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Insulin secretion and sensitivity after simultaneous pancreas-kidney transplantation estimated by continuous infusion of glucose with model assessment.

BACKGROUND: Monitoring of insulin secretion and sensitivity after pancreas transplantation remains a practical problem. METHODS: We introduced the simple structural model, continuous infusion of glucose with model assessment (CIGMA), to obtain insulin secretion and insulin sensitivity estimations after 35 successful simultaneous pancreas-kidney transplantations. Eighteen non-diabetic kidney transplant recipients were used as control group. RESULTS: The baseline characteristics were equal between the two groups except for higher fasting insulin levels in the pancreas transplant group. After the 1-hr CIGMA glucose load, the pancreas transplant group reached a mean +/- SD blood glucose of 8.2+/-1.7 mmol/L compared with 7.3+/-1.0 mmol/L in the control group (P = 0.05). Concurrent stimulated insulin and C-peptide levels were 48+/-28 mU/L and 2.3+/-0.9 nmol/L in the pancreas transplant group compared with 36+/-21 mU/L and 2.9+/-1.1 nmol/L in the control group (P = 0.1 and P = 0.03, respectively). Both the CIGMA estimation for secretion as well as the CIGMA estimation for sensitivity were lower in pancreas transplant group (P = 0.003 and P = 0.01, respectively). Mean +/- SE coefficients of variation for the model estimations were 15+/-4% for secretion and 17+/-6% for sensitivity. CONCLUSIONS: We conclude that CIGMA can be used clinically to evaluate carbohydrate metabolism in pancreas-kidney transplant recipients. These patients have a reduction in insulin secretory capacity and evidence of more insulin resistance than non-diabetic kidney transplant recipients.

Adult↗

Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome.

Large interventional studies have shown that statins may reduce the incidence of type 2 diabetes mellitus. However, it is uncertain whether short-term statin therapy can affect insulin sensitivity in patients with the metabolic syndrome. We evaluated the effect of atorvastatin (10 mg/day) in 10 insulin-resistant subjects (age 40 +/- 12 years, body mass index 33.6 +/- 5.2 kg/m(2), triglycerides 2.84 +/- 1.99 mmol/L [249 +/- 175 mg/dl], glucose 6.06 +/- 0.67 mmol/L [109 +/- 12 mg/dl)] using the homeostasis model assessment (HOMA) index (parameter of insulin resistance derived from fasting glucose and fasting insulin concentrations; 5.7 +/- 2.6) in a randomized placebo-controlled, double-blind, crossover study. Subjects were randomized to receive placebo or atorvastatin, each given for 6 weeks separated by a 6-week wash-out period. At the beginning and end of each treatment phase, the patients underwent an oral glucose tolerance test, a 72-hour continuous glucose measurement, and a detailed lipid determination, including a standardized fat tolerance test. Compared with placebo, atorvastatin resulted in a significant (p = 0.05) reduction in the HOMA index (-21%), fasting C-peptides (-18%), glucose (area under the curve during the oral glucose tolerance test, -7%), and a borderline (p = 0.08) reduction of insulin (-18%). The parameters derived from the continuous 72-hour glucose monitoring did not change. A significant reduction also occurred in the total and low-density lipoprotein cholesterol concentrations, although the fasting and postprandial triglyceride concentrations did not change significantly. However, we found a significant correlation between atorvastatin-induced changes in the HOMA and baseline HOMA and between the atorvastatin-induced changes in triglycerides and insulin concentrations. The free-fatty acid, interleukin-6, and high sensitivity C-reactive protein concentrations did not change. Our data indicated that in insulin-resistant, nondiabetic subjects, 6 weeks of atorvastatin (10 mg/day) resulted in significant improvement in insulin sensitivity.

Adult↗

Fluorescence-based glucose sensors.

