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The artificial beta cell (Biostator) in the adjustment of instable diabetics--results after 20 months.

In 55 poorly controlled insulin-dependent diabetics, we tried to discover criteria for an improvement of metabolism by means of the "artificial beta-cell" (Biostator). To this end, during the first 24 h of hospitalization, blood glucose was monitored continuously under conventional insulin therapy (monitoring period). Insulin requirement was determined during the next 24 h by the artificial beta-cell (feedback period). Corrections of diabetes regimen were made with reference to the insulin consumption during the feedback period and to the extent of the postprandial blood sugar increases and decreases during the monitoring period. The resulting new diabetes regimen led to a significant improvement of the daily blood sugar profiles.

Artificial Organs↗

Evaluation of exogenous insulin homoeostasis by the artificial pancreas in insulin-dependent diabetes.

With the artificial pancreas used by the authors, insulin was delivered through a venous infusion and the rate of delivery was adjusted according to data provided by a continuous blood glucose monitor. After different trials we selected control algorithms integrating two parameters: instantaneous blood glucose concentration and increasing or decreasing patterns of blood glucose. A constant basal insulin infusion rate was added and improved the control of glycaemic excursions. Different parameters concerning exogenous insulin homoeostasis were determined. The delay to reach an insulin effect was 18+/-2 min and was shortened by a priming-dose at the beginning of the infusion. The insulin effect remained for 28+/-2 min after the infusion had been stopped, but differences were noted in the morning (21+/-2 min), in the afternoon (32+/-2 min) and during the night (25+/-3 min). Insulin needs were evaluated during meals. Related to the amount of carbohydrates, the doses fell from 0.53 units/hr/g of carbohydrate for breakfast to 0.15 for dinner. From these data, it appears that the efficiency of exogenous insulin exhibits a circadian rhythm.

Adolescent↗

Detection of intestinal ischemia using a microdialysis technique in an animal model.

The purpose of this study was to use a microdialysis technique to demonstrate the metabolic changes that occur in the intestinal wall during ischemia in vivo. Continuous monitoring of glucose, lactate, and glycerol using a microdialysis technique was performed in the jejunal wall of 10 pigs during steady-state and occlusive ischemia. The microdialysis catheters were introduced 50, 80, and 110 cm from the ligament of Treitz. Occlusive ischemia was established to two segments after steady state was reached. Microdialysate samples were collected from ischemic/nonischemic intestinal segments simultaneously every 20 minutes. For comparison with the microdialysis measurements, systemic blood samples were drawn from the cannulated femoral artery and analyzed consecutively. A significant increase of microdialysate lactate and a significant decrease of microdialysate glucose were found during occlusive ischemia as compared to the preischemic samples and samples from the nonischemic control catheters. The microdialysate glycerol increased during ischemia, but later than the lactate. No changes were observed in systemic serum lactate, serum glucose, pH, p co(2), and p o(2), but serum potassium increased by 1.1 mmole (median) during ischemia. Microdialysis measured in the intestinal wall identifies local ischemia and may be a new method for the monitoring of intestinal perfusion.

Animals↗

Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin pump therapy.

Although subcutaneous insulin infusion from portable pumps is the current optimal therapy for type 1 diabetic patients, implantable pumps using the intraperitoneal route allow increased blood glucose stability and lowered incidence of severe hypoglycemia. Subcutaneously implanted enzymatic glucose sensors provide continuous interstitial glucose monitoring, but this may differ from the real-time blood glucose levels. Preliminary investigations of intravascular enzymatic sensors demonstrate their clinical acceptability and accuracy and the possibility of developing closed-loop insulin delivery by combination with implantable pumps.

Biosensing Techniques↗

Simulations of the frequency response of implantable glucose sensors.

The response of enzyme electrode glucose sensors implanted in tissues to physiologic blood glucose oscillations is simulated. Models describe both oxygen-based and peroxide-based glucose sensors in spatially homogeneous medium simulating some mass transfer properties of tissue. Pass-through ratios and delays are reported as a function of frequency for the oxygen-based sensor, and the effects on continuous blood glucose monitoring are illustrated using data from the literature. Certain peroxide-based sensor designs may produce common signals for different glucose concentrations, a characteristic not found in oxygen-based sensors. The dynamic response depends on the frequency of glucose oscillation and is sensitive to sensor type, enzyme activity, and diffusional resistance.

