Relationship of Insulin Sensitivity, Insulin Secretion, and Adiposity With Insulin Clearance in a Multiethnic Population: The Insulin Resistance Atherosclerosis Study

Epidemiological investigations increasingly employ dietary-pattern techniques to fully integrate dietary data. The present study evaluated the relationship of dietary patterns identified by cluster analysis with measures of insulin sensitivity (SI) and adiposity in the multi-ethnic, multi-centre Insulin Resistance Atherosclerosis Study (IRAS, 1992–94). Cross-sectional data from 980 middle-aged adults, of whom 67% had normal and 33% had impaired glucose tolerance, were analysed. Usual dietary intake was obtained by an interviewer-administered, validated food-frequency questionnaire. Outcomes included SI, fasting insulin (FI), BMI and waist circumference. The relationship of dietary patterns to log(SI+1), log(FI), BMI and waist circumference was modelled with multivariable linear regressions. Cluster analysis identified six distinct diet patterns – ‘dark bread’, ‘wine’, ‘fruits’, ‘low-frequency eaters’, ‘fries’ and ‘white bread’. The ‘white bread’ and the ‘fries’ patterns over-represented the Hispanic IRAS population predominantly from two centres, while the ‘wine’ and ‘dark bread’ groups were dominated by non-Hispanic whites. The dietary patterns were associated significantly with each of the outcomes first at the crude, clinical level (P<0·001). Furthermore, they were significantly associated with FI, BMI and waist circumference independent of age, sex, race or ethnicity, clinic, family history of diabetes, smoking and activity (P<0.004), whereas significance was lost for SI. Studying the total dietary behaviour via a pattern approach allowed us to focus both on the qualitative and quantitative dimensions of diet. The present study identified highly consistent associations of distinct dietary patterns with measures of insulin resistance and adiposity, which are risk factors for diabetes and heart disease.

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Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Metabolites ◽

10.3390/metabo11070420 ◽

2021 ◽

Vol 11 (7) ◽

pp. 420

Author(s):

Alexis C. Wood ◽

Elizabeth T. Jensen ◽

Alain G. Bertoni ◽

Gautam Ramesh ◽

Stephen S. Rich ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Evaluation Study ◽

Disposition Index ◽

Insulin Clearance ◽

Relative Role ◽

Operating Characteristics ◽

Longitudinal Evaluation

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

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Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22157797 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7797

Author(s):

Joseph A. M. J. L. Janssen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Insulin Secretion ◽

Early Stage ◽

Insulin Clearance ◽

Future Research ◽

Age Related ◽

Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

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Vagotomy Reduces Insulin Clearance in Obese Mice Programmed by Low-Protein Diet in the Adolescence

Neural Plasticity ◽

10.1155/2017/9652978 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Camila Lubaczeuski ◽

Luciana Mateus Gonçalves ◽

Jean Franciesco Vettorazzi ◽

Mirian Ayumi Kurauti ◽

Junia Carolina Santos-Silva ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

High Fat Diet ◽

Insulin Clearance ◽

Protein Diet ◽

Low Protein Diet ◽

High Fat ◽

Insulin Degrading Enzyme ◽

Low Protein

The aim of this study was to investigate the effect of subdiaphragmatic vagotomy on insulin sensitivity, secretion, and degradation in metabolic programmed mice, induced by a low-protein diet early in life, followed by exposure to a high-fat diet in adulthood. Weaned 30-day-old C57Bl/6 mice were submitted to a low-protein diet (6% protein). After 4 weeks, the mice were distributed into three groups: LP group, which continued receiving a low-protein diet; LP + HF group, which started to receive a high-fat diet; and LP + HFvag group, which underwent vagotomy and also was kept at a high-fat diet. Glucose-stimulated insulin secretion (GSIS) in isolated islets, ipGTT, ipITT, in vivo insulin clearance, and liver expression of the insulin-degrading enzyme (IDE) was accessed. Vagotomy improved glucose tolerance and reduced insulin secretion but did not alter adiposity and insulin sensitivity in the LP + HFvag, compared with the LP + HF group. Improvement in glucose tolerance was accompanied by increased insulinemia, probably due to a diminished insulin clearance, as judged by the lower C-peptide : insulin ratio, during the ipGTT. Finally, vagotomy also reduced liver IDE expression in this group. In conclusion, when submitted to vagotomy, the metabolic programmed mice showed improved glucose tolerance, associated with an increase of plasma insulin concentration as a result of insulin clearance reduction, a phenomenon probably due to diminished liver IDE expression.

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Insulin Sensitivity, Insulinemia, and Coronary Artery Disease: The Insulin Resistance Atherosclerosis Study

Diabetes Care ◽

10.2337/diacare.27.3.781 ◽

2004 ◽

Vol 27 (3) ◽

pp. 781-787 ◽

Cited By ~ 84

Author(s):

M. Rewers ◽

D. Zaccaro ◽

R. D'Agostino ◽

S. Haffner ◽

M. F. Saad ◽

...

Keyword(s):

Insulin Resistance ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Insulin Sensitivity ◽

Artery Disease ◽

Insulin Resistance Atherosclerosis Study

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Dietary fat and insulin sensitivity in a triethnic population: the role of obesity. The Insulin Resistance Atherosclerosis Study (IRAS)

American Journal of Clinical Nutrition ◽

10.1093/ajcn/65.1.79 ◽

1997 ◽

Vol 65 (1) ◽

pp. 79-87 ◽

Cited By ~ 125

Author(s):

E J Mayer-Davis ◽

J H Monaco ◽

H M Hoen ◽

S Carmichael ◽

M Z Vitolins ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Dietary Fat ◽

Insulin Resistance Atherosclerosis Study

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Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

10.2337/figshare.16797871 ◽

2021 ◽

Author(s):

Xingjing Liu ◽

Peng Sun ◽

Qingzhao Yuan ◽

Jinyang Xie ◽

Ting Xiao ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Chow Diet ◽

Β Cells ◽

Pancreatic Β Cells ◽

Calcium Calmodulin Dependent ◽

Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the Cask gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

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Effect of liver fat on insulin clearance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00444.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1709-E1715 ◽

Cited By ~ 129

Author(s):

Anna Kotronen ◽

Satu Vehkavaara ◽

Anneli Seppälä-Lindroos ◽

Robert Bergholm ◽

Hannele Yki-Järvinen

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Fat Content ◽

Insulin Clearance ◽

Liver Fat ◽

Hepatic Insulin Resistance ◽

Model Assessment ◽

Liver Fat Content ◽

Hepatic Insulin Sensitivity ◽

Impaired Insulin

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 ± 1 yr, body mass index (BMI) 26.3 ± 0.5 kg/m2]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU·kg−1·min−1for 240 min) clamp technique combined with the infusion of [3-3H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ∼40% higher ( P < 0.0001) in the high (15.0 ± 1.5%) compared with the low (1.8 ± 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml·kg fat free mass−1·min−1) was inversely related to liver fat content ( r = −0.52, P < 0.0001), independent of age, sex, and BMI ( r = −0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0–41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance ( r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity ( r = −0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.

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Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Journal of Endocrinology ◽

10.1530/joe-13-0177 ◽

2013 ◽

Vol 219 (2) ◽

pp. 173-182 ◽

Cited By ~ 28

Author(s):

P Brandimarti ◽

J M Costa-Júnior ◽

S M Ferreira ◽

A O Protzek ◽

G J Santos ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Secretion ◽

Alternative Splicing ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Clearance ◽

Cafeteria Diet ◽

Mrna Levels ◽

Insulin Degrading Enzyme ◽

Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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