Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes

Rohana J Wright, David E Newby, David Stirling, Christopher A Ludlam, Ian A Macdonald, Brian M Frier, Rohana J Wright, David E Newby, David Stirling, Christopher A Ludlam, Ian A Macdonald, Brian M Frier

Abstract

Objective: To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes.

Research design and methods: We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry.

Results: In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (P <or= 0.02). Inflammation was triggered with CD40 expression increasing maximally at 24 h (3.13 +/- 2.3% vs. 2.06 +/- 1.0%) after hypoglycemia (P = 0.009). Both sCD40L and hsCRP (P = 0.02) increased with a nonsignificant rise in vWF and tPA, indicating a possible endothelial effect. A reduction in sCD40L, tPA, and P-selectin occurred during euglycemia (P = 0.03, P <or= 0.006, and P = 0.006, respectively). In type 1 diabetes, both CD40 expression (5.54 +/- 4.4% vs. 3.65 +/- 1.8%; P = 0.006) and plasma sCD40L concentrations increased during hypoglycemia (peak 3.41 +/- 3.2 vs. 2.85 +/- 2.8 ng/ml; P = 0.03). Platelet-monocyte aggregation also increased significantly at 24 h after hypoglycemia (P = 0.03). A decline in vWF and P-selectin occurred during euglycemia (P <or= 0.04).

Conclusions: Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury.

Figures

Figure 1
Figure 1
A: Blood glucose concentrations during hyperinsulinemic hypoglycemic and euglycemic clamp studies. B: Epinephrine responses to experimental procedures.i. nondiabetic subjects; ii. subjects with type 1 diabetes.
Figure 2
Figure 2
Platelet activation in response to experimental hypoglycemia and euglycemia. A: Platelet-monocyte aggregation. B: Soluble P-selectin, i. Nondiabetic subjects, ii. Subjects with type 1 diabetes.

References

    1. Hanssen KF, Dahl-Jørgensen K, Lauritzen T, Feldt-Rasmussen B, Brinchmann-Hansen O, Deckert T: Diabetic control and microvascular complications: the near-normoglycaemic experience. Diabetologia 1986; 29: 677–684
    1. Frier BM, Hilsted J: Does hypoglycaemia aggravate the complications of diabetes? Lancet 1985; 2: 1175–1177
    1. Wright RJ, Frier BM: Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008; 24: 353–363
    1. Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Jr, Probstfield JL, Simons-Morton DG. Friedewald WT Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545–2559
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129–139
    1. Frier BM, Corrall RJ, Davidson NM, Webber RG, Dewar A, French EB: Peripheral blood cell changes in response to acute hypoglycaemia in man. Eur J Clin Inv 1983; 13: 33–39
    1. Fisher BM, Quin JD, Rumley A, Lennie SE, Small M, MacCuish AC, Lowe GD: Effects of acute insulin-induced hypoglycaemia on haemostasis, fibrinolysis and haemorheology in insulin-dependent diabetic patients and control subjects. Clin Sci 1991; 80: 525–531
    1. Trovati M, Anfossi G, Cavalot F, Vitali S, Massucco P, Mularoni E, Schinco P, Tamponi G, Emanuelli G: Studies on mechanisms involved in hypoglycemia-induced platelet activation. Diabetes 1986; 35: 818–825
    1. Galloway PJ, Thomson GA, Fisher BM, Semple CG: Insulin-induced hypoglycemia induces a rise in C-reactive protein (Letter). Diabetes Care 2000; 23: 861.
    1. Dotson S, Freeman R, Failing HJ, Adler GK: Hypoglycemia increases serum interleukin-6 levels in healthy men and women. Diabetes Care 2008; 31: 1222–1223
    1. Wright RJ, Macleod KM, Perros P, Johnston N, Webb DJ, Frier BM: Plasma endothelin response to acute hypoglycaemia in adults with type 1 diabetes. Diabet Med 2007; 24: 1039–1042
    1. Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002; 105: 1135–1143
    1. De Fronzo R, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 273: E214–E223
    1. Abumrad NN, Rabin D, Diamond MP, Lacy WW: Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism 1981; 30: 936–940
    1. Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994; 17: 697–703
    1. Thompson CJ, Baylis PH: Endocrine changes during insulin-induced hypoglycaemia. In Hypoglycaemia and Diabetes: Clinical and Physiological Aspects. Frier BM, Fisher BM. Eds. Edward Arnold, London, U.K., 1993, p. 116–131
    1. Rydzewski A, Urano T, Nagai N, Takada Y, Katoh-Oishi Y, Taminato T, Yoshimi T, Takada A: Diurnal variation in serum remnant-like lipoproteins, platelet aggregation and fibrinolysis in healthy volunteers. Haemostasis 1997; 27: 305–314
    1. Dandona P, Chauduri A, Ghanim H, Mohanty P: Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol 2009; 53 ( Suppl. 5): S14–S20
    1. Schönbeck U, Libby P: CD40 signaling and plaque instability. Circ Res 2001; 89: 1092–1103
    1. Mach F, Schönbeck U, Libby P: CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998; 137(Suppl.): S89–S95
    1. Razavi Nematollahi L, Kitabchi AE, Kitabchi AE, Stentz FB, Wan JY, Larijani BA, Tehrani MM, Gozashti MH, Omidfar K, Taheri E: Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. Metabolism 2009; 58: 443–448
    1. Steel CM, French EB, Aitchison WR: Studies on adrenaline-induced leucocytosis in normal man. I. The role of the spleen and of the thoracic duct. Br J Haematol 1971; 21: 413–421
    1. Fisher BM, Hepburn DA, Smith JG, Frier BM: The effect of alpha-adrenergic blockade on responses of peripheral blood cells to acute insulin-induced hypoglycaemia in humans. Eur J Clin Invest 1990; 20: 51–55
    1. Takeda H, Kishikawa H, Shinohara M, Miyata T, Suzaki K, Fukushima H, Ichinose K, Shichiri M: Effect of alpha 2-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in type 2 (noninsulin-dependent) diabetes mellitus. Diabetologia 1988; 31: 657–663
    1. Kerr D, Richardson T: Counterregulatory deficiencies in diabetes. In Hypoglycaemia in Clinical Diabetes. 2nd edition. Frier BM, Fisher M. Eds. John Wiley and Sons, Chichester, U.K., 2007, p. 121–140

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться