Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms

Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

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Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00339.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. E353-E358 ◽

Cited By ~ 41

Author(s):

Marcello Maggio ◽

Fulvio Lauretani ◽

Gian Paolo Ceda ◽

Stefania Bandinelli ◽

Shehzad Basaria ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Older Women ◽

Inflammatory Markers ◽

Hormone Replacement ◽

Sex Hormone Binding Globulin ◽

Bilateral Oophorectomy ◽

Age Related ◽

Increased Risk ◽

Igf I

Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone ( P < 0.001), IL-6 ( P < 0.001), CRP ( P < 0.001), and HOMA ( P < 0.001) and lower levels of SHBG ( P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS ( P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.

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Cardiovascular events in patients with type 2 diabetes

The British Journal of Diabetes ◽

10.1177/1474651402002001s0201 ◽

2002 ◽

Vol 2 (1_suppl) ◽

pp. S4-S8

Author(s):

Erland Erdmann

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Risk Factor ◽

Adverse Effects ◽

Cardiovascular Events ◽

Left Ventricular ◽

Diabetic Patients ◽

Increased Risk

Diabetes is a common risk factor for cardiovascular disease. Coronary heart disease and left ventricular dysfunction are more common in diabetic patients than in non-diabetic patients, and diabetic patients benefit less from revascularisation procedures. This increased risk can only partly be explained by the adverse effects of diabetes on established risk factors; hence, a substantial part of the excess risk must be attributable to direct effects of hyperglycaemia and diabetes. In type 2 diabetes, hyperinsulinaemia, insulin resistance and hyperglycaemia have a number of potential adverse effects, including effects on endothelial function and coagulation. Risk factor modification has been shown to reduce the occurrence of cardiovascular events in patients with diabetes; indeed, diabetic patients appear to benefit more in absolute terms than non-diabetic patients. There is thus a strong case for intensive treatment of risk factors, including insulin resistance and hyperglycaemia, in patients with type 2 diabetes.

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Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

Journal of Translational Medicine ◽

10.1186/s12967-019-2096-8 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 4

Author(s):

Haya Al-Sulaiti ◽

Ilhame Diboun ◽

Maha V. Agha ◽

Fatima F. S. Mohamed ◽

Stephen Atkin ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Serum Samples ◽

Metabolic Markers ◽

Insulin Resistant ◽

Increased Risk ◽

Novel Biomarkers ◽

Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

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Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease

International Journal of Stroke ◽

10.1177/1747493018816425 ◽

2018 ◽

Vol 14 (6) ◽

pp. 639-645 ◽

Cited By ~ 1

Author(s):

Jennifer L Dearborn ◽

Catherine M Viscoli ◽

Silvio E Inzucchi ◽

Lawrence H Young ◽

Walter N Kernan

Keyword(s):

Myocardial Infarction ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Obesity Paradox ◽

Normal Weight ◽

Diabetic Patients ◽

Insulin Resistant ◽

Increased Risk ◽

All Cause Mortality ◽

Patients At Risk

Background The obesity paradox refers to the finding in observational studies that patients with obesity have a better prognosis after stroke than normal weight patients. Aim To test the hypothesis that there might be important heterogeneity within the obese stroke population, such that those with metabolic syndrome would be at higher risk for stroke or myocardial infarction and all-cause mortality compared to patients without metabolic syndrome. Methods The Insulin Resistance Intervention after Stroke trial enrolled non-diabetic patients with a recent ischemic stroke or transient ischemic attack and insulin resistance. We examined the association between metabolic syndrome and outcome risk in patients with normal weight at entry (body mass index (BMI) = 18.5–24.9 kg/m2), overweight (BMI = 25–29.9 kg/m2), or obesity (BMI ≥ 30 kg/m2). Analyses were adjusted for demographic features, treatment assignment, smoking, and major comorbid conditions. Results Metabolic syndrome was not associated with greater risk for stroke or myocardial infarction among 1536 patients who were overweight (adjusted hazard ratio (HR), 0.95; 95% confidence interval (CI): 0.69–1.31) or 1626 obese patients (adjusted HR, 1.00; 95% CI: 0.70–1.41). However, among 567 patients with a normal BMI, metabolic syndrome was associated with increased risk for stroke or myocardial infarction (adjusted HR, 2.05; 95% CI: 1.25–3.37), and all-cause mortality (adjusted HR, 1.70; 95% CI: 1.03–2.81) compared to patients without metabolic syndrome. Conclusions The presence of metabolic syndrome identified normal weight patients with insulin resistance but no diabetes who have a higher risk of adverse cardiovascular outcomes, compared with patients without metabolic syndrome.

