The disposition index: adjustment for peripheral vs. hepatic insulin sensitivity?

J Physiol 588.5 (2010) pp 759 764 759 TOPICAL REVIEW The disposition index: adjustment for peripheral vs. hepatic insulin sensitivity? K. Færch, C. Brøns, A. C. Alibegovic and A. Vaag Steno Diabetes Center, Gentofte, Denmark The assessment of pancreatic β cell function in humans is challenging because of a complex interplay between insulin secretion, insulin sensitivity and hepatic insulin extraction. Simplified, the relationship between insulin secretion and insulin sensitivity can be described by an approximate hyperbola with the product of the two variables being constant for individuals with the same degree of glucose tolerance (the disposition index). Strengths and limitations of the disposition index have been widely debated in the literature. In this review we will focus on another and until recently unrecognized dimension of the disposition index, namely the issue of adjusting insulin secretion for hepatic versus peripheral insulin sensitivity. An underlying assumption of this issue is that the liver as compared to muscle plays a different role in the regulation of in vivo insulin secretion. (Received 2 November 2009; accepted after revision 19 January 2010; first published online 25 January 2010) Corresponding author K. Færch: Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Email: krif@steno.dk Abbreviations FSIGT, frequently sampled intravenous glucose tolerance test; GIP, glucose-dependent insulinotropic polypeptide; i-ifg, isolated impaired fasting glycaemia; IVGTT, intravenous glucose tolerance test; NGT, normal glucose tolerance. To improve our understanding of glucose regulation and type 2 diabetes pathophysiology, we need continuously to improve and develop novel and more advanced methods to assess in vivo pancreatic β cell function. The assessment of in vivo β cell function in humans is challenging because insulin secretion, insulin sensitivity and hepatic insulin extraction interact with each others in complicated closed loop systems (Cobelli et al. 2007). An important aspect of the control of in vivo insulin secretion is that in healthy individuals with normal glucose tolerance, a reduction in insulin sensitivity is normally accompanied by a compensatory up-regulation of insulin secretion. Simplified, this relationship between insulin sensitivity and insulin secretion is thought to be approximately hyperbolic so that the product of the two variables is constant for individuals with the same degree of glucose tolerance (Kahn et al. 1993). This constant was first termed the disposition factor (Bergman et al. 1981), but is now commonly known as the disposition index. Several strengths and limitations of the disposition index have been widely debated in the literature during the last years. For instance, it has been addressed whether the assumption of a hyperbola is fulfilled (Kahn et al. 1993; Ferrannini & Mari, 2004; Utzschneider et al. 2009), whether individuals with the same disposition index have similar glucose tolerance status (Stumvoll et al. 2003; Stumvoll et al. 2005; Cobelli et al. 2007; Wilkin & Metcalf, 2009), and which estimates of insulin sensitivity and insulin secretion best describe β cell function in humans (Cobelli et al. 2007). What we will discuss in this review is another dimension of the disposition index, namely the issue of adjusting for hepatic insulin sensitivity in addition, or as a complementary approach, to the Kristine Færch (MSc, PhD) and Allan Vaag (Professor, MD, DMSc) do their research at the Steno Diabetes Center in Gentofte in close collaboration with their colleagues Charlotte Brøns (MSc, PhD) and Amra C. Alibegovic (MD, PhD). They all share a genuine interest in the pathophysiology of type 2 diabetes with a particular focus on mechanisms predisposing individuals to type 2 diabetes later in life. Most of their research is based on in vivo studies using human integrative physiological approaches. DOI: 10.1113/jphysiol.2009.184028

760 K. Færch and others J Physiol 588.5 conventional adjustment for whole-body or peripheral insulin sensitivity. Calculation of the disposition index Originally, the disposition index was calculated from insulin sensitivity and acute insulin secretion estimated by the frequently sampled intravenous glucose tolerance test (FSIGT) (Bergman et al. 1981; Kahn et al. 1993). The insulin sensitivity calculated from the FSIGT is assumed to provide an aggregated measure of hepatic and peripheral insulin sensitivity (Bergman et al. 1979), and accordingly, the corresponding disposition index takes into account whole-body insulin sensitivity. In addition to the FSIGT, the disposition index has been widely estimated from