Effect of Metformin on Methylglyoxal Metabolism in Patients with Type 2 Diabetes

Κender, Ζoltan; Fleming, Thomas; Kopf, Stefan; Torzsa, Péter; Grolmusz, Vince; Herzig, Stephan; Schleicher, Erwin; Rácz, Kàroly; Reismann, Péter; Nawroth, Peter P.

doi:10.1055/s-0034-1371818

Cited by 55 publications

(55 citation statements)

References 11 publications

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“…MG-AGEs result from the accumulation of MG 35 , a metabolite of glucose found in blood that is elevated in type 2 diabetes 41 and exacerbated in patients and mice with PDN 5 . Therefore we measured MG-AGE levels and hemoglobin glycation in the form of HbA1c, an AGE considered by clinicians to be the ‘gold standard’ diagnostic for diabetes 81 .…”

Section: Resultsmentioning

confidence: 99%

“…Finally, a multiple drug strategy, such as coadministration of pioglitazone with canagliflozin 105 or geraniol 34 might reduce diabetes without the adverse effects of adipocyte differentiation, fat deposition, and weight gain associated with pioglitazone-only treatment. PDN patients may also benefit from other diabetic drugs such as metformin, which reduces peripheral neuropathic pain 57 and PDN in STZ rats 7, 54 , as well as decreases hyperglycemia, HbA1c, and MG in patients with type 2 diabetes 41 . Future clinical studies could investigate whether the above treatments or other PPARγ-directed therapies alleviate both hyperglycemia and neuropathic pain, as simultaneous inhibition is necessary to maximize quality of life in type 2 diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

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Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Griggs

Donahue

Adkins

et al. 2016

The Journal of Pain

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Thiazolidinedione drugs (TZDs) such as pioglitazone are FDA-approved for the treatment of insulin resistance in type 2 diabetes. However, whether TZDs reduce painful diabetic neuropathy (PDN) remains unknown. Therefore we tested the hypothesis that chronic administration of pioglitazone would reduce PDN in Zucker Diabetic Fatty (ZDFfa/fa) rats. Compared to Zucker Lean (ZLfa/+) controls, ZDF developed: (1) elevated blood glucose, HbA1c, methylglyoxal and insulin; (2) mechanical and thermal hyperalgesia at the hindpaw; (3) increased avoidance of noxious mechanical probes in a mechanical conflict avoidance behavioral assay, the first report of a measure of affective-motivational pain-like behavior in ZDF; and (4) exaggerated lumbar dorsal horn immunohistochemical expression of pressure-evoked phosphorylated extracellular signal-regulated kinase (pERK). Seven weeks of pioglitazone (30 mg · kg−1 · d−1 in food) reduced blood glucose, HbA1c, hyperalgesia, and pERK expression in ZDF. This is the first report to reveal hyperalgesia and spinal sensitization in the same ZDF animals, both evoked by a noxious mechanical stimulus that reflects pressure pain frequently associated with clinical PDN. As pioglitazone provides the combined benefit of reducing hyperglycemia, hyperalgesia, and central sensitization, we suggest that TZDs represent an attractive pharmacotherapy in patients with type 2 diabetes-associated pain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Griggs

Donahue

Adkins

et al. 2016

The Journal of Pain

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“…10,11 While it is possible that AGE reduction is coupled exclusively to lowered glucose levels, increased metabolism of MG by glyoxalase, and direct scavenging, have both been postulated as mechanisms for this effect. 12,13 …”

Section: Introductionmentioning

confidence: 99%

Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans

Kinsky

Hargraves

Anumol

et al. 2016

Chem. Res. Toxicol.

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Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin–MG reaction. The primary product was characterized by 1H, 13C, 2D-HSQC, and HMBC NMR and tandem mass spectrometry. X-ray diffraction analysis determined the structure of the metformin and MG-derived imidazolinone compound as (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yI)guanidine (IMZ). A LC-MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 μM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 μM. Since plasma concentrations of MG range from 40 nM to 4.5 μM, the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications.

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“…The natural vitamin B6 analog, pyridoxamine, is a drug that may potentially be effective in diabetic nephropathy and retinopathy (42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Metformin is also a putative candidate (52)(53)(54). Further studies are required to investigate the effectiveness and application of anti-glycating remedies to bone problems in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Aikawa

Matsubara

Ugaji

et al. 2017

Molecular Medicine Reports

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Abstract.Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end-products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0-mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0-400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non-diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO-derived AGEs, N ε -(carboxymethyl)-lysine and N δ -(5-hydro-5-methyl-4-imida zolone-2-yl)-ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose-dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.

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Effect of Metformin on Methylglyoxal Metabolism in Patients with Type 2 Diabetes

Cited by 55 publications

References 11 publications

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans

Contribution of methylglyoxal to delayed healing of bone injury in diabetes

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