Variation In Blood Glucose Concentration Research Articles

Kinetic modelling of blood glucose variation in a bioartificial pancreas

Methods are presented for assessing the performance of biomaterials for a bioartificial pancreas using a kinetic model of blood glucose variation. The model is composed of simultaneous differential equations that simulate variation of blood glucose concentration of rats outside the biomaterial and decrease of islet number inside the biomaterial. The resulting calculations agree well with the in vivo experimental data and indicate that the characteristics of bioartificial pancreas can be expressed as the actually working number of islets from the viewpoint of rats, regardless of the functioning of the bioartificial pancreas. The contributions of the capability of a biomaterial permeable to insulin and against immune rejection, and other factors that may induce cell death were involved in the actually working number of islets, i.e., the model used a lumped-parameter expression for assessment of the performance of biomaterials for a bioartificial pancreas. This model would be useful as a research tool for analysis of clinical investigation of bioartificial pancreas and physiological significance of blood glucose variation dynamics.

Fisiologia da fadiga muscular. Delimitação conceptual, modelos de estudo e mecanismos de fadiga de origem central e periférica

Muscular fatigue. Definition, models of study and mechanisms of central and peripheral fatigue. Mammalian skeletal muscles are capable of generating enormous forces when appropriately activated. However, repeated attempts to reproduce equivalent force or power output are invariable met with failure, as characterized by an acute and progressive impairment in performance, which may persist for several days or even weeks. This phenomenon is usually named by neuromuscular fatigue. The etiology of muscle fatigue has interested exercise scientists for more than a century, yet definitive agents remain to be identified. The causes of fatigue during exercise include factors that reside in the brain (central fatigue) and in the muscles themselves (peripheral fatigue). The main goals of this review were: (i) to define and to explain the fatigue concept, by pointing out some research areas; (ii) to differentiate the common used experimental models that deal with fatigue with particular focus on in vivo study through electromyography, revealing its potential usefulness; (iii) to briefly analyse some factors involved in central fatigue showing some evidences that relate central fatigue to variations in some brain neurotransmitters and some branched chain amino acids, (iv) to analyse and to describe the different kinds of peripheral fatigue and (v) to review the role of the depletion of some energetic substrates for ATP synthesis as well as intracellular changes in calcium, H+, lactate, phosphate and ADP concentrations in metabolic fatigue. It seems reasonable to relate, at least in part, the variations in blood glucose concentrations, branched chain amino acids and the synthesis of some neurotransmitters to central fatigue. With regard to peripheral fatigue, experimental evidences have demonstrated that the reductions in mioplasmatic calcium levels impair muscle fibre tension during intense muscle contractions. Although changes in H+, lactate, Pi, ADP or ATP concentrations influence fibre strength, they do not seem to be, per se, determinant factors in muscle fatigue.

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.

Effect of experimentally induced diabetes mellitus on serum leptin level and the role of insulin replacement therapy

The regulation of circulating leptin concentration is multifactorial and still understood. Therefore, the present study was designed: (1) to demonstrate the effect of gender on leptin concentration in intact control rats, (2) to evaluate the relationship between serum leptin concentration, serum insulin level and body weight in control rats and streptozotocin (STZ) diabetic rats (untreated and treated with insulin). A total number of 48 healthy adult albino rats of both sexes (24males& 24 females) were used in this study. The animals were divided equally into four groups, each group was subdivided equally into -male and female subgroups. Group 1(G1): served as control group, group 2(G2): experimental diabetics group (not treated) and group 3(G3) & group 4(G4): experimental diabetic group treated with insulin for 2 and 21 days. These groups were examined for the following parameters: body weight, blood glucose level, serum insulin and leptin concentration. It was found that serum leptin level was significantly higher in female than in male control group. However, this difference could not be detected in between male and female rats in all other studied groups. Moreover, a strong positive correlation was found between leptin concentration and insulin hormone level, and body weight in control male and female rats. STZ-induced diabetes associated with a significant rapid decrease in circulating leptin concentration (G2), this decrease was accompanied with a significant decrease in both serum insulin level and body weight, then, it was rapidly reversed by insulin treatment for 2days (G3) and 21 days (G4). There was also a positive correlation between serum leptin concentration, body weight and serum insulin level in this diabetic group. However, leptin was found to change in an inverse proportion to the variation in blood glucose concentration in both male and female diabetic groups. The direct relationship of serum leptin concentration to serum insulin concentration and the inverse relationship of leptin concentration to blood glucose level were preserved in both male and female insulin replacement therapy groups. In conclusion, in adult albino rats, several factors are involved in the regulation of circulating leptin level such as gender, body weight, blood glucose level and serum insulin concentration.

