Search

Objective: To evaluate a fully automated algorithm for the establishment of tight glycemic control in critically ill patients and to compare the results with different routine glucose management protocols of three intensive care units (ICUs) across Europe (Graz, Prague, and London).Research Design and Methods: Sixty patients undergoing cardiac surgery (age 67 +/- 9 years, BMI 27.7 +/- 4.9 kg/m2, 17 women) with postsurgery blood glucose levels >120 mg/dl (6.7 mmol/l) were investigated in three different ICUs (20 per center). Patients were randomized to either blood glucose management (target range 80-110 mg/dl [4.4-6.1 mmol/l]) by the fully automated model predictive control (MPC) algorithm (n = 30, 10 per center) or implemented routine glucose management protocols (n = 30, 10 per center). In all patients, arterial glucose was measured hourly to describe the glucose profile until the end of the ICU stay but for a maximum period of 48 h.Results: Compared with routine protocols, MPC treatment resulted in a significantly higher percentage of time within the target glycemic range (% median [min-max]: 52 [17-92] vs. 19 [0-71]) over 0-24 h (P < 0.01). Improved glycemic control with MPC treatment was confirmed in patients remaining in the ICU for 48 h (0-24 h: 50 [17-71] vs. 21 [4-67], P < 0.05, and 24-48 h: 65 [38-96] vs. 25 [8-79], P < 0.05, for MPC [n = 16] vs. routine protocol [n = 13], respectively). Two hypoglycemic events (<54 mg/dl [3.0 mmol/l]) were observed with routine protocol treatment. No hypoglycemic event occurred with MPC.Conclusions: The data suggest that the MPC algorithm is safe and effective in controlling glycemia in critically ill postsurgery patients. [ABSTRACT FROM AUTHOR]

Objective: We performed a randomized trial to compare three insulin-titration protocols for tight glycemic control (TGC) in a surgical intensive care unit: an absolute glucose (Matias) protocol, a relative glucose change (Bath) protocol, and an enhanced model predictive control (eMPC) algorithm., Research Design and Methods: A total of 120 consecutive patients after cardiac surgery were randomly assigned to the three protocols with a target glycemia range from 4.4 to 6.1 mmol/l. Intravenous insulin was administered continuously or in combination with insulin boluses (Matias protocol). Blood glucose was measured in 1- to 4-h intervals as requested by the protocols., Results: The eMPC algorithm gave the best performance as assessed by time to target (8.8 +/- 2.2 vs. 10.9 +/- 1.0 vs. 12.3 +/- 1.9 h; eMPC vs. Matias vs. Bath, respectively; P < 0.05), average blood glucose after reaching the target (5.2 +/- 0.1 vs. 6.2 +/- 0.1 vs. 5.8 +/- 0.1 mmol/l; P < 0.01), time in target (62.8 +/- 4.4 vs. 48.4 +/- 3.28 vs. 55.5 +/- 3.2%; P < 0.05), time in hyperglycemia >8.3 mmol/l (1.3 +/- 1.2 vs. 12.8 +/- 2.2 vs. 6.5 +/- 2.0%; P < 0.05), and sampling interval (2.3 +/- 0.1 vs. 2.1 +/- 0.1 vs. 1.8 +/- 0.1 h; P < 0.05). However, time in hypoglycemia risk range (2.9-4.3 mmol/l) in the eMPC group was the longest (22.2 +/- 1.9 vs. 10.9 +/- 1.5 vs. 13.1 +/- 1.6; P < 0.05). No severe hypoglycemic episode (<2.3 mmol/l) occurred in the eMPC group compared with one in the Matias group and two in the Bath group., Conclusions: The eMPC algorithm provided the best TGC without increasing the risk of severe hypoglycemia while requiring the fewest glucose measurements. Overall, all protocols were safe and effective in the maintenance of TGC in cardiac surgery patients.

Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice with a gene deletion of the acid-labile subunit (ALSKO) demonstrate a 65% reduction in circulating IGF-1 levels, with normal GH levels and no signs of insulin resistance. To further clarify the relative roles of increased GH and decreased IGF-1 levels in the development of insulin resistance, we crossed the two mouse lines and created a double knockout mouse (LID+ALSKO). LID+ALSKO mice demonstrate a further reduction in circulating IGF-1 levels (85%) and a concomitant 10-fold increase in GH levels. Insulin tolerance tests showed an improvement in insulin responsiveness in the LID+ALSKO mice compared with controls; LID mice were very insulin insensitive. Surprisingly, insulin sensitivity, while improved in white adipose tissue and in muscle, was unchanged in the liver. The lack of improvement in liver insulin sensitivity may reflect the absence of IGF-1 receptors or increased triglyceride levels in the liver. The present study suggests that whereas GH plays a major role in inducing insulin resistance, IGF-1 may have a direct modulatory role.

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.

To determine the role of adipocytes and the tissue-specific nature in the insulin sensitizing action of rosiglitazone, we examined the effects of 3 weeks of rosiglitazone treatment on insulin signaling and action during hyperinsulinemic-euglycemic clamps in awake A-ZIP/F-1 (fatless), fat-transplanted fatless, and wild-type littermate mice. We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. These effects of rosiglitazone treatment were associated with 50% decreases in triglyceride and fatty acyl-CoA contents in the skeletal muscle of rosiglitazone-treated fatless mice. In contrast, rosiglitazone treatment exacerbated hepatic insulin resistance in the fatless mice and did not affect already reduced IRS-2-associated PI 3-kinase activity in liver. The worsening of insulin action in liver was associated with 30% increases in triglyceride and fatty acyl-CoA contents in the liver of rosiglitazone-treated fatless mice. In conclusion, these data support the hypothesis that rosiglitazone treatment enhanced insulin action in skeletal muscle mostly by its ability to repartition fat away from skeletal muscle.

The virtually fatless A-ZIP/F-1 mouse is profoundly insulin resistant, diabetic, and a good model for humans with severe generalized lipoatrophy. Like a number of other mouse models of diabetes, the A-ZIP/F-1 mouse has elevated serum corticosterone levels. Leptin infusion lowers the corticosterone levels, suggesting that leptin deficiency contributes to the hypercorticosteronemic state. To test the hypothesis that the increased glucocorticoids contribute to the diabetes and insulin resistance, we examined the effect of adrenalectomy on A-ZIP/F-1 mice. Adrenalectomy significantly decreased the blood glucose, serum insulin, and glycated hemoglobin levels. Hyperinsulinemic-euglycemic clamps were performed to characterize the changes in whole-body and tissue insulin sensitivity. The adrenalectomized A-ZIP/F-1 mice displayed a marked improvement in insulin-induced suppression of endogenous glucose production, indicating increased hepatic insulin sensitivity. Adrenalectomy also increased muscle glucose uptake and glycogen synthesis. These results suggest that the chronically increased serum corticosterone levels contribute to the diabetes of the A-ZIP/F-1 mice and that removal of the glucocorticoid excess improves the insulin sensitivity in both muscle and liver.