Continuous infusion of subcutaneous compared to intravenous insulin for tight glycaemic control in medical intensive care unit patients

The aim of this randomised controlled study was to compare continuous subcutaneous insulin infusion using an insulin pump with the traditional continuous intravenous infusion method for tight glycaemic control. Sixty patients admitted to our University Hospital medical intensive care unit with an initial blood glucose level over 6.1 mmol/l, were enrolled and randomised into two treatment groups: the subcutaneous insulin group received continuous subcutaneous insulin infusion and the intravenous group received insulin by traditional intravenous infusion with infusers. Three patients died in the first 24 hours and were excluded from the final analysis. Insulin therapy was administered to both groups according to the previously designed and used protocol in the department. The target glucose level was 4.4 to 6.1 mmol/l. There was no significant difference in mortality between the groups. However mean blood glucose level was found to be lower (6.56+/-0.82 mmol/l vs. 7.85+/-1.6 mmol/l, P=0.00055) in the subcutaneous insulin group. According to Vogelzang's hyperglycaemic index, better glycaemic control was achieved in the subcutaneous insulin group while there was no significant difference in terms of hypoglycaemic events. Daily insulin bolus and infusion requirements were also significantly lower in the subcutaneous insulin group. Despite the small number of patients involved in this study in a medical intensive care unit, strict blood glucose control using a subcutaneous insulin pump was achieved more efficiently than the traditional intravenous infusion method without increasing hypoglycaemic events.     

Evaluation of the effect of gain on the meal response of an automated closed-loop insulin delivery system

A continuous closed-loop insulin delivery system using subcutaneous insulin delivery was evaluated in eight diabetic canines. Continuous glucose profiles were obtained by extrapolation of blood glucose measurements. Insulin delivery rate was calculated, using a model of beta-cell insulin secretion, and delivered with a Medtronic MiniMed subcutaneous infusion pump. The model acts like a classic proportional-integral-derivative controller, delivering insulin in proportion to glucose above target, history of past glucose values, and glucose rate of change. For each dog, a proportional gain was set relative to the open-loop total daily dose (TDD) of insulin. Additional gains based on 0.5 x TDD and 1.5 x TDD were also evaluated (gain dose response). Control was initiated 4 h before the meal with a target of 6.7 mmol/l. At the time of the meal, glucose was similar for all three gains (6.0 +/- 0.3, 5.2 +/- 0.3, and 4.9 +/- 0.5 mmol/l for 0.5 x TDD, TDD, and 1.5 x TDD, respectively; P > 0.05) with near-target values restored at the end of experiments (8.2 +/- 0.9, 6.0 +/- 0.6, and 6.0 +/- 0.5, respectively). The peak postprandial glucose level decreased significantly with increasing gain (12.1 +/- 0.6, 9.6 +/- 1.0, and 8.5 +/- 0.6 mmol/l, respectively; P < 0.05). The data demonstrate that closed-loop insulin delivery using the subcutaneous site can provide stable glycemic control within a range of gain.     

Implementation of a tight glycaemic control protocol using a web-based insulin dose calculator

We describe the implementation of a glucose control protocol supported by a web-based insulin dose calculator in a 16-bedded intensive care unit. The protocol was introduced and then modified after 15 months' use. Glucose concentrations were retrospectively reviewed and compared for the 9-month period before introduction of the protocol (288 patients), for 15 months after its introduction (502 patients) and for a further 5 months after its modification to increase insulin dose (101 patients). The mean (SD) blood glucose concentrations decreased from 7.3 (1.8) mmol.l(-1) to 6.6 (1.6) mmol.l(-1) and then to 6.2 (1.3) mmol.l(-1). The proportion of values < 8.0 mmol.l(-1) increased from 69% to 81% and then to 89%. Blood glucose concentrations were increased by the use of intravenous nutrition and by vasoactive drugs but not by the administration of propofol. The odds ratio [95% CI] for death for glucose values > 8.0 mmol.l(-1) was 2.10 [1.19-3.73] compared to values < 6.1 mmol.l(-1). However, patient mortality remained constant during the study. Glycaemic control was improved outside a research setting using a protocol supported by a web-based insulin dose calculator.     