measures of insulin sensitivity and insulin secretion derived from the euglycaemic hyperinsulinemic clamp technique in combination with the intravenous glucose tolerance test (IVGTT) (Abdul-Ghani et al. 2006a; Færch et al. 2008; Laakso et al. 2008). Using high supra-physiological insulin infusion rates during euglycaemic clamps (40 80 mu m 2 min 1 ), hepatic glucose production is almost fully suppressed (DeFronzo et al. 1979), and 80 90% of glucose disposal occurs in peripheral tissues (predominantly skeletal muscles) (DeFronzo & Tripathy, 2009). Therefore, the clamp technique does not provide an aggregated measure of hepatic and peripheral insulin sensitivity to the same extent as the FSIGT method; it mainly provides an estimate of peripheral insulin sensitivity. When using insulin sensitivity derived from a euglycaemic hyperinsulinaemic clamp in the calculation of the disposition index it may therefore be relevant to additionally calculate a disposition index based on hepatic insulin sensitivity. Since fasting plasma glucose levels are mainly influenced by a feedback loop between the liver and the pancreas (Turner & Holman, 1976) and because >75% of endogenous glucose production originates in the liver (Stumvoll et al. 1997), a valid estimate of hepatic insulin resistance can be obtained by multiplying basal endogenous glucose production with basal insulin levels (Matsuda & DeFronzo, 1999). Thus, hepatic insulin sensitivity can be calculated as 1/(endogenous glucose production basal insulin concentration), which may be used in the calculation of a hepatic insulin secretion disposition index (Brøns et al. 2009; Alibegovic et al. 2009). Why focus on the liver? There are many reasons to focus on the liver in addition to the periphery when considering in vivo insulin secretion and its relationship to insulin action. Both peripheral and hepatic insulin resistance are common features in type 2 diabetes (DeFronzo, 2009), but before diabetes is manifest, insulin resistance can occur separately and/or with different degrees in liver versus skeletal muscles as illustrated in their different contributions to either impaired fasting glycaemia or impaired glucose tolerance (Abdul-Ghani et al. 2006b; Færchet al. 2009). Hepatic insulin sensitivity and peripheral insulin sensitivity are strongly interrelated, but hepatic insulin sensitivity explains only about half of the variation in peripheral insulin sensitivity (r 2 = 0.46) (Abdul-Ghani et al. 2008). Thus, many individuals are discordant for hepatic and peripheral insulin sensitivity (Abdul-Ghani et al. 2008; Brøns et al. 2009; Alibegovic et al. 2009), and given the different physiological roles of the liver versus the periphery, it may be too simplistic only to relate insulin secretion to peripheral insulin sensitivity when calculating the disposition index. In addition, the fact that glucose levels increase when insulin sensitivity decreases despite appropriate β cell compensation a feature termed glucose allostasis (Stumvoll et al. 2003) is consistent with the idea that the commonly used disposition index may not adequately reflect β cell compensation in all individuals. Data supporting the concept of a hepatic disposition index Despite the obvious importance of focusing on hepatic insulin resistance when studying the pathogenesis of type 2 diabetes, only two studies have so far addressed the issue of adjusting insulin secretion for hepatic insulin sensitivity in addition to the conventional adjustment for peripheral or whole-body insulin sensitivity. Recently, it was demonstrated that short-term high-fat overfeeding in young healthy men caused an elevated first-phase insulin response in an absolute sense (Brøns et al. 2009). Interestingly, hepatic insulin sensitivity was significantly decreased in response to the high-fat overfeeding, but surprisingly peripheral insulin sensitivity was unaltered. Therefore, two different disposition indices of insulin secretion were calculated: one based on peripheral insulin sensitivity and one based on hepatic insulin sensitivity. As expected from the absolute values but not from the aprioriassumption the disposition index calculated from peripheral insulin sensitivity was disproportionately and significantly elevated after the high-fat diet (Fig. 1A). According to the assumptions inherent in the disposition index (Kahn et al. 1993), an interpretation of this finding would be that glucose tolerance had improved, which seemed not to be the case. The disposition index calculated from hepatic insulin sensitivity was unaltered after the high-fat diet (Fig. 1B), so it was concluded that the insulin secretion was increased to compensate for the degree of hepatic insulin resistance (Brøns et al. 2009).

