Transhepatic absorption and biliary excretion of insulin.

The application of insulin to the liver in rats is followed by an increase of the insulin concentration in the bile. The pathway of insulin from the liver surface to the bile may include a secretory process by the hepatic cells, or it may bypass the hepatic cells, using direct anatomical pathways from blood and lymph to bile. The concentration of insulin in arterial and venous blood, in lymph, and in bile was measured following application of insulin to the liver surface and following peritoneal or intravenous administration. The results confirm that insulin is absorbed from the surface of the liver, but the glucose modulating effect was less effective than after intravenous administration. The insulin concentration in bile was increased after insulin administration by all routes, with the highest and most prolonged increases found after intraperitoneal administration. The results suggest that following transhepatic and intravenous administration, insulin reaches the bile without passing through the liver cells.

Calcium channel blockers in the management of hypertension in the elderly.

Calcium channel blockers seem to be particularly suitable for elderly hypertensive patients since these agents do not cause salt and fluid retention, postural hypotension, sedation, depression, or biochemical abnormalities. Moreover, their use is compatible with several common diseases of old age, such as diabetes, obstructive lung disease, and peripheral vascular disease. We recently conducted a study in 21 patients (average age, 79 +/- 2 years) who completed an eight-week trial with 20-mg nifedipine tablets taken twice daily. Mean blood pressure decreased from 191 +/- 2/96 +/- 2 mm Hg to 151 +/- 4/80 +/- 3 mm Hg. In 15 patients (71 percent), blood pressure decreased to less than or equal to 160/90 mm Hg; in four additional patients (19 percent), diastolic blood pressure decreased by 15 to 25 percent. Thus, there was a sustained lowering of blood pressure in 90 percent of the participants receiving nifedipine monotherapy. A review of recent studies in elderly hypertensive patients revealed similarly favorable results with calcium channel blockers given alone or in combination with other agents. The accumulating data suggest that these compounds may offer a useful new approach to the treatment of hypertension in old age. However, in these studies, the number of patients and the duration of follow-up need to be extended to confirm the favorable impression obtained thus far.

Studies on transhepatic insulin absorption.

The intraperitoneal administration of insulin has been recommended because it was found to effectively control the plasma glucose level. Several authors have suggested that intraperitoneal insulin administration may be more "physiological" and therefore preferable because the insulin is absorbed into the portal venous system without, however, identifying the exact pathways. The possibility that insulin is absorbed through the surface of the liver was investigated in rats. The results show that insulin is absorbed rapidly by this route, but the effect on glucose modulation is similar to that of insulin given by other routes. In contrast, the effect on glucose modulation was delayed following insulin administration into the lower peritoneal cavity with exclusion of the liver.

Computer-assisted insulin dosage adjustment.

We report our first experience with a new microprocessor device for assisting individuals with diabetes in the adjustment of insulin therapy. The computer weighs 200 g and can receive, store, and analyze patient-entered capillary blood glucose (CBG) data on an ongoing basis. Changes in the injected mixtures of short- and intermediate-acting insulins are recommended according to algorithms designed to bring the premeal CBG levels to any desired target value set by the physician. Throughout the present study, the premeal target glucose level was set to 110 mg/dl. Seven (type I) insulin-dependent diabetic individuals ranging in age from 11 to 43 yr were selected to participate in the first use of a BCMC (Better Control Medical Computers, Inc., Toronto, Ontario, Canada) computer on an outpatient basis. All subjects were concerned about diabetes control and were fully informed about as well as thoroughly practiced in the use of manual insulin dosage adjustment schemes, based on approximately equal to 4 times daily CBG estimation, as currently taught in our diabetes clinics. During the last 7 days of the control period of self-adjustment, their mean +/- SEM CBG levels (measured before breakfast, lunch, dinner, and bedtime snack) were, respectively, 178 +/- 20, 187 +/- 35, 208 +/- 22, and 207 +/- 13 mg/dl. Immediately after the control period they were given the device and were instructed in the procedure for entering glycemic data and following manufacturer's recommendations in regard to insulin dosages. This experimental period lasted 8 wk and the outcome was assessed as before. Thus, 8 wk after starting daily use of the instrument, all glycemic values measured as before had fallen significantly (P less than 0.005-0.05) closer to normal: 116 +/- 9, 110 +/- 6, 148 +/- 15, and 135 +/- 9 mg/dl, respectively. Concurrently there was also a significant (P less than 0.01) reduction in the variability of glycemia measured before the main meals.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of platelet adhesion by antiplatelet drugs helps prevent cardiovascular complications of diabetes mellitus.

If it could be shown that: The abnormal platelet function in diabetes contributes to the development of cardiovascular complications of diabetes, the abnormal platelet function is a consequence of the diabetic state, the level of blood sugar control or insulin administration, antiplatelet drugs improve the abnormal platelet function independent of the diabetic state and its treatment, the altered platelet function induced by antiplatelet drugs diminishes the evolution of cardiovascular complications, the addition of antiplatelet drugs to the management of diabetes may be reasonable. Specifically designed animal experiments are necessary to provide the scientific basis for designing appropriate clinical trials.

Nifedipine in the treatment of hypertension in the elderly.

The effect of nifedipine monotherapy, retard tablets, 20 mg bid, was evaluated in 23 hypertensive patients, mean age, 79 +/- 2 years. Twenty-one patients completed an eight-week study. Blood pressure (BP) decreased to 160/90 mm Hg in 15 patients; in four additional patients diastolic BP dropped by 15% to 28%. In a subset of five patients with isolated systolic hypertension, a significant reduction in systolic BP was noted. Side effects were relatively mild and only two patients discontinued the study. The results suggest that nifedipine monotherapy offers an alternative, logic, therapeutic approach to hypertension in the elderly.