The effect of an intensive education programme on the glycaemic control of type I diabetic patients

The effect of patient education on glycaemic control in insulin-dependent diabetes mellitus was assessed in 20 patients selected from the Diabetes Clinic, Groote Schuur Hospital. Education in all aspects of self-care was given to small groups of between 5 and 7 patients. Biochemical tests including measurement of fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c), were performed during a 6-week 'control' period before the educational course, and again during a 6-week 'test' period after it. The mean HbA1c fell from 10.05 +/- 0.43% at the end of the control period to 8.47 +/- 0.25% at the end of the test period (P less than 0.001). FBG levels dropped from 13.53 +/- 0.84 mmol/l at the commencement of the study to 10.83 +/- 1.29 mmol/l before the educational course, and to 9.41 +/- 0.72 mmol/l at the completion of the study. We therefore conclude that intensive education of this nature is of benefit in improving glycaemic control, at least in the short term.     

Mechanism by which metformin reduces glucose production in type 2 diabetes

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.     

Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion

GLUT2-/- mice reexpressing GLUT1 or GLUT2 in their beta-cells (RIPGLUT1 x GLUT2-/- or RIPGLUT2 x GLUT2-/- mice) have nearly normal glucose-stimulated insulin secretion but show high glucagonemia in the fed state. Because this suggested impaired control of glucagon secretion, we set out to directly evaluate the control of glucagonemia by variations in blood glucose concentrations. Using fasted RIPGLUT1 x GLUT2-/- mice, we showed that glucagonemia was no longer increased by hypoglycemic (2.5 mmol/l glucose) clamps or suppressed by hyperglycemic (10 and 20 mmol/l glucose) clamps. However, an increase in plasma glucagon levels was detected when glycemia was decreased to < or =1 mmol/l, indicating preserved glucagon secretory ability, but of reduced sensitivity to glucopenia. To evaluate whether the high-fed glucagonemia could be due to an abnormally increased tone of the autonomic nervous system, fed mutant mice were injected with the ganglionic blockers hexamethonium and chlorisondamine. Both drugs lead to a rapid return of glucagonemia to the levels found in control fed mice. We conclude that 1) in the absence of GLUT2, there is an impaired control of glucagon secretion by low or high glucose; 2) this impaired glucagon secretory activity cannot be due to absence of GLUT2 from alpha-cells because these cells do not normally express this transporter; 3) this dysregulation may be due to inactivation of GLUT2-dependent glucose sensors located outside the endocrine pancreas and controlling glucagon secretion; and 4) because fed hyperglucagonemia is rapidly reversed by ganglionic blockers, this suggests that in the absence of GLUT2, there is an increased activity of the autonomic nervous system stimulating glucagon secretion during the fed state.     

Strategies for managing the diabetic patient

Diabetes mellitus is now classified as either ‘type 1’ (failure of endogenous insulin production) or ‘type 2’ (‘insulin resistance’) and can be diagnosed if fasting blood glucose is >6.1 mmol/l (110 mg/dl) on two separate occasions or there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. The prevalence of the disease is rising and may be as great as 12–14% in western populations aged over 40 years. Diabetes is complicated by micro- and macrovascular consequences of chronically elevated blood glucose concentrations, and diabetic patients are over-represented in hospital populations, particularly among patients requiring surgical interventions. It is associated with increased perioperative mortality and morbidity. Evidence is now accumulating that intensive glycaemic monitoring and the administration of insulin infusions to achieve tight glycaemic control are associated with an improvement of both perioperative mortality and morbidity.     

Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog.