J Physiol 588.5 The disposition index 761 In another recent study, 13 healthy young male first-degree relatives of type 2 diabetes patients and 20 matched controls were examined with an IVGTT and a euglycaemic hyperinsulinaemic clamp (Alibegovic et al. 2009). The first-degree relatives exhibited normal peripheral insulin sensitivity and a normal first-phase insulin response, so the disposition index calculated from peripheral insulin sensitivity did not differ between first-degree relatives and controls (Fig. 2A). However, the first-degree relatives had a severe degree of hepatic insulin resistance, and accordingly, a reduced disposition index was calculated from hepatic insulin sensitivity (Fig. 2B) (Alibegovic et al. 2009). Altogether, what appeared to be a normal β cell function when expressed in relation to peripheral insulin sensitivity was in fact not normal when hepatic insulin sensitivity was taken into account. This supports the idea that it may be too simplistic only to focus on and correct for peripheral insulin sensitivity when in vivo β cell functionality is to be determined. Potential mechanisms and limitations The specific molecular feedback mechanisms and signals between pancreas, liver and muscle and perhaps even other tissues are not fully understood. However, parallel with hepatic insulin resistance significantly elevated levels of glucose-dependent insulinotropic polypeptide (GIP) was found after 5 days of high-fat overfeeding in young healthy men (Brøns et al. 2009). These elevated GIP levels could potentially have contributed to the elevated insulin secretion observed after the high-fat diet, but also the elevated glucose levels per se (due to hepatic insulin resistance) could have contributed. The liver enzyme aspartate aminotransferase was also elevated after the high-fat diet (Brøns et al. 2009), indicating accumulation of fat in the liver. Since fat accumulation in the liver may affect insulin clearance (Goto et al. 1995), it could be argued that the observed differences in disposition indices when calculated from peripheral vs. hepatic insulin sensitivity may be due to differences in the rate of insulin clearance. However, during the euglycaemic hyperinsulinaemic clamps as performed in the two studies, steady state plasma insulin concentrations did not differ between the study groups (Alibegovic et al. 2009; Brøns et al. 2009), indicating similar insulin clearance rates. One potential concern in using the fasting plasma insulin level in the calculation of hepatic insulin sensitivity, and subsequently in the calculation of a hepatic disposition index, could be that there may be an intrinsic interdependence between the measure of fasting Figure 1. Disposition indices after control diet or 5 days of high-fat overfeeding Disposition indices (means + S.E.M.) derived from peripheral insulin sensitivity (A) and hepatic insulin sensitivity (B) after control diet or 5 days of high-fat overfeeding in 26 healthy young men (Data are published in Brøns et al. 2009). Figure 2. Disposition indices in healthy first-degree relatives of type 2 diabetes patients and healthy controls Disposition indices (means + S.E.M.) derived from peripheral insulin sensitivity (A) and hepatic insulin sensitivity (B) in 13 healthy first-degree relatives of type 2 diabetes patients and 20 healthy controls (Data are published in Alibegovic et al. 2009).