Effect of experimentally induced diabetes mellitus on serum leptin level and the role of insulin replacement therapy

The regulation of circulating leptin concentration is multifactorial and still understood. Therefore, the present study was designed: (1) to demonstrate the effect of gender on leptin concentration in intact control rats, (2) to evaluate the relationship between serum leptin concentration, serum insulin level and body weight in control rats and streptozotocin (STZ) diabetic rats (untreated and treated with insulin). A total number of 48 healthy adult albino rats of both sexes (24males& 24 females) were used in this study. The animals were divided equally into four groups, each group was subdivided equally into -male and female subgroups. Group 1(G1): served as control group, group 2(G2): experimental diabetics group (not treated) and group 3(G3) & group 4(G4): experimental diabetic group treated with insulin for 2 and 21 days. These groups were examined for the following parameters: body weight, blood glucose level, serum insulin and leptin concentration. It was found that serum leptin level was significantly higher in female than in male control group. However, this difference could not be detected in between male and female rats in all other studied groups. Moreover, a strong positive correlation was found between leptin concentration and insulin hormone level, and body weight in control male and female rats. STZ-induced diabetes associated with a significant rapid decrease in circulating leptin concentration (G2), this decrease was accompanied with a significant decrease in both serum insulin level and body weight, then, it was rapidly reversed by insulin treatment for 2days (G3) and 21 days (G4). There was also a positive correlation between serum leptin concentration, body weight and serum insulin level in this diabetic group. However, leptin was found to change in an inverse proportion to the variation in blood glucose concentration in both male and female diabetic groups. The direct relationship of serum leptin concentration to serum insulin concentration and the inverse relationship of leptin concentration to blood glucose level were preserved in both male and female insulin replacement therapy groups. In conclusion, in adult albino rats, several factors are involved in the regulation of circulating leptin level such as gender, body weight, blood glucose level and serum insulin concentration.

GLUT2 in pancreatic and extra-pancreatic gluco-detection (review).

Detection of variations in blood glucose concentrations by pancreatic beta-cells and a subsequent appropriate secretion of insulin are key events in the control of glucose homeostasis. Because a decreased capability to sense glycemic changes is a hallmark of type 2 diabetes, the glucose signalling pathway leading to insulin secretion in pancreatic beta-cells has been extensively studied. This signalling mechanism depends on glucose metabolism and requires the presence of specific molecules such as GLUT2, glucokinase and the K(ATP) channel subunits Kir6.2 and SUR1. Other cells are also able to sense variations in glycemia or in local glucose concentrations and to modulate different physiological functions participating in the general control of glucose and energy homeostasis. These include cells forming the hepatoportal vein glucose sensor, which controls glucose storage in the liver, counterregulation, food intake and glucose utilization by peripheral tissues and neurons in the hypothalamus and brainstem whose firing rates are modulated by local variations in glucose concentrations or, when not protected by a blood-brain barrier, directly by changes in blood glucose levels. These glucose-sensing neurons are involved in the control of insulin and glucagon secretion, food intake and energy expenditure. Here, recent physiological studies performed with GLUT2-/- mice will be described, which indicate that this transporter is essential for glucose sensing by pancreatic beta-cells, by the hepatoportal sensor and by sensors, probably located centrally, which control activity of the autonomic nervous system and stimulate glucagon secretion. These studies may pave the way to a fine dissection of the molecular and cellular components of extra-pancreatic glucose sensors involved in the control of glucose and energy homeostasis.

Physiological variations in blood glucose concentration affect oesophageal motility and sensation in normal subjects.