There is an urgent need to develop technology for continuous in vivo glucose monitoring in subjects with diabetes mellitus. Problems with existing devices based on electrochemistry have encouraged alternative approaches to glucose sensing in recent years, and those based on fluorescence intensity and lifetime have special advantages, including sensitivity and the potential for non-invasive measurement when near-infrared light is used. Several receptors have been employed to detect glucose in fluorescence sensors, and these include the lectin concanavalin A (Con A), enzymes such as glucose oxidase, glucose dehydrogenase and hexokinase/glucokinase, bacterial glucose-binding protein, and boronic acid derivatives (which bind the diols of sugars). Techniques include measuring changes in fluorescence resonance energy transfer (FRET) between a fluorescent donor and an acceptor either within a protein which undergoes glucose-induced changes in conformation or because of competitive displacement; measurement of glucose-induced changes in intrinsic fluorescence of enzymes (e.g. due to tryptophan residues in hexokinase) or extrinsic fluorophores (e.g. using environmentally sensitive fluorophores to signal protein conformation). Non-invasive glucose monitoring can be accomplished by measurement of cell autofluorescence due to NAD(P)H, and fluorescent markers of mitochondrial metabolism can signal changes in extracellular glucose concentration. Here we review the principles of operation, context and current status of the various approaches to fluorescence-based glucose sensing.

Biosensing Techniques↗

Glycaemic instability is an underestimated problem in Type II diabetes.

The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA(1c) (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration >10 mmol/l) was hardly present (2+/-1% or 0.4+/-0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55+/-7% of the time (13+/-2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46+/-7%; P<0.01 as determined by ANOVA) to the total amount of hyperglycaemia and postprandial glycaemic instability. In the diabetes patients, blood HbA(1c) content correlated well with the duration of hyperglycaemia and the postprandial glucose responses (P<0.05). In conclusion, CGMS determinations show that standard measurements of glycaemic control underestimate the amount of hyperglycaemia prevalent during real-life conditions in Type II diabetes. Given the macro- and micro-vascular damage caused by postprandial hyperglycaemia, CGMS provides an excellent tool to evaluate alternative therapeutic strategies to reduce hyperglycaemic blood glucose excursions.

Blood Glucose↗

Glucose disappearance in biological treatment systems.

Laboratory scale anaerobic and aerobic treatment units were conditioned with a daily slug-feed of glucose. After a period of acclimation and stabilization, glucose disappearance was monitored continuously after the slug feed. A continuous sampling apparatus is described. Mathematical analysis of the data indicate zero-order reactions for both biological treatment systems.

Journal Article↗

Variants of the tissue-sensor array window chamber.

Sensors are being developed that can be implanted in tissues for continuous monitoring of oxygen, glucose, and other metabolites. However, there have been difficulties in inferring metabolite concentrations in blood from the signals of tissue sensors due to the properties of tissues at the implant site and local physiological phenomena that can affect sensor responses. A multisensor array has been previously developed for implantation in a hamster skinfold window chamber preparation to study these effects. The preparation allows recording of concentration-dependent signals from multiple sensors while nondestructively visualizing the adjacent tissue and microvascular function. Variants of the tissue-sensor array window chamber described here have respective advantages over the original chamber design, including improved tissue visualization and reduced surgical intervention, and allow exposure of the sensor to different tissues. Results indicate that mass transfer within tissues is heterogeneous, and sensor signals are affected by variable perfusion of local microvasculature in addition to vascular metabolite concentration. These observations suggest new strategies for sensor design and operation. Window chamber variants are important tools for validation of implanted sensors.

Animals↗

Growth hormone response to hypoglycemia under gamma-hydroxybutyrate narco-analgesia in the rat.

