Aetiology
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Diabetes Mellitus Type 2Published by: Domus Medica | SSMGLast published: 2017Diabète sucré de type 2Published by: SSMG | Domus MedicaLast published: 2017Type 2 diabetes often presents in people with a background genetic predisposition, and is characterised by insulin resistance and relative insulin deficiency. Insulin resistance is aggravated by ageing, overweight (body mass index [BMI] 25.0 to 29.9 kg/m²), and obesity (BMI >30 kg/m²) in particular. In addition to older age, overweight/obesity and genetic predisposition, other strong risk factors for type 2 diabetes include gestational diabetes, non-diabetic hyperglycaemia, polycystic ovary syndrome, hypertension, dyslipidaemia, cardiovascular disease, and stress. Additional risk factors have also been implicated, but their association is weaker and/or less well defined, for example insomnia, depression, autism, statin use, smoking, and caffeine consumption.[16][17][18]
Among people with pre-diabetes/diabetes and obesity, weight loss often reduces the degree of insulin resistance and may delay diabetes onset or ameliorate diabetes severity and thereby reduce risk of long-term complications. Insulin resistance affects primarily the liver, muscle, and adipocytes, and it is characterised by complex derangements in cellular receptors, intracellular glucose kinase function, and other intracellular metabolic processes.[19] The complexity and variety of these derangements suggest that what is now classified as type 2 diabetes may be, in fact, a larger group of conditions that await future definition.
Pathophysiology
In type 2 diabetes, insufficient levels of insulin fail to meet the elevated demand caused by an increased insulin resistance.[20] Adaptive changes in beta-cell mass and beta-cell function typically allow the regulation of insulin demand during insulin resistance. If functional beta-cell compensation becomes insufficient, a cycle of incomplete glucose clearance and subsequent elevated blood glucose contributes to further deterioration of beta-cell mass and function. The increased beta-cell workload results in functional exhaustion, possible dedifferentiation, and, finally, beta-cell death.[20] Beta-cell function is estimated to be decreased by about 50% to 80% at the time of diagnosis of type 2 diabetes, and protection and recovery of beta-cell function should be a main treatment and prevention target.[20]
While insulin resistance in the muscle and liver, along with beta-cell failure, form the three core pathophysiological components of type 2 diabetes, other contributing pathophysiological factors have been implicated in the development of glucose intolerance in type 2 diabetes.[21] Specifically fat cells (accelerated lipolysis), the gastrointestinal tract (incretin deficiency/resistance), alpha-cells (hyperglucagonaemia), the kidney (increased glucose reabsorption), and the brain (insulin resistance) also play important roles.[21] In 2009, DeFronzo collectively called these eight factors the ‘Ominous Octet’.[21]
The precise mechanism by which the diabetic metabolic state leads to microvascular and macrovascular complications is only partly understood, but probably involves both uncontrolled blood pressure (BP) and uncontrolled glucose. Mechanisms may involve defects in aldose reductase and other metabolic pathways, and damage to tissues from accumulation of glycated end products. With respect to macrovascular complications, high BP and glucose raise risk, but so do lipid abnormalities and tobacco use. One unifying theory postulates the existence of a metabolic syndrome that includes diabetes mellitus, hypertension, dyslipidaemias, and obesity, and predisposes to coronary heart disease, stroke, and peripheral artery disease.[19][22][23] However, this theory is not universally accepted as more clinically useful than assessing individual cardiovascular risk factors.[24][25]
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