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Review
. 2022 Jan 6;23(2):596.
doi: 10.3390/ijms23020596.

Insulin Clearance in Obesity and Type 2 Diabetes

Han-Chow E Koh  1 , Chao Cao  1 , Bettina Mittendorfer  1
Affiliations
Review

Insulin Clearance in Obesity and Type 2 Diabetes

Han-Chow E Koh et al. Int J Mol Sci. .

Abstract

Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

Keywords: insulin clearance; insulin extraction; insulin secretion.

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Conflict of interest statement

The authors report no conflict of interest relevant to this article.

Figures

Figure 1
Figure 1
Insulin appearance in and removal from the circulation. Insulin is produced by pancreatic β cells and secreted into the portal vein, which delivers the newly produced insulin to the liver. The liver extracts approximately half of the newly secreted insulin. The remaining insulin is delivered to the systemic arterial circulation via the hepatic veins. Extrahepatic tissues extract some of the insulin from the arterial circulation during the first pass; the remaining insulin is removed in subsequent passes through the liver and extrahepatic tissues. Organ sizes in the figure are depicted according to their importance in determining plasma insulin concentration, rather than proportional to their actual size.
Figure 2
Figure 2
Insulin transport across the endothelium and cellular insulin uptake. Insulin must first pass through the endothelial cell layer of capillaries into the interstitium. The liver sinusoidal endothelial cell layer is fenestrated and highly permeable to insulin, allowing free flow of insulin towards hepatocytes. In skeletal muscles and adipose tissue, insulin crosses the tight endothelial cell layer via receptor-mediated endocytosis-exocytosis, fluid-phase transport, and paracellular transport. Receptor-mediated transcellular transport represents the key route of entry when blood insulin concentration is low and fluid-phase transcellular transport and paracellular transport take over when blood insulin concentration is high. Once in the interstitium, insulin binds to insulin receptors on parenchymal cells, which causes the translocation of the insulin–insulin receptor complex into the cytosol via endocytosis. Insulin is degraded inside the endosomes by insulin degrading enzyme and the receptors start to return to the cell surface.
Figure 3
Figure 3
Relationship between insulin delivery and tissue insulin uptake and plasma clearance rate (adapted from references [12,13,14,15,16,72]). As insulin delivery to tissue increases, the fractional extraction of insulin (proportion of the amount delivered that is taken up) and plasma clearance of insulin decrease in the liver and skeletal muscles but increase in the kidneys. Furthermore, liver insulin uptake becomes saturated at approximately 1800 pmol/min whereas extra-hepatic insulin uptake is not saturable within the physiological range of insulin delivery to tissues. Note: arterial plasma insulin concentration in these experiments ranged from approximately 50 pM during basal conditions to approximately 9000 pM during the highest dose insulin infusion. Endogenous insulin secretion was inhibited by somatostatin infusion and insulin was infused into a peripheral vein. So, hepatic insulin delivery occurred almost exclusively via the arterial circulation, and hepatic insulin delivery at any arterial insulin concentration was, therefore, much less than during postprandial conditions when endogenous insulin secretion occurs into the portal vein. Abbreviations: Basal, overnight fasted condition; FE, fractional extraction.
Figure 4
Figure 4
Hepatic insulin delivery during basal and postprandial conditions and during intravenous and oral glucose tolerance tests. Hepatic insulin delivery rates were calculated as described in reference [18] with average insulin secretion and plasma insulin concentration values reported in the literature. See text for details. Abbreviations: IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test.
Figure 5
Figure 5
Effect of obesity, insulin resistance, and type 2 diabetes on basal and postprandial plasma insulin clearance rate. Left panel: Whole-body plasma insulin clearance rate during basal conditions and for three hours after glucose ingestion. Right panel: Plasma insulin clearance rate in relationship to insulin delivery to tissues during basal conditions and during the early postprandial period. Adapted from references [3,8,83]. Abbreviations: ICR, insulin clearance rate; IS, insulin sensitive; IR, insulin resistant; Ob, obese; T2D, type 2 diabetes.
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References

    1. Ferrannini E. A Journey in Diabetes: From Clinical Physiology to Novel Therapeutics: The 2020 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021;70:338–346. doi: 10.2337/dbi20-0028. - DOI - PMC - PubMed
    1. DeFronzo R.A. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795. doi: 10.2337/db09-9028. - DOI - PMC - PubMed
    1. Mittendorfer B., Patterson B.W., Smith G.I., Yoshino M., Klein S. Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status. J. Clin. Investig. 2021:e154068. doi: 10.1172/JCI154068. online ahead of print . - DOI - PMC - PubMed
    1. Esser N., Utzschneider K.M., Kahn S.E. Early beta cell dysfunction vs. insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia. Diabetologia. 2020;63:2007–2021. doi: 10.1007/s00125-020-05245-x. - DOI - PubMed
    1. Bergman R.N., Finegood D.T., Kahn S.E. The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes. Eur. J. Clin. Investig. 2002;32((Suppl. S3)):35–45. doi: 10.1046/j.1365-2362.32.s3.5.x. - DOI - PubMed