A marked elevation in the blood glucose concentration (approximately 15 mmol L-1) slows oesophageal peristalsis. Recent studies indicate that changes in blood glucose within the normal postprandial range affect gastric motility and emptying. The aim of this study was to investigate whether such alterations in blood glucose also affect oesophageal motility. In eight healthy subjects oesophageal motility and sensation to balloon distension were measured on two separate days while blood glucose concentrations were stabilized with an insulin-glucose clamp at 4 mmol L-1 and 8 mmol L-1. Peristaltic velocity in the proximal oesophagus and over the oesophagus as a whole was faster at a plasma glucose concentration of 8 mmol L-1 compared with those at 4 mmol L-1 (proximal 3.3 +/- 0.3 cm s-1 vs 2.6 +/- 0.2 cm s-1, P < 0.05, total 3.1 +/- 0.2 cm s-1 vs 2.7 +/- 0.2 cm s-1, P < 0.005) but there were no differences in wave amplitude or duration, or basal lower oesophageal sphincter pressure (LOSP). The threshold for initial perception of oesophageal distension was lower at a plasma glucose of 8 mmol L-1 (2.9 +/- 0.5 mL vs 4.9 +/- 1.0 mL, P < 0.05). physiological variations in plasma glucose concentration influence oesophageal motility and sensation. These observations suggest that in order to minimize effects of varying plasma glucose levels on oesophageal motility, manometry should be performed under the same fasting or fed conditions when oesophageal motor function is evaluated.

Rotation of the anatomic regions used for insulin injections and day‐to‐day variability of plasma glucose in Type 1 diabetic subjects

AbstractThe paper by Bantle and colleagues from the University of Minnesota, Minneapolis, assesses the day‐to‐day variation in blood glucose concentrations following the commonly employed clinical practice or rotating anatomical sites for insulin injection.Twelve patients with insulin‐dependent diabetes had blood glucose profiles measured following insulin injections given in the abdomen for three days and then rotated around the arms, abdomen and thighs for three days using a cross‐over protocol. Considerable variation in terms of insulin absorption was found between the different injections sites and there was significantly less variability if insulin injections were confined to the abdomen alone.By following the common clinical practice of rotating sites for insulin injection, considerable day‐to‐day variation in blood glucose concentration can result from differences in insulin absorption. Therefore, the authors recommend that patients restrict insulin injections to a single site, preferably the abdomen, to reduce this variation and allow greater precision of insulin administration.The second paper by Jonathan Thow and Philip Home reviews the technique of insulin injection and, in particular, the depth of needle insertion. They observe that the change in the angle of insulin injection from 45° to a near perpendicular injection has important considerations in terms of insulin absorption, particularly for the thin patient.In such patients insulin may be injected almost into the muscle layer beneath the subcutaneous tissue, which will lead to variability in insulin absorption, often at a much quicker rate.A greater and more variable effect of physical exercise was also noted with intra muscular injection. Variability of insulin absorption after intra muscular injection also occurs between different types of insulin. Isophane insulins show considerable variability and are best not given via the intra muscular route.

Reducing Blood Glucose Variability by Use of Abdominal Insulin Injection Sites

Virtually all patients with type I diabetes are familiar with inexplicable fluctuations in blood glucose concentration that expose them to both hypoglycemia and hyperglycemia. It is commonly assumed that such fluctuations are due, in large part, to variations in food intake, physical activities, and emotional state. However, substantial day-to-day variation in blood glucose concentration is observed when diet, exercise, emotional state, insulin dosage, and timing of insulin administration are held constant. This suggests that variation in the rate of absorption of insulin from the subcutaneous injection sites may be an important factor causing those fluctuations. Variations in insulin absorption are increased if the anatomic regions used for injections are rotated. A recent study completed at the University of Minnesota Hospital and Clinic indicates that it is inadvisable for type I diabetic subjects to rotate insulin injection regions; rather, insulin injections should be confined to a single anatomic region (usually the abdomen) as this will decrease day-to-day variability in blood glucose concentration. Such a decrease should allow greater precision in adjusting insulin doses, thereby helping achieve good control.

Intramuscular Versus Subcutaneous Injection of Unmodified Insulin: Consequences for Blood Glucose Control in Patients with Type 1 Diabetes Mellitus

