Intraoperative glucose control in diabetic and nondiabetic patients during cardiac surgery

OBJECTIVE: The purpose of this study was to evaluate intraoperative glucose control. DESIGN: Prospective unblinded study. SETTING: Tertiary care center. PARTICIPANTS: Diabetic (n = 17) and nondiabetic (n = 23) patients undergoing elective cardiac surgery. INTERVENTIONS: Diabetics received a modified insulin regimen consisting of a fixed rate infusion of regular insulin, 10 U/m2/h, and a variable infusion of D10W, adjusted to maintain glucose between 101 to 140 mg/dL. MEASUREMENTS AND MAIN RESULTS: Baseline glucose was higher in diabetics versus nondiabetics (mean +/- standard error of the mean: 203 +/- 27 v 117 +/- 3 mg/dL, p < 0.005). After baseline, insulin levels were increased in diabetics to 410 to 568 microU/mL. Corresponding insulin levels in nondiabetics were 12 to 40 microU/mL. Compared with baseline, glucose was decreased by 10% +/- 29% in diabetics during hypothermic cardiopulmonary bypass and increased by 21% +/- 30% in nondiabetics (p < 0.005). After discontinuation of bypass, glucose was lower in diabetics (137 +/- 12 mg/dL) versus nondiabetics (162 +/- 8 mg/dL, p < 0.005). Nine diabetics had adequate intraoperative glycemic control during hypothermic bypass (glucose 123 +/- 8 mg/dL, insulin 550 +/- 68 microU/mL, glucose infusion rate 1.87 +/- 0.29 mg/kg/min), 6 approached adequate control near the end of surgery (glucose 147 +/- 8 mg/dL, insulin 483 +/- 86 microU/mL, glucose infusion rate 0.35 +/- 0.05 mg/kg/min), and 2 never achieved control. Diabetics with elevated initial glucose >300 mg/dL did not achieve adequate glycemic control. Four diabetics (3 with renal failure) required injection of 50% dextrose after bypass for hypoglycemia. CONCLUSION: Adequate glycemic control can be achieved in most diabetics during cardiac surgery using a modified insulin clamp technique provided initial glucose is <300 mg/dL.     

Surviving native beta-cells determine outcome of syngeneic intraportal islet transplantation

In moderately diabetic rats (plasma glucose 20-30 mmol/L), where there is some residual pancreatic islet function, normoglycemia can be restored by transplantation of pancreatic islets into the liver via the portal vein. To examine whether normoglycemia can also be achieved in more severely diabetic animals (which more closely resemble human type I diabetes), we have compared the effect of transplanting 1000 islets intraportally in Lewis rats made moderately diabetic (55 mg/kg streptozotocin injected IP while nonfasting) or severely diabetic (65 mg/kg streptozotocin injected IP while fasting). In the moderately diabetic rats in which residual pancreatic insulin was 128 +/- 40 mU insulin (2.0% of control), plasma glucose stabilized (32 +/- 2.8 mmol/L at 1 week, 34 +/- 2 mmol/L at 3 weeks) as did body weight (falling from 290 +/- 5 to 265 +/- 5 g at 1 week and 253 +/- 6 g at 3 weeks). In contrast, in severely diabetic rats in which residual pancreatic insulin was only 13.5 +/- 4.2 mU insulin (0.21% of control), there was a progressive rise in plasma glucose (30 +/- 1.3 mmol/L at 1 week, 49 +/- 4 mmol/L at 2 weeks, and 67 +/- 7 mmol/L at 3 weeks) and a progressive fall in body weight (from 304 +/- 10 to 260 +/- 5 g by week 1 and to 209 +/- 6 g by week 3). Following islet transplantation, nonfasting plasma glucose normalized in moderately diabetic rats (10.5 +/- 0.6 vs. 9.1 +/- 0.6 mmol/L in nondiabetic controls, NS) after 23 +/- 5 days. In contrast, in the severely diabetic rats plasma glucose stabilized at 32 +/- 5 mmol/L (p < 0.05 compared to moderately diabetic group) but did not normalize. This difference was not attributable to different plasma glucose levels at the time of transplantation (35.1 +/- 1.8 in moderately diabetic vs. 32.5 +/- 2.5 mmol/L in severely diabetic rats). These observations demonstrate that residual native beta-cells (equivalent to only 60-80 islets) contribute to the survival or function of intraportally transplanted islets.     