Intraportal infusion of small amounts of fructose markedly augmented net hepatic glucose uptake (NHGU) during hyperglycemic hyperinsulinemia in conscious dogs. In this study, we examined whether the inclusion of catalytic amounts of fructose with a glucose load reduces postprandial hyperglycemia and the pancreatic beta-cell response to a glucose load in conscious 42-h-fasted dogs. Each study consisted of an equilibration (-140 to -40 min), control (-40 to 0 min), and test period (0-240 min). During the latter period, glucose (44.4 micromol x kg(-1) x min(-1)) was continuously given intraduodenally with (2.22 micromol x kg(-1) x min(-1)) or without fructose. The glucose appearance rate in portal vein blood was not significantly different with or without the inclusion of fructose (41.3 +/- 2.7 vs. 37.3 +/- 8.3 micromol x kg(-1) x min(-1), respectively). In response to glucose infusion without the inclusion of fructose, the net hepatic glucose balance switched from output to uptake (from 10 +/- 2 to 11 +/- 4 micromol x kg(-1) x min(-1)) by 30 min and averaged 17 +/- 6 micromol x kg(-1) x min(-1). The fractional extraction of glucose by the liver during the infusion period was 7 +/- 2%. Net glycogen deposition was 2.44 mmol glucose equivalent/kg body wt; 49% of deposited glycogen was synthesized via the direct pathway. Net hepatic lactate production was 1.4 mmol/kg body wt. Arterial blood glucose rose from 4.1 +/- 0.2 to 7.3 +/- 0.4 mmol/l, and arterial plasma insulin rose from 42 +/- 6 to 258 +/- 66 pmol/l at 30 min, after which they decreased to 7.0 +/- 0.5 mmol/l and 198 +/- 66 pmol/l, respectively. Arterial plasma glucagon decreased from 54 +/- 7 to 32 +/- 3 ng/l. In response to intraduodenal glucose infusion in the presence of fructose, net hepatic glucose balance switched from 9 +/- 1 micromol x kg(-1) x min(-1) output to 12 +/- 3 and 28 +/- 5 micromol x kg(-1) x min(-1) uptake by 15 and 30 min, respectively. The average NHGU (28 +/- 5 micromol x kg(-1) x min(-1)) and fractional extraction during infusion period (12 +/- 2%), net glycogen deposition (3.68 mmol glucose equivalent/kg body wt), net hepatic lactate production (3.27 mmol/kg), and glycogen synthesis via the direct pathway (68%) were significantly higher (P < 0.05) compared to that in the absence of fructose. The increases in arterial blood glucose (from 4.4 +/- 0.1 to 6.4 +/- 0.2 mmol/l at 30 min) and arterial plasma insulin (from 48 +/- 6 to 126 +/- 30 pmol/l at 30 min) were significantly smaller (P < 0.05). In summary, the inclusion of small amounts of fructose with a glucose load augmented NHGU, increased hepatic glycogen synthesis via the direct pathway, and augmented hepatic glycolysis. As a result, postprandial hyperglycemia and insulin release by the pancreatic beta-cell were reduced. In conclusion, catalytic amounts of fructose have the ability to improve glucose tolerance.     

Glycemic targets in critically ill adults: A mini-review

Illness-induced hyperglycemia impairs neutrophil function, increases pro-inflammatory cytokines, inhibits fibrinolysis, and promotes cellular damage. In turn, these mechanisms lead to pneumonia and surgical site infections, prolonged mechanical ventilation, prolonged hospitalization, and increased mortality. For optimal glucose control, blood glucose measurements need to be done accurately, frequently, and promptly. When choosing glycemic targets, one should keep the glycemic variability < 4 mmol/L and avoid targeting a lower limit of blood glucose < 4.4 mmol/L. The upper limit of blood glucose should be set according to casemix and the quality of glucose control. A lower glycemic target range (i.e., blood glucose 4.5-7.8 mmol/L) would be favored for patients without diabetes mellitus, with traumatic brain injury, or who are at risk of surgical site infection. To avoid harm from hypoglycemia, strict adherence to glycemic control protocols and timely glucose measurements are required. In contrast, a higher glycemic target range (i.e., blood glucose 7.8-10 mmol/L) would be favored as a default choice for medical-surgical patients and patients with diabetes mellitus. These targets may be modified if technical advances for blood glucose measurement and control can be achieved.     

Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery

Background. The clinical benefits of glucose–insulin–potassium(GIK) and tight glycaemic control in patients undergoing coronaryartery bypass grafting (CABG) may be partly explained by ananti-inflammatory effect. We applied GIK as a hyperinsulinaemicnormoglycaemic clamp for >25 h and quantified its effecton systemic inflammation in patients undergoing CABG. Methods. Data obtained in 21 non-diabetic patients with normalleft ventricular function scheduled for elective coronary arterysurgery, who were randomly allocated to a control or GIK group,were analysed. In GIK patients, regular insulin was infusedat a fixed rate of 0.1 IU kg^–1 h^–1. The infusionrate of glucose (30%) was adjusted to maintain blood glucoselevels within a target range of 4.0–5.5 mmol litre^–1.Plasma concentrations of interleukins 6, 8 and 10, C-reactiveprotein (CRP) and serum amyloid A (SAA) were measured on theday of surgery and on the first and second postoperative days(POD1 and POD2). Results. In the GIK group hypoglycaemia (glucose <2.2 mmollitre^–1) did not occur, whereas hyperglycemia (glucose>6.1 mmol litre^–1) developed in 15% of all measurements.In control patients, hyperglycaemia developed in >80% ofall measurements in the presence of low endogenous insulin levels.CRP and SAA levels increased in both groups, with maximum levelsmeasured on POD2. GIK treatment significantly reduced CRP andSAA levels. Interleukin levels increased significantly in bothgroups following cardiopulmonary bypass, but no differenceswere found between the groups. Conclusion. Hyperinsulinaemic normoglycaemic clamp is an effectivemethod of maintaining tight glycaemic control in patients undergoingCABG and it attenuates the systemic inflammatory response inthese patients. This effect may partly contribute to the reportedbeneficial effect of glycaemic control in patients undergoingCABG.     

Blood glucose control in critically ill perioperative patients

Hyperglycemia is common in critically ill patients with approximately 90% of patients treated in an intensive care unit (ICU) developing blood glucose concentrations greater than 110 mg x dl(-1). Recently the international multicentre NICE-SUGAR study reported increased mortality with adopting intensive glucose control for critically ill patients and recent meta-analyses do not support this approach. Whilst the initial trials in Leuven produced enthusiasm and recommendations for intensive blood glucose control, the results of the NICE-SUGAR study have resulted in the more moderate recommendation to target a blood glucose concentration between 144 and 180 mg x dl(-1). As critical care practitioners paid greater attention to glycemic control it became clear that currently used point-of-care measuring systems are not accurate enough to target tight glucose control. Unresolved issues include whether increased blood glucose variability is inherently harmful and whether even moderate hypoglycemia can be tolerated in the quest for tighter blood glucose control. Until another level I evidence will be available, clinicians would be well advised to hasten slowly and abide by the age-old adage to "first, do no harm".     

扫描式葡萄糖监测系统在肝移植术后早期受者中的应用研究

目的探讨扫描式葡萄糖监测(FGM)系统在肝移植术后早期受者中的应用。 方法选取2019年4月至8月在中山大学附属第一医院器官移植中心行同种异体肝移植术的28例受者，应用FGM系统(美国雅培公司)连续监测组织间液葡萄糖浓度。同时采集受者清晨空腹血液标本，使用全自动生化分析仪检测静脉血糖值作为参考，评估FGM血糖值临床应用的精准性。使用R语言3.6.1软件进行克拉克误差网格分析。采用配对t检验或秩和检验比较术后第1周与第2周FGM结果，采用Pearson相关分析比较FGM血糖值与静脉血糖值的相关性。计算FGM血糖值与静脉血糖值配对数据的平均相对误差绝对值(MARD)和决定系数r²，比较两种血糖检测方法的一致性。P<0.05为差异有统计学意义。 结果28例受者平均佩戴FGM系统时间为(12.5±2.4)d(7～14 d)，佩戴期间均未出现过敏、瘙痒、皮肤红斑、青紫和疼痛等不良反应，均未出现传感器脱落。FGM系统佩戴期间，28例受者预估糖化血红蛋白为(6.7±1.7)%，FGM血糖值为(8±3)mmol/L，目标范围内时间为(72±34)%，低于和高于目标范围时间中位数分别为1%和8%。3例受者FGM血糖值全程在目标范围内，23例出现过高于目标范围，14例出现过低于目标范围。肝移植术后第2周FGM血糖值低于术后第1周，分别为(8±3)、(9±4)mmol/L，差异有统计学意义(t＝2.4，P<0.05)；术后第2周低于目标范围时间中位数(1%)高于术后第1周(0%)，差异有统计学意义(z＝-2.5，P<0.05)。FGM系统佩戴期间共采集244对空腹FGM血糖值与静脉血糖值，平均血糖值分别为(7±4)、(8±4)mmol/L，二者呈高度正相关(r＝0.976，P<0.05)。以全自动生化分析仪检测的静脉血糖值作为参考，克拉克误差网格分析结果示：FGM血糖值有93%(227/244)落在A区，有7%(17/244)落在B区。MARD＝9.8%，r²＝0.95。 结论FGM系统在肝移植术后早期受者中的临床应用是可行的，与常规间断末梢血糖监测方法相比，可监测到更多血糖异常事件及其持续时间，并及时采取有效治疗措施，控制血糖水平在最佳范围。     

