Fall In Plasma Glucose Concentration Research Articles

Hyperglycemic Emergencies in Adults

Hyperglycemic Emergencies in Adults

Glucagon Supports Postabsorptive Plasma Glucose Concentrations in Humans With Biologically Optimal Insulin Levels

OBJECTIVEBased on the premise that postabsorptive patients with type 1 diabetes receiving intravenous insulin in a dose that maintains stable euglycemia are receiving biologically optimal insulin replacement, we tested the hypothesis that glucagon supports postabsorptive plasma glucose concentrations in humans.RESEARCH DESIGN AND METHODSFourteen patients with type 1 diabetes were studied after an overnight fast on up to five occasions. Insulin was infused intravenously to hold plasma glucose concentrations at ∼100 mg/dl (5.6 mmol/l) overnight and fixed from −60 to 240 min the following morning. From 0 through 180 min the patients also received 1) saline, 2) octreotide 30 ng · kg−1 · min−1 with growth hormone replacement or octreotide with growth hormone, plus 3) glucagon in doses of 0.5 ng · kg−1 · min−1, 4) 1.0 ng · kg−1 · min−1, and 5) 2.0 ng · kg−1 · min−1.RESULTSCompared with a mean ± SE of 98 ± 5 mg/dl (5.4 ± 0.3 mmol/l) at 180 min during saline, mean plasma glucose concentrations declined to 58 ± 1 mg/dl (3.2 ± 0.1 mmol/l) (P < 0.001) at 180 min during octreotide plus saline and were 104 ± 16 mg/dl (5.8 ± 0.9 mmol/l) (NS), 143 ± 13 mg/dl (7.9 ± 0.7 mmol/l) (P = 0.004), and 160 ± 15 mg/dl (8.9 ± 0.8 mmol/l) (P < 0.001) at 180 min during octreotide plus glucagon in doses of 0.5, 1.0, and 2.0 ng · kg−1 · min−1, respectively.CONCLUSIONSIn the setting of biologically optimal insulin replacement, suppression of glucagon secretion with octreotide caused a progressive fall in plasma glucose concentrations that was prevented by glucagon replacement. These data document that glucagon supports postabsorptive glucose concentrations in humans.

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

OBJECTIVEHypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures.RESEARCH DESIGN AND METHODSWe developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump–treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 ± 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 ± 0.8%).RESULTSPlasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children's Hospital of Pittsburgh was higher.CONCLUSIONSThese data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.

Provocation of Kainic Acid Receptor mRNA Changes in the Rat Paraventricular Nucleus by Insulin‐Induced Hypoglycaemia

Hypoglycaemia induced by insulin injection is a powerful stimulus to the hypothalamic-pituitary-adrenal (HPA) axis and drives the secretion of corticotropin-releasing hormone and vasopressin from the neurones in the paraventricular nucleus (PVN), as well as the downstream hormones, adrenocorticotropic hormone and corticosterone. In some brain regions, hypoglycaemia also provokes increases in extracellular fluid concentrations of glutamate. Regulation of glutamatergic mechanisms could be involved in the control of the HPA axis during hypoglycaemic stress and one potential site of regulation might be at the receptors for glutamate, which are expressed in the PVN. Insulin (2.0 IU/kg, i.p.) or saline was administered to adult male Sprague-Dawley rats and the animals were sacrificed 30 min, 180 min and 24 h after injection. The amount of several kainic acid-preferring glutamate receptor mRNAs (i.e. KA2, GluR5 and GluR6) were assessed in the PVN by in situ hybridisation histochemistry. Injection of insulin induced a rapid fall in plasma glucose concentrations, which was mirrored by an increase in plasma corticosterone concentrations. KA2 and GluR5 mRNAs are highly expressed within the rat PVN, and responded to hypoglycaemia with robust increases in expression that endured beyond the period of hypoglycaemia itself. However, GluR6 mRNA is expressed in the areas adjacent to the PVN and hypoglycaemic stress failed to alter expression of this mRNA. These experiments suggest that kainic acid-preferring glutamate receptors are responsive to changes in plasma glucose concentrations and may participate in the activation of the PVN neurones during hypoglycaemic stress.

