Insulin Clearance in Health and Disease

Literature Cited

1. 1.

   Norton L, Shannon C, Gastaldelli A, DeFronzo RA. 2022. Insulin: the master regulator of glucose metabolism. Metabolism 129:155142
   [Google Scholar]
2. 2.

   Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA 2005. β-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J. Clin. Endocrinol. Metab. 90:493–500
   [Google Scholar]
3. 3.

   Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA 2004. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 47:31–39
   [Google Scholar]
4. 4.

   Hammerman MR. 1985. Interaction of insulin with the renal proximal tubular cell. Am. J. Physiol. 249:F1–11
   [Google Scholar]
5. 5.

   Ferrannini E, Wahren J, Faber OK, Felig P, Binder C, DeFronzo RA. 1983. Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am. J. Physiol. Renal Physiol. 244:E517–27
   [Google Scholar]
6. 6.

   Rabkin R, Simon NM, Steiner S, Colwell JA. 1970. Effect of renal disease on renal uptake and excretion of insulin in man. N. Engl. J. Med. 282:182–87
   [Google Scholar]
7. 7.

   Sonksen PH, McCormick JR, Egdahl RH, Soeldner JS. 1971. Distribution and binding of insulin in the dog hindlimb. Am. J. Physiol. 221:1672–80
   [Google Scholar]
8. 8.

   DeFronzo RA. 2009. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–95
   [Google Scholar]
9. 9.

   Gastaldelli A, Abdul Ghani M, DeFronzo RA 2021. Adaptation of insulin clearance to metabolic demand is a key determinant of glucose tolerance. Diabetes 70:377–85
   [Google Scholar]
10. 10.

    Bizzotto R, Trico D, Natali A, Gastaldelli A, Muscelli E et al. 2021. New insights on the interactions between insulin clearance and the main glucose homeostasis mechanisms. Diabetes Care 44:2115–23
    [Google Scholar]
11. 11.

    Polidori DC, Bergman RN, Chung ST, Sumner AE. 2016. Hepatic and extrahepatic insulin clearance are differentially regulated: results from a novel model-based analysis of intravenous glucose tolerance data. Diabetes 65:1556–64
    [Google Scholar]
12. 12.

    Jung SH, Jung CH, Reaven GM, Kim SH. 2018. Adapting to insulin resistance in obesity: role of insulin secretion and clearance. Diabetologia 61:681–87
    [Google Scholar]
13. 13.

    Ader M, Stefanovski D, Kim SP, Richey JM, Ionut V et al. 2014. Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog. Obesity 22:1238–45
    [Google Scholar]
14. 14.

    Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H et al. 1988. Quantitative study of insulin secretion and clearance in normal and obese subjects. J. Clin. Investig. 81:435–41
    [Google Scholar]
15. 15.

    Kim SH, Reaven GM. 2016. Insulin clearance: an underappreciated modulator of plasma insulin concentration. J. Investig. Med. 64:1162–65
    [Google Scholar]
16. 16.

    Gastaldelli A, Cusi K. 2019. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep 1:312–28
    [Google Scholar]
17. 17.

    Pajvani UB, Accili D. 2015. The new biology of diabetes. Diabetologia 58:2459–68
    [Google Scholar]
18. 18.

    Burns SF, Bacha F, Lee SJ, Tfayli H, Gungor N, Arslanian SA. 2011. Declining β-cell function relative to insulin sensitivity with escalating OGTT 2-h glucose concentrations in the nondiabetic through the diabetic range in overweight youth. Diabetes Care 34:2033–40
    [Google Scholar]
19. 19.

    Ferrannini E, Natali A, Muscelli E, Nilsson PM, Golay A et al. 2011. Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study. Diabetologia 54:1507–16
    [Google Scholar]
20. 20.

    Stancakova A, Javorsky M, Kuulasmaa T, Haffner SM, Kuusisto J, Laakso M. 2009. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes 58:1212–21
    [Google Scholar]
21. 21.

    Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW et al. 2020. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J. Clin. Investig. 130:3305–14
    [Google Scholar]
22. 22.

    Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. 1986. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N. Engl. J. Med. 315:215–19
    [Google Scholar]
23. 23.

    Amiel SA, Caprio S, Sherwin RS, Plewe G, Haymond MW, Tamborlane WV. 1991. Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism. J. Clin. Endocrinol. Metab. 72:277–82
    [Google Scholar]
24. 24.