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Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00598.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. E1161-E1169 ◽

Cited By ~ 83

Author(s):

Cédric Dray ◽

Cyrille Debard ◽

Jennifer Jager ◽

Emmanuel Disse ◽

Danièle Daviaud ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Receptor Expression ◽

Diabetic Patients ◽

Mrna Levels ◽

Type 2 Diabetic Patients ◽

Insulin Resistant ◽

Type 2 Diabetic

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/ db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/ db mice. APJ expression was decreased in both HF-fed and db/ db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.

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Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients

Acta Endocrinologica ◽

10.1530/eje-13-0557 ◽

2014 ◽

Vol 170 (2) ◽

pp. 237-245 ◽

Cited By ~ 13

Author(s):

Guoyu Tong ◽

Xiaomin Hua ◽

Yingjie Zhong ◽

Kui Zhang ◽

Guangyu Gu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Therapy ◽

Sex Hormone Binding Globulin ◽

Diabetic Patients ◽

Newly Diagnosed ◽

Hormone Binding ◽

Type 2 Diabetic Patients ◽

C Peptide ◽

Type 2 Diabetic

ObjectiveMany studies have shown that low sex hormone-binding globulin (SHBG) is associated with insulin resistance, but only few studies have examined how serum SHBG is regulated by insulin in humans. This interventional study aimed to investigate the effect of insulin therapy (IT) on serum SHBG levels in newly diagnosed type 2 diabetic patients.MethodsA total of 80 newly diagnosed type 2 diabetic subjects were enrolled and randomly grouped into a 2-week intensive IT with/without metformin. Serum SHBG, total testosterone, glucose, liver enzymes, lipids, insulin, and C-peptide levels were measured before and after IT.ResultsBefore IT, serum SHBG levels were negatively correlated with BMI, waist circumference (WC), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GT), triglyceride (TG), fasting insulin, and C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR), and positively with HDL-C (all P for trend <0.05), after adjustment for age and sex. IT increased serum SHBG levels from 26.5±14.5 to 33.2±15.0 nmol/l (P<0.001), increased by 25.2% (95% CI, 20.3 to 30.9%, P<0.001). In a multiple linear regression model adjusting for age, sex, BMI, and WC, the decreases in ΔALT (standardized regression coefficient β=−0.374, P=0.012) and ΔTG (β=−0.380, P=0.020) were independent contributors to the increase in ΔSHBG.ConclusionsIT increases serum SHBG likely through improving insulin resistance and liver function.

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The ACAA-insertion/deletion polymorphism at the 3′ UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance

Acta Endocrinologica ◽

10.1530/eje.1.02217 ◽

2006 ◽

Vol 155 (2) ◽

pp. 331-336 ◽

Cited By ~ 11

Author(s):

Gemma Villuendas ◽

José I Botella-Carretero ◽

Abel López-Bermejo ◽

Carme Gubern ◽

Wifredo Ricart ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mexican Americans ◽

Receptor Gene ◽

Diabetic Patients ◽

Surrogate Markers ◽

Wild Type ◽

Deletion Polymorphism ◽

Insulin Resistant

Objective: The IGF-II receptor gene (IGFIIR) is located at chromosome 6q26, a region that harbors a genetic marker linked to insulin-resistant traits in Mexican–Americans. In the present study conducted in Spaniards, we tested a common polymorphism in IGFIIR for association with type 2 diabetes and insulin-resistant traits. Design: Case–control association study. Methods: One hundred and forty-five type 2 diabetic patients and 217 non-diabetic controls were genotyped for the ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR. Phenotyping included anthropometrics and a metabolic profile, including serum lipid levels and surrogate indexes of insulin resistance whenever possible. Results: Diabetic patients were more frequently homozygous for the wild type 144 bp allele of IGFIIR compared with controls (diabetic patients 77.2%, controls 51.6%, P<0.001) suggesting a potential protective role against type 2 diabetes for the IGFIIR 140 bp variant. Carrying 140 bp alleles was associated with an odds ratio of having diabetes of 0.290 (95% confidence interval 0.109–0.770), and controls homozygous for the wild type 144 bp allele presented with lower insulin and triglyceride levels, which are proxies for insulin resistance. Conclusions: The ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR is associated with type 2 diabetes and influences surrogate markers of insulin resistance in non-diabetic subjects.

