ArticlePublisher preview available

Reappraisal of attenuated insulin sensitivity in the evolution of non-alcoholic fatty liver disease

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract and Figures

Background/objectives: It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease (NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution. Subjects/methods: We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single point insulin sensitivity estimator (SPISE = [600 × HDL-c0.185]/[TG0.2 × BMI1.338]), correlating with 1/HOMA-IR in an independent cohort (n = 1537, Spearman rho = 0.519, P < 0.01). Fatty liver (FL) was diagnosed by ultrasonography and diabetes by fasting plasma glucose (FPG) ≥ 7 mmol/L and/or glycohemoglobin A1c ≥ 6.5%. Multinominal comparison was performed with incident FL (FLw/oDM, n = 486), diabetes (DMw/oFL, n = 171), and FL plus diabetes (FL/diabetes, n = 58) as targets; none of the above (n = 4,138) was the control. SPISE was taken as a predictor with adjustment for covariates. Trajectory of SPISE during the 5 years before development of each condition was also assessed. Results: With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FLw/oDM and FL/diabetes with OR (95% CI) 3.47 (2.60-4.63) and 1.78 (1.10-2.87), respectively, and tertile 2 (8.07-10.06) related to FLw/oDM with OR (95% CI) 1.38 (1.03-1.85). Low SPISE was not significantly related to incident diabetes. At -5 years, SPISE was 12% (P < 0.05) and 13% (P < 0.01) lower in those developed FLw/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE in the two groups was 18% and 21% lower than the control, respectively (P < 0.01). Conclusions: Attenuation of Si indexed by SPISE was a risk factor for NAFLD.
This content is subject to copyright. Terms and conditions apply.
European Journal of Clinical Nutrition (2019) 73:770775
https://doi.org/10.1038/s41430-018-0246-3
ARTICLE
Carbohydrates, glycemic index and diabetes mellitus
Reappraisal of attenuated insulin sensitivity in the evolution of
non-alcoholic fatty liver disease
Takahiro Miyakoshi1Hiroyuki Sagesaka1Yuka Sato1Kazuko Hirbayashi2Hideo Koike2Koh Yamashita1
Seiichi Usuda3Kendo Kiyosawa3Masanori Shimodaira4Toru Aizawa1
Received: 21 January 2018 / Revised: 16 April 2018 / Accepted: 8 May 2018 / Published online: 17 July 2018
© Macmillan Publishers Limited, part of Springer Nature 2018
Abstract
Background/objectives It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease
(NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution.
Subjects/methods We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single
point insulin sensitivity estimator (SPISE =[600 × HDL-c0.185]/[TG0.2 ×BMI
1.338]), correlating with 1/HOMA-IR in an
independent cohort (n=1537, Spearman rho =0.519, P< 0.01). Fatty liver (FL) was diagnosed by ultrasonography and
diabetes by fasting plasma glucose (FPG) 7 mmol/L and/or glycohemoglobin A1c 6.5%. Multinominal comparison was
performed with incident FL (FLw/oDM,n=486), diabetes (DMw/oFL,n=171), and FL plus diabetes (FL/diabetes, n=58) as
targets; none of the above (n=4,138) was the control. SPISE was taken as a predictor with adjustment for covariates.
Trajectory of SPISE during the 5 years before development of each condition was also assessed.
Results With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FLw/oDM and FL/diabetes with
OR (95% CI) 3.47 (2.604.63) and 1.78 (1.102.87), respectively, and tertile 2 (8.0710.06) related to FLw/oDM with OR
(95% CI) 1.38 (1.031.85). Low SPISE was not signicantly related to incident diabetes. At 5 years, SPISE was 12% (P<
0.05) and 13% (P< 0.01) lower in those developed FLw/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE
in the two groups was 18% and 21% lower than the control, respectively (P< 0.01).
Conclusions Attenuation of Si indexed by SPISE was a risk factor for NAFLD.
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a globally
prevalent disease; further, non-alcoholic steatohepatitis, a
severe, advanced form of NAFLD, can progress to liver
cirrhosis and hepatocellular carcinoma [1,2]. Metabolic
abnormality in NAFLD resembles that of diabetes, with
attenuated insulin sensitivity (Si) playing a central role [1
5]. However, it is unclear if attenuated Si is a cause or
consequence of NAFLD. With the increasing access to a
large number of adult health records, we critically examined
the signicance of attenuated Si in NAFLD evolution.
