Hepatic Insulin Clearance Is Closely Related to Metabolic Syndrome Components

Abstract

OBJECTIVEInsulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome.RESEARCH DESIGN AND METHODSIndividuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated.RESULTSBoth HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97–1.31], P = 0.12, and HICISR 1.38 [0.88–2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92–1.36], P = 0.26, and HICISR 1.31 [0.74–2.33] P = 0.36), although point estimates reached no statistical significance.CONCLUSIONSHIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.

Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

“…Insulin clearance, which occurs mostly in liver and to a lower extent in kidney, but not in skeletal muscle or white adipose tissue (WAT), plays a pivotal role in promoting insulin sensitivity (4). If impaired, it contributes to mounting hyperinsulinemia in obese humans (5, 6), thus constituting a risk factor for metabolic syndrome (7,8).Our studies on the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein that is highly expressed in liver and kidney, but not WAT or skeletal muscle (9), support these findings. Upon its phosphorylation by the insulin receptor, CEACAM1 promotes insulin clearance by upregulating receptor-mediated insulin uptake into clathrin-coated pits and degradation in hepatocytes (10).…”

“…Insulin clearance, which occurs mostly in liver and to a lower extent in kidney, but not in skeletal muscle or white adipose tissue (WAT), plays a pivotal role in promoting insulin sensitivity (4). If impaired, it contributes to mounting hyperinsulinemia in obese humans (5, 6), thus constituting a risk factor for metabolic syndrome (7,8).…”

“…Then 1 ml of the homogenate was added to a sealed beaker containing 1 ml of solution A and left at 30°C for 45 min. Solution A: 0.2 mM of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate (0.5 mCi/ml) (American Radiolabeled Chemicals Inc.) and 2 mM ATP in incubation buffer (100 mM sucrose, 10 mM Tris-HCl, 5 mM potassium phosphate, 80 mM KCl, 1 mM MgCl 2 , 2 mM l-carnitine, 0.1 mM malic acid, 0.05 mM CoA, 1mM dithiothreitol, 0.2 mM EDTA, and 0.5% BSA, pH 7.4). Benzothonium hydroxide (Sigma-Aldrich) was added to a basket attached to the sealed beaker and the reaction was terminated with perchloric acid to recover the radioactive acid soluble metabolites (29).…”

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT)

“…There is increasing evidence that hyperinsulinaemia in the insulin-resistant state reflects two pathophysiological processes: an increase in insulin secretion and a decrease in hepatic insulin clearance (HIC) [27]. Based on the OGTT data, HIC C-peptide was calculated using the ratio of incremental areas under the insulin and C-peptide curve:…”

The Lipogenic Effect of Insulin Revisited

“…Several investigations have followed to explore this connection in various animal models (Ader et al 2014 ), and in individuals with obesity (Jones et al 2000 ;Meistas et al 1983 ) and predisposition to metabolic syndrome and type 2 diabetes (Lee et al 2013 ;Pivovarova et al 2013 ). The insulin-degrading enzyme has been identifi ed as a diabetes susceptibility gene (Sladek et al 2007 ;Zeggini et al 2007 ).…”