762 K. Færch and others J Physiol 588.5 insulin concentration and first-phase insulin response. Although this to some unknown extent may affect the relationship between hepatic insulin sensitivity and in vivo insulin secretion, it should be noted that the fasting insulin concentration and first-phase insulin response are measured during different metabolic states, and that they may therefore not reflect the same regulatory mechanisms. First-phase insulin response is calculated from plasma insulin levels as determined after exogenous glucose stimulation, thereby reflecting an open loop response. In contrast, the fasting plasma insulin level is determined by a closed loop feedback system between the pancreas on one side and the liver on the other (Turner & Holman, 1976). Thus, the fasting insulin levels will mainly reflect the degree of insulin needed for inhibiting hepatic glucose production (as long as hepatic glucose production is within the normal (non-diabetic) range). Intuitively, the fasting plasma insulin concentration is therefore likely to reflect hepatic insulin resistance more than pancreatic insulin secretion capacity per se, atleast in healthy non-diabetic subjects. Nevertheless, more data are needed to accurately assess the role and impact of the interdependence between fasting plasma insulin concentration and first-phase insulin response in the calculation of hepatic versus peripheral disposition indices. Besides insulin secretion and insulin sensitivity, glucose tolerance may to some unknown extent be influenced by non-insulin-mediated glucose disposal, which could also potentially influence estimates of hepatic versus peripheral insulin sensitivity. However, in the two studies (Alibegovic et al. 2009; Brøns et al. 2009)glucose turnover rates used to calculate both hepatic and peripheral insulin sensitivity were performed during euglycaemia in the same individuals. Therefore, it seems unlikely that the calculations of hepatic versus peripheral disposition indices reflect differential effects of non-insulin-mediated glucose disposal. Figure 3. Relationship between first phase insulin response and hepatic and peripheral insulin sensitivity indices Relationship between first phase insulin response (pmol l 1 ) and hepatic insulin sensitivity index (A), and between first phase insulin response and peripheral insulin sensitivity index in individuals with normal glucose tolerance (NGT, n = 20), isolated impaired fasting glycaemia (i-ifg, n = 17), and isolated impaired glucose tolerance (i-igt, n = 26) (B) (Færch et al. 2008). The mean (S.D.) hepatic disposition index was 27.1 (18.5) in individuals with NGT, 19.2 (34.6) in those with i-ifg and 17.9 (9.2) in those with i-igt with no significant difference between individuals with i-ifg and i-igt (P = 0.838). The corresponding mean (S.D.) values for the peripheral disposition indices were 47.7 (32.1) in those with NGT, 21.2 (10.9) in those with i-ifg and 26.2 (17.9) in those with i-igt (P = 0.461 for difference between i-ifg and i-igt).

J Physiol 588.5 The disposition index 763 The relationship between insulin secretion and hepatic insulin sensitivity An important assumption for calculating the traditional disposition index is that the relationship between insulin secretion and insulin sensitivity is hyperbolic (Kahn et al. 1993). It could therefore be argued that a hyperbolic relationship between insulin secretion and hepatic insulin sensitivity should be required for hepatic insulin sensitivity to be used in the calculation of the disposition index. We have plotted data on first-phase insulin response against hepatic insulin sensitivity (Fig. 3A)andperipheral insulin sensitivity (Fig. 3B) from well-characterized men and women with normal glucose tolerance (NGT), isolated impaired fasting glycaemia (i-ifg), and isolated impaired glucose tolerance (i-igt)(færch et al. 2008). Visual examination of Fig. 3A and B suggests that hepatic insulin sensitivity seems to be at least as good as or even better than peripheral insulin sensitivity in fitting a hyperbolic function in individuals with different glucose tolerance status, and statistical analysis of the data supported this notion. Ideally, the slope of the regression line of the log-transformed variables of first-phase insulin response and insulin sensitivity should be 1.0 if the data fit a hyperbolic function in