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.     

Increased transcapillary escape rate of albumin in nondiabetic men in response to hyperinsulinemia

Diabetic patients manifest increased vascular permeability. To determine whether insulin per se might increase vascular permeability, five nondiabetic men were studied by the hyperinsulinemic-euglycemic clamp technique. Each subject received a 0.72-nmol/kg body wt i.v. insulin bolus, followed by a 72-pmol.kg-1.min-1 insulin infusion for 4 h. Euglycemia was maintained by the Biostator glucose controller. At 7 h of study, 10 microCi i.v. 125I-labeled albumin was injected as bolus dose. Frequent blood samples were drawn during the next 70 min for determination of the transcapillary escape rate (TER) of albumin. Subjects returned 1-2 wk later for a control study, during which 0.45% saline was infused at a rate identical to the dextrose and insulin infusion rates during the hyperinsulinemic clamp. The mean +/- SE serum insulin levels during the hyperinsulinemic clamp and saline infusion were 9786 +/- 126 and 46 +/- 4 pM, respectively, whereas serum glucose during the two sessions was similar (5.0 +/- 0.2 vs. 4.8 +/- 0.1 mM, NS). Identical fluid volumes were infused during the two sessions (1767 +/- 197 ml/7 h), and urine outputs did not differ significantly (1615 +/- 309 vs. 1035 +/- 248 ml/7 h). The TER of albumin was greater in all five men after hyperinsulinemia than after saline infusion (18.3 +/- 2.7 vs. -2.8 +/- 2.3%/h, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of insulin secretory patterns in obese nondiabetic LA/N-cp and obese diabetic SHR/N-cp rats. Role of hyperglycemia

Obese diabetic SHR/N-(cp/cp) rats are a genetic model for non-insulin-dependent diabetes mellitus. When SHR/N-cp rats are overtly diabetic, they are hyperinsulinemic and hyperglycemic in the fed state when consuming commercial chow or semipurified high-carbohydrate diets. Obese SHR/N-cp rats were hyperinsulinemic by 4 wk of age, although hyperglycemia did not appear until 3-4 wk later and was exacerbated by a high-sucrose diet (mean +/- SE 1488 +/- 238 microU/ml insulin and 425 +/- 51 mg/dl glucose). The control SHR/N-cp rats (+/?) on the sucrose diet remained lean and normoglycemic. The obese diabetic SHR/N-cp rats showed three alterations in pancreas perfusion data (not present in control rats): 1) paradoxically high insulin secretion at low glucose levels (2.5 mM), 2) secretion of insulin in response to arginine (10 mM) in the absence of glucose, and 3) impaired response of insulin secretion to high glucose (16.7 mM). To determine whether hyperglycemia was responsible for the abnormalities of insulin secretion, perfusion studies were conducted in obese nondiabetic LA/N-cp rats and compared with the SHR/N-cp rats. The obese LA/N-cp rats resembled the corpulent SHR/N-cp rats in every way, except that they were normoglycemic on the sucrose diet. The obese LA/N-cp rats had two of the three alterations in insulin secretion shown by obese SHR/N-cp rats, lacking only the impaired response to high glucose, suggesting that hyperglycemia was required for that defect to occur.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated in vivo insulin clearance in pima indians with non-insulin-dependent diabetes mellitus