    Burke GL, Webber LS, Srinivasan SR, Radhakrishnamurthy B, Freedman DS, Berenson GS. 1986. Fasting plasma glucose and insulin levels and their relationship to cardiovascular risk factors in children: Bogalusa Heart Study. Metabolism 35:441–46
    [Google Scholar]
25. 25.

    Caprio S, Plewe G, Diamond MP, Simonson DC, Boulware SD et al. 1989. Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J. Pediatr. 114:963–67
    [Google Scholar]
26. 26.

    Arslanian SA, Kalhan SC. 1994. Correlations between fatty acid and glucose metabolism. Potential explanation of insulin resistance of puberty. Diabetes 43:908–14
    [Google Scholar]
27. 27.

    Bracho-Romero E, Reaven GM. 1977. Effect of age and weight on plasma glucose and insulin responses in the rat. J. Am. Geriatr. Soc. 25:299–302
    [Google Scholar]
28. 28.

    Gatford KL, De Blasio MJ, Thavaneswaran P, Robinson JS, McMillen IC, Owens JA. 2004. Postnatal ontogeny of glucose homeostasis and insulin action in sheep. Am. J. Physiol. Endocrinol. Metab. 286:E1050–59
    [Google Scholar]
29. 29.

    Moran A, Jacobs DR Jr., Steinberger J, Hong CP, Prineas R et al. 1999. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes 48:2039–44
    [Google Scholar]
30. 30.

    Ball GD, Huang TT, Gower BA, Cruz ML, Shaibi GQ et al. 2006. Longitudinal changes in insulin sensitivity, insulin secretion, and β-cell function during puberty. J. Pediatr. 148:16–22
    [Google Scholar]
31. 31.

    Goran MI, Gower BA. 2001. Longitudinal study on pubertal insulin resistance. Diabetes 50:2444–50
    [Google Scholar]
32. 32.

    Hoffman RP, Vicini P, Sivitz WI, Cobelli C. 2000. Pubertal adolescent male-female differences in insulin sensitivity and glucose effectiveness determined by the one compartment minimal model. Pediatr. Res. 48:384–88
    [Google Scholar]
33. 33.

    Hannon TS, Janosky J, Arslanian SA. 2006. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Pediatr. Res. 60:759–63
    [Google Scholar]
34. 34.

    Miller JD, Tannenbaum GS, Colle E, Guyda HJ. 1982. Daytime pulsatile growth hormone secretion during childhood and adolescence. J. Clin. Endocrinol. Metab. 55:989–94
    [Google Scholar]
35. 35.

    Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB et al. 2012. Diabetes in older adults. Diabetes Care 35:2650–64
    [Google Scholar]
36. 36.

    Bellary S, Kyrou I, Brown JE, Bailey CJ. 2021. Type 2 diabetes mellitus in older adults: clinical considerations and management. Nat. Rev. Endocrinol. 17:534–48
    [Google Scholar]
37. 37.

    de Jesus, Garduno-Garcia J, Gastaldelli A, DeFronzo RA, Lertwattanarak R, Holst JJ, Musi N. 2018. Older subjects with β-cell dysfunction have an accentuated incretin release. J. Clin. Endocrinol. Metab. 103:2613–19
    [Google Scholar]
38. 38.

    Finucane FM, Sharp SJ, Hatunic M, Sleigh A, De Lucia Rolfe E et al. 2014. Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals. Diabetol. Metab. Syndr. 6:43
    [Google Scholar]
39. 39.

    Pacini G, Beccaro F, Valerio A, Nosadini R, Crepaldi G. 1990. Reduced beta-cell secretion and insulin hepatic extraction in healthy elderly subjects. J. Am. Geriatr. Soc. 38:1283–89
    [Google Scholar]
40. 40.

    Ahren B, Pacini G. 1998. Age-related reduction in glucose elimination is accompanied by reduced glucose effectiveness and increased hepatic insulin extraction in man. J. Clin. Endocrinol. Metab. 83:3350–56
    [Google Scholar]
41. 41.

    Najjar SM, Perdomo G. 2019. Hepatic insulin clearance: mechanism and physiology. Physiology 34:198–215
    [Google Scholar]
42. 42.

    Marmentini C, Soares GM, Bronczek GA, Piovan S, Mareze-Costa CE et al. 2021. Aging reduces insulin clearance in mice. Front. Endocrinol. 12:679492
    [Google Scholar]
43. 43.

    Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE. 2002. β-Cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 51:2170–78
    [Google Scholar]
44. 44.

    Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R. 2005. β-Cell function across the spectrum of glucose tolerance in obese youth. Diabetes 54:1735–43
    [Google Scholar]
45. 45.

    Group TS. 2013. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and beta-cell function in TODAY. Diabetes Care 36:1749–57
    [Google Scholar]
46. 46.

    RISE Consortium 2018. Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: II. Observations using the oral glucose tolerance test. Diabetes Care 41:1707–16
    [Google Scholar]
47. 47.

    Lee CC, Haffner SM, Wagenknecht LE, Lorenzo C, Norris JM et al. 2013. Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study. Diabetes Care 36:901–7
    [Google Scholar]
48. 48.

    Shah MH, Piaggi P, Looker HC, Paddock E, Krakoff J, Chang DC. 2021. Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans. Diabetologia 64:914–22
    [Google Scholar]
49. 49.

    Brancati FL, Kao WH, Folsom AR, Watson RL, Szklo M. 2000. Incident type 2 diabetes mellitus in African American and white adults: the Atherosclerosis Risk in Communities Study. JAMA 283:2253–59
    [Google Scholar]
50. 50.

    Arslanian SA, Saad R, Lewy V, Danadian K, Janosky J. 2002. Hyperinsulinemia in African-American children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes 51:3014–19
    [Google Scholar]
51. 51.

    Chandler-Laney PC, Phadke RP, Granger WM, Munoz JA, Man CD et al. 2010. Adiposity and β-cell function: relationships differ with ethnicity and age. Obesity 18:2086–92
    [Google Scholar]
52. 52.

    Koh HE, Patterson BW, Reeds DN, Mittendorfer B 2022. Insulin sensitivity and kinetics in African American and White people with obesity: Insights from different study protocols. Obesity 30:655–65
    [Google Scholar]
53. 53.

    Piccinini F, Polidori DC, Gower BA, Bergman RN. 2017. Hepatic but not extrahepatic insulin clearance is lower in African American than in European American women. Diabetes 66:2564–70
    [Google Scholar]
54. 54.

    Hasson BR, Apovian C, Istfan N. 2015. Racial/ethnic differences in insulin resistance and beta cell function: relationship to racial disparities in type 2 diabetes among African Americans versus Caucasians. Curr. Obes. Rep. 4:241–49
    [Google Scholar]
55. 55.

    Gower BA, Granger WM, Franklin F, Shewchuk RM, Goran MI. 2002. Contribution of insulin secretion and clearance to glucose-induced insulin concentration in African-American and Caucasian children. J. Clin. Endocrinol. Metab. 87:2218–24
    [Google Scholar]
56. 56.

    Marwitz SE, Gaines MV, Brady SM, Mi SJ, Broadney MM et al. 2020. Cross-sectional and longitudinal examination of insulin sensitivity and secretion across puberty among non-Hispanic Black and White children. Endocrinol. Metab. 35:847–57
    [Google Scholar]
57. 57.

    Piccinini F, Polidori DC, Gower BA, Fernandez JR, Bergman RN. 2018. Dissection of hepatic versus extra-hepatic insulin clearance: ethnic differences in childhood. Diabetes Obes. Metab. 20:2869–75
    [Google Scholar]
58. 58.

    Piccinini F, Bergman RN. 2020. The measurement of insulin clearance. Diabetes Care 43:2296–302
    [Google Scholar]
59. 59.

    Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. 2022. β cell function and plasma insulin clearance in people with obesity and different glycemic status. J. Clin. Investig. 132:e154068
    [Google Scholar]
60. 60.

    Meijer RI, Barrett EJ. 2021. The insulin receptor mediates insulin's early plasma clearance by liver, muscle, and kidney. Biomedicines 9:37
    [Google Scholar]
61. 61.

    Gastaldelli A, DeFronzo RA, Salehi M. 2021. Comment on Piccinini and Bergman. The measurement of insulin clearance. Diabetes Care 2020.; 43:2296–2302 Diabetes Care 44:e98–99
    [Google Scholar]
62. 62.

    DeFronzo RA. 1997. Pathogenesis of type 2 diabetes: Metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 5:177–269
    [Google Scholar]
63. 63.

    Edgerton DS, Scott M, Farmer B, Williams PE, Madsen P et al. 2019. Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery. JCI Insight 5:e126974
    [Google Scholar]
64. 64.

