Acute cardiovascular effects of insulin in hyperglycaemic type I diabetics.

Cardiovascular responses to high-dose (0.100 IE kg-1 h-1) and low-dose insulin infusion (0.005-0.01 IE kg-1 h-1) were examined in eight hyperglycaemic, resting type I diabetics. Mean blood glucose dropped from 15.9 to 7.1 mmol l-1 and from 14.4 to 12.6 mmol l-1, respectively, during 1 h. Blood pressure and heart rate did not change. There were no significant changes in absolute or relative left ventricular volumes, the 95% confidence interval (CI) for the difference between the doses in left ventricular ejection fraction was -6 to 8%. Calf blood volume increased on high-dose insulin (p = 0.05, CI for the difference over low-dose insulin 0.0 to 4.6 ml 100 ml-1 tissue). Blood flow increased with 1.6 ml 100 ml-1 tissue min-1 with high-dose insulin and with 0.6 ml 100 ml-1 tissue min-1 with low-dose (CI for the difference -0.5 to 3.4). Noradrenaline increases were small and there was no difference between the doses (p = 0.47).

Influence of short term verapamil treatment on glucose metabolism in patients with non-insulin dependent diabetes mellitus.

The effect of a sustained-release verapamil preparation on glucose metabolism was investigated in 10 patients with non-insulin dependent diabetes mellitus. In a single blind cross-over study verapamil 240 mg b.d. for 1 week lowered fasting plasma glucose from a mean value of 11.6 mmol/l to 10.3 mmol.l-1, and the fasting glucose appearance rate was decreased from 1.5 to 1.2 mmol.min-1. The decrease in fasting plasma glucose and glucose appearance rate was not related to the steady state plasma concentration of verapamil, nor-verapamil and the metabolites D.617 and D.620. After oral glucose administration a tendency to lower plasma glucose values was found after verapamil administration. Plasma insulin, C-peptide, total and C-terminal glucagon were not significantly different in the placebo and the verapamil studies, neither in the fasting state nor after glucose. It is concluded that brief verapamil treatment decreases fasting plasma glucose and glucose turn-over in non-insulin dependent diabetics, possibly by inhibition of gluconeogenesis.

Short time effects of growth hormone on glucose metabolism and insulin and glucagon secretion in normal man.

The present study was undertaken in order to evaluate the acute metabolic and hormonal effects of human growth hormone in healthy subjects. Glucose turnover, plasma glucose, FFA, insulin, C-peptide, glucagon, and somatostatin concentrations were determined in the fasting state after a bolus injection of placebo or growth hormone in quantities producing increases in plasma growth hormone levels within the normal physiological range. We found that growth hormone administration resulted in negligible changes in plasma glucose, no significant changes in appearance or disappearance rates of glucose, a moderate increase in FFA and a moderate fall in plasma insulin, C-peptide and glucagon concentrations, while plasma somatostatin levels were unchanged. These findings suggest that rapid changes in plasma growth hormone concentrations, corresponding to the fluctuations seen during normal daily life, may play a role in the short time regulation of blood glucose concentration through an inhibition of insulin and glucagon secretion.

Effects of nonselective and beta-1-selective blockade on glucose metabolism and hormone responses during insulin-induced hypoglycemia in normal man.

The effects of nonselective beta-blockade (propranolol) and beta-1-selective blockade (atenolol) on glucose metabolism during insulin-induced hypoglycemia were studied in eight normal subjects during constant infusion of 3-[3H]glucose. Propranolol and to a lesser extent atenolol prolonged the hypoglycemic response to insulin. After maximal hypoglycemia a significant increase in glucose uptake rate was seen after propranolol and a corresponding trend was found in the atenolol experiments. The two beta-blockers did not influence glucose production rate after insulin administration. FFA concentration declined rapidly after insulin. Propranolol delayed the subsequent normalization of FFA whereas atenolol had no significant effect. Propranolol increased epinephrine and GH responses to hypoglycemia, whereas atenolol had no effect. Neither of the two beta-blockers influenced the concentrations of glucagon, norepinephrine, and PRL. It is concluded that nonselective beta-blockade prolongs the hypoglycemic response to insulin through an increased tissue uptake of glucose which is not counteracted by an increased glucose production. It is suggested that nonselective beta-blockade increases muscle glucose uptake by lowering FFA concentrations. beta-Blocker inhibition of the antiinsulin effect of epinephrine on glucose uptake in muscle can, however, not be excluded.