Plasma immuno-reactive growth-hormone (RIA-GH) concentrations were investigated under in vivo continuous blood glucose (BG) monitoring after administration of gamma-hydroxybutyrate (GHB) as well as during spontaneous or insulin-induced hypoglycemia. During the narco-analgesia by GHB a marked secretory episode is consistently observed. This secretion peak is not accurately time related with GHB administration and seems to fade off in aging animals. Strictly controlled hypoglycemia elicits a consistent and specific GH release. In contrast deep hypoglycemic levels resulting in a state of metabolic stress inhibit GH secretion. Our results suggest that previous data on the GH regulation pattern during hypoglycemia may depend upon the anesthetic used and/or nonspecific stress responses following deep hypoglycemia. The above mentioned experimental conditions indicate that GH metabolic regulation is not fundamentally different in rodents and primates.

Aminobutyrates↗

Counterregulatory hormones during moderate, insulin-induced, blood glucose decrements in man.

To verify whether a significant increase in levels of counterregulatory hormones occurs in the course of mild blood glucose decrements, we infused regular insulin iv over 65 min in two groups of healthy volunteers (group A, n= 7; group B, n = 6) at a constant rate (group A, 0.05 U/kg; group B, 0.025 U/kg). All subjects were connected to an artificial endocrine pancreas (Biostator) for continuous blood glucose (BG) monitoring. Plasma insulin, glucagon, and GH were determined by specific RIAs. Plasma norepinephrine, epinephrine, and cortisol were measured by sensitive fluorimetric methods. A moderate fall in BG occurred from 91 +/- 1.5 mg/dl (mean +/- SEM) to a nadir of 56 +/- 4.5 mg/ml at 45 min in group A and from 81 +/- 2.5 to a nadir of 64 +/- 4.9 mg/dl at 45 min in group B. In both groups A and B, the increases in plasma glucagon and catecholamine levels, which remained strictly in the physiological range, appeared concomitant and were significant at 45 min (P less than or equal to 0.05 vs. basal), while the increases in plasma cortisol and GH concentrations were clearly delayed. The increments for all counterregulatory hormones (expressed as the area to minutes ratio) except GH, were significantly greater in group A than in group B ( P less than or equal to 0.01). There was a significant correlation between these increases, including that of GH and the BG decrease, calculated in all subjects investigated. These results suggest that the mechanisms involved for the release of counterregulatory hormones such as glucagon, catecholamines, cortisol, and GH are very sensitive to a moderate decrease in BG concentration and that there is a close relationship between this hormonal response and the degree of the BG decrements obtained.

Adult↗

Peptic ulcer and gastric acid secretion in patients with insulinoma.

We evaluated the incidence of associated peptic ulcers and the gastric acid secretion in our 20 series of insulinoma, and obtained the following results: 1) Four out of 20 patients (20%) with insulinoma were associated with peptic ulcers. 2) Except for the maximum acid concentration, the preoperative gastric secretion tests, such as the basal acid output and maximum acid output, failed to indicate hyperacidity in those patients. And patients with a short duration of illness by insulinoma neither showed hyperacidity nor were associated with peptic ulcers. 3) A tendency of reduced gastric acid secretion and the amelioration of peptic ulcers was observed in those who underwent the extirpation of insulinoma. 4) In the most recent case received gastric analysis with continuous monitoring of blood glucose level, an increase of basal acid output was observed during the hypoglycemic period in which the blood glucose levels reduced to around 30 mg/100 ml. These results indicate that the low blood glucose level and the high gastric acid secretion produced under the condition on an empty stomach, may be important factors related to the high association rates of the peptic ulcers in patients with insulinoma.

Adenoma, Islet Cell↗

Reproducibility of glucose measurements using the glucose sensor.