Effect of peritonitis on insulin and glucose absorption during peritoneal dialysis in diabetic rats

The intraperitoneal route is frequently used for the administration of insulin in diabetic continuous ambulatory peritoneal dialysis patients. However, there is conflicting evidence as to whether the dosage of intraperitoneal insulin should be increased or decreased during peritonitis in these patients. Glucose and insulin absorption and glycaemic control were evaluated in 2-hour exchanges using 15 ml of 2.5% dextrose dialysis solution in diabetic rats with (group 1) and without (group 2) peritonitis. Fasting blood glucose values at the beginning of the study exchanges were mean +/- SD 17.9 +/- 3.3 mmol/l in group 1 and 18.2 +/- 3.5 mmol/l in group 2. Even though group 1 had a higher percentage absorption of dialysate glucose (65 +/- 19 vs. 47 +/- 7%; p less than 0.05) and higher percentage absorption of dialysate insulin (49 +/- 12 vs. 44 +/- 14%; p less than 0.1), the hypoglycaemic response to the standard intraperitoneal dose of insulin was similar in each group. Plasma C peptide levels remained very low in both groups, thus excluding significant endogenous release of insulin. These data indicate that peritonitis per se does not change intraperitoneal insulin requirements during standardized peritoneal dialysis exchanges in diabetic rats. Insulin requirements may also be unaltered during peritonitis in diabetic continuous ambulatory peritoneal dialysis patients, provided that dialysate glucose load and oral carbohydrate intake are kept constant.     

Glucose-mediated glucose disposal in insulin-resistant normoglycemic relatives of type 2 diabetic patients

With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 microg/h), insulin (0.25 mU x kg(-1) x min(-1)), glucagon (0.5 ng x kg(-1) x min(-1)), growth hormone (6 ng x kg(-1) x min(-1)), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (approximately 12 mmol/l) over the last 2 h. Fasting plasma insulin (PI) concentrations were elevated in the relatives compared with control subjects (49 +/- 6 vs. 32 +/- 5 pmol/l, P < 0.04), whereas plasma glucose (PG) was not (5.6 +/- 0.1 vs. 5.5 +/-0.1 mmol/l). At the end (i.e., 4.5-5.0 h) of the euglycemic clamp (PG, 6.1 +/- 0.4 vs. 5.6 +/- 0.1 mmol/l; PI, 78 +/- 5 vs. 73 +/-6 pmol/l), peripheral glucose uptake (Rd(euglycemia)) was decreased in the relatives (2.93 +/- 0.08 vs. 3.70 +/-0.23 mg x min(-1) x kg(-1) fat free mass [FFM], P < 0.005), due to a decreased nonoxidative glucose disposal (0.83 +/-0.21 vs. 1.62 +/- 0.19 mg x min(-1) x kg(-1) FFM, P < 0.01), but hepatic glucose production (HGP) was increased (1.97 +/-0.19 vs. 1.50 +/- 0.13 mg x min(-1) x kg(-1) FFM, P < 0.05). At the matched end of the hyperglycemic clamp (PG, 12.7 +/-0.2 vs. 12.6 +/- 0.2 mmol/l; PI, 87 +/- 5 vs. 78 +/- 7 pmol/l), peripheral glucose disposal (Rd(hyperglycemia)) (5.52 +/- 0.22 vs. 5.92 +/- 0.29 mg x min(-1) x kg(-1) FFM, NS), nonoxidative glucose disposal (2.93 +/- 0.18 vs. 2.78 +/- 0.25 mg x min(-1) x kg(-1) FFM, NS), and HGP(hyperglycemia) (1.20 +/- 0.09 vs. 1.37 +/-0.23 mg x min(-1) x kg(-1) FFM, NS) were all identical. When the effectiveness of glucose itself on glucose uptake and production [(Rd(hyperglycemia) - Rd(euglycemia))/deltaPG and (HGP(euglycemia)- HGP(hyperglycemia))/deltaPG] was calculated, the relatives had a 22% increase in peripheral uptake (0.022 +/- 0.002 vs. 0.018 +/- 0.002 mg x min(-1) x kg(-1) FFM per mg/dl), due to a significantly increased nonoxidative glucose metabolism and enhanced suppression of HGP (0.0076 +/- 0.0021 vs. 0.0011 +/- 0.0022 mg x min(-1) x kg(-1) FFM per mg/dl, P < 0.05). In conclusion, in insulin-resistant relatives of DM2 patients, whole-body glucose-mediated glucose disposal is increased by GE enhancement of the muscle nonoxidative glucose pathway and by GE enhancement of the suppression of HGP. These mechanisms may represent a compensatory mechanism to the ongoing insulin resistance of these relatives.     