Moreover, special attention was paid for understanding the
aggregate interrelationship between NAFLD and diabetes.
As a quantitative index of Si, the single point insulin sen-
sitivity estimator (SPISE) [6] was used. SPISE validation
was performed by the authors in an independent Japanese
population. SPISE can be calculated using body mass index
(BMI), high-density lipoprotein cholesterol (HDL-c), and
triglycerides (TG) [6]; therefore, it can be easily used for the
general health examination.
*Toru Aizawa
taizawax@ai-hosp.or.jp
1Diabetes Center, Aizawa Hospital, Matsumoto, Japan
2Health Center, Aizawa Hospital, Matsumoto, Japan
3Department of Gastroenterology, Aizawa Hospital,
Matsumoto, Japan
4Takara Clinic, Nagokuma Kanae 2511, Iida, Japan
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41430-018-0246-3) contains supplementary
material, which is available to authorized users.
1234567890();,:
1234567890();,:
Content courtesy of Springer Nature, terms of use apply. Rights reserved
... Thus, this study indicates that SPISE-IR should be useful and even preferred among surrogate fasting insulin resistance indexes, with the advantage of being easily available in clinical practice, using only fasting blood lipids and BMI, and without the necessity to analyze insulin or NEFA variables. Likewise, SPISE-IR should be applicable in clinical studies on treatment of cardiovascular risk factors for risk prediction of CHD, type 2 diabetes (34), non-alcoholic fatty liver disease (42), and also possibly useful for complementary evaluation of insulin resistance in obese patients suitable for gastric bypass operations. Further clinical controlled studies should be valuable to validate the clinical utility of SPISE as a biomarker, to be used in prevention of future CHD and type 2 diabetes (34), as well as in the prevention of non-alcoholic fatty liver disease (42). ...
... Likewise, SPISE-IR should be applicable in clinical studies on treatment of cardiovascular risk factors for risk prediction of CHD, type 2 diabetes (34), non-alcoholic fatty liver disease (42), and also possibly useful for complementary evaluation of insulin resistance in obese patients suitable for gastric bypass operations. Further clinical controlled studies should be valuable to validate the clinical utility of SPISE as a biomarker, to be used in prevention of future CHD and type 2 diabetes (34), as well as in the prevention of non-alcoholic fatty liver disease (42). ...
Article
Full-text available
Background: Fasting insulin resistance indexes are used extensively nowadays. We intended to analyze a new recently presented fasting index, SPISE (sensitivity formula: 600 × HDL-cholesterol0.185/triglycerides0.2/BMI1.338), in comparison with three previously known fasting indexes, regarding correlation with the insulin clamp index, and for the predictive effects of future long-term risks of coronary heart disease (CHD) or manifest type 2 diabetes. Methods: A total of 1049 71-year-old male subjects from the Swedish ULSAM study, median follow-up 8 years, were included. All subjects performed the euglycemic insulin clamp, and analyses of four fasting insulin resistance indexes: SPISE-IR (= 10/SPISE), QUICKI-IR, Log HOMA-IR, and Revised QUICKI-IR. Results: Spearman correlation coefficients with the insulin clamp were 0.60–0.62 for all indexes. Area under curve at ROC analysis was 0.80 for SPISE-IR, and 0.84 for QUICKI-IR, Log HOMA-IR, and Rev QUICKI-IR. Adjusted hazard ratios per 1 SD index increase for long-term risk CHD were similar in all patients: 1.20–1.24 (p = 0.02–0.03). However, comparing the highest quartile (recommended to define insulin resistance) with the lower quartiles, SPISE-IR was the strongest and the only statistically significant insulin resistance index: HR 1.53 (p = 0.02). Adjusted odds ratios per 1 SD index increase for long-term risk of type 2 diabetes were fairly similar (p < 0.001) in all patients: 1.62 for SPISE-IR, 1.97 for QUICKI-IR and Log HOMA-IR, and 2.04 for Rev QUICKI-IR, and also when comparing the highest versus the lower quartiles: 2.8–3.1 (p < 0.001). Conclusion: SPISE, easily applicable, performed equally well as other fasting insulin indexes previously recommended for clinical use, regarding correlation with the insulin clamp, and as predictor for future long-term risks of CHD or type 2 diabetes.
