Arindam Bandyopadhyay

Anti-Inflammatory and Profibrinolytic Effect of Insulin in Acute ST-Segment–Elevation Myocardial Infarction

Background—The clinical benefits of insulin previously observed in acute ST-segment–elevation myocardial infarction (STEMI) may be partially explained by an anti-inflammatory effect. We assessed this potential effect of insulin in STEMI patients treated with fibrinolytics. Methods and Results—Thirty-two patients receiving reteplase were randomly assigned infusions of either insulin at 2.5 U/h, dextrose, and potassium (GIK) or normal saline and potassium (C) for 48 hours. Plasma concentrations of high-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), plasminogen activator inhibitor-1 (PAI-1), creatine kinase (CK), and CK-MB were measured at baseline and sequentially for 48 hours. Total p47phox protein in mononuclear cells was measured in a subgroup of 13 subjects. Baseline CRP and SAA were significantly increased (2- to 4-fold) at 24 and 48 hours in each group (P <0.01). However, in the insulin group, there was a significant (P <0.05) attenuation of the absolute rise in concentration of CRP and SAA from baseline. The absolute increase of CRP and SAA was reduced by 40% (CRP) and 50% (SAA) at 24 hours and at 48 hours compared with the control group. The absolute increase in PAI-1 from baseline and the percentage increase in p47phox over 48 hours were significantly (P <0.05) lower in the insulin-treated group. CK-MB peaked earlier and tended to be lower in insulin-treated subjects, especially in patients with inferior MI. Conclusions—Insulin has an anti-inflammatory and profibrinolytic effect in patients with acute MI. These effects may contribute to the clinical benefits of insulin in STEMI.

Insulin Suppresses Endotoxin Induced Oxidative, Nitrosative and Inflammatory Stress in Humans

OBJECTIVE To investigate whether insulin reduces the magnitude of oxidative, nitrosative, and inflammatory stress and tissue damage responses induced by endotoxin (lipopolysaccharide [LPS]). RESEARCH DESIGN AND METHODS Nine normal subjects were injected intravenously with 2 ng/kg LPS prepared from Escherichia coli. Ten others were infused with insulin (2 units/h) for 6 h in addition to the LPS injection along with 100 ml/h of 5% dextrose to maintain normoglycemia. RESULTS LPS injection induced a rapid increase in plasma concentrations of nitric oxide metabolites, nitrite and nitrate (NOM), and thiobarbituric acid–reacting substances (TBARS), an increase in reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs), and marked increases in plasma free fatty acids, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibition factor (MIF), C-reactive protein, resistin, visfatin, lipopolysaccharide binding protein (LBP), high mobility group-B1 (HMG-B1), and myoglobin concentrations. The coinfusion of insulin led to a total elimination of the increase in NOM, free fatty acids, and TBARS and a significant reduction in ROS generation by PMNLs and plasma MIF, visfatin, and myoglobin concentrations. Insulin did not affect TNF-α, MCP-1, IL-6, LBP, resistin, and HMG-B1 increases induced by the LPS. CONCLUSIONS Insulin reduces significantly several key mediators of oxidative, nitrosative, and inflammatory stress and tissue damage induced by LPS. These effects of insulin require further investigation for its potential use as anti-inflammatory therapy for endotoxemia.

The combination of insulin and metformin in treatment of non-insulin-dependent diabetes mellitus.