The GLP‐1 system as a therapeutic target

Glucagon‐like peptide‐1 (GLP‐1) was first isolated and sequenced twenty years ago. It has been shown to have many effects in man. GLP‐1 stimulates insulin secretion, delays gastric emptying, decreases glucagon levels and reduces appetite, all resulting in a fall in plasma glucose concentrations. More recently, evidence suggests it can stimulate beta cell neogenesis and improve cardiovascular function, and may even be neuroprotective. It is no surprise that this peptide is of increasing interest as a target for the treatment of diabetes. None of the drugs currently available for diabetes are able to achieve targets in all patients and none of them are without side effects. The multiple modes of action of GLP‐1 together with its low propensity for hypoglycaemia appear to give it advantages over currently available treatment modalities. In this review I shall examine the data suggesting that medications modelled on the GLP‐1 system may provide a new therapeutic option for diabetes in the future.

Hormonal control of metabolism: regulation of plasma glucose

Blood glucose concentration represents the net flux of glucose entering and leaving the blood. Glucose is delivered to the blood from the liver following ingestion of carbohydrate, from the breakdown of glycogen (the storage form of glucose) and from endogenous glucose synthesis. Glucose is removed from the blood by a number of organs and tissues, notably the brain, skeletal muscle, liver and adipose tissue. With this variety of means of entry and exit from the blood, and the complications arising from too high or too low a glucose concentration, the regulation of blood glucose is complex. Many factors affect the delivery of glucose to, and its removal from, the blood. These include dietary carbohydrate and fat, the circulating free fatty acid concentration, exercise, hypoxia and the actions of several hormones. The plasma glucose concentration is regulated by a number of hormones. Some, such as insulin, promote the clearance of glucose from the plasma, while others, including glucagon, growth hormone, and catecholamines, stimulate the production and release of glucose into the blood. A fall in plasma glucose concentration evokes a number of counter-regulatory measures designed to restore plasma glucose levels, and avoid hypoglycaemia. Basically this response involves an increase in the release of glucose into the circulation, and a decrease in tissue glucose uptake.

The pharmacokinetics of s.c. Semitard MC, human NPH ge, Rapitard MC and human NPH 30:70 ge insulin in healthy, non-diabetic subjects

Background: Plasma glucose and insulin responses to Semitard MC versus human NPH ge and Rapitard MC versus human NPH 30:70 ge were examined in fasted healthy, non-diabetic subjects. Methods: Twelve male subjects with a mean (±S.D.) age of 33.9±11.1 years and a BMI of 24.9±2.9 kg/m 2 were each involved on four separate study days 1 week apart. After fasting samples were taken, 0.2 U/kg of the allocated insulin preparation was injected subcutaneously (s.c.) as a bolus into the anterior abdominal wall. Blood samples were taken over the next 24 h. Results: Subcutaneous injection of Semitard MC caused a greater fall in plasma glucose concentration and lower mean plasma glucose levels throughout the study compared to NPH, reflecting the higher insulin concentrations observed during the 24-h study period. Following s.c. Rapitard MC the plasma glucose levels were consistently higher than those achieved with human NPH 30:70 ge as a result of the lower concentrations of insulin with Rapitard MC insulin. Conclusions: To obtain the same level of glycaemic control, transferring patients from Semitard MC to human NPH may require a dose increase of 30% in the first instance to be adjusted upwards as deemed necessary. Transferring patients from Rapitard MC to human NPH 30:70 ge, a dose reduction of 25% may be required. Frequent home blood glucose monitoring should be carried out.