In vivo insulin clearance in 10 subjects with non-insulin-dependent diabetes mellitus (NIDDM) has been compared with clearance in eight equally obese nondiabetic control subjects by two different methods. The first approach consisted of determining the metabolic clearance rates of exogenously infused insulin (MCRI) during hyperinsulinemic (100 mU/m2/min) glucose clamp studies. The results indicated that mean (+/- SEM) MCRI was 1.4-fold greater in the diabetic subjects (436 +/- 22 ml/m2/min) than in the controls (325 +/- 24 ml/m2/min, P less than 0.005), resulting in a lower steady-state plasma insulin concentration in the diabetic (255 +/- 8 microU/ml) compared with the nondiabetic subjects (329 +/- 29 microU/ml, P less than 0.001). The impact of NIDDM on insulin removal rates was also estimated by a second method in which extraction of endogenously secreted insulin (EXTI) in response to an oral glucose load was calculated from the integrated area above basal of plasma insulin (IRI) and of plasma C-peptide (CPR), an estimate of beta-cell secretion. The results demonstrated that fractional extraction of endogenously secreted insulin (EXTI = 100 [(CPR - IRI)/CPR]) was also 1.2-fold greater for diabetic subjects (88.9 +/- 2.5%) than for nondiabetic controls (72.0 +/- 2.8%, P less than 0.001). Finally, these two independent measurements of in vivo insulin removal rates (MCRI and EXTI) were significantly correlated with each other (r = 0.71, P less than 0.002). These observations are consistent with the view that elevated insulin clearance may contribute to the postchallenge hypoinsulinemia of NIDDM in Pima Indians.     

Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients

The gastric peptide ghrelin augments and the adipocyte-derived hormone leptin reduces appetite and food intake. In the central nervous system, insulin directly decreases hunger sensation but could also act indirectly by modulating ghrelin and leptin secretion. This study examines dose-dependent effects of insulin on plasma ghrelin and leptin concentrations during hyperinsulinemic (1, 2, and 4 mU x kg(-1) x min(-1))-euglycemic clamp tests in six nondiabetic (control subjects) and six type 2 diabetic patients. Type 2 diabetic patients were studied before and after prolonged (12-h and 67-h) variable intravenous insulin treatment aiming at near-normoglycemia (115 +/- 4 mg/dl). Nondiabetic subjects were also studied during saline infusion, which did not affect ghrelin but decreased leptin by 19 +/- 6% (P < 0.03). In control subjects, plasma ghrelin decreased at all clamp steps (-17 +/- 1, -27 +/- 6, and -33 +/- 4%, respectively; P < 0.006 vs. baseline), whereas leptin increased by 35 +/- 11% (P < 0.05). In type 2 diabetic patients without insulin treatment, ghrelin decreased by 18 +/- 7% (P < 0.05) only after 4 mU x kg(-1) x min(-1) insulin infusion and leptin increased by 19 +/- 6% (P < 0.05). After prolonged insulin treatment and near-normoglycemia, ghrelin and leptin remained unchanged in type 2 diabetic patients during the clamps. In conclusion, insulin reduces plasma ghrelin in nondiabetic patients and, to a lesser extent, in type 2 diabetic patients before insulin therapy. These findings indicate an indirect effect of insulin via ghrelin on the suppression of hunger sensation and appetite.     

Timely bolus insulin for glucose control during cardiopulmonary bypass

Hyperglycemia during cardiopulmonary bypass (CPB) with glucose containing cardioplegia is common; normoglycemia is difficult to maintain and failure to do so may result in worse outcomes. The purpose of this quality improvement initiative was to show that a simple timely insulin bolus is more effective for glucose control during CPB with glucose containing cardioplegia than conventional (not standardized) glucose management in historical case-matched controls. A single bolus of insulin (.2 international units per kilogram; iu/kg) was administered, at the time of aortic cannulation, to 211 consecutive patients undergoing cardiac surgery with CPB and glucose containing cardioplegia. A further .1 iu/kg bolus of insulin was given for blood glucose (BG) measurements greater than 10.0 mmol/L (180 mg/dL) during CPB. The control group of 211 historical case-matched patients had glucose management according to anesthesiologist preference (insulin as a bolus, bolus plus infusion, infusion only, or no insulin). The frequency of hyperglycemia (BG > 11.0 mmol/L; 198 mg/dL) during CPB was significantly less in the study group (22; 10.5%) than in the control group (117; 55.5%) (p < .0001). Hyperglycemia in the first 6 hours in the intensive care unit was also significantly less frequent in the study group (5; 2.4%) than in the control group (14; 6.6%) (p = .03). Severe hypoglycemia (BG < 2.8 mmol/L; 50.4 mg/dL) occurred in one patient (.47%) in the timely bolus insulin group and five patients (2.3%) in the control group (p = .09). The timely bolus insulin method is more efficacious, but equally safe, in preventing hyperglycemia during CPB with glucose containing cardioplegia, compared with conventional (not standardized) insulin treatment in historical case-matched controls.     