Effectiveness of combined nifedipine and propranolol treatment in hypertension.

The long-term antihypertensive effect of combined nifedipine and propranolol therapy was assessed in an open trial in 26 hypertensive patients (19 men, seven women, mean age 53 years). On propranolol alone (160 to 240 mg/day), the patients' average sitting blood pressure was 192 +/- 5/114 +/- 2 mm Hg. Propranolol was continued in a fixed dose and nifedipine was added in a dose that was gradually increased from 30 to 90 mg/day to achieve blood pressure (BP) values below 160/95 mm Hg. Twenty-two patients remained on the combined regimen for 14 to 30 weeks. Their BP decreased to 136 +/- 3/84 +/- 2 mm Hg on an average daily dose of 59.5 mg nifedipine. Seventeen of the 22 subjects were subsequently treated sequentially with propranolol alone, combined therapy, and nifedipine alone, to assess the relative efficacy of each mode of therapy. The combined regimen was found to be more effective than either drug alone. Side effects occurred in 13 of 26 patients. Four dropped out 4 to 11 weeks after starting nifedipine because of either intolerable flushing (2), allergic rash (1), or headache (1). Nine subjects experienced mild reactions that were well tolerated. It is concluded that the combined use of propranolol and nifedipine is effective in the long-term treatment of moderately severe hypertension and offers an alternative therapeutic approach that deserves further evaluation.

The combination of propranolol and nifedipine in the treatment of hypertension: acute and long term effects.

The long term efficacy and tolerability of nifedipine combined with propranolol was assessed in a group of hypertensive patients inadequately controlled on propranolol alone. Twenty-six subjects were initially treated with propranolol in a constant daily dose of 160-240 mg, for up to 4 weeks. Nifedipine, 30 mg/day, was added and the dose was titrated upwards to 90 mg/day to achieve normal blood pressure. In 22 patients receiving the combined therapy for 14-30 weeks, mean arterial pressure dropped from 138 +/- 3 mmHg to 102 +/- 2 mmHg. Thirteen patients experienced untoward effects, and 4 discontinued the study. In the remaining 9, side effects were mild and well tolerated. Seventeen patients were subsequently treated sequentially with propranolol alone, combined therapy and nifedipine alone, to assess the efficacy of each regimen and the additive effect of each drug. The combined regimen was found to be more effective than either drug alone. A subgroup continued either combined therapy (14) or nifedipine monotherapy (3) and was followed for up to 9 months. Blood pressure control was maintained in the majority, but 4 more patients dropped out because of side effects. We conclude that the long term use of nifedipine combined with propranolol is effective and relatively well tolerated, and may offer an alternative approach to the treatment of moderately severe hypertension.

Continuous ambulatory peritoneal dialysis in diabetics with end-stage renal disease.

Twenty diabetics with end-stage renal disease who had never previously received dialysis treatment were treated with continuous ambulatory peritoneal dialysis for periods of two to 36 months (average, 14.5). Intraperitoneal administration of insulin achieved good control of blood sugar. Even though creatinine clearance decreased significantly (P = 0.001), control of blood urea nitrogen and serum creatinine was adequate. Hemoglobin and serum albumin levels increased significantly (P = 0.005 and 0.04, respectively). Similarly, there was a significant increase in serum triglycerides and alkaline phosphatase (P = 0.02 and 0.05). Blood pressure became normal without medications in all but one of the patients. Retinopathy, neuropathy, and osteodystrophy remained unchanged. Peritonitis developed once in every 20.6 patient-months--a rate similar to that observed in nondiabetics. The calculated survival rate was 93 per cent at one year; the calculated rate of continuation on ambulatory peritoneal dialysis was 87 per cent. We conclude that continuous ambulatory dialysis with intraperitoneal administration of insulin is a good alternative treatment for diabetics with end-stage renal disease.

Insulin, glucagon, and amino acids during glycemic control by the artificial pancreas in diabetic man.

The artificial endocrine pancreas (AEP) can normalize glycemia at rest and with meals. To determine whether insulin, glucagon, and amino acid profiles are also normalized, nine diabetics on subcutaneous insulin (S/C) and AEP control were compared to ten normal controls (NC). Glycemia was monitored continuously over 10 hr during which meals were consumed. Insulin infusion rate, and the levels of immunoreactive insulin (IRI) (in NC), free insulin (in S/C and AEP), C-peptide, glucagon, and amino acids are reported. Glycemia in AEP started at somewhat higher levels than in NC, but with breakfast and thereafter, it was identical. In S/C, hyperglycemia prevailed throughout, with no systematic change in free IRI. In AEP, both basal and peak free insulin levels, measured in four patients, were significantly higher than in NC. C-peptide values were significantly lower in diabetics and did not change with meals. Basal glucagon values were not different in the three groups and changes with meals were of small magnitude. Branched chain amino acids were higher in S/C and did not increase as in NC. In AEP, levels were lower than NC after the first two meals. Similarly, lysine and threonine were lower in AEP than in NC at the same times. Alanine, though similar at the onset, was lower 2 hr postbreakfast and higher 2 hrs postsupper in AEP and S/C compared to NC. These studies demonstrate that glycemic control with AEP is accompanied by hyperinsulinemia, which could account for the amino acid responses and the small alterations in immunoreactive glucagon (IRG) patterns. Further refinement is needed to obtain full normalization of metabolic profiles.