Leucocyte Mobilization and Release of Neutrophil Elastase Following Acute Insulin‐induced Hypoglycaemia in Normal Humans

Collier, Andrew; Patrick, A.W.; Hepburn, David; Bell, D.; Jackson, M; Dawes, J.; Frier, B M

doi:10.1111/j.1464-5491.1990.tb01432.x

Cited by 36 publications

(27 citation statements)

References 16 publications

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“…Both factors are known to increase WBC counts by increasing neutrophil influx from marrow storage and decreasing efflux from the blood stream (32,33). In addition, cortisol and insulin may increase the WBC count by stimulating leptin secretion from adipocytes (34).…”

Section: Discussionmentioning

confidence: 99%

Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

et al. 2005

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OBJECTIVE -Because of increasing evidence that white blood cells (WBCs) play a role in the development and progression of diabetes complications, this study aimed to investigate the relation of circulating total and differential leukocyte counts to nephropathy in patients with type 2 diabetes. Plasma leptin levels were also measured to investigate their role in peripheral leukocytosis.RESEARCH DESIGN AND METHODS -For this study, 1,480 subjects with type 2 diabetes who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The total and differential leukocyte profiles of peripheral blood were measured and plasma leptin was examined by enzyme-linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with linear and logistic regression to calculate the effects of leukocyte count on diabetic nephropathy.RESULTS -The peripheral total WBC, monocyte, and neutrophil counts increased in parallel with the advancement of diabetic nephropathy. In contrast, the lymphocyte count decreased. When WBC counts were analyzed per quartile and as continuous variables after adjusting for age, sex, and other known risk factors with multiple regression analysis, peripheral total WBC, monocyte, neutrophil, and lymphocyte counts were independently and significantly associated with diabetic nephropathy. Plasma leptin levels increased in patients with nephropathy and correlated significantly with total WBC count (r ϭ 0.194, P ϭ 0.014).CONCLUSIONS -Because leukocytes are activated and secrete cytokines in the diabetic state and leptin stimulates leukocyte proliferation and differentiation, our results suggest that circulating leukocytes contribute to the development and progression of nephropathy, partially through the effects of leptin, in patients with type 2 diabetes. Diabetes Care 28:1710 -1717, 2005P eripheral white blood cell (WBC) count has been shown to be associated with insulin resistance, type 2 diabetes (1-4), coronary artery disease (CAD) (5-8), stroke (5,8), and diabetes micro-and macrovascular complications (9,10). An association between leukocytes counts and CAD has been observed in prospective and retrospective cohort studies as well as in case-control studies; this association persists after adjusting for multiple coronary heart disease (CHD) risk factors, including smoking (11).Peripheral blood leukocytes are composed of polymorphonuclear cells, inc l u d i n g m o n o c y t e s a s w e l l a s lymphocytes. Polymorpho-and mononuclear leukocytes can be activated by advanced glycation end products (12), oxidative stress (13,14), angiotensin II (15), and cytokines (16) in a state of hyperglycemia. Leukocytes may be activated through the release of cytokines, such as tumor necrosis factor-␣ (TNF-␣) (17,18), transforming growth factor ␤1 (19), superoxide (20), nuclear factor B (NF-B) (21), monocyte chemoattractant protein 1, interleukin-1␤, and others (17) to participate in the pathogenesis of diabetic micro-and m...

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Section: Discussionmentioning

confidence: 99%

Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

et al. 2005

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“…Hypoglycemia induces a hypercoagulant state in humans via increased platelet aggregation and changes in plasma concentrations of coagulation factors. 12,13,38,39 For example, it has been shown that factor VIII was increased 2-fold after 30 minutes of hypoglycemia. 13 Hypoglycemia may also be responsible for initiating an inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…In 1 study, hypoglycemia was associated with a 3-fold increase in the neutrophil count and an elevation in neutrophil elastase, a potent proteolytic enzyme. 39 Long-QT syndrome is well recognized as being associated with an increased risk of sudden cardiac death. 40 More worryingly, acute hypoglycemia has been demonstrated to produce prolongation of the corrected QT interval by up to 35% in patients with type 1 DM, with values reaching Ͼ550 milliseconds.…”

