Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes

Min, Se Hee; Oh, Tae Jung; Baek, Seung-Hoon; Lee, D.-H.; Kim, K.M.; Moon, Joon Ho; Choi, Sung Hee; Park, Kyong Soo; Jang, Hak Chul; Lim, Soo

doi:10.1016/j.diabet.2017.09.006

Cited by 39 publications

(35 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, sodium-glucose cotransporter-2 (SGLT2) inhibitor treatment for T2DM may elicit ketonemia that is reminiscent of the mild elevations induced by ketogenic diets. These mild elevations may be related to the ability of SGLT2 inhibitors to reduce plasma glucose via renal elimination, stimulate lipolysis, elicit weight loss and enhance insulin sensitivity [8][9][10]. Consequently, physicians or patients may want to monitor ketone bodies to ensure these diets are managed correctly and are having beneficial effects while not causing very high ketone body levels [11].…”

Section: Introductionmentioning

confidence: 99%

Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index

Garcia

Shalaurova

Matyus

et al. 2020

JCM

View full text Add to dashboard Cite

Background: Quantifying mildly elevated ketone bodies is clinically and pathophysiologically relevant, especially in the context of disease states as well as for monitoring of various diets and exercise regimens. As an alternative assay for measuring ketone bodies in the clinical laboratory, a nuclear magnetic resonance (NMR) spectroscopy-based test was developed for quantification of β-hydroxybutyrate (β-HB), acetoacetate (AcAc) and acetone. Methods: The ketone body assay was evaluated for precision, linearity and stability and method comparisons were performed. In addition, plasma ketone bodies were measured in the Insulin Resistance Atherosclerosis Study (IRAS, n = 1198; 373 type 2 diabetes mellitus (T2DM) subjects). Results: β-HB and AcAc quantified using NMR and mass spectrometry and acetone quantified using NMR and gas chromatography/mass spectrometry were highly correlated (R2 = 0.996, 0.994, and 0.994 for β-HB, AcAc, acetone, respectively). Coefficients of variation (%CVs) for intra- and inter-assay precision ranged from 1.3% to 9.3%, 3.1% to 7.7%, and 3.8% to 9.1%, for β-HB, AcAc and acetone, respectively. In the IRAS, ketone bodies were elevated in subjects with T2DM versus non-diabetic individuals (p = 0.011 to ≤0.001). Age- and sex-adjusted multivariable linear regression analysis revealed that total ketone bodies and β-HB were associated directly with free fatty acids (FFAs) and T2DM and inversely with triglycerides and insulin resistance as measured by the Lipoprotein Insulin Resistance Index. Conclusions: Concentrations of the three main ketone bodies can be determined by NMR with good clinical performance, are elevated in T2DM and are inversely associated with triglycerides and insulin resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index

Garcia

Shalaurova

Matyus

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…Treatment of DM patients with SGLT2 inhibitors reduces plasma glucose level and also induces multiple hemodynamic, neurohumoral, and metabolic changes that potentially influence cardiac pathology. Recently, the myocardial fuel hypothesis for cardioprotection afforded by SGLT2 inhibitors has received attention (Ferrannini et al, 2016b;Mudaliar et al, 2016) because SGLT2 inhibitors increase blood b-hydroxybutyrate (bOHB) levels (Ferrannini et al, 2016a;Min et al, 2018). Under physiologic conditions, fatty acid and glucose are the main energy substrates in the heart, where energy sources are switched based on workload and substrate availability.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Oshima¹,

Miki²,

Kuno³

et al. 2018

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial b-hydroxybutyrate (bOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of bOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

show abstract

“…Another noteworthy characteristic of SGLT2i is that they are associated with elevated plasma ketone levels in humans . SGLT2i enhance glucosuria by effectively lowering plasma glucose levels, resulting in decreased fasting insulin and increased fasting glucagon . These hormonal changes cause upregulation of lipolysis in adipose tissue, and also promote a shift in whole‐body substrate utilization from carbohydrate to fat, which mechanistically explains the elevation of ketone bodies in patients treated with SGLT2i .…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] SGLT2i enhance glucosuria by effectively lowering plasma glucose levels, resulting in decreased fasting insulin and increased fasting glucagon. [13][14][15] These hormonal changes cause upregulation of lipolysis in adipose tissue, 12,16 and also promote a shift in whole-body substrate utilization from carbohydrate to fat, which mechanistically explains the elevation of ketone bodies in patients treated with SGLT2i. 14 However, the role of SGLT2i in ketone body metabolism in tissues other than liver is largely unknown.…”

mentioning

confidence: 99%

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

Kim

Lee

Kim

et al. 2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

Aim: To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models.Materials and methods: Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed.Results: In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. Conclusions:SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration. K E Y W O R D Santidiabetic drug, empagliflozin, sodium-glucose cotransporter 2 inhibitors

show abstract

Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes

Cited by 39 publications

References 18 publications

Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index

Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

Contact Info

Product

Resources

About