... A number of studies previously investigated the relationship between the SPISE index and insulin-derived indicators of insulin homeostasis [23,24,[36][37][38][39]; data showed that the SPISE index was comparable to Matsuda-ISI, QUICKI and HOMA-IR when used for the identification of conditions of altered insulin sensitivity in adults [23]. Moreover, lower SPISE index significantly correlated in adults or adolescents with the presence of T2D [36], metabolic syndrome [37,39], risk of cardiovascular diseases [36], non-alcoholic fatty liver disease (NAFLD) [38], abdominal obesity, higher levels of C-reactive protein (CRP) and lower levels of adiponectin [24]. ...
... A number of studies previously investigated the relationship between the SPISE index and insulin-derived indicators of insulin homeostasis [23,24,[36][37][38][39]; data showed that the SPISE index was comparable to Matsuda-ISI, QUICKI and HOMA-IR when used for the identification of conditions of altered insulin sensitivity in adults [23]. Moreover, lower SPISE index significantly correlated in adults or adolescents with the presence of T2D [36], metabolic syndrome [37,39], risk of cardiovascular diseases [36], non-alcoholic fatty liver disease (NAFLD) [38], abdominal obesity, higher levels of C-reactive protein (CRP) and lower levels of adiponectin [24]. Finally, in line with our results obtained in youths, Sagesaka et al. demonstrated that basal SPISE index was significantly lower in adults who developed T2D 10 years later in comparison to those who did not progress to diabetes, in a longitudinal investigation on over 27,000 individuals without diabetes [40]. ...
Article
Full-text available
Purpose To investigate the relationship between the single-point insulin sensitivity estimator (SPISE) index, an insulin sensitivity indicator validated in adolescents and adults, and metabolic profile in overweight/obese children, and to evaluate whether basal SPISE is predictive of impaired glucose regulation (IGR) development later in life. Methods The SPISE index (= 600 × HDL 0.185 /Triglycerides 0.2 × BMI 1.338 ) was calculated in 909 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy, and in 99 normal-weight, age-, sex-comparable children, selected as a reference group, together with other insulin-derived indicators of insulin sensitivity/resistance. 200 overweight/obese children were followed-up for 6.5 [3.5–10] years, data were used for longitudinal retrospective investigations. Results At baseline, 96/909 (11%) overweight/obese children had IGR; in this subgroup, SPISE was significantly lower than in normo-glycaemic youths (6.3 ± 1.7 vs. 7 ± 1.6, p < 0.001). The SPISE index correlated positively with the insulin sensitivity index (ISI) and the disposition index (DI), negatively with age, blood pressure, HOMA-IR, basal and 120 min blood glucose and insulin (all p values < 0.001). A correlation between SPISE, HOMA-IR and ISI was also reported in normal-weight children. At the 6.5-year follow-up, lower basal SPISE—but not ISI or HOMA-IR—was an independent predictor of IGR development (OR = 3.89(1.65–9.13), p = 0.002; AUROC: 0.82(0.72–0.92), p < 0.001). Conclusion In children, low SPISE index is significantly associated with metabolic abnormalities and predicts the development of IGR in life.
... Among these, the SPISE was developed as an easy and affordable tool for the evaluation of whole-body insulin sensitivity, which is comparable to clamp-derived M-value in sensitivity as well as specificity (19). Several studies have evaluated the SPISE in adult as well as juvenile populations (20,(41)(42)(43)(44)(45)(46). Correa-Burrows et al. assessed SPISE for its validity in diagnosing cardiometabolic risks, namely IR and metabolic syndrome, in post-pubertal Hispanic adolescents. ...
Article
Full-text available
Background Attenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity. Materials and Methods Ninety-nine pubertal subjects with obesity (13.5 ± 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 ± 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (≤5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5. Results SPISE was lower in NAFLD (male: 4.8 ± 1.2, female: 4.5 ± 1.1) than in non-NAFLD group (male 6.0 ± 1.6, female 5.6 ± 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%). Conclusion SPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.
