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PROF. HIROTAKA WATADA (Orcid ID : 0000-0001-5961-1816) DR. YOSHIFUMI TAMURA (Orcid ID : 0000-0002-1685-7821) Article type

: Editorial

Impaired insulin clearance as a cause rather than a consequence of insulin resistance

Hirotaka Watada1-4, Yoshifumi Tamura1,2

Department of Metabolism & Endocrinology, 2Sportology Center, 3Center for

1

Therapeutic Innovations in Diabetes, 4Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo,

Japan

Address correspondence to: Prof. Hirotaka Watada Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Tel: +81-3-5802-1579 Fax: +81-3-3813-5996 E-mail: [email protected] Word Count: 1,474 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jdi.12717 This article is protected by copyright. All rights reserved.

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Short Title: Insulin clearance and Type 2 diabetes mellitus

Impaired insulin sensitivity and reduced  cell function have been regarded as the two major physiological defects in type 2 diabetes mellitus. It is generally accepted that the initial defect in this disease is insulin resistance, which is typically elicited by overeating and decreased physical activity, both of which are tightly linked with obesity.  cells then compensate for insulin resistance by enhancing insulin secretion. However, the various cellular stresses caused by the insulin-resistant state reduce the ability of  cells to secrete insulin and eventually lead to rising blood glucose levels. Whereas decreased insulin clearance is also observed very early in the development of type 2 diabetes mellitus, this change had generally been regarded as a mechanism for compensating for impaired insulin sensitivity by increasing serum insulin levels.

However, if decreased insulin clearance is a compensatory mechanism for impaired

insulin sensitivity, insulin resistance should appear earlier than decreased insulin clearance during the transition from a metabolically normal state to the onset of impaired glucose metabolism. Although no studies have evaluated serial changes in insulin sensitivity and clearance during the development of moderate insulin resistance, cross-sectional data regarding the relation between insulin resistance and clearance have provided useful information on this issue. Insulin clearance is known to be lower in obese than non-obese individuals; however, it was also found to be lower in metabolically unhealthy obese subjects than those who were healthy (1). In addition, we recently investigated insulin sensitivity in muscles and liver and insulin clearance using a two-step hyperinsulinemic euglycemic clamp in healthy, non-obese Japanese men (2). After dividing these subjects into two groups according to insulin clearance, we investigated the clinical features of the subjects with lower

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insulin clearance and identified decreased insulin sensitivity in muscles but not in the liver.

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Furthermore, in these healthy subjects, decreased insulin clearance was correlated with decreased insulin sensitivity in muscles. These data demonstrate that even in a relatively healthy population, there are variations in insulin clearance, and individuals with decreased insulin clearance show moderate insulin resistance. This evidence suggests that reverse dynamics are plausible: impaired insulin clearance may precede and induce insulin resistance. If this is true, then insulin clearance may be genetically defined.

The onset of type 2 diabetes mellitus is highly affected by genetic factors.

Genome-wide association studies identified several single nucleotide polymorphisms associated with susceptibility to type 2 diabetes mellitus. One of these is located in an exon of the Slc30A8 gene, which encodes ZnT8. ZnT8 is a Zn transporter that is characteristically expressed in the membranes of insulin-containing granules, and transports Zn from the cytosol to the intragranular space. Zn is essential in the formation of insulin hexamers, which crystallize within the granule lumens due to their low solubility and form the dense-core granules observed in electron microscopy. Mice with -cell specific Slc30A8-deficiency show loss of the translucent halo space around the dense cores, suggesting that ZnT8 is essential for the accumulation of Zn in the secretory granules (3). Indeed, the disruption of Slc30A8 in  cells resulted in reduced Zn secretion from these cells. Hence, the analysis of Mice with -cell specific Slc30A8-deficiencyrevealed roles of  cell-secreted Zn. Consequently, we found at least two roles of the Zn on blood insulin levels. First, these mice showed enhanced insulin secretion, probably due to mitigation of the activating effect of Zn on KATP channels. Second, these mice showed enhanced insulin clearance because Zn inhibits insulin clearance in the liver. The findings of enhanced insulin secretion and clearance in mice with -cell specific Slc30A8-deficiencyare the opposite of those in human individuals with a high


susceptibility to type 2 diabetes mellitus. Indeed, subjects with loss-of-function mutations in

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ZnT8 were protected against the onset of type 2 diabetes mellitus (4). Although the mechanism of this phenomenon is still unknown, these results suggest that a genetic factor related to insulin clearance could contribute to the susceptibility to type 2 diabetes mellitus.

