Insulin therapy in patients with type 2 diabetes and high insulin resistance is associated with increased risk of complications and mortality

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor β (TGFβ), insulin-like growth factor (IGF) and Wnt-β-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.

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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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The association between insulin therapy and depression in patients with type 2 diabetes mellitus: a meta-analysis

BMJ Open ◽

10.1136/bmjopen-2017-020062 ◽

2018 ◽

Vol 8 (11) ◽

pp. e020062 ◽

Cited By ~ 10

Author(s):

Xiaosu Bai ◽

Zhiming Liu ◽

Zhisen Li ◽

Dewen Yan

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Therapy ◽

Depressive Disorders ◽

Meta Analysis ◽

Epidemiological Studies ◽

Cochrane Library ◽

Increased Risk

ObjectivesSeveral patients with type 2 diabetes mellitus (T2DM) have depressive disorders. Whether insulin treatment was associated with increased risk of depression remains controversial. We performed a meta-analysis to evaluate the association of insulin therapy and depression.DesignA meta-analysis.MethodsWe conducted a systematic search of PubMed, PsycINFO, Embase and the Cochrane Library from their inception to April 2016. Epidemiological studies comparing the prevalence of depression between insulin users and non-insulin users were included. A random-effects model was used for meta-analysis. The adjusted and crude data were analysed.ResultsTwenty-eight studies were included. Of these, 12 studies presented with adjusted ORs. Insulin therapy was significantly associated with increased risk of depression (OR=1.41, 95% CI 1.13 to 1.76, p=0.003). Twenty-four studies provided crude data. Insulin therapy was also associated with an odds for developing depression (OR=1.59, 95% CI 1.41 to 1.80, p<0.001). When comparing insulin therapy with oral antidiabetic drugs, significant association was observed for adjusted (OR=1.42, 95% CI 1.08 to 1.86, p=0.008) and crude (OR=1.61, 95% CI 1.35 to 1.93, p<0.001) data.ConclusionsOur meta-analysis confirmed that patients on insulin therapy were significantly associated with the risk of depressive symptoms.

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Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Nature Communications ◽

10.1038/s41467-021-26536-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chuanyan Wu ◽

Yan Borné ◽

Rui Gao ◽

Maykel López Rodriguez ◽

William C. Roell ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Genome Wide Association Study ◽

Regulatory Protein ◽

Alcoholic Fatty Liver ◽

Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

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Does insulin therapy lead to an increased risk of cancer in type 2 diabetes mellitus?

Practical Diabetes International ◽

10.1002/pdi.757 ◽

2005 ◽

Vol 22 (3) ◽

pp. 77-78 ◽

Cited By ~ 1

Author(s):

James Brown ◽

Miles Fisher

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Therapy ◽

Increased Risk ◽

Risk Of Cancer

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Myopia and Early Onset Type 2 Diabetes: A Nationwide Cohort Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab669 ◽

2021 ◽

Author(s):

Alon Peled ◽

Itamar Raz ◽

Inbar Zucker ◽

Estela Derazne ◽

Jacob Megreli ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cohort Study ◽

Young Adulthood ◽

Military Service ◽

High Myopia ◽

Continuous Variable ◽

Dependent Manner ◽

Increased Risk

Abstract Objective A correlation between myopia and insulin-resistance has been suggested. We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Design Population-based, retrospective, cohort study. Methods 1,329,705 adolescents (579,543 women, 43.6%) aged 16-19 years, medically examined before mandatory military service during 1993-2012; and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P<0.001). For women, T2D incidence rates (per 100,000 person-years) were 16.6, 19.2, and 25.1 for those without myopia, and with mild-to-moderate and high myopia, respectively. These corresponded to HRs of 1.29 (95%CI 1.14-1.45) and 1.63 (1.21-2.18) for women with mild-to-moderate and high myopia, respectively, compared to those without myopia, after adjustment for age at study entry, birth year, adolescent BMI, cognitive performance, socioeconomic status, and immigration status. Results persisted in extensive sensitivity and subgroup analyses. When managed as a continuous variable, every 1 diopter lower spherical equivalent yielded a 6.5% higher adjusted HR for T2D incidence (P= 0.003). There was no significant association among men. Conclusions For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

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MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

Acta Endocrinologica ◽

10.1530/eje-16-0488 ◽

2017 ◽

Vol 176 (2) ◽

pp. R67-R78 ◽

Cited By ~ 37

Author(s):

Charlotte Brøns ◽

Louise Groth Grunnet

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Cellular Localization ◽

Future Research ◽

Causal Mechanism ◽

Increased Risk ◽

Adipose Tissue Expandability

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

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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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