Section: Discussionmentioning

confidence: 99%

Acute Hypoglycemia Decreases Myocardial Blood Flow Reserve in Patients With Type 1 Diabetes Mellitus and in Healthy Humans

Rana¹,

Byrne²,

Kerr³

et al. 2011

Circulation

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Background-Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects. Methods and Results-Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; PϽ0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, Ϫ0.36; 95% confidence interval, Ϫ0.50 to Ϫ0.23; PϽ0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, Ϫ0.37; 95% confidence interval, Ϫ0.55 to Ϫ0.19; Pϭ0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, Ϫ0.52; 95% confidence interval, Ϫ0.70 to Ϫ0.34; PϽ0.0001). Conclusions-Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals. (Circulation. 2011;124:1548-1556.)Key Words: diabetes mellitus Ⅲ echocardiography Ⅲ hypoglycemia Ⅲ insulin Ⅲ regional blood flow S everal studies have shown that hypoglycemia is associated with an increase in cardiovascular mortality (CVM). [1][2][3][4][5][6] This association has been demonstrated in people with and without established coronary artery disease. [1][2][3] Importantly, patients with acute coronary syndromes appear to have worse short-and long-term outcomes if they experience hypoglycemia in the acute phase of their presentation. [2][3][4] For example, in patients with diabetes mellitus (DM) and acute coronary syndromes, hypoglycemia within 48 hours of their admission was associated with a 2-fold increase in all-cause mortality over a 2-year follow-up. 2 Similarly, Pinto et al 3 showed that patients with ST-segment-elevation myocardial infarction and an admission blood glucose Ͻ4.5 mmol/L had a 3-fold increased rate of adverse outcomes (defined as 30-day mortality and myocardial infarction). Furthermore, in the same study, patients w...

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“…Strict glycaemia control using intensive insulin therapy increases the risk of hypoglycaemia. While it is well known that hypoglycaemia affects cognition, mood and consciousness, it also has profound effects on blood constituents [7,8], inflammatory cytokine level [9,10], and coagulation and fibrinolysis factors [11,12], mainly through the sympathoadrenal response to hypoglycaemia. These data suggest that hypoglycaemia induced by insulin injection may be implicated in the progression of atherosclerosis; however, there are no convincing in vivo data in support of this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Repetitive hypoglycaemia increases serum adrenaline and induces monocyte adhesion to the endothelium in rat thoracic aorta

et al. 2011

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Aims/hypothesis Severe hypoglycaemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect and mechanism of hypoglycaemia on the progression of atherosclerosis remains largely unknown. As a first step towards elucidating the above, we investigated the effect of hypoglycaemia on monocyte-endothelial interaction. Methods Insulin was injected intraperitoneally once every 3 days for 5 weeks in Goto-Kakizaki rats, a non-obese rat model of type 2 diabetes. We counted the number of monocytes adherent to the endothelium of thoracic aorta as an index of early atherosclerogenesis. Cultured HUVEC were used to investigate the mechanism of action. Results Insulin treatment increased the number of monocytes adherent to the vascular endothelium. This increase was abrogated by injection of glucose with insulin. Amosulalol, an α-1 and β-adrenoreceptor antagonist, suppressed monocyte adhesion to endothelium and levels of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in the endothelial surface, which had been enhanced by insulin-induced hypoglycaemia. In HUVEC, adrenaline (epinephrine) significantly increased nuclear translocation of nuclear factor-κB (NF-κB) p65 and levels of adhesion molecules, effects that were abrogated following addition of SQ22536, a specific adenyl cyclase inhibitor. Conclusions/interpretation Our data indicate that repetitive hypoglycaemia induced by insulin enhanced monocyte adhesion to endothelial cells in Goto-Kakizaki rat aorta through enhanced adrenaline activity and that the latter stimulated intracellular cAMP, leading to nuclear translocation of NF-κB with subsequent production of adhesion molecules in endothelial cells.

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Leucocyte Mobilization and Release of Neutrophil Elastase Following Acute Insulin‐induced Hypoglycaemia in Normal Humans

Cited by 36 publications

References 16 publications

Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

Acute Hypoglycemia Decreases Myocardial Blood Flow Reserve in Patients With Type 1 Diabetes Mellitus and in Healthy Humans

Repetitive hypoglycaemia increases serum adrenaline and induces monocyte adhesion to the endothelium in rat thoracic aorta

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