The effects of agonistic behaviour and nutritional stress on both the success of pregnancy and various plasma constituents in Angora goats

This paper describes the effect of dietary restriction on agonistic behaviour, body weight and various plasma constituents (progesterone, oestrogen, glucose and cortisol) in ten Angora goats (mean 7.4 years; range 4 to 9 years) from 100 ± 7.1 days of gestation for a 6 week period. The treatment resulted in a gradual fall in plasma glucose concentration from a mean of 2.60 mmol l −1 to 1.67 mmol l −1. The two lowest ranked does developed pregnancy toxaemia and overall pregnancy failure amounted to 44% compared with 10% in ten control does. Mean body weight decreased in the restricted diet group by approximately 1 kg over the 7 weeks whilst it increased in the control group by approximately 5 kg. Group mean body weights differed ( P < 0.05) on Weeks 6 and 7. Of the variables tested, body weight was the single most important factor determining the level of agonistic behaviour and thus dominance ranking. Plasma glucose concentration was positively correlated ( P < 0.01) with agonistic activity initiated and negatively correlated ( P < 0.01) (restricted diet group only) with agonistic activity received. Mean plasma cortisol tended to increase during the 7th week of the trial (6th week of dietary restriction) in the underfed group. It is suggested that under situations where pregnant goats are subjected to dietary restriction in late pregnancy (e.g. during drought conditions) both level of nutrient intake and agonistic behaviour in the goats must be considered in attempts to ameliorate the problem.

Clinical and pathological studies in horses with hepatic disease

In horses with hepatic necrosis, lipidosis, neoplasia and cirrhosis, progression of the disease was studied by serial measurements of total serum bile acid concentrations and of plasma glutamate dehydrogenase (GD) and gamma glutamyl transferase (gamma GT) and by liver biopsy. Plasma ammonia concentrations were significantly elevated compared to clinically normal horses, but such changes were not always accompanied by a decline in plasma urea concentration. A fall in plasma glucose concentration carried a guarded prognosis. These were all invaluable aids in early diagnosis and throughout the disease course. The study suggests that other factors, such as hypokalaemia, alkalosis, short chain volatile fatty acids, false and true neurotransmitters, may be important in the pathogenesis of hepatic coma in the horse.

The circulating molecular weight forms of infused recombinant insulin-like growth factor-I and effects on glucose and fat metabolism in lambs

We have investigated the relationship between the plasma distribution of infused recombinant insulin-like growth factor-I across the insulin-like growth factor binding proteins and the resultant effects on glucose and fat metabolism. The studies were performed in 24-h fasted ram lambs which received primed constant infusions of 3H labelled glucose tracer. When isotopic equilibrium had been reached, the animals received 90-min infusions of human insulin-like growth factor-I at various doses (2.5, 20, 40 and 120 micrograms.kg-1.h-1, n = 3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40 micrograms.kg-1.h-1 (from 185 +/- 14 micrograms/l to 442 +/- 41 micrograms/l, p less than 0.05) and 120 micrograms.kg-1.h-1 (from 181 +/- 2 micrograms/l to 953 +/- 39 micrograms/l, p less than 0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable (less than 15 micrograms/l) at the end of the 2.5 and 20 micrograms.kg-1.h-1 doses, but were significantly elevated at the end of the 40 and 120 micrograms.kg-1.h-1 infusions (to 71 +/- 14 micrograms/l, p less than 0.05 and 176 +/- 55 micrograms/l, p less than 0.01 respectively). The infused insulin-like growth factor-I associated primarily with 35-60 kilodalton binding proteins. Glucose kinetics were significantly altered only by the highest dose infusion, during which there was a fall in plasma glucose concentration from 3.5 +/- 0.2 mmol/l to 1.9 +/- 0.2 mmol/l (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin absorption accelerated by alpha-adrenergic blockade at injection site.

The effect of the addition of phenoxybenzamine to a regular insulin preparation on the absorption of insulin and plasma glucose concentrations was investigated in five normal subjects. The addition of phenoxybenzamine (20 micrograms) to insulin (0.2 U/kg body wt) resulted in an acceleration of insulin absorption, with a higher and earlier peak insulin concentration at 45 min and higher insulin concentrations throughout the 180 min of investigation. With phenoxybenzamine, plasma glucose concentrations fell more rapidly; nadirs were lower and more rapidly achieved. Two subjects experienced hypoglycemic symptoms when phenoxybenzamine was added to insulin. It is concluded that the addition of phenoxybenzamine to subcutaneously injected insulin increases the bioavailability of insulin for at least 3 h, which leads to a greater fall in plasma glucose concentrations.

