Maternal residual beta-cell function and the outcome of diabetic pregnancy.

Preservation of own insulin production (residual pancreatic beta-cell function) has been shown to have a beneficial effect on glycemic control in insulin-dependent diabetic subjects, and its total lack has been suggested to be an independent risk factor during diabetic pregnancy. We studied the influence of residual beta-cell activity on the glucose control and the outcome of pregnancy in 29 diabetic women by sequentially measuring gestational postprandial plasma C-peptide (CPR) levels, diurnal blood glucose curves and blood glycosylated hemoglobin (Hb A1c) and by analyzing the morbidity and mortality of the offsprings. The 9 diabetics with moderate own insulin secretion (CPR levels over 1.0 microgram/l, White classes B and C, later referred to as group I) had significantly better glucose control than the remaining 20 subjects with lower CPR values (White classes C, D and NF, later referred to as group II) (figure 1, table I). There were two intrauterine deaths, both in group II. These deaths (one caused by multiple congenital contracture syndrome and the other by severe intrauterine growth retardation without any evident cause) could not be straightly connected with diabetes. Respiratory distress syndrome was seen in group II only. There was no other significant difference in the neonatal morbidity between the two groups (table II). All mothers of RDS infants were in White class NF where the birthweight was also smaller than in classes B and C. These were the only differences in neonatal morbidity between the White classes (table III). In conclusion, moderate residual beta-cell function seemed to be clinically important in maintaining strict glucose control during gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Residual B-cell function and glycaemic control in diabetic pregnancy.

Serum C-peptide immunoreactivity (CPR), mean blood glucose and blood glycosylated haemoglobin Hb A1c were measured in 23 insulin-dependent diabetic women at 11-12, 23-24, 33-34 and 37-38 gestational weeks in order to elucidate changes in residual B-cell function during pregnancy and their influence on the glycaemic control. CPR values generally increased at the 23-33 gestational weeks, with a significant difference between the mean of the peak values and the mean of the values at the first admission. When the subjects were divided into two groups on the basis of the residual B-cell function at the first admission, the glycaemic control during pregnancy was significantly better in those with higher residual B-cell activity. The overall prevalence of marked residual B-cell activity was higher than previously reported in non-pregnant insulin-dependent diabetic subjects. The results indicate clinically important enhancement in residual B-cell function during pregnancy. The mechanism of this improvement is poorly known although the more strict management of diabetes during gestation may be an important factor.

Serum low-density lipoprotein and high-density lipoprotein cholesterol, and liver size in subjects on drugs inducing hepatic microsomal enzymes.

Serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentration and the ratio between them, major risk factors of coronary heart disease, and liver size were investigated in 18 subjects who were on enzyme-inducing anticonvulsants, phenytoin alone or in combination with phenobarbital and/or carbamazepine. The subjects with a high liver cytochrome P-450, indicating hepatic microsomal enzyme induction, who showed an increase in liver size, had an elevated high-density lipoprotein concentration and high-density lipoprotein cholesterol/total cholesterol ratio, and a reduced low/high-density lipoprotein cholesterol ratio. The high-density lipoprotein cholesterol concentration and its ratio to total cholesterol were directly and related to the ratio between low and high-density lipoprotein cholesterol were inversely related to the extent of liver enlargement. The serum cholesterol distribution profile associated with an increase in liver size was typical of subjects with a low risk of coronary heart disease. The results suggest that enzyme-inducers, such as phenytoin and phenobarbital, induce structural and functional changes in hepatocellular membranes associated with liver enlargement and cholesterol distribution characteristic of low susceptibility to atherosclerotic vascular disease.

Drug metabolism in diabetic subjects with fatty livers.

The effect of fatty degeneration of liver parenchyma on drug metabolism was investigated in 21 obese non-insulin-dependent diabetic subjects by measuring plasma antipyrine kinetics, hepatic cytochrome P-450, liver size and the extent of fatty infiltration. The hepatic drug metabolising capacity, as measured by total antipyrine clearance and the estimated total amount of cytochrome P-450, was at the same level as in non-diabetic control subjects with normal livers. Relative antipyrine clearance (per unit weight of liver) and cytochrome P-450 concentrations were significantly lower in the diabetics than in controls. The extent of fatty infiltration correlated poorly with the indices of drug metabolism. In non-insulin-dependent diabetics, slight to moderate hepatic fatty infiltration, without more serious structural distortion interfering with hepatic blood flow or hepatocellular function, seems to have only a minor influence on drug metabolism.

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants.

Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater inthe epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.

Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.

1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P-450) indices of the activity of the hepatic mixed function oxidase system. 3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.

Liver size and indices of drug metabolism in epileptics.

1 The relationship between liver size and in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) drug metabolism was investigated in twenty-one epileptics on long-term anticonvulsant therapy and in controls. 2 The epileptics exhibited significant enlargement of the liver and enhancement of drug metabolism compared to the controls. 3 Liver size correlated to antipyrine kinetics only in controls. Concentration of cytochrome P-450 in liver biopsy specimens correlated with liver size neither in controls nor in epileptics. 4 The total hepatic cytochrome P-450, estimated on the basis of liver weight and cytochrome P-450 concentration of biopsy samples, correlated linearly with antipyrine kinetics, except in patients with the most severely disturbed liver architecture. 5 Measurement of liver size is essential when comparing in vivo and in vitro drug metabolism, but the changes in liver histology are also of great importance.

Liver size and indices of drug metabolism in alcoholics.

The role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severly impaired in vivo drug metabolism may be due to derangement of blood flow.

Drug metabolism in epileptics: in vivo and in vitro correlations.

1. The effect of inducing drug therapy on the relationship between in vitro (cytochrome P-450 content) and in vivo (antipyrine kinetics) was investigated by comparing eleven consecutively treated epileptics with two groups of controls, eleven subjects with normal liver histology and eleven disease matched non-epileptics, all underwent diagnostice liver biopsy. 2. The epileptics had significantly higher cytochrom P-450 level in biopsies and they also metabolized antipyrine faster than the controls. 3. Decrease in antipyrine half-life in epileptics was related with alterations in liver histology, whereas the level of cytochrome P-450 was not. 4. There was a linear relationship between these two indices of enzyme induction when regressed on logarithmic data.

Size and blood flow of the liver estimated by 99Tcm scanning.

In 14 healthy volunteers a method has been evaluated for simultaneous estimation of liver size and blood flow by dynamic gamma camera recording of Tc-sulfur colloid uptake in R--E cells of the liver. The reproducibility and convenience of the method was found to be such as to make it suitable for both scientific and routine clinical work.