[Alcoholic ketoacidosis. An important differential diagnosis from diabetic ketoacidosis]. / Die alkoholische Ketoacidose. Eine wichtige Differentialdiagnose zur diabetischen Ketoacidose.

Ketoacidosis developed in two patients, a woman aged 36 and a man aged 55 years, 48 and 36 hours, respectively, after a bout of drinking alcohol to excess. Both were dehydrated with hyperventilation and signs of cachexia. Other findings were polydipsia, polyuria, loss of weight and (in the woman) abdominal pain. Biochemical tests revealed a marked metabolic acidosis (pH 7.00 and 7.09, respectively), base deficit of -25 and -20 mmol/l, hyperglycaemia (210 and 297 mg/dl) and hyperkalaemia (6.3 and 6.0 mmol/l). Treatment with insulin and fluids, as well as normalization of the electrolytes, brought about rapid regression of the metabolic disorder and restoration of the carbohydrate metabolism. Both patients were discharged without medication or dietary prescription, other than abstinence from alcohol.

Functional and morphologic characterization of human insulinomas.

Circulating levels of insulin, proinsulin-like component, glucagon, growth hormone, and pancreatic polypeptide were measured in 12 patients with functioning insulinomas, and the suppressibility of serum insulin by somatostatin and diazoxide was assessed before surgical removal of the tumors. The hormone content of the tumors was evaluated by radioimmunoassay and by immunofluorescence and the structure of the tumor cells by electron microscopy. Based on these findings, we propose a new classification of insulinomas in two groups: group A is characterized morphologically by abundant well-granulated typical B-cells, trabecular arrangement of tumor cells, and uniform insulin immunofluorescence; functionally, these tumors are associated with a moderate elevation of proinsulin-like component and with an almost complete suppressibility of serum insulin by somatostatin and diazoxide. In contrast, tumors of group B are characterized by scarce well-granulated typical B-cells, a medullary-type histologic structure, and irregular insulin immunofluorescence; functionally these tumors show elevated circulating levels of proinsulin-like component and a marked resistance of insulin secretion to somatostatin and diazoxide inhibition. This way of separating human insulinomas in groups A and B represents a simplification of existing classifications and emphasizes the quantitative ultrastructure in relationship to suppressibility of insulin secretion. The proposed classification of human insulinomas in groups A and B, however, does not allow the assessment of the clinical or histopathologic malignancy of the tumors.

Amino acids and lipoproteins in plasma of duodenopancreatectomized patients: effects of glucagon in physiological amounts.

Duodenopancreatectomy induces a severe glucagon deficiency and elevated plasma concentrations of alanine, aspartate, glycine, proline, serine, arginine, citrulline, ornithine, phenylalanine and tyrosine. Restoring high physiological plasma glucagon in six such patients by infusing 0.3 mg/24 h of exogenous glucagon reduced significantly (P less than 0.01 or 0.001) the mentioned amino acids (except phenylalanine) and further asparagine, glutamine, methionine and threonine. In six normal subjects the same infusion reduced significantly (P less than 0.05 to 0.001) plasma alanine, asparagine, glutamate, glutamine, glycine, proline, serine, threonine, arginine, ornithine, lysine and tyrosine. However, the effect was significantly (P less than 0.01 or 0.001) less marked for alanine, glutamine, glycine, methionine, serine, threonine and arginine. This particular glucagon sensitivity of duodenopancreatectomized patients suggests that glucagon deficiency is the cause of their hyperaminacidaemia. By contrast, lipoprotein concentrations were virtually unaffected by either glucagon deficiency or its replacement. In the light of the marked hypoaminacidaemia in glucagonoma patients these results attribute to glucagon a major role as a regulator of protein metabolism.

Subcutaneous use of regular human insulin (Novo): pharmacokinetics and continuous insulin infusion therapy.

