Role of fatty liver in the association between obesity and reduced hepatic insulin clearance

Matsubayashi, Yasuhiro; Yoshida, Akihiro; Suganami, Hideki; Ishiguro, Hajime; Yamamoto, Masahiko; Fujihara, Kazuya; Kodama, Satoru; Tanaka, Shiro; Kaku, Kohei

doi:10.1016/j.diabet.2017.12.003

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…A cross-sectional study of 80 non-diabetic subjects showed that increased liver fat, measured using proton magnetic resonance spectroscopy, was associated with impaired IC 15. Similar findings demonstrating declines in IC with increased liver fat have also been observed in diabetic subjects 8 32. Evidence to date from human studies, however, has been insufficient to confirm or refute these hypotheses.…”

Section: Discussionmentioning

confidence: 95%

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort

Semnani‐Azad

Johnston

Lee

et al. 2019

BMJ Open Diab Res Care

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ObjectiveTo evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D).Research design and methodsAdults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (ICFASTING) and areas under the curve of C peptide-to-insulin (ICAUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC.ResultsIC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in ICFASTING and ICAUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia.ConclusionsOur findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

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Section: Discussionmentioning

confidence: 95%

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort

Semnani‐Azad

Johnston

Lee

et al. 2019

BMJ Open Diab Res Care

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“…Further, an increase in the ratio of fasting C‐peptide to IRI levels, suggesting hepatic insulin clearance, was reported to be correlated with the improved peripheral insulin sensitivity after an intervention with a 4‐month hypocaloric diet . In addition, the ratio of fasting C‐peptide to IRI was positively correlated with insulin sensitivity indices in people with T2DM . The changed insulin clearance via TOFO‐induced weight loss, leading to improved insulin sensitivity, might therefore contribute to the reduced insulin levels.…”

Section: Discussionmentioning

confidence: 95%

“…26 In addition, the ratio of fasting C-peptide to IRI was positively correlated with insulin sensitivity indices in people with T2DM. 27 The changed insulin clearance via TOFO-induced weight loss, leading to improved insulin sensitivity, might therefore contribute to the reduced insulin levels. With regard to fasting C-peptide levels, the correction of hyperglycaemia via an SGLT2 inhibitor was reported to improve insulin secretion capacity, 24 and insulin secretion, calculated according to glucose and C-peptide levels after a meal tolerance test, was reported to be improved by an SGLT2 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Basal insulin secretion capacity predicts the initial response and maximum levels of beta‐hydroxybutyrate during therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin, in relation to weight loss

Sato

Nunoi

Kaku

et al. 2019

Diabetes Obesity Metabolism

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Aims To investigate predictors of the initial response of beta‐hydroxybutyrate (BHB) and maximum BHB (max‐BHB) values during long‐term therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. Methods We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max‐BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. Results Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2, respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* μmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max‐BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C‐peptide levels compared with the lower three quartiles. Conclusions Lower basal insulin secretion capacity might predict greater initial BHB elevations and max‐BHB levels during long‐term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.

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“…In addition, assessments at baseline and 24 weeks after administration of TOFO or placebo included body weight, body mass index (BMI) and waist circumference. As in our previous report, the presence of FL was estimated using a cut‐off value based on the FL index (FLI) (e 0.953 × loge (TG) + 0.139*BMI + 0.718*loge (γGTP) + 0.053 × waist circumference – 15.745 )/(1 + e 0.953 × loge (TG) + 0.139 × BMI + 0.718 × loge (γGTP) + 0.053 × waist circumference – 15.745 ) × 100 . An FLI ≥35 for males and ≥ 20 for females determined the presence of FL, while an FLI <35 for males and < 20 for females ruled out FL according to a report targeting over 30 000 Asians .…”

Section: Methodsmentioning

confidence: 99%

“…Details of the protocol for the MTT were previously described . In short, after fasting for at least 10 h, participants attended the medical institution participating in the clinical trials and underwent an MTT with a test meal.…”

Section: Methodsmentioning

confidence: 99%

Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

Matsubayashi

Yoshida

Suganami

et al. 2020

Diabetes Obesity Metabolism

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Aims: Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose-cotransporter 2 inhibitors (SGLTis) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2is on hepatic insulin clearance. We examined the impact of an SGLT2i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2i and the mechanism of the effects of SGLT2i.Materials and methods: Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C-peptide and insulin levels derived from oral meal tolerance test data (C-peptide AUC 0-120 min /insulin AUC 0-120 min : HIC CIR ). The correlation of HIC CIR via the SGLT2i with other clinical variables was analysed using multivariate analysis.Results: HIC CIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P <0.001) and β-hydroxybutyrate (BHB) was significantly elevated (P <0.001). Changes in HIC CIR were significantly correlated with changes in TG and BHB via TOFO.Conclusions: Increased HIC CIR was significantly associated with reduced TG via TOFO and contributed to the greater increase in BHB compared with placebo in addition to the correction of hyperinsulinaemia.

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Role of fatty liver in the association between obesity and reduced hepatic insulin clearance

Cited by 17 publications

References 30 publications

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort

Basal insulin secretion capacity predicts the initial response and maximum levels of beta‐hydroxybutyrate during therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin, in relation to weight loss

Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

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