these individuals. For each glucose tolerance group, the slopes of the regression lines between the log-transformed variables of first-phase insulin response and hepatic and peripheral insulin sensitivity were tested with Deming s regression (Sprent, 1969), which allows for errors in both the independent and dependent variables (Riggs et al. 1978). The model with hepatic insulin sensitivity gave slopes (95% CI) of 0.84 ( 1.55; 0.32) for those with NGT, 2.46 ( 4.44; 0.19) for those with i-ifg, and 0.78 ( 1.29; 0.28) for those with i-igt. The corresponding slopes for the relationships between the log-transformed first-phase insulin response and peripheral insulin sensitivity were 0.24 ( 0.44; 0.02) for individuals with NGT, 1.1 ( 3.0; 0.47) for those with i-ifg, and 0.68 ( 1.09; 0.20) for those with i-igt. Since 1.0 is included in all of the confidence intervals for hepatic insulin sensitivity, it may be assumed, and at least it cannot be excluded, that a hyperbolic function is the best fit of the data. Thereby, hepatic insulin sensitivity seems to be at least as reasonable to use in the calculation of the disposition index as peripheral insulin sensitivity. The liver is generally thought to play a more important role than muscle in the control of glucose homeostasis during the fasting state as well as during low physiological plasma insulin levels. Conversely, the periphery, and thereby the muscle tissue, may play a more significant role in the control of glucose homeostasis during higher plasma insulin levels as obtained in the postprandial state. Thus, it may be assumed that the hepatic as opposed to the peripheral disposition index is more closely related to the fasting compared with postprandial plasma glucose levels, and vice versa. As illustrated in Fig. 3A,the hepatic disposition index was not significantly lower in individuals with i-ifg compared to those with i-igt. It is therefore not possible definitively to conclude that a decrease in the hepatic disposition index may be more closely related to fasting plasma glucose levels as opposed to plasma glucose levels after an oral glucose tolerance test in non-diabetic individuals. However, additional cross-sectional and prospective data and studies covering an even broader spectrum of individuals ranging from normal glucose tolerance to mild as well as more severe degrees of type 2 diabetes are needed to resolve this issue. Conclusion In conclusion, results from two recent studies indicate that the adjustment for hepatic insulin sensitivity in the calculation of the disposition index provides different information from that of peripheral insulin sensitivity. We therefore suggest future studies to report disposition indices calculated from measures of both peripheral and hepatic insulin sensitivity. It may also be relevant to relate different aspects of β cell function to different sites of insulin sensitivity. The liver and the periphery have different roles in the control of fasting versus postprandial glucose homeostasis (O Rahilly et al. 1994; DeFronzo, 2009; Færch et al. 2009). Therefore, it could be of potential interest to relate basal insulin secretion to hepatic insulin sensitivity, and conversely to relate the challenged and dynamic insulin secretion to peripheral insulin sensitivity. It could also be speculated that other mathematical equations taking into account the ambient degree of insulin sensitivity of both the liver and the periphery would provide better approximations of in vivo β cell function in humans. Indeed, the recent findings underscore that the estimation and understanding of in vivo β cell function and its relationship with insulin sensitivity seem to be far more complex than what is contained in the conventional disposition index as calculated from peripheral insulin sensitivity only, or as from an integration of whole body insulin sensitivity with unknown contributions of different organs. A better understanding of the functional interactions between pancreas, liver and periphery may improve our estimation of in vivo β cell function, and eventually reduce the need to define concepts such as glucose allostasis. References Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D & DeFronzo RA (2006a). Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: Results from the veterans administration genetic epidemiology study. Diabetes 55, 1430 1435.