Effects of sustained insulin-induced hypoglycemia on cardiovascular autonomic regulation in type 1 diabetes

Effects of hypoglycemia on cardiac autonomic regulation may contribute to the occurrence of adverse cardiac events. This study assessed the effects of sustained hyperinsulinemic hypoglycemia on cardiovascular autonomic regulation in type 1 diabetic patients and their nondiabetic counterparts. The study consisted of 16 type 1 diabetic patients and 8 age-matched healthy control subjects who underwent euglycemic and hypoglycemic clamp procedures in a random order. Heart rate variability was measured from continuous electrocardiogram recordings by time and frequency domain methods, along with Poincare plot analysis during both a hyperinsulinemic-euglycemic and hypoglycemic clamp at three different glucose levels (4.5-5.5, 3.0-3.5, and 2.0-2.5 mmol/l). Controlled hypoglycemia resulted in an increase of supine heart rate in both the diabetic patients (from 72 +/- 9 to 80 +/- 11 bpm, P < 0.01) and the control subjects (from 59 +/- 5 to 65 +/- 5 bpm, P < 0.05) and progressive reductions of the high-frequency spectral component and beat-to-beat heart rate variability (SD1; P < 0.05 in the diabetic patients and P < 0.01 in control subjects). No significant changes in heart rate variability occurred during the euglycemic clamp. We conclude that hypoglycemia results in a reduction of cardiac vagal outflow in both diabetic and nondiabetic subjects. Altered autonomic regulation may contribute to the occurrence of cardiac events during hypoglycemia.     

Intraoperative management of hyperglycemia in the cardiac surgical patient

The stress response of cardiac surgery leads to hyperglycemia, and undergoing cardiopulmonary bypass magnifies this response greatly. Counter-regulatory hormones, the cytokine response, and the automatic nervous system are all part of the coordinated host response that can lead to hyperglycemia. Postoperative hyperglycemia is associated with worsened perioperative outcomes, and there are data demonstrating this to also be true for the intraoperative period. Many factors affect intraoperative glucose control, including cardiopulmonary pump (CPB) prime fluid composition, temperature while on CPB, and medications such as catecholamines and glucocorticoids. Intraoperative glucose control has a significant impact on postoperative outcomes. No optimal intraoperative insulin regimen has been identified, but continuous intravenous infusions appear to be superior to intermittent sliding scale dosing. In addition, the technique of hyperinsulinemic glucose clamp shows the greatest promise of achieving normoglycemia while on CPB.     

Hyperglycemia decreases glucose uptake in type I diabetes

It has recently been postulated that hyperglycemia per se may contribute to insulin resistance in diabetes. To examine this possibility directly, we measured glucose uptake after 24 h of hyperglycemia (281 +/- 16 mg/dl) and normoglycemia (99 +/- 6 mg/dl) in 10 type I (insulin-dependent) diabetic patients (age 33 +/- 3 yr, relative body wt 102 +/- 3%) treated with continuous subcutaneous insulin infusion. Hyperglycemia was induced by an intravenous glucose infusion, whereas saline was administered during the control day. During both studies the patient received a similar diet and insulin dose. After hyper- and normoglycemia, a primed continuous infusion of insulin (40 mU X m-2 X min-1) was started, and plasma glucose was adjusted to and maintained at 142 +/- 2 and 140 +/- 2 mg/dl, respectively, during 60-160 min of insulin infusion. The rate of glucose uptake after hyperglycemia averaged 8.3 +/- 1.1 mg X kg-1 X min-1, which was lower than the rate after the normoglycemic period (10.1 +/- 1.2 mg X kg-1 X min-1, P less than .001). In conclusion, short-term hyperglycemia reduces glucose uptake in type I diabetic patients. Thus, part of the glucose or insulin resistance in these patients may be caused by hyperglycemia per se.     

Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy

More than 40% of HIV-infected patients on highly active antiretroviral therapy (HAART) experience fat redistribution (lipodystrophy), a syndrome associated with insulin resistance primarily affecting insulin-stimulated nonoxidative glucose metabolism (NOGM(ins)). Skeletal muscle biopsies, obtained from 18 lipodystrophic nondiabetic patients (LIPO) and 18 nondiabetic patients without lipodystrophy (NONLIPO) before and during hyperinsulinemic (40 mU.m(-2).min(-1))-euglycemic clamps, were analyzed for insulin signaling effectors. All patients were on HAART. Both LIPO and NONLIPO patients were normoglycemic (4.9 +/- 0.1 and 4.8 +/- 0.1 mmol/l, respectively); however, NOGM(ins) was reduced by 49% in LIPO patients (P < 0.001). NOGM(ins) correlated positively with insulin-stimulated glycogen synthase activity (I-form, P < 0.001, n = 36). Glycogen synthase activity (I-form) correlated inversely with phosphorylation of glycogen synthase sites 2+2a (P < 0.001, n = 36) and sites 3a+b (P < 0.001, n = 36) during clamp. Incremental glycogen synthase-kinase-3alpha and -3beta phosphorylation was attenuated in LIPO patients (Ps < 0.05). Insulin-stimulated Akt Ser473 and Akt Thr308 phosphorylation was decreased in LIPO patients (P < 0.05), whereas insulin receptor substrate-1-associated phosphatidylinositol (PI) 3-kinase activity increased significantly (P < 0.001) and similarly (NS) in both groups during clamp. Thus, low glycogen synthase activity explained impaired NOGM(ins) in HIV lipodystrophy, and insulin signaling defects were downstream of PI 3-kinase at the level of Akt. These results suggest mechanisms for the insulin resistance greatly enhancing the risk of type 2 diabetes in HIV lipodystrophy.     

Insulin action during pregnancy. Studies with the euglycemic clamp technique

To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.     

Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients

Gluconeogenesis (GNG) is enhanced in type 2 diabetes. In experimental animals, insulin at high doses decreases the incorporation of labeled GNG precursors into plasma glucose. Whether physiological hyperinsulinemia has any effect on total GNG in humans has not been determined. We combined the insulin clamp with the (2)H(2)O technique to measure total GNG in 33 subjects with type 2 diabetes (BMI 29.0 +/- 0.6 kg/m(2), fasting plasma glucose 8.1 +/- 0.3 mmol/l) and in 9 nondiabetic BMI-matched subjects after 16 h of fasting and after euglycemic hyperinsulinemia. A primed-constant infusion of 6,6-(2)H-glucose was used to monitor endogenous glucose output (EGO); insulin (40 mU. min(-1). m(-2)) was then infused while clamping plasma glucose for 2 h (at 5.8 +/- 0.1 and 4.9 +/- 0.2 mmol/l for diabetic and control subjects, respectively). In the fasting state, EGO averaged 15.2 +/- 0.4 micromol. min(-1). kg(-1)(ffm) (62% from GNG) in diabetic subjects and 12.2 +/- 0.7 micromol. min(-1). kg(-1)(ffm) (55% from GNG) in control subjects (P < 0.05 or less for both fluxes). Glycogenolysis (EGO - GNG) was similar in the two groups (P = NS). During the last 40 min of the clamp, both EGO and GNG were significantly (P < 0.01 or less, compared with fasting) inhibited (EGO 7.1 +/- 0.9 and 3.6 +/- 0.5 and GNG 7.9 +/- 0.5 and 4.5 +/- 1.0 respectively) but remained significantly (P < 0.05) higher in diabetic subjects, whereas glycogenolysis was suppressed completely and equally in both groups. During hyperinsulinemia, GNG micromol. min(-1). kg(-1)(ffm) in diabetic and control subjects, was reciprocally related to plasma glucose clearance. In conclusion, physiological hyperinsulinemia suppresses GNG by approximately 20%, while completely blocking glycogenolysis. Resistance of GNG (to insulin suppression) and resistance of glucose uptake (to insulin stimulation) are coupled phenomena. In type 2 diabetes, the excess GNG of the fasting state is carried over to the insulinized state, thereby contributing to glucose overproduction under both conditions.     

Hepatic glycogen metabolism in type 1 diabetes after long-term near normoglycemia.