Glyburide in Non-Insulin-Dependent Diabetes

Glyburide, a second-generation sulfonylurea compound, was combined with insulin to evaluate its therapeutic effectiveness in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM), poorly controlled by insulin alone. Patients were studied before and three months after the addition of glyburide to their insulin program. Fasting plasma glucose concentration fell an average of 57 mg/dL, associated with an approximately 25% reduction in postprandial glucose response. Therapeutic responses varied widely from patient to patient; the greatest improvement in diabetic control was seen in heavier patients, who had retained the ability to secrete insulin in response to meals and who were not excessively insulin resistant. The glyburide-induced fall in plasma glucose concentration was associated with improvements in both insulin secretion and insulin action, but only the enhanced insulin action correlated with the reduction in fasting and postprandial glucose levels. Thus, diabetic control was significantly improved by glyburide. Combined insulin-sulfonylurea therapy may be useful in the treatment of NIDDM that cannot be easily controlled with either agent alone.

Glyburide in non-insulin-dependent diabetes. Its therapeutic effect in patients with disease poorly controlled by insulin alone.

Glyburide, a second-generation sulfonylurea compound, was combined with insulin to evaluate its therapeutic effectiveness in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM), poorly controlled by insulin alone. Patients were studied before and three months after the addition of glyburide to their insulin program. Fasting plasma glucose concentration fell an average of 57 mg/dL, associated with an approximately 25% reduction in postprandial glucose response. Therapeutic responses varied widely from patient to patient; the greatest improvement in diabetic control was seen in heavier patients, who had retained the ability to secrete insulin in response to meals and who were not excessively insulin resistant. The glyburide-induced fall in plasma glucose concentration was associated with improvements in both insulin secretion and insulin action, but only the enhanced insulin action correlated with the reduction in fasting and postprandial glucose levels. Thus, diabetic control was significantly improved by glyburide. Combined insulin-sulfonylurea therapy may be useful in the treatment of NIDDM that cannot be easily controlled with either agent alone.

Glucose kinetics in nondiabetic and diabetic women during the third trimester of pregnancy

Glucose kinetics were measured with 78% enrichedd-[U-13C] glucose by the prime constant infusion technique during the third trimester of pregnancy in nine nondiabetic women, nine insulin-dependent diabetic women, six gestational diabetic women, and five control women (nonpregnant, nondiabetic) after an overnight fast. The patients not dependent on insulin were diagnosed as diabetic by oral glucose tolerance tests with the use of O'Sullivan and Mahan's criteria as modified by Carpenter and Coustan during the third trimester. The turnover studies were repeated post partum (6 weeks to 5 months after delivery) in 14 of the 24 pregnant subjects. All pregnant groups had a progressive fall in plasma glucose concentration during the study, but there was a steady state of plasma glucose concentration during the turnover period. In comparison to the control subjects, both the pregnant nondiabetic and pregnant insulin-dependent diabetic women had significantly higher plasma insulin concentrations throughout the study (p < 0.05). There were no differences in the glucose turnover rate between any of the pregnant groups (1.7 ± 0.2 mg · kg−1min−1 in pregnant nondiabetic women; 1.5 ± 0.2 mg · kg−1min−1 in pregnant insulin-dependent diabetic women; and 2.1 ± 0.4 mg · kg−1min−1 in gestational diabetic women) and the control group of women (1.8 ± 0.2 mg · kg−1min−1) (mean ± SEM). When the pregnant patients were studied post partum, the glucose turnover rate was similar when referenced to body weight; however, because of a 9.6% to 14.5% fall in weight post partum, the absolute values were higher in the pregnant women. We conclude that, in the basal state after an overnight fast, (1) both nondiabetic and diabetic patients accelerated their glucose turnover rate during pregnancy to provide for increased maternal and fetoplacental metabolic requirements, and (2) in the diabetic subjects the nearly normal plasma glucose and insulin concentrations and other metabolic parameters, as well as the glucose turnover rate, suggested good metabolic control during pregnancy in most of the insulin-dependent and in all of the gestational diabetic patients.

