Association of Ketone Body Levels With Hyperglycemia and Type 2 Diabetes in 9,398 Finnish Men

Mahendran, Yuvaraj; Vangipurapu, Jagadish; Cederberg, Henna; Stančáková, Alena; Pihlajamäki, Jussi; Soininen, Pasi; Kangas, Antti J.; Paananen, Jussi; Civelek, Mete; Saleem, Niyas K.; Pajukanta, Päivi; Lusis, Aldons J.; Bonnycastle, Lori L.; Morken, Mario A.; Collins, Francis S.; Mohlke, Karen L.; Boehnke, Michael; Ala‐Korpela, Mika; Kuusisto, Johanna; Laakso, Markku

doi:10.2337/db12-1363

Cited by 120 publications

(128 citation statements)

References 40 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Ketone bodies in blood are biomarker of energy source instead of diminished glucose utilities in diabetic hyperglycaemia 35, 36, which are high levels in individuals with diabetic hyperglycaemia 36 or in obese control relative to lean in DIO rat 37. Thus, this result suggested that SKL‐14959 might improve the glucose metabolism in peripheral tissues, resulted in decrease lipid deposition.…”

Section: Discussionmentioning

confidence: 99%

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

Nakamura¹,

Tanimoto²,

Mizuno³

et al. 2018

Obesity Science & Practice

View full text Add to dashboard Cite

SummaryObjectiveGastric inhibitory polypeptide plays a role in glucose and lipid metabolism and is associated with obesity and insulin resistance. The objective of this study is to confirm the anti‐obesity effects of the gastric inhibitory polypeptide receptor antagonist, SKL‐14959, on diet‐induced obesity mice.MethodDiet‐induced obesity mice at 20 weeks of age were administered with or without SKL‐14959 for 96 d. Body weight and food intake were monitored throughout the experiment. Mice were sacrificed, and physiological and biochemical markers were measured, and then histochemical and gene expression analyses were also performed. In further studies, mice were orally gavaged with [14C]‐oleic acid to investigate the excursion of digested lipids.ResultsSKL‐14959 significantly suppressed weight gain without affecting food intake, decreased triacylglycerol contents in the liver and the muscle and the intensity stained with oil‐red in the liver. It also improved plasma glutamic pyruvic transaminase and 3‐hydroxybutyrate levels in addition to notably down‐regulated relative gene expression of srebf1 and dgat1 in the liver despite not altering in the adipose tissue. Furthermore, SKL‐14959 showed remarkable inhibition of lipid uptake in the adipose tissue after the oil challenge.ConclusionSKL‐14959 inhibited lipids uptake and improved lipids metabolism, results in suppression of body‐weight gain.

show abstract

Section: Discussionmentioning

confidence: 99%

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

Nakamura¹,

Tanimoto²,

Mizuno³

et al. 2018

Obesity Science & Practice

View full text Add to dashboard Cite

show abstract

“…Obese humans and mice exhibit diminished whole-body ketone body turnover (26,29). Furthermore, circulating ketone body concentrations are generally decreased in obese humans (24,25,27) and serve as predictive biomarkers for conversion to type 2 diabetes in patients with impaired fasting glucose (73). Compared with BMI-matched individuals, obese patients with NAFLD exhibit increased hepatic glucose production and TCA cycle flux without augmented ketogenesis (28).…”

Section: Discussionmentioning

confidence: 99%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

View full text Add to dashboard Cite

R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

show abstract

“…2A and B). Dietary questionnaires, urinary excretion of pyrraline-an advanced glycation end product sourced only from food (21), and fasting plasma ketone body concentrations in the normal range in all subjects (22) suggested that food consumption was similar throughout the study (Table 2). Clinical safety indicators were normal at study entry and remained unchanged throughout the placebo and tRES-HESP treatment periods (Supplementary Table 1).…”

Section: Improved Clinical Metabolic and Vascular Health With Tres-hementioning

confidence: 99%

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

et al. 2016

View full text Add to dashboard Cite

Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m 2 ), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (237%, P < 0.05) and total body methylglyoxal-protein glycation (214%, P < 0.01). It decreased fasting and postprandial plasma glucose (25%, P < 0.01, and 28%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL $ min 21 $ m 22, P < 0.02), and improved arterial dilatation Dbrachial artery flowmediated dilatation/Ddilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (210%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

show abstract

Association of Ketone Body Levels With Hyperglycemia and Type 2 Diabetes in 9,398 Finnish Men

Cited by 120 publications

References 40 publications

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

Contact Info

Product

Resources

About