Introduction to Diabetes Mellitus

Yup, another post about diabetes... as if this post, this post and this post weren't enough for you :P

History of Diabetes

Diabetes has been around for a very long time. As early as 1500BC, the Ancient Egyptian physician Hesy-Ra wrote about a disease involving frequent urination. Another early text called the Susruta (which was written by an Indian physician of the same name), dating from around 1500-600BC, also wrote about some symptoms of diabetes (frequent urination, thirst, and so on). Other ancient physicians that mentioned diabetes include Appolonius of Memphis (~250BC) and Aretaeus the Cappodacian (~1st century AD).

Types of Diabetes

As you (hopefully) know, the main types of diabetes are type 1 and type 2. Patients with type 1 diabetes have β-cell destruction for some reason (sometimes some kind of autoimmune disease), but they only start showing symptoms when there are less than around 10% of their total β-cells remaining. Patients with type 2 diabetes acquire insulin resistance. At first, β-cell activity increases in order to compensate, but eventually β-cell function declines. It's important to note that decline in β-cell function doesn't occur in everyone: some people with insulin resistance do not develop diabetes. Type 2 diabetes is associated with metabolic syndrome, which is discussed here.

Aside from type 1 and type 2 diabetes, there are many other types of diabetes. These include gestational diabetes, other genetic conditions (e.g. mitochondrial conditions), pancreatic destruction (due to surgery, pancreatitis, etc.), endocrinopathies (e.g. Cushing's syndrome), drug/chemical-induced diabetes (e.g. glucocorticoids, atypical antipsychotics), infections (e.g. congenital rubella) and other immune problems (e.g. anti-insulin receptor antibodies). Phew! That was quite a list!

Diagnostic Criteria

Diagnostic criteria for diabetes are as follows:

• Fasting glucose >= 7mmol/L (normal < 6.1, though some other sources say 3.5 - 5.5 mmol/L)
• Random glucose test or 2hr post 75g glucose (in oral glucose tolerance test) >= 11.1 mmol/L (normal < 7.8)
• HbA1c (glycosylated haemoglobin) >= 6.5% (normal 4-6%. <7% indicates good control, >8% indicates poor control)

If your values are between the "normal" and "diabetic" ranges, you may be considered to have IFG (impaired fasting glucose) or IGT (impaired glucose tolerance). These conditions are also sometimes known as "pre-diabetes."

Prevalence

• Age- Type 2 diabetes becomes more prevalent as you get older, as living longer gives your β-cells more time to crash and burn.
• Geographical location- The Western Pacific area (Australia and surrounding islands) has one of the highest rates of diabetes. Some of the small islands near Australia have particularly high rates of diabetes.
• Ethnicity- Caucasians seem to have the lowest risk of developing diabetes. Many indigenous populations are at relatively high risk of diabetes.
• Genetics- Type 1 diabetes has a genetic component. If one person has diabetes, the chance that a monozygotic twin also has it is 50%, whereas the chance for a sibling is 5%, the chance for the father is 6%, and the chance for the mother is 2%. The "high-risk" HLA alleles are DR3, DR4 and DQ8.

Function of Insulin

See earlier post: Glucose Metabolism and Diabetes

Insulin was discovered by Banting and Best in 1921 and was used for treatment in 1922.

Insulin signals via the insulin receptor, which I have discussed here.

Insulin Resistance

As mentioned above, type 2 diabetes is associated with insulin resistance. Insulin resistance affects various different parts of the body: adipose tissue increases lipolysis and decreases triglyceride clearance and glucose uptake, muscle tissue decreases triglyceride clearance and glucose uptake, and the liver increases glucose output and decreases glucose uptake. Insulin resistance is associated with increased central abdominal fat, particularly intra-abdominal fat (not subcutaneous fat, which is why liposuction isn't always helpful). It's important to note that even lean people can have a lot of central abdominal fat.

There are several theories as to why abdominal fat leads to insulin resistance. The "lipid oversupply hypothesis" simply suggests that the oversupply of lipids to muscle leads to insulin resistance. The "adipokine hypothesis" suggests that signalling molecules secreted by adipose tissue, such as leptin, can lead to insulin resistance. PPARγ agonists (glitazones/TZDs) stimulate uptake of fat by subcutaneous fat cells, reducing fatty acid supply to the muscles and liver, which in turn reduces insulin resistance.

Now for a note on brown fat, which I've discussed in more detail here. Brown fat in adults is sometimes known as "beige fat." Studies have suggested that during exercise, muscles release irisin, which may help convert white fat to beige fat.

Complications

See previous post: Diabetes Mellitus

Some pathways that may lead to hyperglycaemic damage include the polyol, hexosamine, protein kinase C and AGE pathways. These pathways are most associated with microvascular complications (i.e. damage to small blood vessels of the eyes, kidneys etc.). Macrovascular complications (e.g. coronary heart disease) are more related to an acceleration of atherosclerosis, which in turn might be due to an increase in prothrombotic cytokines. New medications for diabetes must be tested for cardiovascular outcomes, given that diabetes tends to raise risk for cardiovascular disease.