Algorithms↗

Dual-approach analysis of gut microbiome in patients with type 1 diabetes and diabetic kidney disease.

BACKGROUND: Type 1 diabetes (T1D) is a multifactorial autoimmune disease mediated by genetic, epigenetic, and environmental factors. Diabetic kidney disease (DKD) is a major complication of diabetes mellitus which affects 30-40% of T1D patients. Increasing evidence suggests the significant role of the microbiome in the progression of both T1D and DKD. MATERIALS AND METHODS: Here we recruited 76 T1D patients and 22 healthy controls and combined data from sigmoid colon biopsy samples analysed with V3-V4 region amplification of 16S rRNA gene and shotgun metagenomics data obtained from faecal samples. Additionally, we compared T1D patients with and without progression of DKD. RESULTS: We observed significant differences within both sample types at various taxonomic and functional levels. T1D patient microbiota detected using biopsy samples had a lower abundance of the Bacteroides genus when compared to healthy controls. Significantly, despite only a few taxonomic differences patients with and without DKD progression were vastly different at the functional pathway level within the faecal samples - we observed 2 and 61 enriched pathways in these groups. respectively, with several of these pathways linked to the mediation of renal function. CONCLUSION: Altogether, we present novel data about microbial signatures relevant to T1D and DKD progression, which partly supports previous data and also presents possible tissue type or population-specific elements. DKD progression is characterized with significant differences within the functional level of the gut microbiome.

Humans↗

GlucoWatch G2 Biographer alarm reliability during hypoglycemia in children.

BACKGROUND: The GlucoWatch G2 Biographer (GW2B) (Cygnus, Inc., Redwood City, CA) provides near-continuous monitoring of glucose values in near real time. This device is equipped with two types of alarms to detect hypoglycemia. The hypoglycemia alarm is triggered when the current glucose measurement falls below the level set by the user. The "down alert" alarm is triggered when extrapolation of the current glucose trend anticipates hypoglycemia to occur within the next 20 min. METHODS: We used data from an inpatient accuracy study to assess the performance of these alarms. During a 24-h clinical research center stay, 89 children and adolescents with Type 1 diabetes mellitus (3.5-17.7 years old) wore 174 GW2B devices and had frequent serum glucose determinations during the day and night. RESULTS: Sensitivity to detect hypoglycemia (reference glucose < or = 60 mg/dL) during an insulin-induced hypoglycemia test was 24% with the hypoglycemia alarm alone and 88% when combined with the down alert alarm. Overnight sensitivity from 11 p.m. to 6 a.m. was 23% with the hypoglycemia alarm alone and 77% when combined with the down alert alarm. For 16% of hypoglycemia alarms, the reference glucose was above 70 mg/dL for 30 min before and after the time of the alarm. For the two alarm types combined, the corresponding false-positive rate increased to 62%. CONCLUSIONS: The down alert alarm substantially improves the sensitivity of the GW2B to detect hypoglycemia at the price of a large increase in the false alarm rate. The utility of these alarms in the day-to-day management of children with diabetes remains to be determined.

Adolescent↗

Haemodynamic effects of a single large dose of insulin in open heart surgery.

The haemodynamic effects of a single dose of 0.35, 1.5 or 7.5 IU fast acting insulin X kg bw-1 were studied in 24 patients undergoing aortocoronary bypass grafting. No inotropic drugs were used. Blood glucose was measured using a continuous blood glucose monitoring system, and was kept at the preinsulin level by administration of a 40% glucose solution. Injection of 0.35 or 1.5 IU X kg bw-1 of insulin did not have significant haemodynamic effects. Injection of 7.5 IU X kg bw-1 of insulin resulted in significant changes in cardiac index (+20.8%) and in total peripheral resistance (-13.9%) within 2 min. After 10 min a reduction of 16.8% was found in the diastolic pulmonary artery pressure. These haemodynamic effects occurred before glucose had been infused. The arterial pressure and the heart rate were unaffected. It is concluded that the injection of 7.5 IU X kg bw-1 of insulin results in an increase in cardiac index in patients who have undergone open heart surgery. The effects are not primarily related to stimulation of glycolysis.