Lipid Metabolism in Non-Insulin-Dependent Diabetes Mellitus

Plasma lipid concentration and lipoprotein composition were studied before and after several months of glipizide treatment in 23 patients with non-insulin-dependent diabetes mellitus. The mean (+/- SEM) plasma glucose level fell 87 mg/dL, and the fall in plasma glucose concentration was correlated with a reduction in plasma triglyceride, very low-density lipoprotein triglyceride, cholesterol, and low-density lipoprotein cholesterol levels. Furthermore, there was a statistically significant increase in the plasma high-density lipoprotein cholesterol to total cholesterol ratio. Thus, improved diabetic control in patients treated with glipizide with non-insulin-dependent diabetes mellitus leads to changes in lipoprotein metabolism thought to be beneficial in terms of known cardiovascular risk factors.

Renal function and effects of partial rehydration during diabetic ketoacidosis.

Although diabetic ketoacidosis is characterized by increased renal excretion of glucose, ketone bodies, and nitrogenous compounds, there are few quantitative studies pertaining to renal function during this state. Therefore, renal function was studied in 10 adult patients in moderate to severe diabetic ketoacidosis before insulin administration. Admission plasma concentrations were: glucose 21.4 (9.2–39.4) mM or 386 (166–710) mg/dl, acetoacetate 3.0 (1.3–7.4) mM, beta-hydroxybutyrate 7.9 (2.9–15.2) mM, acetone 4.4 (1.3–8.9) mM, and HCO3 12.8 (9.5–17.8) mM. Arterial blood pH was 7.28 (7.21–7.38). Partial rehydration was achieved with 0.45% saline. Inulin was used to measure GFR. Renal clearance of acetoacetate, beta-hydroxybutyrate, acetone, glucose, and urinary excretion of nitrogenous compounds were determined. Partial rehydration reduced plasma glucose concentration, primarily because of renal excretion, amounting to 384 ± 73 μmol/min or 69 ± 13 mg/min. Partial rehydration had no effect on plasma ketone bodies, on bicarbonate or urea concentrations, or on arterial pH. Partial rehydration had no effect on ketone body or nitrogenous compound excretory rates. Reabsorptive rates of acetoacetate, beta-hydroxybutyrate, acetone, and glucose increased linearly with their filtered loads, and no maximal renal tubular transport rates were demonstrated for any ketone body or glucose. Because renal absorption of ketone bodies was less than 100%, ketonuria increased as filtered loads increase. Unlike ketone bodies, glucose reabsorptive rate was directly related to GFR. Total renal excretion of nitrogen in the forms of urea, ammonium, creatinine, and uric acid amounted to 16 ± 2 mg/min. This huge loss of body nitrogen reflected ongoing protein catabolism and not heightened renal excretion of preformed compounds, as the plasma concentrations of urea, creatinine, and uric acid did not change during the study. Urea nitrogen accounted for 12 ± 2 mg/min (72%) of the total nitrogen excreted. Ammonium excretion was markedly augmented, ranging from 76 to 537 μmol/min, and was inversely related to arterial pH. We conclude that the fall in plasma glucose concentration is primarily caused by renal glucose excretion, and that the absence of a maximal renal tubular reab-sorption rate for either acetoacetate (AcAc) or beta-hydroxybutyrate (β-OHB) serves to mitigate urinary losses of sodium and potassium during diabetic ketoacidosis.

The effect of somatostatin on the intestinal transport of glucose in vivo and in vitro in the rat.

