BIOL212- Biochemistry of Disease

Metabolic Disorders: Diabetes

Diabetes mellitus is, after heart disease and cancer, the third leading cause of death in the west.

Insulin is either not secreted in sufficient amounts or does not efficiently stimulate its target cells.

Insulin-stimulated glucose uptake

Insulin-stimulated glucose entry into cells is impaired and, cells are ‘starved’ of glucose.

Blood glucose levels become elevated and glucose ‘spills over’ into the urine.

Triglyceride hydrolysis, fatty acid oxidation, gluconeogenesis and ketone body formation are all accelerated.

Ketone bodies are acidic and their accumulation puts a strain on the buffering capacity of the blood and on the ultrafiltration activity of the kidney, which controls blood pH by excreting excess H+ into the urine. H+ excretion is accompanied by Na+, K+, Pi and H2O excretion leading to dehydration and a decrease in blood volume. This can, ultimately, be life-threatening.

There are 2 major forms of diabetes mellitus: Insulin-dependent or juvenile-onset diabetes mellitus (IDDM or Type I diabetes), which usually occurs suddenly in childhood.

Non-insulin dependent or maturity-onset diabetes mellitus (NIDDM or Type II diabetes), which usually develops gradually after the age of 40.

The insulin polypeptide.

Insulin-dependent diabetes Insulin is absent or nearly so because the pancreas lacks, or has defective, b-cells.

This usually arises as a consequence of an autoimmune response that selectively destroys b-cells. Typically, the disease develops over several years as the immune system slowly destroys the b-cells. Only when > 80% of these cells are destroyed do the classic symptoms of diabetes emerge.

Individuals require daily insulin injections and must follow carefully balanced diet and take regular exercise.

Life spans may be reduced as a result of degenerative complications, such as kidney malfunction, nerve impairment and cardiovascular disease that arise form the imprecise metabolic control provided by periodic insulin injections.

Hyperglycaemia also leads to blindness through retinal degradation and glucosylation of lens proteins which causes cataracts.

Insulin pen

Insulin pump

Non-insulin dependent diabetes Type II diabetes accounts for > 90% of diagnosed cases of diabetes and affects ~20% of the population over 65 years of age.

Complex mode of inheritance with interactions between several different susceptibility genes (i.e. this is a clinically and genetically heterogeneous disorder). There are normal or greatly elevated insulin levels and symptoms usually arise as a consequence of a lack of fully functional insulin receptors.

Cells do not respond normally to insulin and are therefore insulin resistant.

The hyperglycaemia that accompanies insulin resistance induces the pancreatic b-cells to increase production of insulin. However, the high basal level of insulin secretion diminishes the ability of the b-cells to respond to further increases in blood glucose. Consequently, the hyperglycemia tends to worsen with time. Increased insulin production resulting from overeating may eventually suppress the synthesis of insulin receptor. This is consistent with the observation that diet alone often decreases the severity of the disease.

Mutations in the insulin receptor are associated with this form of diabetes.

These mutations produce alterations in insulin binding (a-subunit) or tyrosine kinase activity (b subunit).

Maturity-onset diabetes of the young A form of non-insulin dependent diabetes, called maturity-onset diabetes of the young (MODY) appears by age 25 and is the result of a mutation in the glucokinase gene.

Prevalence may be much higher than commonly believed because younger individuals are often asymptomatic. Transmitted in a dominant fashion - mutation of the MODY2 gene on chromosome 7.

Human glucokinase

MODY 2 is the structural gene for glucokinase and has two tissue-specific promoters, one of which is active in b-cells and the other in liver cells. Human b-cell glucokinase mRNA is the product of exons 1a and 2-10 whereas liver glucokinase mRNA is derived from exons 1b and 2-10.

Over 30 different mutations have been identified in the glucokinase gene in MODY patients.

MODY patients with glucokinase mutations have fasting glucose levels of 6.1-7.8 mM. (Normal blood concentrations range from 3.6 – 5.8mM).

This mild hyperglycaemic syndrome is generally stable over time and can usually be treated with dietary therapy alone or diet and oral hypoglycaemic agents.

How do b-cells respond to blood glucose levels? In healthy humans the pancreas responds to increases in the concentration of blood glucose by secreting insulin.

b-cells contain GLUT 2 - the high km glucose transporter protein.

Glucose enters b-cells at a rate proportional to its plasma concentration and subsequent metabolism (via glucokinase action) generates the signal for insulin secretion.

Glucokinase catalyses the phosphorylation of glucose to G6P.

The properties of glucokinase distinguish it from other mammalian hexokinases.

It has a high km for glucose.

Essentially all the G6P produced by the glucokinase reaction is degraded to pyruvate and then converted to acetyl CoA for oxidation by the Citric Acid Cycle.

This means that the b-cell’s rate of oxidative phosphorylation is directly linked to the availability of glucose and respiratory activity regulates insulin synthesis and secretion.

The age-dependent decline in mitochondrial oxidative capacity may explain the age-dependent onset on non-insulin dependent diabetes.

Summary In insulin-dependent diabetes, insulin is absent because the pancreas lacks functional b-cells.

In non-insulin dependent diabetes there are normal or elevated insulin levels and symptoms usually arise as a consequence of a lack of functional insulin receptors. Maturity-onset diabetes of the young (MODY) is the result of a mutation in the glucokinase gene.

Glucokinase plays an essential role in the coordination of insulin release with glucose supply (it is the glucose ‘sensor’).

Essentially all the G6P produced by the glucokinase reaction is converted to acetyl CoA for oxidation by the Citric Acid Cycle.

The b-cell’s rate of oxidative phosphorylation is directly linked to the availability of glucose and respiratory activity regulates insulin synthesis and secretion.