OBJECTIVE: Recent studies have confirmed that improved glycemic control decreases the risk of diabetic complications in type 1 and type 2 diabetic patients. The Minimed glucose sensor allows continuous 72-h glucose monitoring and represents a potentially important tool to improve diabetes management. Its use is currently limited to the health care team. Our aim was to evaluate the reproducibility of data provided by the device by comparing data provided by two sensors worn simultaneously by the same subject. RESEARCH DESIGN AND METHODS: A total of 11 subjects (6 type 1 and 3 type 2 diabetic patients and 2 healthy subjects) agreed to wear two sensors and perform at least four daily finger-stick glucose determinations during 72 h. The simultaneous glucose values provided by the sensors were compared. To determine the clinical implications of the glucose data, each day was divided into eight periods, and for each period the glucose range was rated as satisfactory, too high, or too low by a blinded clinician experienced in interpreting glucose sensor data in the clinical setting. The evaluation of glycemic levels based on the recordings of the two sensors were compared for each paired time interval. RESULTS: We discarded 18% of the sensor data for technical reasons. Examined as a group, the remaining 3,370 paired data points in all 11 patients were highly correlated (r = 0.84). However, when individual pairs were evaluated, large differences in the glucose values were apparent, with differences of >10% in 70% of the measurements and >50% in 7% of the measurements. Moreover, clinical evaluation of the glucose range provided simultaneously by two sensors was concordant for only 65% of the evaluation periods. CONCLUSION: In a real-life setting, the accuracy of data provided by the Minimed glucose sensor may be less than expected. To avoid therapeutic errors, sensor findings should be confirmed by independent means before clinical decisions are made.

Blood Glucose↗

Computer-controlled bedside monitoring and infusion system.

A mult-channel system for continuous bedside monitoring of glucose, pH pCO2 and automatic computer-controlled infusion of insulin, glucose, potassium, and bicarbonate solutions is described. Regulatory algorithms are presented for correction of metabolic acidosis and hyperglycemia with and without acidosis.

Acidosis↗

Portable insulin infusion pumps as an alternative means of insulin delivery in type I diabetes. Report on 11 patients.

In many cases of type I diabetes it is extremely difficult to maintain adequate long-term diabetic control. Over the last decade a better understanding has been gained of the relationship between hyperglycaemia and the onset of diabetic microvascular disease. Because of this new techniques are being developed to improve diabetic control; one of these is the use of portable 'open loop' insulin infusion pumps. The results achieved in the first 11 patients to use the Auto-Syringe AS-6C insulin infusion pump on an outpatient basis for longer than 4 months are described. A highly significant improvement in fasting blood glucose levels, 2-hour postprandial blood glucose levels, mean blood glucose levels, glycosylated haemoglobin levels and mean glycaemic excursions was noted in all patients. No cutaneous complications developed despite the use of indwelling subcutaneous needles for up to 4 days at a time. Patient acceptability was excellent and none of the patients had any problems in adapting to 24-hour pump use. The importance of correct patient selection and continuous home blood glucose monitoring is stressed. Insulin infusion pumps can provide an alternative and highly efficacious means of maintaining excellent diabetic control in a select group of type 1 diabetics. However, it is essential that the physician be trained in the use of these pumps and that adequate back-up services are available.

Adult↗

Development of a highly responsive needle-type glucose sensor using polyimide for a wearable artificial endocrine pancreas.

To produce a long-life, stable, miniature glucose sensor for a wearable artificial endocrine pancreas (WAEP), we developed a novel microneedle-type glucose sensor using polyimide, designated the PI sensor (outer diameter, 0.3 mm; length, 16 mm), and investigated its characteristics in vitro and in vivo. In the in vitro study, we tested the sensor in 0.9% NaCl solution with varying glucose concentrations and observed an excellent linear relationship between the sensor output and glucose concentration (range: 0-500 mg/100 ml). In in vivo experiments, the PI sensor was inserted into the abdominal subcutaneous tissue of beagle dogs (n = 5), and interstitial fluid glucose concentrations were monitored after sensor calibration. Simultaneously, blood glucose concentrations were also monitored continuously with another PI sensor placed intravenously. The correlation and time delay between subcutaneous tissue glucose (Y) and blood glucose concentrations (X: 30-350 mg/100 ml) were Y = 1.03X + 7.98 (r = 0.969) and 6.6 +/- 1.2 min, respectively. We applied the new WAEP system/PI sensor and an intravenous insulin infusion algorithm developed previously for glycemic control in diabetic dogs. The use of the WAEP system resulted in excellent glycemic control after an oral glucose challenge of 1.5 g/kg (post-challenge blood glucose levels: 176 +/- 18 mg/100 ml at 65 min and 93 +/- 23 mg/100 ml at 240 min), without any hypoglycemia. Thus, we confirmed that our new PI sensor has excellent sensor characteristics in vitro and in vivo. The new WAEP using this sensor is potentially suitable for clinical application.