Using the perpendicular injection technique lean diabetic patients may often inject insulin intramuscularly (IM). Guided by ultrasound measurements of the subcutaneous (SC) thickness of the thigh, the aim of the present study was to re-evaluate the absorption kinetics of unmodified insulin from IM and SC injection sites and to evaluate the consequences of IM injection of unmodified insulin for blood glucose control in Type 1 diabetic patients. T50% values (time until 50% of the injected insulin is absorbed from the injection site) of SC injected, radioactively labelled, human unmodified insulin (125I-Actrapid) were 338 +/- 13 (+/- SE) min, 289 +/- 27 min, and 287 +/- 27 min during rest, light physical activity, and strenuous exercise, respectively. Intramuscularly injected unmodified insulin was absorbed faster, T50% 232 +/- 20 min, 113 +/- 13 min, and 112 +/- 5 min during the same levels of physical activity in the same order. When unmodified insulin (Actrapid) was given IM 30 min before breakfast, lunch, and dinner together with intermediate-acting insulin (Protaphane) SC at 2200 h, a more physiological profile of plasma free insulin and a more stable blood glucose profile was obtained than with SC administration into the thigh. The coefficient of variation of blood glucose concentration during the study (3 days each route) was lower with IM than with SC injection of unmodified insulin (33 +/- 4 vs 43 +/- 3%, p less than 0.01). No difference in frequency of hypoglycaemic attacks was found and patients claimed that IM injection was no more painful than SC injection. These data suggest that IM injection of soluble insulin into the thigh is beneficial.

Rotation of the Anatomic Regions Used for Insulin Injections and Day-to-Day Variability of Plasma Glucose in Type I Diabetic Subjects

Treatment of type I diabetes mellitus is hindered by the often large fluctuations in blood glucose concentration experienced by affected individuals. To determine to what extent day-to-day variation in blood glucose levels can be reduced if insulin is injected in the same anatomic region rather than in different regions using a rotational scheme, as is commonly recommended, 12 type I diabetic subjects were studied. Insulin injections were given in the abdomen for 3 days and rotated among arms, abdomen, and thighs for 3 days using a crossover design with random assignment of treatment order. Blood samples for measurement of plasma glucose levels were obtained at nine scheduled times on each day. Insulin dose, diet, and physical activity were held constant for each subject. During the abdominal injection period, the mean SD of plasma glucose levels and the mean variance of plasma glucose levels were both less at all nine time points than during the rotating injection period. Overall values for the SD of plasma glucose levels were 2.7 +/- 0.2 mmol/L for the abdominal injection period and 3.7 +/- 0.3 mmol/L for the rotating injection period. Overall values for the variance of plasma glucose levels were 9.2 +/- 1.4 mmol2/L2 for the abdominal injection period and 17.4 +/- 2.2 mmol2/L2 for the rotating injection period. We conclude that the common clinical practice of rotating the anatomic regions used for insulin injections increases day-to-day variation in blood glucose concentration. Use of a single anatomic region, eg, the abdomen, for all insulin injections may reduce this variation and allow greater precision in the adjustment of insulin doses.

The Effect of Aldose Reductase Inhibition on Erythrocyte Polyols and Galactitol Accumulation in Diabetic Patients

Erythrocyte sorbitol level has previously been used as a measure of the efficacy of aldose reductase inhibitors, but its value is limited by fluctuations related to variations in blood glucose concentration. The aim of the study was to compare sorbitol content with the ability to accumulate galactitol during ex vivo incubation with galactose, of erythrocytes taken from diabetic patients following administration of a single 600 mg dose of the aldose reductase inhibitor, ponalrestat. Twelve patients were studied in a placebo-controlled crossover trial. Blood glucose levels were not statistically different during the placebo and ponalrestat treatment periods except at 1 h after the dose was taken (10.6 +/- 6.7 vs 7.7 +/- 4.6 mmol l-1 (+/- SD), p less than 0.05). Ponalrestat reduced erythrocyte sorbitol concentrations compared with placebo at 3, 5 and 7 h (0.82 +/- 0.36, 0.69 +/- 0.23, and 0.83 +/- 0.35 mg l-1 vs 1.79 +/- 0.67, 1.68 +/- 0.65, and 1.57 +/- 0.59 mg l-1 respectively, p less than 0.005) and 24 h post-dose (1.57 + 0.45 vs 2.01 + 0.73 mg l-1, p less than 0.05). Ponalrestat also reduced erythrocyte galactitol accumulation at 3, 5 and 24 h post-dose from 5.53 +/- 2.41, 5.43 +/- 1.89, and 5.42 +/- 1.96 mg l-1 2-h-1 to 1.47 +/- 0.30, 1.76 +/- 0.41, and 4.12 +/- 0.72 mg l-1 2-h-1 respectively, p less than 0.01. Galactitol accumulation rate appeared to be a less variable parameter than erythrocyte sorbitol and was not influenced by fluctuations in blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Development and testing of a simple algorithm for a glucose clamp.

