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      Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes

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          Abstract

          OBJECTIVE

          Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown.

          RESEARCH DESIGN AND METHODS

          We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS ( 1H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements.

          RESULTS

          No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH ( P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis ( r = –0.62; P < 0.001) and severity of steatohepatitis ( r s = −0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups.

          CONCLUSIONS

          In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on.

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          Glucose clamp technique: a method for quantifying insulin secretion and resistance.

          Christian R. Andres, Stephanie J. Tobin, R. DeFronzo (1979)
          Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.
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            Endpoints and clinical trial design for nonalcoholic steatohepatitis.

            Arun Sanyal, Elizabeth Brunt, David Kleiner … (2011)
            Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is associated with an increased risk of liver-related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point-of-care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH. This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH. Copyright © 2011 American Association for the Study of Liver Diseases.
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              Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.

              E Bugianesi, A Gastaldelli, E Vanni … (2005)
              Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (iso-abbrev): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): April 2016
                Publication date (Electronic): 09 February 2016
                Volume: 39
                Issue: 4
                Pages: 632-638
                Affiliations
                [1] 1Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
                [2] 2Department of Medicine, University of Florida, Gainesville, FL
                [3] 3Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX
                [4] 4Division of Gastroenterology, Hepatology, and Nutrition, Malcom Randall VA Medical Center, Gainesville, FL
                [5] 5Division of Pathology, Malcom Randall VA Medical Center, Gainesville, FL
                [6] 6Division of Endocrinology, Malcom Randall VA Medical Center, Gainesville, FL
                Author notes
                Corresponding author: Kenneth Cusi, kenneth.cusi@ 123456medicine.ufl.edu .
                Article
                Publisher ID: 1876
                DOI: 10.2337/dc15-1876
                PMC ID: 5864108
                PubMed ID: 26861926
                SO-VID: afbdbdd4-f1f2-46b6-af21-65a9bc585bbc
                Copyright © © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                Date received : 27 August 2015
                Date accepted : 7 January 2016
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 42, Pages: 7
                Funding
                Funded by: Burroughs Wellcome Fund, open-funder-registry 10.13039/100000861;
                Award ID: 1006762.01
                Funded by: American Diabetes Association, open-funder-registry 10.13039/100000041;
                Award ID: 1-08-CR-08
                Funded by: U.S. Department of Veterans Affairs, open-funder-registry 10.13039/100000738;
                Award ID: 1 I01 CX000167-01
                Categories
                Subject: Cardiovascular and Metabolic Risk

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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