Administration, Oral↗

Development of a miniaturized glucose monitoring system by combining a needle-type glucose sensor with microdialysis sampling method. Long-term subcutaneous tissue glucose monitoring in ambulatory diabetic patients.

OBJECTIVE: To develop a reliable and practical glucose monitoring system by combining a needle-type glucose sensor with a microdialysis sampling technique for long-term subcutaneous tissue glucose measurements. RESEARCH DESIGN AND METHODS: A microdialysis Cuprophan hollow-fiber probe (inner diameter, 0.20 mm; length, 15 mm) was perfused with isotonic saline solution (120 microliters/h) and glucose concentrations in the dialysate were measured by a needle-type glucose sensor extracorporeally. This system was tested both in vitro and in vivo. Subcutaneous tissue glucose concentrations were then monitored continuously in 5 healthy and 8 diabetic volunteers for 7 to 8 days. A hollow-fiber probe was inserted into the abdominal subcutaneous tissue. RESULTS: This monitoring system achieved excellent results in vitro. Subcutaneous tissue glucose concentrations were measured in a wide range from 1.7 to > 27.8 mM glucose, with a time delay of 6.9 +/- 1.2 min associated with a rise in glucose and 8.8 +/- 1.6 min with a fall in the glucose level (means +/- SE). The overall correlation between subcutaneous tissue (Y) and blood (X) glucose concentration was Y = 1.08X + 0.19 (r = 0.99). The subcutaneous tissue glucose concentration could be monitored precisely for 4 days without any in vivo calibrations and for 7 days by introducing in vivo calibrations. CONCLUSIONS: Glycemic excursions could be monitored precisely in the subcutaneous tissue by this microdialysis sampling method with a needle-type glucose sensor in ambulatory diabetic patients.

Adult↗

Glucose correlation with light scattering patterns--a novel method for non-invasive glucose measurements.

To correlate occlusion red near-infrared spectroscopy technology with intravenous and interstitial glucose levels, occlusion red near-infrared spectroscopy and glucose levels were measured in five subjects with diabetes mellitus during a stepped hyperinsulinemic hypoglycemic clamp. Validation was achieved using a standard error grid and linear correlations. During hyperinsulinemic hypoglycemic clamp linear correlation was significant at r = 0.836, and the intercept was 43.3 mg/dL. Of the glucose measurements, 94.3% were assigned to zones A and B of the standard error grid, the zones of the greatest therapeutic relevance. Expected interference from serum triglycerides, catecholamines, and cortisol was not apparent. These results demonstrate the applicability of occlusion red near-infrared spectroscopy for in vivo glucose monitoring. The technology has implications for continuous non-invasive glucose sensing.

Adult↗

Effects of microdialysis catheter insertion into the subcutaneous adipose tissue assessed by the SCGM1 system.