    Eggleston EM, Jahn LA, Barrett EJ. 2007. Hyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: evidence that a saturable process mediates muscle insulin uptake. Diabetes 56:2958–63
    [Google Scholar]
65. 65.

    Peiris AN, Mueller RA, Smith GA, Struve MF, Kissebah AH. 1986. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J. Clin. Investig. 78:1648–57
    [Google Scholar]
66. 66.

    Hansen BC, Striffler JS, Bodkin NL. 1993. Decreased hepatic insulin extraction precedes overt noninsulin dependent (Type II) diabetes in obese monkeys. Obes. Res. 1:252–60
    [Google Scholar]
67. 67.

    Escobar O, Mizuma H, Sothern MS, Blecker U, Udall JN Jr. et al. 1999. Hepatic insulin clearance increases after weight loss in obese children and adolescents. Am. J. Med. Sci. 317:282–86
    [Google Scholar]
68. 68.

    Rossell R, Gomis R, Casamitjana R, Segura R, Vilardell E, Rivera F. 1983. Reduced hepatic insulin extraction in obesity: relationship with plasma insulin levels. J. Clin. Endocrinol. Metab. 56:608–11
    [Google Scholar]
69. 69.

    Bonora E, Zavaroni I, Coscelli C, Butturini U. 1983. Decreased hepatic insulin extraction in subjects with mild glucose intolerance. Metabolism 32:438–46
    [Google Scholar]
70. 70.

    Giugliano D, Quatraro A, Minei A, De Rosa N, Coppola L, D'Onofrio F 1993. Hyperinsulinemia in hypertension: increased secretion, reduced clearance or both?. J. Endocrinol. Investig. 16:315–21
    [Google Scholar]
71. 71.

    Galderisi A, Polidori D, Weiss R, Giannini C, Pierpont B et al. 2019. Lower insulin clearance parallels a reduced insulin sensitivity in obese youths and is associated with a decline in β-cell function over time. Diabetes 68:2074–84
    [Google Scholar]
72. 72.

    Kim SP, Ellmerer M, Kirkman EL, Bergman RN. 2007. β-Cell “rest” accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model. Am. J. Physiol. Endocrinol. Metab. 292:E1581–89
    [Google Scholar]
73. 73.

    Zarghamravanbakhsh P, Frenkel M, Poretsky L. 2021. Metabolic causes and consequences of nonalcoholic fatty liver disease (NAFLD). Metabol. Open 12:100149
    [Google Scholar]
74. 74.

    Guerra S, Mocciaro G, Gastaldelli A. 2022. Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non-alcoholic steatohepatitis. Eur. J. Clin. Investig. 52:e13695
    [Google Scholar]
75. 75.

    Rosso C, Kazankov K, Younes R, Esmaili S, Marietti M et al. 2019. Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J. Hepatol. 71:1012–21
    [Google Scholar]
76. 76.

    Huh JY, Saltiel AR. 2021. Roles of IκB kinases and TANK-binding kinase 1 in hepatic lipid metabolism and nonalcoholic fatty liver disease. Exp. Mol. Med. 53:1697–705
    [Google Scholar]
77. 77.

    Svegliati-Baroni G, Gaggini M, Carli F, Barbieri C, Cucco M et al. 2020. Mechanisms for increased risk of diabetes in chronic liver diseases. Liver Int 40:2489–99
    [Google Scholar]
78. 78.

    Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Jarvinen H. 2008. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135:122–30
    [Google Scholar]
79. 79.

    Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y et al. 2007. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133:496–506
    [Google Scholar]
80. 80.

    Bril F, Lomonaco R, Orsak B, Ortiz-Lopez C, Webb A et al. 2014. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology 59:2178–87
    [Google Scholar]
81. 81.

    Matsubayashi Y, Yoshida A, Suganami H, Ishiguro H, Yamamoto M et al. 2018. Role of fatty liver in the association between obesity and reduced hepatic insulin clearance. Diabetes Metab 44:135–42
    [Google Scholar]
82. 82.

    Boden G. 2006. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr. Diab. Rep. 6:177–81
    [Google Scholar]
83. 83.

    Reaven GM. 1995. Pathophysiology of insulin resistance in human disease. Physiol. Rev. 75:473–86
    [Google Scholar]
84. 84.

