ABSTRACT
Metformin is a first-line medication for type 2 diabetes mellitus (T2DM). Based on its universal use, the consideration of inter-individual variability and development of predictive biomarkers are clinically significant. We aimed to identify endogenous markers of metformin responses using a pharmacometabolomic approach. Twenty-nine patients with early-phase T2DM were enrolled and orally administered metformin daily for 6 months. A total of 22 subjects were included in the final analysis. Patients were defined as responders or non-responders based on changes in their glycated haemoglobin A1c (HbA1c) from baseline, over 3 months. Urine metabolites at baseline, as well as at the 3 and 6 month follow-ups after the start of treatment were analysed using gas chromatography-mass spectrometry and evaluated with multivariate analyses. Metabolites distinguishable between the two response groups were obtained at baseline, as well as at the 3 and 6 month follow-ups, and significantly different metabolites were listed as markers of metformin response. Among the identified metabolites, citric acid, myoinositol, and hippuric acid levels showed particularly significant differences between the non-responder and responder groups. We thus identified different metabolite profiles in the two groups of T2DM patients after metformin administration, using pharmacometabolomics. These results might facilitate a better understanding and prediction of metformin response and its variability in individual patients.
Subject(s)
Biomarkers , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Biological Variation, Population , Blood Glucose , Diabetes Mellitus, Type 2/diagnosis , Female , Gas Chromatography-Mass Spectrometry , Glycated Hemoglobin , Humans , Hypoglycemic Agents/administration & dosage , Male , Metabolic Networks and Pathways , Metabolomics/methods , Metformin/administration & dosage , Middle Aged , Prognosis , ROC Curve , Treatment OutcomeABSTRACT
Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia caused by insulin autoantibodies in the absence of exogenous insulin administration. Some drugs containing sulfhydryl compounds are known to initiate the onset of IAS. A 67-year-old female who had diabetes for 5 years visited the outpatient clinic at our institution due to diabetic peripheral polyneuropathy. She was prescribed α-lipoic acid (ALA), which contains two sulfur atoms. Two weeks later, she complained of recurrent hypoglycemic symptoms. We detected a high level of insulin and high titers of insulin autoantibodies. Her human leukocyte antigen (HLA) genotype included the DRB1*0406 allele, which indicates a high level of susceptibility to IAS. She was treated with prednisolone. After this episode, she experienced two more hypoglycemic events after taking ALA for diabetic neuropathy in other hospitals. As ALA can be used to treat diabetic peripheral polyneuropathy, physician discretion is advised based on the possibility of IAS due to ALA in diabetic patients.
ABSTRACT
Transforming growth factor-beta (TGF-beta) is a pro-sclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. betaig-h3 is an extracellular matrix protein which is induced in many cells by TGF-beta. This study examined urinary betaig-h3 excretion in diabetic patients with elevated urinary albumin excretion and the clinical application of urinary betaig-h3 as a marker of diabetic nephropathy. Urinary and serum betaig-h3 levels were determined by enzyme-linked immunosorbent assay in 163 type 2 diabetic patients and 101 healthy control subjects of comparable age and weight. The ratio of urinary betaig-h3 and TGF-beta to creatinine was analyzed in patients with different degree of nephropathy. The betaig-h3 to creatinine ratio in urine was elevated in all groups of type 2 diabetics with normoalbuminuria (101.6 +/- 9.27), microalbuminuria (120.2 +/- 14.48), and overt proteinuria (146.3 +/- 16.34), when compared with control subjects (64.8 +/- 7.14) (P < 0.01). There was a positive correlation between urinary betaig-h3 and TGF-beta excretion rate and a positive correlation between urinary betaig-h3 and albumin excretion rate (AER). These data show that urinary levels of betaig-h3 are elevated in type 2 diabetic patients with nephropathy and may be used as a marker of diabetic nephropathy.
