Investigating the Pathogenesis and Risk of Type 2 Diabetes

Clinical Applications of Metabolomics

Theodore W Ng; Anmar A Khan; Peter J Meikle


Clin Lipidology. 2012;7(6):641-659. 

In This Article

Abstract and Introduction


Many countries are facing an obesity epidemic and an associated increase in Type 2 diabetes (T2D). T2D and its complications are major causes of morbidity and mortality worldwide. To tackle this growing problem a concerted effort on multiple fronts will be required. Early intervention has been demonstrated to prevent or even reverse disease progression, therefore risk assessment to target limited resources to those at greatest risk will improve the cost efficacy of health budgets. A clearer understanding of the pathogenesis at the molecular level may provide us with new therapeutic targets, while improved monitoring of disease and response to treatment will provide for a personalized medicine approach to maximize health outcomes. Metabolomics is a powerful approach to unravel the complex relationships between metabolism, obesity and progression to T2D and, at the same time, has potential as a clinical tool for risk assessment and monitoring of disease.


The Australian population is in the midst of an obesity epidemic; associated with this is a dramatic increase in the prevalence of Type 2 diabetes (T2D) and its precursor, impaired glucose tolerance (IGT). If the current pattern continues in Australia, the prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. More than one-third of individuals will develop diabetes within their lifetime and there will be an additional 1 million Australians with diabetes by the year 2025.[1] This epidemic is not restricted to Australia, with the WHO estimating that more than 346 million people around the world have T2D and that diabetes-related deaths will double between 2005 and 2030.[201]

T2D is characterized by insulin resistance (IR), dysfunctional secretion of insulin from pancreatic β-cells or both.[2] The resulting elevated plasma glucose can result in a number of chronic complications including neuropathy, nephropathy, retinopathy and peripheral arterial disease.[2,202] T2D is also a major risk factor for cardiovascular disease,[3] with three out of five diabetic patients developing cardiovascular disease.[203] These diabetic complications lead to significant morbidity and mortality for T2D patients (Figure 1).

Figure 1.

Risk factors, metabolic abnormalities and complications of Type 2 diabetes.
Genetic and environmental risk factors are associated with metabolic abnormalities in multiple tissues/organs that manifest as dyslipidemia, oxidative stress and inflammation. These can progress to insulin resistance, impaired glucose tolerance and ultimately Type 2 diabetes. Diabetic complications can affect multiple organs leading to increased morbidity and mortality.
BCAA: Branched-chain amino acid.

Dyslipidemia, obesity and other symptoms of the metabolic syndrome are known risk factors for the development of T2D.[4] However, the causal relationship between lipid metabolism and the pathogenesis of T2D is still poorly understood. Furthermore, the relationship between elevated blood glucose, the hallmark of T2D, and the development of microvascular and macrovascular diabetic complications is also poorly defined. Lifestyle, including smoking, diet and activity levels can also influence the disease process,[5–7] but again the metabolic basis for this is not clear.

A key unmet medical need in the prevention and management of T2D is the ability to differentiate between those who are at increased risk versus those at low risk of disease development and, if they have already been diagnosed, progression to the development of micro- and macro-vascular complications. Early detection of diabetes or the identification of those at increased risk provides the opportunity for early treatment to prevent onset or progression of the disease.[4,8]