We tested the impact of long-term near normoglycemia (HbA(1c) <7% for >1 year) on glycogen metabolism in seven type 1 diabetic and seven matched nondiabetic subjects after a mixed meal. Glycemic profiles (6.2 +/- 0.10 vs. 5.9 +/- 0.07 mmol/l; P < 0.05) of diabetic patients were approximated to that of nondiabetic subjects by variable insulin infusion. Rates of hepatic glycogen synthesis and breakdown were calculated from the glycogen concentration time curves between 7:30 P.M. and 8:00 A.M. using in vivo (13)C nuclear magnetic resonance spectroscopy. Glucose production was determined with D-[6,6-(2)H(2)]glucose, and the hepatic uridine-diphosphate glucose pool was sampled with acetaminophen. Glycogen synthesis and breakdown as well as glucose production were identical in diabetic and healthy subjects: 7.3 +/- 0.9 vs. 7.1 +/- 0.7, 4.2 +/- 0.5 vs. 3.8 +/- 0.3, and 8.7 +/- 0.5 vs. 8.4 +/- 0.7 micromol x kg(-1) x min(-1), respectively. Although portal vein insulin concentrations were doubled, the flux through the indirect pathway of glycogen synthesis remained higher in type 1 diabetic subjects: approximately 70 vs. approximately 50%; P < 0.05. In conclusion, combined long- and short-term intensified insulin substitution normalizes rates of hepatic glycogen synthesis but not the contribution of gluconeogenesis to glycogen synthesis in type 1 diabetes.     

Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.

Perioperative GIK therapy has been advocated to ensure adequate energy substrate levels during cardiac surgery. However, hyperglycemia should be avoided because it may worsen neurologic outcome after cerebral ischemia. A prospective, randomized, clinical comparison was performed between two prebypass infusion regimens in 32 elective nondiabetic CABG patients. Sixteen patients (GIK group) received glucose, 0.6 g/kg/h, insulin, 0.12 U/kg/h, and KCl, 0.12 mmol/kg/h, from the induction of anesthesia to the start of CPB; while the remaining 16 patients (R group) received only Ringer's acetate. The pump prime was glucose free and a blood cardioplegia technique was used in both groups. No differences were found between the groups with regard to myocardial injury; the CK-MB enzyme fractions were elevated to a similar degree and the frequency of postoperative ECG changes were similar in both groups. Likewise, there were no differences in hemodynamic changes, need for inotropic support, arrhythmia frequency, or duration of ICU stay. The GIK patients had higher blood glucose (P < 0.05) and insulin levels (P < 0.01); blood glucose increased to 12.4 +/- 5.4 mmol/L (mean +/- SD) at cannulation, with a drop after starting bypass. Interindividual variation in GIK patients was great, with glucose values ranging between 20.1 mmol/L at cannulation to 2.0 mmol/L after starting CPB. A hyperglycemic response was seen in both groups during rewarming: 15.0 +/- 4.2 and 15.0 +/- 3.1 mmol/L in GIK and R patients, respectively. It is concluded that prebypass GIK infusion had no clinical benefits for elective CABG patients as compared to Ringer's acetate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aminated β-1,3-d-glucan improves wound healing in diabetic db/db mice

Delayed wound healing in diabetes is caused by neuropathy, vascular changes, and impaired cellular response to the injury. Macrophages are crucial in normal wound healing, and impaired functions of these cells have been shown in diabetes. beta-1,3-D-glucans stimulate macrophage function. This open-label study was performed to see if aminated beta-1,3-D-glucan (AG) stimulates wound healing in diabetes. Four groups (1-4) of diabetic db/db mice and one nondiabetic control group, db/+(5) were studied: group 1 (n=11): topical AG; group 2 (n=10): topical AG and subcutaneous insulin; group 3 (n=14): topical placebo and subcutaneous insulin; group 4 (n=10): diabetic control (placebo); group 5 (n=12): normal control (placebo). At the end of the experiments fasting blood glucose and A1C were (mean +/- SE) as follows: Group 1: 30.5 +/- 1.9 mmol/L and 11.3 +/- 0.6%; group 2: 12.0 +/- 1.7 mmol/L and 8.0 +/- 0.6%; group 3: 15.4 +/- 2.4 mmol/L and 7.4 +/- 0.3%; group 4: 32.6 +/- 2.6 mmol/L and 12.3 +/- 0.6%; group 5: 7.2 +/- 0.4 mmol/L and 3.9 +/- 0.04%, respectively. The closed wound area was the same in group 1 (AG alone) and group 2 (AG plus insulin) after 17 days, 57.3 +/- 4.7 vs. 50.1 +/- 4.9% (p=0.7).The results of these two groups were superior to group 3 (insulin treatment alone, 32.0 +/- 4.3%, p<0.001) and diabetic controls (38.2 +/- 5.1%, p=0.001). The macrophage-stimulant AG improves wound healing in db/db mice.     