Article
Full-text available
Purpose We aimed to clarify the onset of diabetes. Methods Data from 27,392 non-diabetic health examinees was retrospectively analyzed for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index (BMI) and the single point insulin sensitivity estimator (SPISE), an index of insulin sensitivity (Si), 10 years prior to diagnosis of prediabetes (n=4,781) or diabetes (n=1,061) were separately assessed by mixed effects model. Diabetes and prediabetes was diagnosed by the ADA definition on the basis of FPG and HbA1c values. Results In individuals who developed diabetes, mean FPG and BMI were significantly higher (respectively, P<0.01 each) and SPISE lower than those who did not at -10 years; FPG 101.5 mg/dL vs 94.5 mg/dL, BMI 24.0 kg/m² vs 22.7 kg/m² and SPISE 7.32 vs 8.34, P<0.01 each). These measurements in subjects who developed prediabetes were slightly but definitely different from those who did not, already at -10 years: FPG 91.8 mg/dl vs 89.6 mg/dl, BMI 22.6 kg/m² vs 22.1 kg/m² and SPISE 8.44 vs 8.82; P<0.01 each. In both cases, the differences were progressively greater toward year 0, the time of diabetes or prediabetes diagnosis. Conclusions FPG was significantly elevated in those developed diabetes at least 10 years before diagnosis of diabetes, and this was also the case in those developed prediabetes. Glucose dysregulation precedes diagnosis of diabetes at least for 20 years.
Article
Full-text available
Non-alcoholic fatty liver (NAFL) is an independent risk factor for the development of type 2 diabetes (T2DM). We examined metabolic perturbations in patients with NAFL, patients with T2DM, and control (CON) subjects with normal intrahepatic lipid (IHL) content. A two-step (10 mU/m2 /min; 40 mU/m2/min) hyperinsulinemic–euglycemic clamp was performed in 11 NAFL, 13 T2DM, and 11 CON subjects, all matched for BMI, and aerobic fitness. IHL content was measured using proton magnetic resonance spectroscopy. Because of high IHL content variability in T2DM patients, this group was separated into a high IHL content group (IHL ≥ 5.0%, T2DM+NAFL) and a normal IHL content group (IHL < 5.0%, T2DM-non-NAFL) for further analysis. IHL content was increased in NAFL and T2DM+NAFL subjects (P<0.050 versus CON and T2DM-non-NAFL subjects). Adipose tissue insulin sensitivity index (Adipo-IRi) was higher in NAFL (P<0.050 versus CON and T2DM-non-NAFL subjects) and in T2DM+NAFL subjects (P=0.055 versus CON subjects, P<0.050 versus T2DM-non-NAFL subjects). Suppression of plasma-free fatty acids (P=0.046) was lower in NAFL compared with CON subjects, with intermediate values for T2DM-non-NAFL, and T2DM+NAFL subjects. Suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disposal (ΔRd) was comparable between NAFL, T2DM-non-NAFL, and T2DM+NAFL subjects (all P>0.05), and was lower in comparison with CON subjects (all P<0.01). Metabolic flexibility was lower in T2DM-non-NAFL subjects (P=0.047) and NAFL subjects (P=0.059) compared with CON subjects. Adipo-IRi (r=0.652, P<0.001), hepatic insulin resistance index (HIRi) (r=0.576, P=0.001), and ΔRd (r=−0.653, P<0.001) correlated with IHL content. Individuals with NAFL suffer from metabolic perturbations to a similar degree as T2DM patients. NAFL is an important feature leading to severe insulin resistance and should be viewed as a serious health threat for the development of T2DM. ClinicalTrials.gov: NCT01317576
Article
Full-text available
Recognition of the close relationship of nonalcoholic fatty liver disease (NAFLD) with diabetes mellitus 2, obesity, metabolic syndrome, and cardiovascular disease has stimulated growing interest in NAFLD as a public health problem. Serum alanine aminotransferase (ALT) has been proposed as a marker of NAFLD, but levels are within the range currently considered “normal” in a large proportion of NAFLD subjects. The aim of the study was to determine the diagnostic accuracy of serum ALT for identifying individuals with NAFLD, using 3-Tesla (T) magnetic resonance spectroscopy (¹H-MRS). A cross-sectional study was conducted in 129 healthy subjects. Liver triglyceride content was quantified by ¹H-MRS. NAFLD was defined as liver triglyceride content greater than 5.56%. Liver triglyceride content was >5.56% in 79 participants (NAFLD) and lower in the remaining 50 (normal). Serum ALT levels correlated positively with liver triglyceride content (r = 0.58, P < .001), Homeostatic Model Assessment for Insulin Resistance (r = 0.32, P < .01), and fasting insulin (r = 0.31, P < .01), and inversely correlated with adiponectin (r = 0.35, P < .01) and high-density lipoprotein cholesterol (r = 0.32, P < .01). Regression analysis showed that serum ALT was the best predictor of NAFLD (P < .01). Optimal serum ALT cut-off to predict NAFLD was 23 IU/L (area under receiver-operating characteristic curve: 0.93; sensitivity: 0.94; specificity: 0.72). This study shows that serum ALT is a sensitive and accurate biomarker of NAFLD if the “normal” ALT value is revised and established at a lower level. An ALT threshold of 23 IU/L identified 94% of individuals with NAFLD in the present series, using 3-T ¹H-MRS for liver triglyceride quantification.
