Type 2 diabetes is primarily defined by elevated blood glucose, but other disease characteristics include central obesity and a lack of physical activity. The earliest molecular changes leading to type 2 diabetes are not well defined but are thought to include blood vessel dysfunction in addition to a rise in blood glucose. A research team led by Anderson et al.1 investigated early metabolic changes in prehyperglycemic subjects and found some interesting results.

To identify subjects at increased risk for developing diabetes, Anderson et al.1 selected women who had previously been enrolled in a Hyperglycemia and Pregnancy Outcomes Study (HPOS). The presence of high blood glucose during pregnancy—often due to gestational diabetes—increases susceptibility to diabetes later in life, so researchers selected 18 women who had experienced gestational diabetes during their last trimester of pregnancy. The intermediate risk group included 45 subjects with third-trimester blood glucose levels in the upper quartile of normal, but below the limit for gestational diabetes. The control group included 43 subjects who were below the median glucose values during their third trimester. The researchers hypothesized that significant differences would exist in the serum metabolic profiles of the three groups.

Twenty-two months post-birth, the research team measured anthropometric and biochemical indicators for each subject. They observed significant differences between the risk groups in waist circumferences as well as in levels of adiponectin, fasting glucose, post-prandial glucose and hemoglobin A1C. However these last three measurements were still within the “normal” range for all subjects and none of the subjects were diagnosed with diabetes at the time of the study.

The researchers analyzed serum samples from each subject using liquid chromatography mass spectrometry. After thorough principal component analysis and statistical evaluation, researchers compared the serum metabolic profiles between the increased risk, intermediate risk and control groups.

Levels of numerous metabolites differed significantly between the three groups. Of the 3552 metabolite features identified:

  • 43 metabolites differed between the intermediate risk group and controls,
  • 69 metabolites differed between the increased risk group and controls, and
  • 72 metabolites differed between the intermediate and increased risk groups.
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The metabolites that differed between the increased and intermediate risk groups and the control group included phospholipids, acylcarnitines, short and long chain fatty acids and diglycerides. Other significant differences were seen in the levels of bile acids, steroids, prostanoids and amino acid metabolites.

The researchers discussed the possible functions of each of these metabolites, however their most interesting suggestion was that a metabolic progression occurs in early diabetes. Some metabolic changes occur by the time subjects reach the intermediate risk stage, and other metabolic changes become apparent at the increased risk stage.

The main points of this study:

  • Metabolic changes precede clinical changes in diabetes.
  • The earliest changes are those that regulate systemic lipid metabolism and hormone secretion/responsiveness.
  • Significant metabolic changes occur before hyperglycemia and these changes may happen sequentially.
  • New definitions of diabetes are required because diabetes is not solely defined by hyperglycemia.

The results of this study are similar to another2 covered in a previous blog post, which used LC-MS to identify prehypertension-associated plasma metabolites. In that study researchers identified ten lysophosphatidylcholines, concluding that lysoPC (16:0) is the most important plasma metabolite for evaluating the difference between the prehypertensive group and individuals with normal blood pressure. Both of these studies add to the growing body of research towards understanding and treating hypertension and diabetes.

  1. Anderson SG, Dunn WB , Banerjee M et al. Evidence that multiple defects in lipid regulation occur before hyperglycemia during the prodrome of type-2 diabetes. PLoS One. 2014 Sep 3;9(9):e103217. doi: 10.1371/journal.pone.0103217.
  1. Kim M, Jung S, Kim SY, Lee S-H, Lee JH. Prehypertension-associated elevation in circulating lysophosphatidlycholines, Lp-PLA2 activity, and oxidative stress. PLoS One. 2014 May 6;9(5):e96735. doi: 10.1371/journal.pone.0096735.