Adult↗

Gold and Clarke Questionnaires Identify Different People With Insulin-Treated Diabetes and Impaired Awareness of Hypoglycaemia in Almost 60% of Cases: A Post Hoc Analysis From the Hypo-METRICS Study.

AIMS: Gold and Clarke questionnaires are used to identify impaired awareness of hypoglycaemia (IAH) and severe hypoglycaemic event (SHE) risk in people with diabetes (pwD). We explored their overlap, including Clarke's Hypoglycaemia Awareness Status (Clarke-HAS) subfactor, and subsection differences in SHE incidence (Gold, Clarke, overlap). MATERIALS AND METHODS: This post hoc analysis of the Hypo-METRICS study recruited pwD on insulin (type 1: T1D; type 2: T2D) with &#x2265;&#x2009;1 hypoglycaemic event in the previous 3 months. IAH was defined as Gold &#x2265;&#x2009;4, Clarke &#x2265;&#x2009;4, Clarke-HAS &#x2265;&#x2009;2. RESULTS: Gold and Clarke were completed by 232 pwT1D and 285 pwT2D (age: 47 vs. 62&#x2009;years, p&#x2009;<&#x2009;0.001; HbA1c: 56&#x2009;mmol/mol (7.3%) vs. 57&#x2009;mmol/mol (7.4%), p&#x2009;=&#x2009;0.03). IAH prevalence in T1D vs. T2D was 21% vs. 26% (p&#x2009;=&#x2009;0.1), 14% vs. 18% (p&#x2009;=&#x2009;0.2), and 41% vs. 48% (p&#x2009;=&#x2009;0.2) according to Gold, Clarke and Clarke-HAS. The overlap between Gold &#x2265;&#x2009;4, Clarke &#x2265;&#x2009;4 was 40% (T1D: 45%; T2D: 37%); between Gold &#x2265;&#x2009;4, Clarke-HAS &#x2265;&#x2009;2 it was 45% (T1D: 43%; T2D: 47%). The overlap between Gold &#x2265;&#x2009;4, Clarke &#x2265;&#x2009;4 was 41% vs. 39% in CGM vs. non-CGM users (T1D: 50% vs. 35%; T2D: 32% vs. 40%); between Gold &#x2265;&#x2009;4, Clarke-HAS &#x2265;&#x2009;2 it was 39% vs. 53% (T1D: 38% vs. 54%; T2D: 40% vs. 53%). In the IAH sample, SHE rate was lower in people found with IAH by Gold vs. Clarke, 9% vs. 53%, and in those assessed by Gold-Clarke overlap vs. Clarke, 20% vs. 53% (all p&#x2009;<&#x2009;0.001). CONCLUSIONS: Gold and Clarke show moderate consistency (37%-54%) in identifying IAH in insulin-treated diabetes, with/without CGM use, each associated with different SHE rates, indicating the two questionnaires measure different, independent aspects of IAH.

Humans↗

Microdialysis of adipose tissue.

Although microdialysis has been available for almost two decades, it has only recently been applied in investigations of adipose tissue. The microdialysis technique enables continuous sampling of metabolites and other small molecules from the extracellular space of subcutaneous adipose tissue from intact animals or man, and the exposure of this compartment locally to metabolically active agents without causing generalized effects. To date, the method has been used to measure the steady-state interstitial levels of metabolites and to investigate the regulation of lipolysis and carbohydrate metabolism in situ in subcutaneous adipose tissue. Apart from a great potential for experimental research, the microdialysis method offers several new possibilities for clinical investigation. Because microdialysis probes are easy to implant and cause little discomfort, they may be used for continuous monitoring of glucose and glycerol (lipolysis index) in the treatment of diabetes, obesity and other disorders characterized by disturbances in lipid and carbohydrate metabolism.

Adipose Tissue↗

Multiomics: the intersection of personalized nutrition in cardiometabolic diseases.