764 K. Færch and others J Physiol 588.5 Abdul-Ghani MA, Matsuda M & DeFronzo RA (2008). Strong association between insulin resistance in liver and skeletal muscle in non-diabetic subjects. Diabetic Med 25, 1289 1294. Abdul-Ghani MA, Tripathy D & DeFronzo RA (2006b). Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 29, 1130 1139. Alibegovic AC, Højbjerre L, Sonne MP, van Hall G, Stallknecht B, Dela F & Vaag A (2009). Impact of nine days of bed rest on hepatic and peripheral insulin action, insulin secretion and whole body lipolysis in healthy young male offspring of patients with type 2 diabetes. Diabetes 58, 2749 2756. Bergman RN, Ider YZ, Bowden CR & Cobelli C (1979). Quantitative estimation of insulin sensitivity. Am J Physiol Endocrinol Metab 236, E667 E677. Bergman RN, Phillips LS & Cobelli C (1981). Physiologic evaluation of factors controlling glucose tolerance in man. Measurement of insulin sensitivity and β-cell glucose sensitivity from the response to intravenous glucose. JClin Invest 68, 1456 1467. BrønsC,JensenCB,StorgaardH,HiscockNJ,WhiteA,Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B & Vaag A (2009). Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol 587, 2387 2397. Cobelli C, Toffolo GM, Man CD, Campioni M, Denti P, Caumo A, Butler P & Rizza R (2007). Assessment of β-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab 293, E1 15. DeFronzo RA (2009). Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773 795. DeFronzo RA, Tobin JD & Andres R (1979). Glucose clamp tecnique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab 237, E214 E223. DeFronzo RA & Tripathy D (2009). Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32, S157 S163. Færch K, Borch-Johnsen K, Holst JJ & Vaag A (2009). Pathophysiology and aetiology of impaired fasting glycaemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes? Diabetologia 52, 1714 1723. Færch K, Vaag A, Holst J, Glümer C, Pedersen O & Borch-Johnsen K (2008). Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action. Diabetologia 51, 853 861. Ferrannini E & Mari A (2004). Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia 47, 943 956. Goto T, Onuma T, Takebe K & Kral JG (1995). The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord 19, 841 845. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. (1993). Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42, 1663 1672. Laakso M, Zilinskaite J, Hansen T, Boesgaard T, Vänttinen M, Stancáková A, Jansson PA, Pellmé F, Holst J, Kuulasmaa T, HribalM,SestiG,StefanN,FritscheA,Häring H, Pedersen O & Smith U for the EUGENE2 Consortium (2008). Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia 51, 502 511. Matsuda M & DeFronzo RA (1999). Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp. Diabetes Care 22, 1462 1470. O Rahilly S, Hattersley A, Vaag A & Gray H (1994). Insulin resistance as the major cause of impaired glucose tolerance: a self-fulfilling prophesy? Lancet 344, 585 589. Riggs DS, Guarnieri JA & Addelman S (1978). Fitting straight lines when both variables are subject to error. Life Sci 22, 1305 1360. Sprent P (1969). Law-like relationships in the presence of random variation. In Models in Regression and Related Topics, pp. 29 46. Methuen & Co. Ltd, London. Stumvoll M, Meyer C, Mitrakou A, Nadkarni V & Gerich JE (1997). Renal glucose production and utilization: new aspects in humans. Diabetologia 40, 749 757. Stumvoll M, Tataranni PA & Bogardus C (2005). The hyperbolic law: a 25-year perspective. Diabetologia 48, 207 209. Stumvoll M, Tataranni PA, Stefan N, Vozarova B & Bogardus C (2003). Glucose allostasis. Diabetes 52, 903 909. Turner RC & Holman RR (1976). Insulin rather than glucose homoeostasis in the pathophysiology of diabetes. Lancet 1, 1272 1274. Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, Boyko EJ, Leonetti DL, McNeely MJ, Fujimoto WY & Kahn SE (2009). Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 32, 335 341. Wilkin TJ & Metcalf BS (2009). Glucose allostasis: Emperor s new clothes? Diabetologia 52, 776 778. Acknowledgements We would like to thank senior statistician Bendix Carstensen (Steno Diabetes Center, Gentofte, Denmark) for expert statistical assistance. The authors declare that they have no conflict of interest associated with this manuscript.