leve l. Patients with diabetes caused by glucokinase mutations tend to present in early adulthood a mild clinical course of diabetes.

MODY3 Mutations in the gene encoding hepatocyte nuclear factor HNF-1  cause MODY3. The gene is located on chromosome 12. The majority of patients with HNF-1α mutations have mild symptoms of diabetes and are classified as having type 2 diabetes After an overnight fast insulin secretion is normal, however as the plasma glucose concentration increases to approximately 7.0 to 8.0 mmol/l, insulin secretion does not continue to increase as it would in a non-diabetic person but rather begins to level off.

MODY4 Insulin promoter factor-1 (IPF-1) is a homeodomain transcription factor that is absolutely required for the development of the pancreas. Mutations in the gene that encodes IPF-1 are a rare cause of MODY. IPF-1 is located on chromosome 13q. IPF-1 is implicated in the transcriptional regulation of key β cell specific genes GLUT-2 and glucokinase. Much of the current understanding of this form of MODY is based on studies of a single family. The proband was an infant with permanent neonatal diabetes and pancreatic exocrine insufficiency.

MODY5 HNF-1  is located on chromosome 17q. Mutations in the gene encoding HNF-1  are the cause of an uncommon but distinct form of MODY. MODY5 is characterized by both diabetes mellitus and renal cysts (Beards et al, 1998). There is usually renal dysfunction leading to chronic renal insufficiency and failure. In addition, two of four female carriers in one family had internal genital abnormalities.

MODY6 NeuroD1, also called Beta2, functions as a regulatory switch for endocrine pancreatic development. NeuroD1 is located on chromosome 2. Defective binding of NeuroD1 to target promoters in pancreatic islets leads to development of type 2 diabetes. Persons usually develop this inherited form of diabetes before age 25 years.

Test using for the detection of diabetes The glucose Tolerance Test is used to detect or diagnose diabetes mellitus or impaired glucose tolerance. A fasting blood sample is taken and then 75g of glucose is ingested and samples are taken at 30 minutes interval for two hours. The method usually used for detection is the glucose oxidase method. Glucose oxidase oxidizes glucose to gluconic acid and hydrogen peroxide. Another enzyme peroxidase liberates oxygen, this oxygen oxidizes a dye to give a colour which is proportional to the amount of glucose in the blood.