Effect of Serum Cholesterol on Insulin Secretory Capacity: Shimane CoHRE Study

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Abstract

Objectives

Previous studies indicate that, in addition to the blood glucose level, the lipid level in the blood may affect functions of pancreatic beta cells. In this study, we aimed to examine whether there was a relationship between the serum level of total cholesterol (TC) and the insulin secretory capacity in healthy subjects.

Subjects and Methods

In participants of health examinations conducted from 2006 to 2010, we analyzed data from a total of 2,499 subjects (1,057 men and 1,442 women) after exclusion of individuals with dyslipidemia, thyroid dysfunction, diabetes, HbA1c≥6.5%, or fasting blood glucose≥126 mg/dL. Homeostasis model assessment for beta cell function (HOMA-beta) was utilized as a model representing the pancreatic beta cell function.

Results

Although the serum TC level had a positive correlation with HOMA-beta in a univariate correlation analysis, after adjustment by confounding factors in a multiple regression analysis, HOMA-beta had a negative correlation with TC. This was further confirmed in a multiple logistic regression analysis, showing that higher TC was an independent risk factor for decreased insulin secretory capacity (defined as HOMA-beta≤30%) together with higher age, lower BMI, lower TG, male sex and regular alcohol intake. After the participants were stratified by BMI into three groups, the effect of TC on HOMA-beta increased along with the increase in BMI, and it was highly significant in the highest tertile.

Conclusion

This cross-sectional study indicated that increased serum TC level might be related to the decrease of insulin secretory capacity in aged healthy population and that reduction of TC is more necessary in obese subjects to prevent diabetes.

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Most cited references 17

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International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values

Atsunori Kashiwagi, Masato Kasuga, Eiichi Araki … (2012)

In 1999, the Japan Diabetes Society (JDS) launched the previous version of the diagnostic criteria of diabetes mellitus, in which JDS took initiative in adopting glycated hemoglobin (HbA1c) as an adjunct to the diagnosis of diabetes. In contrast, in 2009 the International Expert Committee composed of the members of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) manifested the recommendation regarding the use of HbA1c in diagnosing diabetes mellitus as an alternative to glucose measurements based on the updated evidence showing that HbA1c has several advantages as a marker of chronic hyperglycemia 2–4 . The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation 5 and Diabetology International 6 . The new diagnostic criterion in Japan came into effect on 1 July 2010. According to the new version of the criteria, HbA1c (JDS) ≥6.1% is now considered to indicate a diabetic type, but the previous diagnosis criteria of high plasma glucose (PG) levels to diagnose diabetes mellitus also need to be confirmed. Those are as follows: (i) FPG ≥126 mg/dL (7.0 mmol/L); (ii) 2‐h PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or (iii) casual PG ≥200 mg/dL (11.1 mmol/L). If both PG criteria and HbA1c in patients have met the diabetic type, those patients are immediately diagnosed to have diabetes mellitus 5,6 . In the report, the HbA1c measurements in Japan are well calibrated with Japanese‐Clinical‐Laboratory‐Use Certified Reference Material (JCCRM). The certified values are determined by a high‐resolution type ion‐exchange high performance liquid chromatography (HPLC) (KO 500 method) and certified using the designated comparison method (DCM) of the Japan Society of Clinical Chemistry (JSCC) and the JDS. After incorporating a proportional bias correction to the value anchored to the peptide mapping method of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), the DCM actually measures β‐N‐mono‐deoxyfructosyl hemoglobin and has an intercept approximately equal to zero against the peptide mapping method of IFCC in measuring fresh raw human blood samples. Furthermore, standardization of HbA1c in Japan was initiated in 1993, and the serial reference materials from JDS Lot 1 to JDS Lot 4 are well certified using the DCM until now. In the new diagnosis criteria 5,6 , the new cut‐point of HbA1c (JDS) for diagnosis of diabetes mellitus is 6.1%, which is equivalent to the internationally‐used HbA1c (National Glycohemoglobin Standardization Program [NGSP]) 6.5%, as HbA1c (NGSP)(%) is reported to be equivalent to 1.019 × HbA1c (JDS)% + 0.3%, which is reasonably estimated by the equation of HbA1c (JDS)% + 0.4%, as the difference between the two equations is within error of HbA1c measurements (2∼3%). However, on 1 October 2011, the Reference Material Institute for Clinical Chemistry Standards (ReCCS, Kanagawa, Japan) was certified as an Asian Secondary Reference Laboratory (ASRL) using the KO 500 method and the reference materials JCCRM411‐2 (JDS Lot 4) after successful completion of NGSP network laboratory certification. Therefore, the HbA1c unit is now traceable to the Diabetes Control and Complications Trial (DCCT) reference method. The comparison was carried out with the Central Primary Reference Laboratory (CPRL) in the University of Missouri School of Medicine. The conversion equation from HbA1c (JDS) to HbA1c (NGSP) units is officially certified as follows: NGSP (%) = 1.02 × JDS (%) + 0.25%; conversely, JDS (%) = 0.980 × NGSP (%) – 0.245%. Based on this equation, in the range of JDS values ≤4.9%, NGSP (%) = JDS (%) + 0.3%; in the range of JDS 5.0∼9.9%, NGSP (%) = JDS (%) + 0.4%; and in the range of JDS 10∼14.9%, NGSP (%) = JDS (%) + 0.5%. These results show that the previous equation of NGSP (%) = JDS (%) + 0.4% is also confirmed in the present equation, considering a 2∼3% error of HbA1c measurements. The council meeting of the JDS finally decided to use HbA1c (NGSP) values in clinical practice from 1 April 2012, although HbA1c (JDS) values will be included until people become familiar with the new expression. Finally, it is also important to emphasize that the new HbA1c (NGSP) values can be directly measured and printed out from 1 April 2012. However, both new diagnostic reference values and target values of glycemic control have been adjusted to those equivalent values of HbA1c (JDS), as shown in the Table 1. Table 1 Differences in glycated hemoglobin values between Japan Diabetes Society and National Glycohemoglobin Standardization Program for assessments of diagnosis and treatment of diabetes mellitus (a) Diagnostic reference values of HbA1c (NGSP) and HbA1c (JDS) Diagnostic reference values HbA1c (NGSP) HbA1c (JDS) Standard range (%) 4.6–6.2 4.3–5.8 Diabetes range (%) ≥6.5 ≥6.1 Possible diabetes range (%) 6.0–6.4 5.6–6.0 High risk range for diabetes (%) 5.6–5.9 5.2–5.5 (b) Assessments of the glycemic control using HbA1c Assessment of control state HbA1c (NGSP) HbA1c (JDS) Excellent (%) <6.2 <5.8 Good (%) 6.2–6.8 5.8–6.4 Fair Inadequate (%) 6.9–7.3 6.5–6.9 Not good (%) 7.4–8.3 7.0–7.9 Poor (%) ≥8.4 ≥8.0 HbA1c, glycated hemoglobin; JDS, Japan Diabetes Society; NGSP, National Glycohemoglobin Standardization Program.