The absorption kinetics of human insulin (Novo) were studied and compared with those of purified porcine insulin preparations in seven healthy men. The absorption of insulin after subcutaneous injection of human insulin (Actrapid, Novo) was significantly accelerated and its hypoglycemic effect significantly stronger when compared with porcine insulin (Actrapid). No differences in the absorption kinetics were observed using human insulin (Monotard, Novo) and porcine insulin (Monotard) preparations, respectively. A clinical trial was designed to determine whether the pharmacokinetic differences were relevant for the clinical use of regular human insulin. The efficacy of human and porcine insulin (Actrapid) was tested in a double-blind crossover protocol in 12 type I diabetic patients treated with continuous subcutaneous insulin infusion. Near-normoglycemia was achieved with both types of insulin. Diurnal blood glucose values and excursions, insulin requirements, the frequency of mild hypoglycemic episodes, and the carbohydrate content of the diet were essentially identical. Thus, the differences between the absorption of human insulin and porcine regular insulin from a subcutaneous depot as observed in the pharmacokinetic studies in normal man do not appear to be relevant in the clinical practice of the subcutaneous insulin replacement therapy in type I diabetes mellitus at near-normoglycemia.

Absorption kinetics of semisynthetic human insulin and biosynthetic (recombinant DNA) human insulin.

Absorption kinetics of subcutaneously injected human insulin (recombinant DNA) and semisynthetic human regular insulin were investigated and compared to the respective porcine insulin preparations in normal volunteers. The absorption of all regular human insulin preparations tested was accelerated as compared to porcine insulins. The clinical relevance of these findings in regard to the treatment of diabetes mellitus appears to be doubtful. As for mixtures of porcine regular and intermediate-acting insulin preparations, the absorption of human regular insulin is not altered when mixed with intermediate-acting human insulin.

Absorption kinetics and biologic effects of subcutaneously injected insulin preparations.

This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20-30 yr). Five experimental protocols were used: effect of changing injection site, effect of temperature change and local massage, effect of aprotinin and human serum, effect of mixing regular insulin with long-acting insulin preparations, and effect of temperature change, muscular exercise, and local massage on the absorption of long-acting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.

The effect of aprotinin on the absorption of subcutaneously injected regular insulin in normal subjects.

The effect of aprotinin on the absorption of regular insulin was assessed in normal man. Ten units of Actrapid insulin were subcutaneously injected together with 1.4 mg aprotinin (i.e., 0.5 ml of Trasylol) or an equivalent volume of physiologic saline (controls) into the thighs of overnight-fasted normal subjects. Aprotinin caused an increase in the rate of insulin entry into the circulation; the absolute amount of insulin that was detected in the circulation during the course of the experiment was also higher. In addition, the onset of the hypoglycemic action of exogenous insulin was significantly accelerated when insulin was administered together with aprotinin. These data suggest that aprotinin increases the absorption rate of subcutaneously injected insulin from its depot into the circulation, possibly by an inhibition of the local degradation of exogenous insulin at the injection site.

Glucagon immunoreactivities and amino acid profile in plasma of duodenopancreatectomized patients.

Glucogon immunoreactivity (IRG) was measured in plasma of duodenopancreatectomized subjects with a nonspecific (K-4023) and a specific (30-K) glucagon antiserum. After an overnight fast, plasma IRG (K-4023) was significantly (P < 0.05) higher in the subjects without pancreas, averaging 782+/-79 (SEM) pgeq/ml, than in the controls (482+/-80 pgeq/ml). IRG (30-K) of 162+/-68 pg/ml did not change during an infusion of arginine (450 mg/kg per 40 min). Insulin deprivation during 3 d in one patient did not restore the IRG response to arginine as reported in depancreatized dogs.Bio-Gel P-30 column chromatography revealed that virtually all IRG (30-K) measured in whole plasma was of different molecular weight than glucagon, and primarily of a mol wt >/= 40,000. Intravenous arginine did not significantly alter the chromatographic pattern of these plasmas. Thus, as postulated by others, duodeno-pancreatectomized humans have virtually no circulating 3,500-dalton glucagon. Hence, the presence of 3,500-dalton glucagon in plasma is not a condition for the diabetic state. It might, nevertheless, when present in normal or excessive amounts, worsen the metabolic state of diabetic patients. Among 14 amino acids measured in plasma of these patients, the concentrations of alanine, serine, ornithine, and arginine were significantly (P < 0.05) elevated to approximately twice that of normal: alanine and serine are both substrates for gluconeogenesis, whereas ornithine and arginine are involved in the formation of urea, the second product of hepatic gluconeogenesis. As the concentrations of branched chain amino acids were not grossly altered, it is hypothesized that this amino acid pattern is a consequence of glucagon deficiency rather than secondary to the diabetic state of these patients.

