Metabolic changes in type 2 diabetes are reflected in peripheral blood cells, revealing aberrant cytotoxicity, a viral signature, and hypoxia inducible factor activity

Abstract

BackgroundMetabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dysglycemia, and a pro-atherogenic plasma lipid profile. MetS creates a high risk for development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), presumably by altering inflammatory responses. Presently, it is unknown how the chronic metabolic disturbances in acute hyperglycemia, MetS and T2DM affect the immune activity of peripheral blood cells.MethodsWe performed genome-wide expression analysis of peripheral blood cells obtained from patients with T2DM (n = 6) and age-, sex- , BMI- and blood pressure-matched obese individuals with MetS (n = 4) and lean healthy normoglycemic controls (n = 3), both under fasting conditions and after controlled induction of acute hyperglycemia during a 70 min hyperglycemic clamp. Differential gene expression during fasting conditions was confirmed by real-time PCR, for which we included additional age-, sex-, BMI-, and blood pressure-matched obese individuals with (n = 4) or without (n = 4) MetS.ResultsPathway and Gene ontology analysis applied to baseline expression profiles of peripheral blood cells from MetS and T2DM patients revealed metabolic changes, highly similar to a reoviral infection gene signature in T2DM patients. Transcription factor binding site analysis indicated that increased HIF-1α activity, a transcription factor induced by either hypoxia or oxidative stress, is responsible for this aberrant metabolic profile in peripheral blood cells from T2DM patients. Acute hyperglycemia in healthy controls resulted in reduced expression of cytotoxicity-related genes, representing NK- and CD8+ cells. In obese controls, MetS and especially T2DM patients, baseline expression of genes involved in cytotoxicity was already low, compared to healthy controls and did not further decrease upon acute hyperglycemia.ConclusionsThe reduced activity of cytotoxic genes in T2DM is explained by chronic hyperglycemia, but its acute effects are restricted to healthy controls. Genome expression of circulating leukocytes from T2DM patients differs from MetS individuals by a specific reovirus signature. Our data thus suggest a role for suppressed anti-viral capacity in the etiology of diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0096-y) contains supplementary material, which is available to authorized users.

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

“…Moreover, AMPK is ubiquitously expressed in mammalian cells and is one of the putative targets of metformin action, and further the presence of hOCT1 (human organic cation transporter 1) on PBMC’s plasma membrane, as also observed in our previous study, facilitates the uptake of metformin into these cells; therefore, it is apt to conclude that metformin is able to exert its effect on mitophagy via AMPK phosphorylation in mononuclear cells as well . In addition, augmented PINK1 expression with metformin therapy showed a significant association with HOMA‐β indices, indicating that hyperglycaemic milieu alters the gene expression profile in PBMCs, which may also be reflected in the insulin‐sensitive tissues, as strengthened by a couple of studies available in the literature . Thus, the use of PBMCs as a cellular model may serve as an early diagnostic and prognostic tool in the management of diabetes.…”

“…23 In addition, augmented PINK1 expression with metformin therapy showed a significant association with HOMA-β indices, indicating that hyperglycaemic milieu alters the gene expression profile in PBMCs, which may also be reflected in the insulin-sensitive tissues, as strengthened by a couple of studies available in the literature. 45,46 Thus, the use of PBMCs as a cellular model may serve as an early diagnostic and prognostic tool in the management of diabetes.…”

Blood pathway analyses reveal differences between prediabetic subjects with or without dyslipidaemia. The Cardiovascular Risk in Young Finns Study

“…44 Granzyme B and PRF1 are also included in the downstream signalling in the naive CD8+ T-cell pathway, which was upregulated in the PR 0 group but not in the PR D group in comparison with the C 0 group. The reason why GZMB, PRF1, and KIR2DL4 were upregulated in the PR 0 group but not in the PR D group and expressed in lower levels in T2DM patients in the study by van der Pouw Kraan et al 43 might be that 1 or more of the components of dyslipidaemia co-regulate the expression of these genes; the T2DM patients in their study 43 met the elevated TG criterion of dyslipidaemia used in our study. However, in another study, the plasma level of granzyme B correlated positively with fasting glucose and HbA1c, as well as with TGs, TC, and LDL-C. 45 The present study has some limitations.…”

“…In T2DM patients, the expression levels of these genes have been reported to be low already and hardly affected by hyperglycaemia. 43 These genes are typically expressed in cells with cytotoxic functions, such as CD8+…”

Peripheral Blood Cells, a Transcriptomic Tool in Nutrigenomic and Obesity Studies: Current State of the Art

“…In the last several years, research about obesity and lifestyles has been intensified due to the worrying increase in the incidence of obesity and unhealthy diet consumption. Blood cells can be a useful tool in this field as increasing evidence exists indicating the potential use of PBC transcriptional profile as a marker of obesity and its co‐morbidities (Obata et al., ; van der Pouw Kraan et al., ).…”