Page created on March 25, 2019. Last updated on June 3, 2020 at 17:57
Genetic factors: The concordance between identical twins is around 80%, indicating a much stronger genetic factor than for 1DM. The specific genetic factors involved are not as well known as for 1DM, but it’s certain that HLA plays no role. Possible genes that are mutated in 2DM include:
- GCGR – the glucagon receptor gene
- TCF7L2 – a transcription factor that is active in β-cells – the most significant gene associated with 2DM
- ATP-gated K+ channel – a channel found on the surface of β-cells that is involved in glucose sensing
Mutations in the gene for glucokinase is important for the development of the special type of DM called MODY. Another gene class called HNF is also involved in MODY.
The pathophysiology department also mentions genes for insulin, insulin receptor, amylin and mitochondrial DNA as possible genetic factors, but I couldn’t find any support for these claims in modern literature.
Environmental factors: Obesity, physical inactivity, diet high in sugar and saturated fats, hypertension, dyslipidaemia and history of gestational diabetes are all important risk factors for developing 2DM. Abdominal obesity is a bigger risk factor than generalized obesity.
There are three factors in the background of 2DM:
- Insulin resistance – peripheral tissues’ inability to react to insulin
- Impaired insulin release from β-cells
- Increased hepatic glucose output
Insulin resistance refers to the condition where cells lose sensitivity to insulin. Every time a cell is exposed to insulin the production of GLUT4 decreases a little. The next time the cell needs energy will higher amounts of insulin be required to activate the same amount of GLUT4. The cell is now slightly more resistant to insulin. Another mechanism of insulin resistance involves decreasing the signal propagation that occurs when the insulin receptor activates the PKB (protein kinase B) pathway. If this pathway is less effective the cell will respond less strongly to the bound insulin. Downregulating the number of insulin receptors is also a mechanism of insulin resistance.
As explained in topic 42 physical activity can directly activate GLUT4 on muscle cells. In the case of physical inactivity will muscle cells only take up glucose in response to insulin, which increases their insulin need, which may increase insulin resistance.
Most people who are obese develop some degree of insulin resistance, but this alone isn’t enough to cause diabetes, as these people will produce more insulin to overcome the increased resistance. Diabetes develops only when the β-cells can’t produce this extra amount of insulin.
Obesity leads to an increased mobilization of free fatty acids, which is associated with insulin resistance and β-cell dysfunction. Obesity is also a chronic inflammatory condition, and the abundance of inflammatory cells and cytokines may contribute to the development of insulin resistance and diabetes.
PPAR-γ is a nuclear receptor that increases insulin sensitivity and decreased plasma glucose levels when activated. This nuclear receptor is activated by certain unsaturated fatty acids and prostaglandins and by a class of drugs called thiazolidinedione, which is used to treat 2DM.
The pathogenesis of 2DM follows these three phases:
- Insulin resistance develops. Insulin secretion increases to overcome the increased resistance
- β-cells eventually become exhausted and insulin secretion starts to decrease
- Insulin secretion eventually becomes insufficient to overcome the increased resistance
Impaired fasting glucose doesn’t develop until the third stage, but impaired glucose tolerance develops already at the first stage. As the peripheral tissues become insulin resistant the β-cells will be unable to produce enough insulin quickly enough to lower the plasma glucose to below 11.1 mmol/L within 2 hours, causing them to score a “pre-diabetes” or “diabetes” on the oral glucose tolerance test (OGTT).
|Phase||Insulin resistance||Fasting plasma insulin||Blood glucose after oral glucose load (OGTT)||Fasting blood glucose|
|I||Mildly increased||Increased||Slightly increased||Normal|
|II||Moderately increased||Decreased compared to phase I||Moderately increased||Normal|
|III||Severely increased||Decreased||Severely increased||Increased|
Phase I and II may be regarded as pre-diabetes. Manifest DM occurs first when there is chronic hyperglycaemia (phase III).
The treatment of 2DM involves lifestyle changes like weight reduction, physical exercise and change of diet. The goal is to maintain a HbA1C of <7 %, corresponding to an average long-term blood glucose of <8.6 mmol/L. If this is not maintained with lifestyle changes oral antidiabetic drugs may be used. Metformin (a type of biguanide) is the first drug of choice. Sulfonylureas, α-glucosidase inhibitors, DPP-4 inhibitors, insulin and other drugs may be used as second choice.
Metformin increases peripheral insulin sensitivity and decreases hepatic gluconeogenesis and intestinal glucose absorption.
4 thoughts on “44. Etiology and pathogenesis of 2DM”
can you please explain how increased mobilazation of NEFA can cause insuline resistance and beta cell dysfunction?
thanks in advance
No, I can’t. I don’t know why, and I’m not sure science as a whole even knows why. I do know that it’s not important to know that, though.
Hi maybe you know this from further knowledge about diabetes but why is phase II considered prediabetes when phase III is already end stage diabetes with necessity for insulin treatment (according to the blue book explanation)?
The blue book is neither good at explaining nor correct a lot of the time. The transition from pre-diabetes to diabetes occurs when the insulin production is insufficient to overcome the insulin resistance, which results in chronic hyperglycaemia. Whether insulin is necessary or not depends on the severity of the chronic hyperglycaemia, and not on the “phase” or “stage” the diabetes is in. An insulin-dependant diabetes can regress into insulin-independent diabetse with correct conservative measures, like weight loss, exercise, etc.