BACKGROUND: Cardiometabolic diseases are among the leading causes of increasing morbidity and mortality worldwide. However, current population-based dietary recommendations do not sufficiently account for biological differences between individuals and therefore do not have the same effect on everyone. The multiomic approach, which incorporates genomic, epigenomic, transcriptomic, proteomic, metabolomic, and microbiome data, facilitates more accurate classification of disease risk and selection of appropriate nutritional interventions by mapping food-disease relationships across different biological layers. METHODS: Through a narrative synthesis of the current literature, we focused on evidence from multiomic studies to assess their ability to guide personalized nutrition strategies based on individual genetic, metabolic, and microbiome characteristics in cardiometabolic diseases. RESULTS: Recent evidence indicates that metabolomic markers have been reported to provide predictive value in addition to classic risk indicators and to increase the predictive power of models when combined with genetic data. Microbiome research shows that glycemic and lipemic responses can be predicted using algorithms based on gut microbiota. Recent clinical studies show that personalized nutrition plans, which evaluate the microbiome and clinical characteristics together, improve continuous glucose monitoring-based glycemic control, glycated hemoglobin levels, and triglycerides more than the classic Mediterranean diet. CONCLUSION: This review summarizes the current multiomic evidence, discusses the methodological and practical challenges in this field, and highlights future priorities. The integration of digital biomarkers obtained from wearable technologies with multiomic systems and artificial intelligence-supported models, when developed in accordance with ethical and equitable access principles, has the potential to support the transition from the discovery phase to patient-centered clinical applications.

Humans↗

Normalization of glycemia in diabetics during meals with insulin and glucagon delivery by the artificial pancreas.

An extracorporeal "closed-loop" system has been employed to maintain glycemia in the normal range during consumption of meals in nine insulin-treated diabetics. This artificial pancreas system incorporated continuous blood glucose monitoring (0.05 ml. per minute, delay time 90 seconds), a computer programed to respond to glycemia, and a hormone delivery system. Intravenous insulin delivery rates were determined by control parameters responsive to both glucose concentration and its rate of change. Because insulin-dependent diabetics often defend themselves poorly against hypoglycemia (in some cases due to inadequate glucagon responses), the instrument was also programed for exogenous glucagon delivery. A priori selection of ideal parameters for insulin and glucagon delivery for each individual is not yet possible. Consequently, when the parameters were used for the first time on each subject, they were varied over a reasonable range. This approach resulted in a corresponding variety of glycemic responses, the average of which characterized a set of initial parameters that is generally applicable. Appropriate control parameters are presented that successfully prevented hypoglycemia. Glucagon delivery directly related to glycemia appeared sufficient for this purpose, thus obviating the need for dextrose administration. This system provides a technique for complete normalization of blood glucose concentration in the types of diabetics tested, during both fed and interprandial periods. It has yielded insights essential to the development of more sophisticated future devices.

Adult↗

Randomized controlled clinical trial of glargine versus ultralente insulin in the treatment of type 1 diabetes.

OBJECTIVE: Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA1c and less glycemic variation and hypoglycemia than ultralente insulin, 22 individuals (aged 44 +/- 14 years [+/-SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA1c of <7.8% were randomized in a crossover design to receive either glargine or ultralente as the basal insulin for 4 months. Aspart insulin was used as the prandial insulin. Physicians providing insulin dose adjustment advice were masked to the type of basal insulin. RESULTS: Treatment with glargine resulted in lower mean HbA1c (6.82 +/- 0.13 vs. 7.02 +/- 0.13, difference: 0.2 +/- 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 +/- 4.74 vs. 62.36 +/- 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 +/- 2.99 vs. 31.3 +/- 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia (P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS: We conclude that while use of either ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA1c and less nocturnal glycemic variability and hypoglycemia.

Adult↗

Comparative study of NPH human insulin (recombinant DNA) and pork insulin in diabetic subjects: preliminary report.

Continuous blood glucose monitoring in six insulin-dependent diabetic patients shows that the biologic action of NPH human insulin (recombinant DNA) and pork insulin is similar. Nevertheless, the activity of NPH human insulin seems faster and more pronounced since minimal glycemia is lower and more rapidly reached after human insulin. The speed of glycemic increase is slightly lower and the decrease is faster with NPH human insulin; thus the area under the NPH human insulin-induced glycemic curve is less wide, but differences are not significant. Our data favor a faster and more potent effect of NPH human insulin.

Adolescent↗

Continuous maternal glucose measurements and fetal glucose and insulin levels after administration of terbutaline in term labor.

