A.J. Barnes

Ketoacidosis in pancreatectomized man.

We investigated the importance of glucagon in the development of diabetic ketoacidosis by withholding insulin from six patients with juvenile-type diabetes and four totally pancreatectomized subjects. Patients were fasting and had previously been maintained on intravenous insulin for 24 hours. In diabetic patients plasma glucagon concentrations rose sharply after withdrawal of insulin, and the increases were accompanied by a rise in blood ketone concentration of 4.1+/-0.7 (S.E.M.) and blood glucose concentration of 12.5+/-1.8 mmol per liter by 12 hours. In the pancreatectomized patients, despite the absence of measurable glucagon, blood ketones rose by 1.8+/-0.8 and blood glucose by 7.7+/-1.5 mmol per liter. Thus, glucagon is not essential for the development of ketoacidosis in diabetes, as has previously been suggested, but it may accelerate the onset of ketonemia and hyperglycemia in situations of insulin deficiency.

SEVERE RETINOPATHY AND MILD CARBOHYDRATE INTOLERANCE: POSSIBLE ROLE OF INSULIN DEFICIENCY AND ELEVATED CIRCULATING GROWTH HORMONE

8 patients with severe progressive diabetic retinopathy despite continued mild carbohydrate intolerance on diet therapy alone were studied; each patient had presented initially with visual deterioration and none had experienced hyperglycaemic symptoms. By comparison with 8 carefully matched diet-treated diabetics without retinopathy, the retinopathy patients had increased circulating growth hormone levels and relative insulin deficiency. Several other factors of possible importance in the aetiology of microangiopathy, including circulating intermediary metabolites, platelet aggregation, blood viscosity, and lipids were similar in the two groups. It is possible that hypoinsulinaemia together with growth hormone excess may contribute to the development of eye disease in these patients with otherwise mild diabetes.

IMPORTANCE OF PITUITARY HORMONES IN ÆTIOLOGY OF DIABETIC KETOACIDOSIS

The role of pituitary hormones in the aetiology of diabetic ketoacidosis was examined by withdrawing insulin from five pituitary-ablated diabetics for a 12-hour period. The rise in blood glucose and ketone-body concentrations was markedly retarded in these patients when compared with five matched juvenile-type diabetic controls with normal pituitary function. When cortisol replacement in the pituitary-ablated patients was increased to reproduce the high plasma concentrations found in severe ketoacidosis, blood ketones and glucose were increased but were still significantly lower than in the control diabetics. It is concluded that pituitary hormones may be important in the development of diabetic ketoacidosis.

Hypotrypsinaemia in diabetes mellitus.

Plasma trypsin concentrations were measured in 403 fasting diabetics and 106 healthy controls. Basal trypsin concentrations in the normal subjects were 88 +/- 6 ng/ml (mean +/- S.E.M.). Mean plasma trypsin concentrations in diabetics treated with diet alone (n = 74) were 45 +/- 2 ng/ml, while in a group of young (less than 35 years, n = 88) insulin-dependent diabetics, they were very low at 29 +/- 2 ng/ml and these levels were inversely related to insulin dosage. The findings may help in the understanding of the pathophysiological changes in the exocrine pancreas in the diabetic state and may also shed some light on the physiological interrelationship between the endocrine and exocrine pancreas.

Hormonal and metabolic rhythms in Cushing's syndrome☆

Hormone and metabolite profiles were investigated over a 12-hr period in six patients with Cushings syndrome, ten age- and sex-matched normal controls, and six moderately obese subjects matched for weight with the patient group. Mean diurnal plasma cortisol levels were 563 +/- 74 nmole/liter in the patients, 275 +/- 22 nmole/liter in normal controls and 241 +/- 32 nmole/liter in obese subjects, with total loss of diurnal changes in Cushings syndrome. Fasting blood glucose concentration was similar in all groups although mild hyperglycemia occurred after meals in the Cushings patients compared with normal and obese subjects (mean 12-hr blood glucose: Cushings 6.31 +/- 0.39 mmole/liter; normal controls, 5.32 +/- 0.14 mmole/liter, p < 0.01; obese subjects, 5.41 +/- 0.18 mmole/liter, p < 0.05) despite marked hyperinsulinemia (mean 12-hr serum insulin: Cushings 57.3 +/- 18.2 mU/liter; normal controls, 19.7 +/- 2.5 mU/liter, p < 0.02; obese subjects, 18.1 +/- 4.0 mU/liter, p < 0.05). Concentrations of the gluconeogenic precursors lactate, pyruvate, and alanine were raised in Cushings syndrome, particularly postprandially. Plasma nonesterified fatty acids (NEFA), blood glycerol, and blood ketone body concentrations were comparable in all three groups although the normal diurnal variation in circulating NEFA and ketone body levels was lost in Cushings syndrome. Serum triglyceride (TG) concentrations were grossly elevated in the Cushings patients (mean 12-hr serum TG: Cushings 3.51 +/- 1.23 mmole/liter; normal controls 0.89 +/- 0.19 mmole/liter, p < 0.02; obese subjects, 0.93 +/- 0.23 mmole/liter, p < 0.05) and correlated positively with serum insulin levels. Plasma glucagon concentrations were raised in Cushings syndrome (mean 12-hr plasma glucagon: Cushings 23.2 +/- 3.7 pmole/liter; normal controls 12.3 +/- 1.5 pmole/liter p < 0.01; obese subjects 12.2 +/0 2.0 pmole/liter, p < 0.02) and correlated positively with the serum cortisol but not with blood alanine, suggesting that some stimulatory factor other than alanine was responsible. The metabolic effects of chronic glucocorticoid excess thus may not be explained on the basis of obesity alone. Compensatory hyperinsulinemia limits the disturbance of carbohydrate and lipid metabolism in Cushings syndrome but may be important in production of the hypertriglyceridemia observed.

AUTOIMMUNITY IN DIABETICS INDUCED BY HORMONAL CONTAMINANTS OF INSULIN

Several commercial insulin preparations were found to contain significant quantities of pancreatic glucagon, pancreatic polypeptide (P.P.), vasoactive intestinal peptide (V.I.P.), and somatostatin, though these substances were effectively absent from the new highly purified or monocomponent insulins. Of 448 insulin-dependent diabetics receiving conventional insulins, 63% had circulating antibodies to human P.P., 6% antibodies to V.I.P., 6% to glucagon, and 0.5% to somatostatin. The antibodies were of high affinity and were commonest in the younger diabetics. No antibodies were detected in 167 maturity-onset diabetics, in 125 healthy controls, or in 22 patients treated only with monocomponent insulin. Immunocytochemical testing showed that antibody-positive diabetic plasma reacted specifically against the corresponding hormone-producing pancreatic endocrine cells, against enteroglucagon and somatostatin cells outside the pancreas, and against V.I.P.-containing autonomic nerves throughout the body. The finding of iatrogenic autoimmunity and naturally occurring hormones in large numbers of insulin-dependent diabetics raises important questions about long-term treatment.