The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means +/- SD: age 63 +/- 8 years, BMI 30.1 +/- 4.2 kg/m(2), HbA(1c) 6.5 +/- 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 micro g/kg) of NN2211 or placebo was administered 9 h before the study. beta-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5-12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels. Findings were compared with those in 10 nondiabetic volunteers during the same glucose infusion protocol. In type 2 diabetic subjects, NN2211, in comparison with placebo, increased insulin and C-peptide levels, the ISR area under the curve (AUC) (1,130 +/- 150 vs. 668 +/- 106 pmol/kg; P < 0.001), and the slope of ISR versus plasma glucose (1.26 +/- 0.36 vs. 0.54 +/- 0.18 pmol x l[min(-1) x mmol(-1) x kg(-1)]; P < 0.014), with values similar to those of nondiabetic control subjects (ISR AUC 1,206 +/- 99; slope of ISR versus plasma glucose, 1.44 +/- 0.18). The long-acting GLP-1 derivative, NN2211, restored beta-cell responsiveness to physiological hyperglycemia in type 2 diabetic subjects.     

Perioperative management of total parenteral nutrition, glucose containing solutions, and intraoperative glucose monitoring in paediatric patients: a survey of clinical practice

Infants and children, particularly those who are chronically ill and maintained on total parenteral nutrition (TPN), are at risk for perioperative hypoglycaemia [blood glucose < 2.2 mmol x l(-1) (40 mg x dl(-1))] and hyperglycaemia [blood glucose > 11 mmol x l(-1) (200 mg x dl(-1))]. We surveyed paediatric anaesthesiologists regarding their perioperative management of blood glucose and TPN in paediatric patients to determine the current practice and its perceived success. Questionnaires were mailed to all members of the Study Group on Pediatric Anesthesia and the response rate was 70%. Results indicate that the current perioperative management of blood glucose and TPN is somewhat varied. Furthermore, greater than 10% of those surveyed report that their management results in a variable response in the maintenance of normoglycaemia. While the detrimental effects of perioperative hypoglycaemia and hyperglycaemia are rare, they are serious. A Medline search shows that no studies have been published regarding perioperative management of paediatric patients receiving TPN, although it appears that clinical study is warranted.     

Abnormal glucose handling by the kidney in response to hypoglycemia in type 1 diabetes