Insulin enhances glucose uptake in muscles and suppresses gluconeogenesis in the

liver to reduce blood glucose levels. Also, insulin enhances fat storage in adipose tissues and the liver, but chronic accumulation of fat in these locations impairs the ability of insulin to lower blood glucose levels. A specific feature of metabolically abnormal subjects is selective insulin resistance, characterized by resistance to insulin-mediated glucose uptake in muscles and suppression of gluconeogenesis, but not to enhanced fat storage in adipose tissues and the liver. The accumulated evidence suggests that sustained hyperinsulinemia reduces the expression of Insulin receptor substrate (IRS)-2 but not IRS-1. Accordingly, hyperinsulinemia induces resistance to insulin effects that are highly dependent on IRS-2, such as increasing glucose uptake in muscles via enhanced transportation of insulin through endothelial cells and suppressing gluconeogenesis in the liver; in contrast, fat accumulation in adipose tissues and the liver is highly dependent on IRS-1 and is unaffected (5). Thus, it is reasonable to assume that impaired insulin clearance could cause selective insulin resistance through hyperinsulinemia. Supporting evidence for this model exists in the case of decreased Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-1 function. Upon its phosphorylation, CEACAM-1 promotes the receptor-mediated uptake of insulin in the liver, and thus plays a key role in regulating liver insulin clearance. Although CECAM-1 may have other effects, the inactivation of CECAM-1 in mice causes not only reduced insulin clearance with hyperinsulinemia but also insulin resistance (6).


If this model is applicable to the general human population, there may be at least two

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major etiologies for selective insulin resistance: impaired insulin clearance and obesity (Fig. 1). Theoretically, individuals with insulin resistance due to impaired insulin clearance would be less obese than those with insulin resistance due to obesity. This pattern may be seen in Asian persons with insulin resistance. In particular, South Asians are known to be susceptible to developing insulin resistance with less obesity. A recent study revealed that young, non-diabetic, non-obese South Asian men showed lower insulin clearance than age-matched non-diabetic, non-obese Caucasians (7). These findings, combined with the results of genome-wide linkage analysis showing that insulin clearance is highly heritable, indicate that insulin clearance may be an important genetic factor affecting the onset of selective insulin resistance in less obese subjects.

In summary, the accumulated evidence suggests that impaired insulin clearance and

obesity may be two major and independent causes of insulin resistance. Both of these probably contribute to insulin resistance in most individuals, but the degree of each contribution is highly variable. but it is possible that in typical Asians, impaired insulin clearance may play a more important role than in Caucasians. Confirming this hypothesis could provide important clues regarding the pathophysiology of type 2 diabetes mellitus.

Acknowledgements This study was supported by a High Technology Research Center Grant and by the

Strategic Research Foundation at Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan.


Conflicts of Interest

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The authors have no conflicts of interest regarding this article.

Figure legend

Figure 1 Conceptual model of the development of selective insulin resistance. Left panel showed conceptual steps in the development of selective insulin resistance due to obese. Excess storage of fat in adipose tissues elicits hypoxia and inflammation in adipose tissues, change in secretion of adipocytokines and visceral fat and ectopic fat accumulation due to overflow with fat. These changes induce systemice insulin resistance. To compensate insulin resistance, increased insulin secretion and impaired insulin clearance occur and hyperinsulinemia appears. Hyperinsulinemia decreased IRS-2 mediated insulin effect, thus, results in selective insulin resistance. Right panel shows conceptual steps in the development of selective insulin resistance due to impaired insulin clearance. Different from selective insulin resistance due to obese. The existence of obesity is not essential for the appearance of selective insulin resistance in this case. However, selective insulin resistance induces lipid accumulation in adipose tissue and liver, thus, most of these cases accompany with modest overweight.

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