The glucose clamp technique is widely used in clinical research studies to maintain a constant blood glucose (BG) level during metabolic perturbation. An algorithm is used to set the rate of an intravenous glucose infusion according to measured BG concentrations. Currently used clamp algorithms are unnecessarily complex. This paper describes the development and use of a new algorithm which is simpler to implement. The algorithm employs proportional and differential feedback control. Discrete BG sampling with a sampling period of 5 min is used. Computer simulation with a two-compartment model of glucose dynamics was used to refine the algorithm. A Monte Carlo approach was adopted to examine the effects of random variations in measured BG concentrations and the elapsed time between blood sampling and adjustment of the glucose infusion rate. A coefficient of variation in BG concentration of less than 4 per cent was predicted for a euglycemic clamp. This was confirmed when the algorithm was applied in clinical research studies. This degree of BG control compares well with other published algorithms.

Relation of hemoglobin A 1 and blood glucose to cardiac function in diabetes mellitus

To examine the relation of short- and long-term changes in glucose metabolism to cardiac function, radionuclide cineangiography and echocardiography were performed in 10 young insulin-dependent diabetic patients without clinical evidence of heart disease. Cardiac assessments were performed before and after both acute variations in blood glucose, and induction of chronic “tight glucose control” involving normalization of hemoglobin A 1 concentrations. In diabetic patients, left ventricular (LV) ejection fraction (EF) at normal blood glucose concentration was indistinguishable from values in 11 normal subjects. However, during hyperglycemia (about 300 mg/dl), the average EF at rest was 61%, significantly higher than that during normoglycemia (56%, p <0.001). No significant change in LV diastolic dimension was noted in associated with shifts between high and normal blood glucose concentrations. Normalization of hemoglobin A 1 was achieved within 6 to 25 weeks. This alteration had no significant effect on LVEF, mitral valve E-F slope, or the response of systolic function to blood glucose levels. In addition, no correlation was found between LVEF and hemoglobin A 1 concentrations in 4 of 5 evaluation periods. Thus, in young insulin-dependent diabetic patients without overt heart disease, variation in blood glucose concentration is associated with small but significant variation in EF at rest; normalization of hemoglobin A 1 has no significant effect on LVEF or the response of systolic function to blood glucose levels.

Blood glucose in marine Penaeid Prawns. III. Variation in relation to ovarian growth in Parapenaeopsis Hardwickii (Miers) (Crustacea, Decapoda, Penaeidae)

In the present study on female Parapenaeopsis hardwickii information is presented concerning the variation in blood glucose concentration during the different stages (I to V) of ovarian growth. A direct proportionality was found between blood glucose level and ovary growth. There was an incessant hike in blood glucose level as ovary development proceeds from stage I to IV but a drastic downfall was noticed in stage V, i.e. in the spawned prawns. Physiological significance of these findings are discussed.

Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects. A glucose dose-response study.

The dose-response curve for glucose-induced insulin release obtained by infusing glucose at four to five different rates to normal subjects was sine-shaped, the insulin secretion starting at a blood glucose concentration of about 100 to 125 mg. per 100 ml. The steepest rise in plasma insulin occurred between blood glucose levels of 200 and 350 mg. per 100 ml. When blood sugar was increased further, the plasma insulin curve started to level off. There were no differences in the dose-response characteristics of the early and late insulin responses to glucose infusion. In prediabetic subjects variations in blood glucose concentration between the fasting level and about 300 mg. per 100 ml. were accompanied by only a minor insulin response. Further eleva-ation of blood glucose to 450 to 650 mg. per 100 ml. induced a normal initial insulin response in two out of the eight prediabetics, while the late response was normalized in almost all of them. Thus, the insulin-glucose dose-response curves in the prediabetics seemed to be similar to those of the normals but shifted toward higher blood glucose concentrations. In subjects with mild maturity-onset diabetes or glucose intolerance only, there seemed to exist a further shift to the right of the dose-response curves. These findings suggest that (1) the mechanisms governing the early and late insulin responses to glucose are of identical nature, and (2) the decreased insulin response to glucose in prediabetics and mild diabetics is a relative one, very high glucose concentrations being capable of eliciting normal responses. These findings are compatible with our hypothesis that the defective insulin release in prediabetes and diabetes is due to a decrease in the sensitivity of the glucose receptor of the pancreatic β cell which transmits the glucose signal for insulin release.