Hearing sensitivity in patients with myxoedema before and after treatment with l-thyroxine.

Fifteen patients with confirmed myxoedema, median age 76 years, were consecutively referred for audiological evaluation. The diagnosis of myxoedema was based on the symptomatology, typical clinical appearance, increased TSH level and decreased T4. The audiological evaluation included routine ENT-examination, pure-tone octave audiometry, determination of speech reception threshold and discrimination score. The function of the middle ear was evaluated by impedance audiometry, indicating both middle ear pressure and stapedial reflex thresholds elicited by contralateral stimulation. All patients were evaluated in the myxoedematous state before treatment with l-thyroxine and reevaluated when treated and found euthyroid, both by the clinical investigation and as judged by chemical thyroid parameters. Bilateral symmetrical or nearly symmetrical sensorineural hearing loss was demonstrated in all patients before treatment. The results indicate that in elderly patients with myxoedema no improvement in hearing sensitivity can be demonstrated upon l-thyroxine medication. Patients with myxoedema at this age demonstrate neither more nor less degree of hearing loss when related to an age-matched group of hearing impaired patients. In patients with myxoedema the hearing impairment is found to be equal to that of an age and sex matched control group exhibiting true age-related hearing loss.

The efficacy and safety of human insulin (Novo) in insulin-dependent diabetic patients.

Fifty-one insulin-dependent diabetic patients, 26 children and 25 adults, participated in an open uncontrolled study of the safety and efficacy of human insulin (Novo). The patients, who had previously been treated exclusively with porcine insulin, were followed in two outpatient clinics during a 3-mo study period. During the study period the patients' mean insulin dose and postprandial blood glucose level, as well as the number of hypoglycemic episodes, did not change. The level of hemoglobin A1c was unchanged in the children but fell in the adult patients. None of the patients developed lipoatrophy or experienced any allergy or adverse reaction. One patient died of causes unrelated to the diabetes. Mean insulin-binding IgG did not change during the 3-mo study period. After 12 mo of treatment no significant differences were found between the mean level of insulin-binding IgG in patients who had continued treatment with human insulin and patients who had resumed treatment with porcine insulin after the 3-mo study period. It is concluded within the framework of this study that human insulin is safe and that no major differences in metabolic effect between purified porcine insulin and human insulin could be demonstrated. Thus, patients can be transferred from purified porcine insulin to human insulin without any special precautions.

Acid glycosaminoglycans in myxoedema.

Acid glycosaminoglycans were measured in the tissues of a virtually untreated 83-year-old woman with myxoedema. Intercellular oedema was demonstrated histologically in the tongue, myocardium, striated muscles, and in the skin. Tissue oedema was absent in two female control patients. All tissues from the patient with myxoedema, apart from the stomach, showed high concentrations of hyaluronic acid, but there was no consistent elevation of chondroitin-4,6-sulphate, heparan sulphate or dermatan sulphate. The accumulation of hyaluronic acid might contribute to the oedema formation in myxoedema.

Effect of metabolic regulation on renal leakiness to dextran molecules in short-term insulin-dependent diabetics.