Article
NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.
Article
A hypothesis that postchallenge hyperglycemia in subjects with low body weight (BW) may be in part due to small glucose volume (Gv) was tested. We studied 11,411 non-diabetic subjects with a mean BW of 63.3 kg. 5,282 of them were followed for a mean of 5.3 years. In another group of 1,537 non-diabetic subjects, insulin sensitivity, secretion, and a product of the two (index of whole body insulin action) were determined. Corrected 2 hour-plasma glucose (2hPGcorr) during a 75 g oral glucose tolerance test in subjects with BW ≤ 59 kg was calculated as, 2hPGcorr=〖δPG〗_2h ·ECW/[16.1 (males) or 15.3 (females)] + fasting PG (FPG) where PG2h and ECW denoted PG increment in 2 hours and extracellular water (surrogate of glucose volume (Gv)), respectively. 16.1 and 15.3 were ECW of males and females, respectively, with BW = 59 kg. Multivariate analyses for BW with adjustment for age, sex and percentage body fat were undertaken. BW was, across its entire range, positively correlated with FPG (P < 0.01). Whereas BW was correlated with 2hPG and δPG2h in a skewed J-shape, with inflections at around 60 kg (P for non-linearity < 0.01 for each). Nonetheless, in those with BW ≤ 59 kg, insulin sensitivity, secretion and action were unattenuated and incident diabetes was less compared to heavier counterparts. BW was linearly correlated with 2hPGcorr, i.e., the J-shape correlation was mitigated by the correction. In conclusion, postchallenge hyperglycemia in low BW subjects is in part due to small GV rather than impaired glucose metabolism.
Article
Elevated plasma triglycerides (TGs) are early key features of conditions associated with a dysregulation in glucose metabolism and may predict the development of type 2 diabetes (T2D) over time. Although the acute ingestion of lipid, either mixed with or shortly before the meal, is neutral or slightly beneficial on glucose tolerance, a short-term increase in plasma TGs induced by either an i.v. lipid infusion or a high-fat diet produces a deterioration of glucose control. Accordingly, chronic lowering of plasma TGs by fibrates improves glucose homeostasis and may also prevent T2D. The chronic effects of the elevation of dietary lipid intake are less clear, particularly in humans, being the quality of fat probably more important than total fat intake. Although on the bases of the available experimental and clinical evidence it cannot be easily disentangled, with respect to elevated non-esterified fatty acids (NEFA) the relative contribution of elevated TGs to glucose homeostasis disregulation seems to be greater and also more plausible. In conclusion, although the association between elevated plasma TGs and impaired glucose tolerance is commonly considered not causative or merely a consequence of NEFA-mediated lipotoxicity, the available data suggest that TGs per se may directly contribute to disorders of glucose metabolism.
Article
Traditionally, obesity and its related diseases are considered problems in Western countries. However, in the past two decades, urbanization in many Asian countries has led to sedentary lifestyle and overnutrition, and has set the stage for the epidemic of obesity. This article reviews the epidemiological trend of obesity in Asia with special emphasis on the emerging condition of non-alcoholic fatty liver disease (NAFLD). Currently, the population prevalence of NAFLD in Asia is around 25%, similar to that in many Western countries. While hepatocellular carcinoma and end-stage liver disease secondary to NAFLD remain uncommon, a rising trend has recently been observed. Around 8-19% of Asians with body mass index less than 25 kg/m² are also found to have NAFLD, a condition often described as “lean” or “non-obese” NAFLD. Although the condition is generally less severe than that in more obese patients, steatohepatitis and fibrotic disease are well recognized in non-obese patients with NAFLD. Central adiposity, insulin resistance and weight gain are major risk factors, and genetic predisposition such as the PNPLA3 polymorphism appears to be more important in the development of NAFLD in the non-obese population. Lifestyle modification remains the cornerstone for the management of obesity and NAFLD, but few patients can achieve adequate weight reduction and even fewer can maintain the weight in the long run. While a few agents have entered phase 3 development for steatohepatitis, Asian patients are underrepresented in most drug trials. Future studies should define the optimal management of obesity and NAFLD in Asia.