The possibility that somatostatin has a direct inhibitory effect on intestinal D-glucose absorption was studied in rats using intact intestinal loops and everted jejunal segments. Somatostatin infusion in vivo produced a significant fall in plasma glucose concentration (P less than 0.001) and a fall in pooled plasma insulin concentration to 51% of control values. However, somatostatin infusion did not alter significantly from control values the rate of glucose disappearance from the perfused jejunal lumen in vivo or the appearance of gut-derived plasma glucose. The lack of an inhibitory effect of somatostatin on glucose absorption in vivo was confirmed using two in vitro studies. When increasing concentrations of somatostatin (0-10(4) ng/ml-1) were added to both mucosal and serosal solutions, no significant differences were seen for net transmural flux or unidirectional flux of D-glucose in everted jejunal segments. These studies suggest that somatostatin in the rat does not influence plasma glucose concentration by inhibiting intestinal glucose transport at physiological concentrations of glucose and over a wide range of somatostatin concentrations.

Immunoreactive glucagon responses to oral glucose, insulin infusion and deprivation, and somatostatin in pancreatectomized man.

In a group of pancreatectomized subjects, immunoreactive glucagon (IRG) concentrations were normal after an overnight fast, increased after oral glucose, were not suppressed by somatostatin (SRIF) or insulin, and in two of four subjects they rose with an arginine infusion. Even though the SRIF infusion failed to lower IRG, there was a fall in plasma glucose concentration in both subjects. In two subjects, endogenous hyperglycemia occurred during insulin withdrawal without a rise in IRG, and, in one subject, mild diabetic ketoacidosis developed with only a minimal rise in IRG. These results support the presence of an extrapancreatic source of IRG in man. Secretion from these extrapancreatic alpha cells appears to be regulated differently than secretion from pancreatic alpha cells.

Validation of I.V. small-dose insulin infusion therapy in diabetic ketoacidosis of depancreatized dogs.

A validation of small-dose insulin infusion therapy was studied by the constant i.v. infusion of various doses of insulin into ketoacidotic depancreatized dogs. Constant insulin infusion of 5 x B, 10 X B, 30 X B and 50 X B (B = 225 microunit/kg/min) was performed for 3 h by mechanical pump. The following results were obtained: (1) plasma concentrations of immunoreactive insulin (IRI) increased proportionally to the dose of infused insulin, but the higher IRI did not result in a greater fall in plasma glucose concentration, correspondingly; the mean rate of fall in plasma glucose concentration of 5 x B was not significantly lower than that of 50 x B; beta-hydroxybutyrate and arterial pH improvements were observed in each group during the 3-h insulin infusion. These data suggested that for the improvement of diabetic ketoacidosis, the insulin infusion rate of more than 30 x B, which raised the plasma IRI levels above the physiological range, was not essential; (2) the necessity of potassium supplementation during the small-dose insulin infusion was suggested if the pre-treatment level of serum potassium was low. These results confirmed that in the absence of infection or severe acidosis small-dose insulin infusion therapy is as effective as the conventional large-dose insulin therapy.

Biological properties of chemically modified insulins. I. Biological activity of proinsulin and insulin modified at A1-glycine and B29-lysine.

Beef insulin, pork proinsulin and four derivatives of beef insulin modified at the A1-B29 site on the molecular surface have been studied. Three derivatives had a synthetic crosslink between the A and B chains. Previous studies with these materials [2, 3 and 5] had demonstrated in vivo bioactivities which were much higher than those displayed in vitro. This paper reports experiments which explain this discrepancy. The analogues were administered at equimolar rates to anaesthetised greyhounds by a priming-dose constant infusion technique and the plasma concentrations achieved were estimated by radioimmunoassay. Proinsulin and the modified insulins were metabolised more slowly than insulin. Biopotency values, which related fall in plasma glucose concentration to the total administered dose of analogue, agreed broadly with published results of conventional in vivo bioassays. On the other hand, calculation of potency in relation to the serum concentration of analogue actually achieved, yielded results which agreed more closely with in vitro assay data. We conclude that for these analogues, reported discrepancies between in vitro and in vivo biopotencies can be largely explained by the different rates at which these materials are metabolised.