Renal clearance of dextran of two ranges of molecular size and glomerular filtration rate (GFR, 51Cr-EDTA) were measured in seven short-term insulin-dependent diabetics (mean age 25 years). Measurements were carried out in the same patient during good and poor metabolic regulation (plasma glucose, mean +/- SEM, 6.5 +/- 0.9 and 14.8 +/- 1.5 mmol/l, respectively). GFR was elevated in all patients during poor metabolic regulation (119 +/- 6 ml/min/1.73 m2, versus 99 +/- 2 ml/min/1.73 m2 during good control, p less than 0.01). The average renal clearance of dextran with molecular weights ranging from 25,000 to 35,000 and 35,000 to 45,000 increased during poor metabolic regulation from 14.8 +/- 0.8 to 19.8 +/- 1.8 ml/min/1.73 m2, and 5.2 +/- 0.3 to 6.8 +/- 0.6 ml/min/1.73 m2, respectively (p less than 0.05). The elevated GFR and renal dextran clearance found during poor metabolic regulation were normalized within one to three weeks of effective insulin treatment. This rapid reversibility can hardly be explained by the previously demonstrated enlargement in glomerular size and filtration surface area, since these alterations remain unchanged after more than one month of insulin treatment. The metabolic regulation did not influence the size-selective properties of the glomerular wall. Therefore, we suggest that the dominating mechanism involved in the GFR and renal dextran clearance alterations is functional, viz. increased filtration pressure.

Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics.

Glucocorticoid administration for 24 hours to phenformin-treated obese diabetics increased blood lactate and lactate/pyruvate (L/P) ratio to higher levels than those found when only one drug was given. In one of 10 subjects, a metabolic acidosis with a blood lactate of 6.2 mmol developed during simultaneous administration of the two drugs. Diabetics treated with phenformin or metformin in equipotent dosages exhibited the highest blood lactate, L/P ratio, and beta-hydroxybutyrate levels during phenformin treatment, both before and during glucocorticoid administration. Ethanol administration to biguanide-treated diabetics resulted in identical increases in blood lactate and L/P ratio during phenformin and metformin treatment. These findings are consistent with the hypothesis that phenformin has a stronger inhibitory effect of gluconeogenesis than metformin. This may be one reason why lactic acidosis is seen much more often in phenformin- than metformin-treated patients.

Metabolic effects of fenfluramine in obese diabetics.

1 In a single-blind, cross-over study fenfluramine in a daily dose of 120 mg was found to reduce the daily blood glucose level moderately in hospitalized obese diabetics treated with a 1200 calorie diabetic diet. 2 After 7 days of treatment, fenfluramine was found not to influence the intravenous glucose tolerance, the insulin response to intravenously administered glucose, or the growth hormone response to arginine. 3 No changes in blood levels of lactate, beta hydroxybutyrate, triglycerides or cholesterol were seen during fenfluramine treatment.

The effect of metabolic regulation on microvascular permeability to small and large molecules in short-term juvenile diabetics.

The microvascular permeability to small and large molecules was studied during good and poor metabolic regulation in ten short duration juvenile diabetics. The following variables were measured; daily urinary albumin and beta2-microglobulin-excretion rates, whole body transcapillary escape rate of albumin (TER), glomerular filtration rate (GFR), capillary filtration coefficient (CFC), and capillary diffusion capacity (CDC). The urinary albumin and beta2-microglobulin concentration were measured by sensitive radioimmunoassays; TER was detemined from the initial disappearance of intravenously injected 125I-labelled human serum albumin; GFR was measured on the forearm by straingauge plethysmography and CDS for 51Cr-EDTA clearance; CFC was measured on the forearm by straingauge plethysmography and CDC, for 51Cr-EDTA was determined in the jyperaemic anterio tibial muscle by the local clearance technique. All the above mentioned variables, except CDC, were significantly increased during poor metabolic regulation, indicating a functional microangiopathy. The mechanisms of these alterations appear to be increased filtration pressure in the microcirculation and/or increased porosity of the microvasculature. The findings of increased microvascular albumin passage are compatible with the hypothesis that the organic - histologicallly demonstrated - diabetic microangiopathy is a long-term effect of periods of increased extravasation of plasma proteins, with subsequent protein deposition in the microvascular wall, i.e. the concept to plasmatic vasculosis.