The frequent occurrence of hypoglycemia in people with type 1 diabetes is attributed to abnormalities in the blood glucose counterregulatory response. In view of recent findings indicating that the kidney contributes to prevent and correct hypoglycemia in healthy subjects, we decided to investigate the role of renal glucose handling in hypoglycemia in type 1 diabetes. Twelve type 1 diabetic patients and 14 age-matched normal individuals were randomized to hyperinsulinemic-euglycemic (n = 6 diabetic subjects and n = 8 control subjects) or hypoglycemic (n = 6 each) clamps with blood glucose maintained either stable near 100 mg/dl (5.6 mmol/l) or reduced to 54 mg/dl (3.0 mmol/l). All study subjects had their renal vein catheterized under fluoroscopy, and net renal glucose balance and renal glucose production and utilization rates were measured using a combination of arteriovenous concentration difference with stable isotope dilution technique. Blood glucose and insulin were comparable in both groups in all studies. In patients with diabetes, elevations in plasma glucagon, epinephrine, and norepinephrine were blunted, and both the compensatory rise in endogenous glucose production and in the net glucose output by the kidney seen in normal subjects with equivalent hypoglycemia were absent. Renal glucose balance switched from a mean +/- SE baseline net uptake of 0.6 +/- 0.4 to a net output of 4.5 +/- 1.3 micromol x kg(-1) x min(-1) in normal subjects, but in patients with diabetes there was no net renal contribution to blood glucose during similar hypoglycemia (mean +/- SE net glucose uptake [baseline 0.7 +/- 0.4] remained at 0.4 +/- 0.3 micromol x kg(-1) x min(-1) in the final 40 min of hypoglycemia; P < 0.01 between groups). We conclude that adrenergic stimulation of glucose output by the kidney, which represents an additional defense mechanism against hypoglycemia in normal subjects, is impaired in patients with type 1 diabetes and contributes to defective glucose counterregulation.     

Diabetes in pregnancy. The use of home blood glucose monitoring and intensive monitoring to ensure favourable perinatal outcome

A combined clinic for pregnant diabetic women was established at Baragwanath Hospital to assess the effects of intensive monitoring of mother and fetus and of good glycaemic control on perinatal outcome. Home blood glucose monitoring was introduced as a method for assessing glycaemic control. Standard methods of maternal and fetal monitoring were used. Sixty-two diabetic pregnancies were evaluated prospectively. Twenty women had diabetes diagnosed for the first time in the current pregnancy and the remaining 42 had established diabetes. All patients followed a diabetic diet, and 95% were treated with insulin. The technique and accurate recording of blood glucose were managed by all patients, and a mean capillary blood glucose of 6.5 mmol/l for the group was achieved. Caesarean section was performed in 52% of cases with a mean period of gestation at the time of delivery for the total study population of 37 weeks. The mean neonatal weight was 3,130 g. The perinatal mortality rate of 64/1,000 was accounted for by 3 stillbirths and 1 early neonatal death. No major congenital anomalies occurred.     

Role of the human kidney in glucose counterregulation.

Animal experiments indicate that the kidney may play an important role in glucose counterregulation. Because the human kidney normally takes up and releases glucose, and since patients with end-stage renal disease are prone to hypoglycemia, we examined whether the kidney is also involved in human glucose counterregulation. Accordingly, we compared renal glucose release (RGR) and uptake (RGU) during 4-h hyperinsulinemic-hypoglycemic (approximately 3.2 mmol/l, n = 9) and -euglycemic (approximately 5 mmol/l, n = 10) control clamp experiments in normal postabsorptive subjects. A combination of renal balance and isotopic ([3H]glucose, [14C]glutamine) techniques was used, which permitted hepatic glucose release (HGR) and glutamine gluconeogenesis to be calculated as the difference between systemic (overall) and renal values. In both experiments, infusion of insulin increased plasma insulin comparably (approximately 210 pmol/l). In euglycemic control experiments, RGR and HGR decreased more than 50% (both P<0.001) and RGU increased approximately 35% (P = 0.02). In hypoglycemic experiments, both HGR (P = 0.034) and RGR (P<0.001) increased to a comparable extent (1.69+/-0.47 and 1.67+/-0.15 pmol x kg-(-1) x min(-1), respectively, P = 0.96) above rates observed in control experiments; hepatic and renal glutamine gluconeogenesis increased by 0.19+/-0.06 (P<0.008) and 0.30+/-0.07 pmol x kg(-1) x min(-1) (P< 0.001), respectively. RGU decreased by 65% compared with control experiments (P<0.001), so that renal glucose balance changed from a net uptake of 80+/-19 micromol/min to a net release of 130+/-9 micromol/min, P< 0.001. These observations provide evidence that the kidney may play an important role in human glucose counterregulation.