    Lewis GF, Carpentier A, Adeli K, Giacca A. 2002. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr. Rev. 23:201–29
    [Google Scholar]
85. 85.

    Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. 2008. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134:424–31
    [Google Scholar]
86. 86.

    Gastaldelli A, Miyazaki Y, Pettiti M, Matsuda M, Mahankali S et al. 2002. Metabolic effects of visceral fat accumulation in type 2 diabetes. J. Clin. Endocrinol. Metab. 87:5098–103
    [Google Scholar]
87. 87.

    Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J et al. 2009. The protein kinase IKKε regulates energy balance in obese mice. Cell 138:961–75
    [Google Scholar]
88. 88.

    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. 2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Investig. 116:3015–25
    [Google Scholar]
89. 89.

    Saltiel AR, Olefsky JM. 2017. Inflammatory mechanisms linking obesity and metabolic disease. J.Clin. Investig. 127:1–4
    [Google Scholar]
90. 90.

    Perreault M, Marette A. 2001. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med. 7:1138–43
    [Google Scholar]
91. 91.

    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT et al. 2002. A central role for JNK in obesity and insulin resistance. Nature 420:333–36
    [Google Scholar]
92. 92.

    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L et al. 2005. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11:183–90
    [Google Scholar]
93. 93.

    Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. 2001. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7:947–53
    [Google Scholar]
94. 94.

    Guo Z, Hensrud DD, Johnson CM, Jensen MD. 1999. Regional postprandial fatty acid metabolism in different obesity phenotypes. Diabetes 48:1586–92
    [Google Scholar]
95. 95.

    Baldeweg SE, Golay A, Natali A, Balkau B, Del Prato S, Coppack SW. 2000. Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR). Eur. J. Clin. Investig. 30:45–52
    [Google Scholar]
96. 96.

    Charles MA, Eschwege E, Thibult N, Claude JR, Warnet JM et al. 1997. The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 40:1101–6
    [Google Scholar]
97. 97.

    Knowler WC, Pettitt DJ, Saad MF, Bennett PH. 1990. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab. Rev. 6:1–27
    [Google Scholar]
98. 98.

    Bergman RN, Van Citters GW, Mittelman SD, Dea MK, Hamilton-Wessler M et al. 2001. Central role of the adipocyte in the metabolic syndrome. J. Investig. Med. 49:119–26
    [Google Scholar]
99. 99.

    Kabir M, Catalano KJ, Ananthnarayan S, Kim SP, Van Citters GW et al. 2005. Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am. J. Physiol. Endocrinol. Metab. 288:E454–61
    [Google Scholar]
100. 100.

     Perry RJ, Camporez JP, Kursawe R, Titchenell PM, Zhang D et al. 2015. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745–58
     [Google Scholar]
101. 101.

     Titchenell PM, Quinn WJ, Lu M, Chu Q, Lu W et al. 2016. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. Cell Metab 23:1154–66
     [Google Scholar]
102. 102.

     Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T et al. 2005. JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 280:35361–71
     [Google Scholar]
103. 103.

     Kim YB, Kotani K, Ciaraldi TP, Henry RR, Kahn BB. 2003. Insulin-stimulated protein kinase C λ/ζ activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction. Diabetes 52:1935–42
     [Google Scholar]
104. 104.

     Svedberg J, Björntorp P, Smith U, Lonnroth P. 1990. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39:570–74
     [Google Scholar]
105. 105.

     Mittelman SD, Van Citters GW, Kim SP, Davis DA, Dea MK et al. 2000. Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response. Diabetes 49:2116–25
     [Google Scholar]
106. 106.

     Svedberg J, Stromblad G, Wirth A, Smith U, Bjorntorp P. 1991. Fatty acids in the portal vein of the rat regulate hepatic insulin clearance. J. Clin. Investig. 88:2054–58
     [Google Scholar]
107. 107.

     Wiesenthal SR, Sandhu H, McCall RH, Tchipashvili V, Yoshii H et al. 1999. Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 48:766–74
     [Google Scholar]
108. 108.

     Hennes MM, Dua A, Kissebah AH. 1997. Effects of free fatty acids and glucose on splanchnic insulin dynamics. Diabetes 46:57–62
     [Google Scholar]
109. 109.

     Bojsen-Møller KN, Dirksen C, Jorgensen NB, Jacobsen SH, Hansen DL et al. 2013. Increased hepatic insulin clearance after Roux-en-Y gastric bypass. J. Clin. Endocrinol. Metab. 98:E1066–71
     [Google Scholar]
110. 110.