[Fractional distribution of anti-glucagon immunoreactivity (GIR) and amino acid concentration in the plasma in duodenopancreatectomized patients; preliminary report]. / Distribution fractionnelle de l'immunoréactivité anti-glucagon (IRG) et concentration des acides aminés dans le plasma de patients duodénopancréatectomisés.

Glucagon immunoreactivity (IRG) was measured in plasma of 8 duodenopancreatectomized patients with antiserum 30-K. Arginine infusions failed to raise plasma IRG, whereas in control subjects IRG rose 3-fold. Column chromatography revealed that the basal IRG measured in these plasmas was not due to glucagon (molecular weight 3485) but to other plasma factors, mainly of high molecular weight. This suggests that diabetes mellitus does not require the presence of glucagon to produce the clinical picture, as suggested by other authors. Plasma levels of the amino acids alanine, serine, ornithine, and arginine were significantly (p less than 0.05) elevated, the former two being gluconeogenic substrates and the latter two constituents of the urea cycle. This amino acid abnormality may be a consequence of glucagon deficiency.

Plasma glucagon in diabetes of haemochromatosis: too low or too high?

Glucagon secretion before and during arginine infusions was tested in 11 patients with diabetes associated with haemochromatosis. The results were compared with those obtained in six normal subjects and five patients with haemochromatosis but normal glucose tolerance. The patients with haemochromatosis, regardless of glucose tolerance, exhibited higer level of plasma immunoreactivity for glucagon (antiserum 30-K) suggesting hyperglucagonaemia. However, additional analysis revealed that a considerable amount of this glucagon immunoreactivity was due to cross-reacting material of high molecular weight, the levels of which were significantly higher in patients with idiopathic haemochromatosis. When this was deducted from the total immunoreactivity measured, the resulting values for true glucagon concentrations were similar to those of normal subjects. The data suggest that (1) patients with idiopathic haemochromatosis, whether or not associated with diabetes, exhibit plasma glucagon levels comparable with those of normal subjects; (2) the plasma of the same patients contains significantly more high-molecular-weight substances reacting with glucagon antiserum 30-K than is present in plasma of normal subjects; and (3) 'hyperglucagonaemia' may be erroneously suggested when glucagon is measured with certain antisera reputed to be specific for glucagon.

[Blood coagulation disorder in islet cell adenoma]. / Zur Frage der Blutgerinnungsstörung bei Inselzelladenomen.

Coagulation physiologic tests were carried out and plasminogen activity and concentration were measured in the case of 6 patients (5 islet cell adenomas and 1 islet cell carcinoma). Except a reduced plasminogen activity in the postoperative phase no other unequivocally pathologic data were found. This phenomenon can probably by attributed to the enhanced plasmin inhibitors of the human plasma. The problem of so-called hypercoagulaemia of these patients can be clarified only after the investigation of the half-lives of the various coagulation factors.

Non-glucoregulatory hormones (T4, T3, rT3, TSH, testosterone) during physical exercise in juvenile type diabetics.

Non-glucoregulatory hormones (T4, T3, rT3, TSH and testosterone) were studied by radioimmunoassay in juvenile-type diabetics in moderate control and in ketosis due to insulin withdrawal and in age matched "normals" during a mild prolonged exercise test. The basal serum hormone levels revealed the following findings: Serum testosterone was markedly lower in diabetics than in normals ( 177 +/- 24 resp. 618 +/- 52 ng/dl). This is in contrast to other studies, but it may reflect decreased testicular function due to an early, clinically not apparent atherosclerotic disease. Serum T3 was significantly lower in diabetics than in normals (110 +/- 16 resp. 145 +/- 19), suggesting an early "low T3-syndrome" in juvenile-type diabetics. However, increased serum rT3 levels were not observed, and serum T4 and TSH were normal. Mild prolonged exercise had no major effects on these nonglucoregulatory hormones. In juvenile-type diabetics the degree of metabolic control had no influence on the response of the mentioned hormones. However, an increased cortisol/testosterone ratio in ketotic diabetics in the basal state with a further increase during exercise was demonstrated, indicating an aggravation of the catabolic state in these patients during exercise.