OBJECTIVE To assess whether, in the treatment of non-insulin-dependent diabetes mellitus (NIDDM), (1) metformin in conjunction with insulin can safely cause a decrease in glycosylated hemoglobin (HbA1c) to 7% or less and (2) this combination therapy may result in weight loss and lower insulin dose in comparison with insulin treatment alone. METHODS Forty patients with NIDDM being treated with insulin on their first visit to the Diabetes Center were identified by retrospective review of medical records of all patients encountered during a 1-year period. These patients were classified into groups who were receiving insulin only (group 1) or insulin + metformin (group 2) at the most recent visit. Group 2 was subdivided into those with a body mass index of either =30 kg/m 2 (group 2A) or >30 kg/m 2 (group 2B). Blood glucose, HbA1c, insulin dose, and weights were analyzed from their initial and most recent visits. RESULTS HbA1c decreased from 10 +/- 2.7% to 7 +/- 1.1% (P<0.01) in group 1 and from 9.8 +/- 2.1% to 7.2 +/- 1.4% (P<0.01) in group 2. The magnitude of decrease in HbA1c, however, was not different between the two groups. Total insulin dose increased from 40 (33 to 50) U/day to 58 (41 to 67) U/day (P<0.05) in group 1 and from 63 (42 to 118) U/day to 67 (50 to 96) U/day in group 2 (not significantly different). The median increase in insulin dose was 8 U in group 1, whereas the median decrease was 3 U in group 2 (P<0.05). Similar decreases were noted in group 2A. The decrease in insulin dose was inversely related to the initial insulin dose per kilogram of body weight in group 2 (r = -0.5; P<0.01). Patients in group 1 had an increase in weight from 75.0 +/- 8.6 kg to 77.7 +/- 9.0 kg (P<0.01), whereas weight decreased from 100.4 +/- 24.2 kg to 98.5 +/- 22.3 kg in group 2 (P<0.05). A decrease in weight was seen even in group 2A. The increase in weight was 3 +/- 3.3 kg in group 1, whereas weight decreased by 1.9 +/- 3.9 kg in group 2 (P<0.01). CONCLUSION Insulin + metformin is safe and is as effective as insulin alone in improving glycemic control in obese and nonobese patients with NIDDM. This combination therapy, however, lowers insulin dose and promotes weight loss, which may be of importance in decreasing the cardiovascular risk factors in these subjects.

Angiotensin II and Inflammation: The Effect of ACE Inhibition and Angiotensin II Receptor Blockade.

ANGIOTENSIN II (Ang II) is a powerful vasoconstrictor that has the function of maintaining an appropriate vasomotor tone in hypovolemic and hypotensive conditions so that an adequate blood pressure can be maintained. This role of Angiotensin II was the first to be recognized, and hence its name. Ang II has several properties in addition to its vasoconstrictor effect. It induces the secretion of aldosterone from the zona glomerulosa of the adrenal cortex. This allows Ang II to induce retention of sodium and water, and to increase the circulating volume significantly along with its vasoconstrictor effect to elevate or maintain normal blood pressure in hypotensive situations. Inappropriately elevated levels of Ang II are likely to cause hypertension through vasoconstriction and through salt and water retention. The best example of this is renal hypertension, in which ischemia of the juxtaglomerular apparatus in the kidney leads to the secretion of renin. Renin, in turn, causes the conversion of angiotensinogen into Ang I, while Ang converting enzyme (ACE) converts Ang I to Ang II. These changes may occur in the circulation (plasma) or in the tissues, in particular the arterial wall. Ang II also exerts a pro-aggregatory effect on blood platelets, and this is decreased by ACE inhibitors.1–3 More recently, it has been shown to exert a pro-inflammatory effect on leukocytes and endothelial cells and mitogenic as well as proinflammatory effects on vascular smooth muscle cells.4–9 It has also been shown to interfere with insulin signal transduction, and it may thus contribute to insulin resistance.10,11 The above mentioned effects of Ang II are mediated through AT1 receptors. Ang II also exerts effects through AT2 receptors. These effects are different and include the release of NO, which is a vasodilator, anti-platelet aggregatory, and antiinflammatory, and which may facilitate insulin action.12–20 The actions mediated by AT2 receptors are diametrically opposite to those mediated through AT1 receptors and are likely to be the dominant actions when AT1 receptors are inactive or are blocked. Studies in both endothelial cells and vascular smooth muscle cells have demonstrated that Ang II, acting via AT type 1 receptor, stimulates NADPH oxidase (different studies have shown actions upon different subunits of this complex) and enhances ROS production.21,22 This decreases NO bioavailability and causes endothelial dysfunction.13 Ang II increases NFB DNA binding, nuclear translocation of p65/p50 subunits, and cytosolic I B degradation.4 Ang II, acting via an AT type 1 receptor, also activates NFB– mediated transcription and gene expression.6 Ang II increases adhesion molecules, cytokines, and chemokines acting through NFB and