     Rega-Kaun G, Kaun C, Jaegersberger G, Prager M, Hackl M et al. 2020. Roux-en-Y-bariatric surgery reduces markers of metabolic syndrome in morbidly obese patients. Obes. Surg. 30:391–400
     [Google Scholar]
111. 111.

     Gastaldelli A, Iaconelli A, Gaggini M, Magnone MC, Veneziani A et al. 2016. Short-term effects of laparoscopic adjustable gastric banding versus Roux-en-Y gastric bypass. Diabetes Care 39:1925–31
     [Google Scholar]
112. 112.

     Bosello O, Zamboni M, Armellini F, Zocca I, Bergamo Andreis IA et al. 1990. Modifications of abdominal fat and hepatic insulin clearance during severe caloric restriction. Ann. Nutr. Metab. 34:359–65
     [Google Scholar]
113. 113.

     Kim MK, Reaven GM, Chen YD, Kim E, Kim SH 2015. Hyperinsulinemia in individuals with obesity: role of insulin clearance. Obesity 23:2430–34
     [Google Scholar]
114. 114.

     Al-Share QY, DeAngelis AM, Lester SG, Bowman TA, Ramakrishnan SK et al. 2015. Forced hepatic overexpression of CEACAM1 curtails diet-induced insulin resistance. Diabetes 64:2780–90
     [Google Scholar]
115. 115.

     Lester SG, Russo L, Ghanem SS, Khuder SS, DeAngelis AM et al. 2015. Hepatic CEACAM1 over-expression protects against diet-induced fibrosis and inflammation in white adipose tissue. Front. Endocrinol. 6:116–22
     [Google Scholar]
116. 116.

     Russo L, Ghadieh HE, Ghanem SS, Al-Share QY, Smiley ZN et al. 2016. Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis. J. Lipid Res. 57:2163–75
     [Google Scholar]
117. 117.

     Choice CV, Howard MJ, Poy MN, Hankin MH, Najjar SM. 1998. Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors. J. Biol. Chem. 273:22194–200
     [Google Scholar]
118. 118.

     Ramakrishnan SK, Khuder SS, Al-Share QY, Russo L, Abdallah SL et al. 2016. PPARα (peroxisome proliferator-activated receptor α) activation reduces hepatic CEACAM1 protein expression to regulate fatty acid oxidation during fasting-refeeding transition. J. Biol. Chem. 291:8121–29
     [Google Scholar]
119. 119.

     Ramakrishnan SK, Russo L, Ghanem SS, Patel PR, Oyarce AM et al. 2016. Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity. J. Biol. Chem. 291:23915–24
     [Google Scholar]
120. 120.

     Najjar SM, Yang Y, Fernstrom MA, Lee SJ, Deangelis AM et al. 2005. Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metab 2:43–53
     [Google Scholar]
121. 121.

     Knutson VP, Ronnett GV, Lane MD. 1983. Rapid, reversible internalization of cell surface insulin receptors. Correlation with insulin-induced down-regulation. J. Biol. Chem. 258:12139–42
     [Google Scholar]
122. 122.

     Poy MN, Yang Y, Rezaei K, Fernstrom MA, Lee AD et al. 2002. CEACAM1 regulates insulin clearance in liver. Nat. Genet. 30:270–76
     [Google Scholar]
123. 123.

     Osborne TF. 2000. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J. Biol. Chem. 275:32379–82
     [Google Scholar]
124. 124.

     Helal RA, Russo L, Ghadieh HE, Muturi HT, Asalla S et al. 2021. Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1. Metabolism 121:154801
     [Google Scholar]
125. 125.

     Ben-Haroush Schyr R, Al-Kurd A, Moalem B, Permyakova A, Israeli H et al. 2021. Sleeve gastrectomy suppresses hepatic glucose production and increases hepatic insulin clearance independent of weight loss. Diabetes 70:2289–98
     [Google Scholar]
126. 126.

     Broh-Kahn RH, Mirsky IA. 1949. The inactivation of insulin by tissue extracts; the effect of fasting on the insulinase content of rat liver. Arch. Biochem. 20:10–14
     [Google Scholar]
127. 127.

     Bril F, Cusi K. 2019. Letter to the Editor: “Hepatic insulin extraction in NAFLD is related to insulin resistance rather than liver fat content. .” J. Clin. Endocrinol. Metab. 104:5249–50
     [Google Scholar]
128. 128.

     Bergman RN, Kabir M, Ader M. 2022. The physiology of insulin clearance. Int. J. Mol. Sci. 23:1826
     [Google Scholar]
129. 129.

     Bergman RN, Piccinini F, Kabir M, Kolka CM, Ader M. 2019. Hypothesis: role of reduced hepatic insulin clearance in the pathogenesis of type 2 diabetes. Diabetes 68:1709–16
     [Google Scholar]
130. 130.

     Marini MA, Frontoni S, Succurro E, Arturi F, Fiorentino TV et al. 2014. Differences in insulin clearance between metabolically healthy and unhealthy obese subjects. Acta Diabetol 51:257–61
     [Google Scholar]
131. 131.

     Koh HE, Cao C, Mittendorfer B. 2022. Insulin clearance in obesity and type 2 diabetes. Int. J. Mol. Sci. 23:596
     [Google Scholar]
132. 132.

     Gorden P, Carpentier JL, Freychet P, LeCam A, Orci L. 1978. Intracellular translocation of iodine-125-labeled insulin: direct demonstration in isolated hepatocytes. Science 200:782–85
     [Google Scholar]
133. 133.

     Satin LS, Butler PC, Ha J, Sherman AS. 2015. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol. Aspects Med. 42:61–77
     [Google Scholar]
134. 134.

     Campbell JE, Newgard CB. 2021. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat. Rev. Mol. Cell. Biol. 22:142–58
     [Google Scholar]
135. 135.

     Janssen JAMJL. 2021. Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer. Int. J. Mol. Sci. 22:7797
     [Google Scholar]
136. 136.

     Corkey BE. 2012. Banting lecture 2011: Hyperinsulinemia: Cause or consequence?. Diabetes 61:4–13
     [Google Scholar]
137. 137.

     Pories WJ, Dohm GL. 2012. Diabetes: Have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care 35:2438–42
     [Google Scholar]
138. 138.

     Bojsen-Møller KN, Lundsgaard AM, Madsbad S, Kiens B, Holst JJ. 2018. Hepatic insulin clearance in regulation of systemic insulin concentrations-role of carbohydrate and energy availability. Diabetes 67:2129–36
     [Google Scholar]
139. 139.

     Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. 2008. Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse?. Diabetes Care 31:Suppl. 2S262–68
     [Google Scholar]
140. 140.

     Ghadieh HE, Russo L, Muturi HT, Ghanem SS, Manaserh IH et al. 2019. Hyperinsulinemia drives hepatic insulin resistance in male mice with liver-specific Ceacam1 deletion independently of lipolysis. Metabolism 93:33–43
     [Google Scholar]
141. 141.

     Wortman MD, Clegg DJ, D'Alessio D, Woods SC, Seeley RJ 2003. C75 inhibits food intake by increasing CNS glucose metabolism. Nat. Med. 9:483–85
     [Google Scholar]
142. 142.

     Gao S, Moran TH, Lopaschuk GD, Butler AA. 2013. Hypothalamic malonyl-CoA and the control of food intake. Physiol. Behav. 122:17–24
     [Google Scholar]
143. 143.

     Chakravarthy MV, Zhu Y, Lopez M, Yin L, Wozniak DF et al. 2007. Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J. Clin. Investig. 117:2539–52
     [Google Scholar]
144. 144.

     Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI et al. 2000. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6:87–97
     [Google Scholar]
145. 145.

     Watada H, Tamura Y. 2017. Impaired insulin clearance as a cause rather than a consequence of insulin resistance. J. Diabetes Investig. 8:723–25
     [Google Scholar]
146. 146.

     Bakker LEH, van Schinkel LD, Guigas B, Streefland TCM, Jonker JT et al. 2014. A 5-day high-fat, high-calorie diet impairs insulin sensitivity in healthy, young South Asian men but not in Caucasian men. Diabetes 63:248–58
     [Google Scholar]
147. 147.

     Kaga H, Tamura Y, Takeno K, Kakehi S, Funayama T et al. 2017. Correlates of insulin clearance in apparently healthy non-obese Japanese men. Sci. Rep. 7:1462
     [Google Scholar]
148. 148.

     Lee W. 2011. The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes. Diagn. Pathol. 6:40
     [Google Scholar]