Maternal blood glucose and fetal blood glucose and insulin levels were studied in 16 women at full-term labor after administration of terbutaline 250 microgram i.v. The maternal blood glucose level was registered by a continuous blood glucose monitoring unit. In all patients studied, the terbutaline injection was followed by a rise in maternal blood glucose within 15 min, lasting for at least one hour. The fetal glucose levels paralleled those of the mothers, but on a lower level. None of the infants demonstrated hypoglycemia during the first 90 min after birth. We conclude that terbutaline administrated in this way has a direct effect on the maternal blood glucose release, and report that no harmful effects on fetal carbohydrate metabolism could be demonstrated.

Blood Glucose↗

2: Recent advances in therapy of diabetes.

As suboptimal blood glucose control has a lasting harmful effect even if control improves later, intensive insulin therapy to minimise hyperglycaemia is now recommended for all patients with type 1 diabetes. The new rapid- and long-acting insulin analogues offer more physiological insulin profiles than traditional insulin preparations. Continuous insulin infusion ("pump therapy") may provide a solution for some patients with frequent hypoglycaemia or hypoglycaemic unawareness. Continuous blood glucose monitoring reveals postprandial hyperglycaemia and asymptomatic nocturnal hypoglycaemia and may be especially useful for programming overnight basal insulin rates for pump therapy. In type 2 diabetes, management should change with disease progression; introduction of insulin should not be delayed if metabolic control becomes suboptimal.

Adolescent↗

[Experiments in evaluation of brain oxygenation and metabolism based on continuous bilateral SjO2 monitoring and metabolic glucose transformations in patients after severe cranio-cerebral injuries].

The study group consisted of 17 patients after severe cranio-cerebral injuries-in GCS below 8. Saturation in both jugular bulbs was measured by using fiberoptic catheters, the concentration of lactate taken from jugular bulbs was measured too. These values were compared to concentration in peripheral arteries. All measurements were started within the first 24 h after trauma and lasted 5 days. Diagnosis of intracranial pathology was established by using CT, which was done directly after admission to the hospital. Interdependence between the state of patient in GOS and variability saturation and concentration of lactate was showed. Desaturation occurred before the neurological sings of intracranial hypertension what had influence on way of treatment and diagnostics. Bilateral measurement of the saturation is more useful to make diagnostic unilateral measurement.

Adult↗

Hypoglycemia in diabetics.

Hypoglycemia in diabetes can be divided into 1) spontaneous hypoglycemic reactions due to absolute or relative overproduction of endogenous insulin or some other blood glucose-lowering substance, as in islet cell adenoma or carcinoma, latent or protodiabetic conditions, (extrapancreatic) tumors and pituitary and/or adrenal disorders; and 2) hypoglycemia caused by exogenous, i.e. therapeutic, measures. The problem of hypoglycemia in insulin-treated diabetics is far from being solved. As revealed by continuous blood glucose monitoring, nocturnal hypoglycemic attacks frequently escape attention especially in juvenile diabetics. Circadian variations in peripheral glucose utilization, rather than changes in plasma insulin activity, are likely to be involved in this mechanism. At least, this was the conclusion drawn from studies carried out by means of a glucose-controlled insulin and glucose infusion system (GCIGIS) -or artificial pancreas-which delivers short-acting insulin and glucose on demand intravenously. Hypoglycemic reactions in patients being treated with oral anti-diabetic agents, on the other hand, should be regarded primarily as one of the side reactions intrinsic to the mechanism of action of some of these drugs, e.g. sulfonylureas, which act mainly via stimulation of secretion of endogenous insulin reserves not responding properly to postprandial blood glucose increments. In the case of glibenclamide, at least partial resensitization of the defective glucose receptor of the beta-cell also becomes operative. A higher incidence of a characteristic type of hypoglycemic reaction was observed soon after glibenclamide therapy was introduced. Better understanding of the drug and dissemination of the information about it to doctors and patients has reduced the number of hypoglycemic reactions caused by glibenclamide to the same proportions as for other sulfonylureas. Hypoglyoemia following therapeutic hypophysectomy retains its position as one of the main hazards of this heroic therapy.

Adenoma, Islet Cell↗