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Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.

Jenelle Timmins, Janine K. Kruit, Michael Hayden … (2007)

Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.

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Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.

S Gunawardana, Mark W Head, David W Piston … (2007)

Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic beta-cells that is independent of the effects of FFAs. Several methods were used to modulate cholesterol levels in intact islets and cultured beta-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents. We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization. This direct effect of cholesterol on beta-cell metabolism opens a novel set of mechanisms that may contribute to beta-cell dysfunction and the onset of diabetes in obese patients.

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Author and article information

Contributors

Marta Letizia Hribal: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 16 February 2016

Publication date Collection: 2016

Volume: 11

Issue: 2

Electronic Location Identifier: e0149452

Affiliations

[1 ]Department of Internal Medicine, Okuizumo Municipal Hospital, Shimane, Japan

[2 ]Department of Laboratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan

[3 ]The Center for Community-based Health Research and Education (CoHRE), Shimane, Japan

[4 ]Department of Functional Pathology, Shimane University Faculty of Medicine, Shimane, Japan

[5 ]Department of Medical Education and Research, Shimane University Faculty of Medicine, Shimane, Japan

University of Catanzaro Magna Graecia, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: MW SY TN SK. Performed the experiments: MW SY TH TN. Analyzed the data: MW SY. Contributed reagents/materials/analysis tools: MW SY TH TN. Wrote the paper: MW SY TN SK.

* E-mail: syano@ 123456med.shimane-u.ac.jp

Article

Publisher ID: PONE-D-15-52044

DOI: 10.1371/journal.pone.0149452

PMC ID: 4755542

PubMed ID: 26881755

SO-VID: d8b1ed2e-3b73-4dca-8b6c-be6a8aed3b41

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 30 November 2015

Date accepted : 1 February 2016

Page count

Figures: 0, Tables: 6, Pages: 9

Funding

The authors received no specific funding for this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

Effect of Serum Cholesterol on Insulin Secretory Capacity: Shimane CoHRE Study

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Abstract

Objectives

Subjects and Methods

Results

Conclusion

Related collections

PLOS Climate

Most cited references 17

International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values

Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.

Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.

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