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Insulin-sensitive and insulin-resistant variants in nonobese Japanese type 2 diabetic patients. The role of triglycerides in insulin resistance

Diabetes Care ◽

10.2337/diacare.22.12.2100 ◽

1999 ◽

Vol 22 (12) ◽

pp. 2100-2101 ◽

Cited By ~ 14

Author(s):

A. Taniguchi ◽

M. Fukushima ◽

M. Sakai ◽

K. Kataoka ◽

K. Miwa ◽

...

Keyword(s):

Insulin Resistance ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Insulin Resistant ◽

Type 2 Diabetic

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Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients

Acta Endocrinologica ◽

10.1530/eje.0.1500207 ◽

2004 ◽

pp. 207-214 ◽

Cited By ~ 42

Author(s):

B Nyholm ◽

MF Nielsen ◽

K Kristensen ◽

S Nielsen ◽

T Ostergard ◽

...

Keyword(s):

Insulin Resistance ◽

Visceral Obesity ◽

Visceral Adiposity ◽

Diabetic Patients ◽

Vo2 Max ◽

Type 2 Diabetic Patients ◽

Insulin Resistant ◽

History Of ◽

Type 2 Diabetic

OBJECTIVE: First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance. DESIGN AND METHODS: We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [3H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio. RESULTS: All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64+/-0.48 vs 9.12+/-0.98 mg/kg ffm/min, P=0.01). Despite similar BMI (25.2+/-0.5 vs 24.8+/-0.7 kg/m2, P=0.61) and overall fat mass (26.4+/-1.6 vs 24.2+/-2.1%, P=0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9+/-10.0 vs 40.1+/-11.3 cm2, P<0.05) and VO2 max was reduced (52.2+/-3.1 vs 63.3+/-3.9 ml/kg ffm/min, P<0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r=-0.52, P<0.05; controls: r=-0.65, P<0.01) and in multiple regression analysis visceral adiposity (P<0.01), VO2 max (P<0.001) and a family history of type 2 diabetes (P<0.05) (r2=0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145+/-10 vs 139+/-15 micromol/min, P=0.74) and the 24 h u-cortisol/creatinine ratio ((24.9+/-1.3 vs 27.4+/-2.0).10(-6), P=0.28) were both comparable in the two groups. CONCLUSION: Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.

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The Relation of IGF-1 and Insulin Resistance in a Sample of Iraqi Obese Type 2 Diabetic Patients with Macrovascular Disease

Baghdad Science Journal ◽

10.21123/bsj.9.4.656-662 ◽

2012 ◽

Vol 9 (4) ◽

pp. 656-662

Author(s):

Baghdad Science Journal

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Body Mass ◽

Diabetic Patients ◽

Model Assessment ◽

Type 2 Diabetic Patients ◽

Type 2 Dm ◽

Increased Risk ◽

Type 2 Diabetic

Type 2 diabetes mellitus(T2DM) is a metabolic disease that is associated with an increased risk for atherosclerosis by 2-4 folds than in non- diabetics. In general population, low IGF-1 has been associated with higher prevalence of cardiovascular disease and mortality .This study aims to find out the relationship between IGF-1 level and other biochemical markers such as Homeostasis Model Assessment insulin resistance(HOMAIR) and Body Mass Index(BMI) in type 2 diabetic patients . This study includes (82) patients (40 females and 42 males) with age range (40-75) years,(34) non obese diabetic patients and (48) obese diabetic patients. The non obese individuals considered as a controls group, all controls and patients groups with type 2 DM, ischemic heart disease and hypertension, and free from other disease by history and clinical exam .The results showed that serum IGF-1 levels were lower in obese diabetic patients than non obese.HOMAIR has been found to be significantly higher in obese than non obese diabetic patients ,there is negative correlation between IGF-1 and HOMAIR. Body mass index (BMI) was in positive correlation with HOMAIR and innegativecorrelationwithIGF-1. Conclusion of this study was the serum level of IGF-1 is significantly lower in obese than non obese type 2 DM , but HOMA IR is significantly higher in obese diabetic subjects .

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