To monitor glucose in patients with diabetes continuously a microdialysis-based glucose sensor system (SCGM1 System, Roche Diagnostics GmbH, Mannheim, Germany) is under clinical development. This system allows monitoring of glucose levels in the subcutaneous interstitial fluid of patients with diabetes for a maximum duration of up to 120 h. The aim of the study was to determine the effect of microdialysis catheter insertion on the stability of the SCGM1 System glucose sensor signal. At four study sites, 47 experiments with the prototype of the novel SCGM1 System were performed in 42 patients with type 1 diabetes; two additional experiments were performed in two healthy volunteers. The microdialysis catheter was inserted in the subcutaneous adipose tissue of the patients in order to measure the glucose concentration in the interstitial fluid continuously. The catheter was perfused with a pump rate of 0.3 microL/min. For method comparison capillary blood glucose measurements were performed as reference values. In addition, the skinfold thickness was measured. Out of the total of 49 experiments 34 were usable. The average monitoring time in these experiments was 106.0 +/- 14.3 h (mean +/- SD). However, for this study the data from the first study day were evaluated in more detail. The analysis showed that during the first 12 h after catheter insertion the sensor signal increased 20% in comparison with the capillary blood glucose values (normalized calibration factor). This leads to a lower normalized calibration factor compared with the following study days. It remains stable in the time thereafter. The skinfold thickness showed no significant effect on the sensor signal. The observed increase in sensor signal in the first hours after insertion of the microdialysis catheter was probably due to a local trauma, which can induce an inflammation reaction. Thereafter, the signal registered by the SCGM1 System was stable and free of drift to the end of the experiment.

Adult↗

[Miniaturization capable, very sensitive polarimeter as detector of an implantable glucose probe. I. Optical amplification of the measuring value].

From a clinical point of view, an implantable telemetric probe for monitoring the blood glucose profile is highly desirable. It should be capable of monitoring the blood glucose level continuously or at regular brief intervals, if necessary requirement-controlled. Apart from blood, measurement can also be made in intercellular tissue fluid, for example, in subcutaneous connective and fatty tissue, because this fluid accurately reflects blood glucose levels after only a brief, but negligible, time lag. Since the functional lifespan of an implantable probe is of decisive importance, only physical sensors, but not bio-sensors can be considered. We are in the process of developing a very sensitive miniaturised detector based on polarimetry, capable of determining the measuring parameter--the spatial orientation of the in-plane vibration of a polarised light beam--with extreme accuracy. This is a very important point, since the physiological and pathological glucose levels modify the in-plane vibration by only a very tiny angle of rotation. The high level of accuracy is achieved by various specific optical amplification mechanisms, and amplification of the electric signal. Two purely optical amplification methods are described here. Simple linear elongation of the optical path of a laser beam within the sample, resulting in a proportional amplification of the measuring signal, is obviously strictly limited in an implantable probe. We therefore developed a technique that preserves the polarisation state of the light beam during reflection. This technique makes possible multiple passage of the light beam through the fluid being sensed, thus elongating the optical path by "folding" the light beam without the need to enlarge the measuring cuvette. In a second possibility, enlargement of the rotation angle can be achieved by reflecting the light beam from a suitable surface, when the orthogonal components of the polarised light beam are reflected to different extents.

Blood Glucose↗

The treatment of unstable type I diabetes: conventional versus portable pump insulin administration.

The treatment of unstable insulin-dependent diabetics (UIDD) is still an unsolved problem. A comparison was made between optimized conventional treatment (OCT) (Ultralente + Actrapid at breakfast, Actrapid at lunch and Actrapid at dinner) and continuous s.c. insulin infusion (CSII) for 30 days in 10 UIDD outpatients. Continuous 24-h blood glucose monitoring with an artificial pancreas, fasting values of HbA1, plasma lipids, growth hormone, glucagon, daily urinary glucose and protein excretion were recorded after each treatment; a daily blood glucose profile was determined every week. Daily mean blood glucose values dropped significantly (p less than 0.01): from 187.2 +/- 66.6 (OCT) to 111.6 +/- 27.0 mg/dl (CSII), and hypoglycemic and ketotic events disappeared during CSII. A significant improvement (p less than 0.01 - p less than 0.001) in all other parameters was also observed. It is suggested that CSII may help to improve metabolic control and the quality of life in UIDD.

Adolescent↗