The effect of glucose priming solutions in diabetic patients undergoing coronary artery bypass grafting

To assess the impact of glucose-containing priming solutions on plasma glucose level in diabetic patients during and after coronary artery bypass graft surgery, we studied 50 diabetic patients and 10 nondiabetic patients who underwent bypass graft surgery. Glucose-containing priming solutions profoundly elevated plasma glucose levels during and after bypass graft surgery. In diabetic patients who received glucose primes, intraoperative peak plasma glucose levels averaged 696 +/- 48 mg/dl as compared with 341 +/- 17 mg/dl in diabetic patients who received nonglucose primes (p less than 0.001). Despite an insulin infusion, diabetic patients underwent a much slower decline in plasma glucose levels postoperatively over a 2-hour period than did nondiabetics (who did not receive an insulin infusion). We conclude that during and immediately after coronary artery bypass surgery in diabetic patients, it is desirable to avoid administration of glucose-containing priming solutions, since such solutions profoundly elevate plasma glucose levels.     

Insulin increases neutrophil count and phagocytic capacity after cardiac surgery

We previously reported that a continuous insulin infusion improves neutrophil phagocytic function after cardiac surgery in diabetic patients. These data suggested that hyperglycemia impairs neutrophil function, and because nondiabetic patients also experience hyperglycemia during cardiac surgery, we hypothesized that a continuous insulin infusion would improve glucose control and neutrophil function in nondiabetic cardiac surgical patients. Patients were randomized to receive either no insulin (Control group) or a continuous insulin infusion (Insulin group), with glucose measurements every 10 min during cardiopulmonary bypass (CPB). Blood glucose was significantly lower in the Insulin group immediately after surgery but not during surgery. When assessed as the percentage of phagocytic cells, neutrophil function was similar in the Control and Insulin groups at baseline (55% and 57%, respectively) and after CPB (38% and 43%, respectively). However, a quantitative determination of neutrophil phagocytic activity showed that whole blood neutrophil phagocytic capacity increased significantly in both groups at 60 min after CPB when compared with their respective baseline values and that the increase in total neutrophil phagocytic capacity was significantly more in the Insulin group compared with the Control group (P = 0.036). This observation was primarily due to a larger increase in the peripheral blood neutrophil count and not to increased activation of neutrophils. IMPLICATIONS: IV insulin, as used in this study, had effects on blood glucose only after cardiac surgery, when it was associated with an increased neutrophil count and a greater total capacity of peripheral blood neutrophils to ingest foreign particles.     

Physiological and pharmacological stimulation of pancreatic islet hormone secretion in type I diabetic pancreas allograft recipients

Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore, whether the denervated pancreas allografts exhibit beta-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated beta-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only, who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin, azathioprine, and prednisone), and 7 healthy control subjects with no family history of diabetes. After PAT, fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean +/- SE 345 +/- 43 pM) compared with control subjects (43 +/- 14 pM) and nondiabetic kidney-transplantation patients (129 +/- 38 pM). After mixed-meal ingestion, the mean incremental integrated insulin area was similar in PAT patients (18 +/- 3 nM.min) compared with kidney-transplantation patients (20 +/- 4 nM.min) and healthy control subjects (21 +/- 3 nM.min). Basal serum C-peptide levels were significantly greater in PAT (1.72 +/- 0.13 nM) and kidney-transplantation (2.15 +/- 0.33 nM) patients than in healthy control subjects (0.50 +/- 0.10 nM; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)