Article
Background and aims: Non-alcoholic fatty liver disease (NAFLD) is frequently associated with atherosclerosis. However, it is unclear whether this association is related to excess fat liver storage per se or to metabolic abnormalities that typically accompany NAFLD. To investigate this, we compared individuals with hepatic steatosis driven by metabolic disturbances to those with hepatic steatosis associated with the rs738409 GG genotype in the patatin-like phospholipase domain-containing 3 gene (PNPLA3). Methods: Carotid intima-media thickness (CIMT), as a surrogate marker of subclinical atherosclerosis, was measured in 83 blood donors with the mutant GG genotype (group G), 100 patients with features of metabolic syndrome (MetS) but the wildtype CC genotype (group M), and 74 blood donors with the wildtype CC genotype (controls). Fatty liver was evaluated by ultrasonography and hepatic fat fraction (HFF) was measured using magnetic resonance (MRS/MRI) in 157 subjects. Results: Compared with group G and controls, group M subjects were older and had increased adiposity indices, dyslipidemia, insulin resistance and elevated transaminase levels (all p < 0.05). They also had a more fatty liver on both ultrasonography and MRS/MRI. After adjustment for confounders (including severity of hepatic steatosis), the median CIMT in group M (0.84 [0.70-0.95] mm) was significantly greater than that in group G (0.66 [0.55-0.74] mm; p < 0.001), which was similar to that in controls (0.70 [0.64-0.81] mm). Results were similar in the subgroup evaluated using MRS/MRI. Conclusions: Excess liver fat accumulation appeared to increase the burden of subclinical atherosclerosis only when it is associated with metabolic abnormalities.
Article
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome (‘Obese/Metabolic NAFLD’) and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n=6) or liver enzymes (n=14). All ultrasonography studies found NAFLD to predict the risk of T2DM independently of age, and in 4 out of 6 studies NAFLD was also a predictor independently of BMI. NAFLD was a predictor of T2DM in all 14 studies where NAFLD was diagnosed by liver enzymes. In 12 of these studies, ALT or AST or GGT were significant predictors of T2DM risk, independently of age and BMI. NAFLD, however, is heterogeneous and may also be caused by common genetic variants. The I148M variant in PNPLA3 and the E167K variant in TM6SF2 are both associated with increased liver fat content, but not features of the metabolic/insulin resistance syndrome. These genetic forms of NAFLD predict NASH and cirrhosis but not T2DM. Taken together these data imply that NAFLD predicts T2DM independently of age and obesity and support the role of hepatic insulin resistance in the pathogenesis of this disease.
Article
Background The triglyceride-to-HDL-cholesterol (TG/HDL)-ratio was introduced as a tool to estimate insulin resistance, as circulating lipid measurements are available in routine settings. Insulin, C-peptide, and free fatty acids are components of other insulin-sensitivity indices, but expensive. Easier and more affordable tools are of interest for both pediatric and adult people. Methods Subjects from the “Relationship Between Insulin Sensitivity and Cardiovascular Disease” (43.9±8.3 years, n=1260) as well as the “Beta-Cell Function in Juvenile Diabetes and Obesity” study cohort (15±1.9 years, n=29) underwent oral-glucose-tolerance-tests and euglycemic clamp-tests for estimation of whole-body-insulin-sensitivity and calculation of insulin-sensitivity indices. To refine the TG/HDL-ratio, mathematical modeling was applied including body mass index (BMI), fasting triglycerides and HDL-cholesterol and compared to the clamp-derived M–value as an estimate of insulin sensitivity. Each modeling result was scored by identification of insulin resistance and correlation coefficient. The Single Point Insulin Sensitivity Estimator (SPISE) was compared to traditional insulin-sensivitity indices using area under the receiver-operating-characteristic curve (aROC) analysis and ChiSquare-test. Results The novel formula for SPISE was computed as follows: SPISE =600*HDL-C^0.185/(triglycerides^0.2*BMI^1.338), with fasting HDL-cholesterol (mg/dL), fasting triglyceride concentrations (mg/dL) and BMI (kg/m2). A cut-off value of 6.61 corresponds to an M-value smaller than 4.7 mg*kg-1*min-1 (aROC: M:0.797). SPISE showed a significantly better aROC than the TG/HDL-cholesterol-ratio. SPISE aROC was comparable to Matsuda’s ISI and equal to QUICKI and HOMA-IR when calculating with M-value. Conclusion The SPISE seems well suited to surrogate whole-body insulin-sensitivity from inexpensive fasting single-point blood draw and BMI in white adolescents and adults.