Diabetologia 16, 211-224 (1979) Diabetologia by Springer-Verlag 1979 Review Articles Catecholamines and Diabetes Mellitus N. J. Christensen Department of Internal Medicine and Endocrinology,Herlev Hospital, and 2nd Clinic of Internal Medicine, .&rhus Kommunehospital,~rhus, Denmark Key words: Adrenaline, angiopathy, autonomic with plasma and tissue concentrations of nor- neuropathy, cardiovascular, catecholamines, diabetes adrenaline and adrenaline. mellitus, glucose, hypoglycemia, hypophysectomy, insulin, isotope-derivative assay, keto-acidosis, myocardial infarction, noradrenaline, sympathetic Catecholamines in Patients with Untreated nervous activity. Diabetes Mellitus The metabolic changes observed in untreated dia- betics are, in many respects, similar to those pro- duced by infusion of catecholamines and include The sympathetic nervous system is of major impor- hyperglycaemia, decreased glucose tolerance, ele- tance in the regulation of several physiological func- vated free fatty acids and ketone bodies in plasma tions, such as cardiovascular and metabolic homeo- and a reduced insulin response to glucose. stasis. The last decade has seen an increasing interest There are important questions concerning a) the in catecholamines as transmitters in the central nerv- possible significance of the catecholamines in the ous system and as regulators of endocrine secretion. development of ketoacidosis and b) whether the There have been considerable advances in the under- catecholamines may be responsible for the abnor- standing of the biochemistry of catecholamines [7, mally low insulin response to glucose which is 56]. observed in most patients with diabetes mellitus. The potential role of catecholamines in a number A number of studies indicate that emotional fac- of human diseases has however, until recent years tors may aggravate the metabolic state in patients been studied to a limited extent due to lack of with diabetes mellitus [82, 83, 107, 141]. Stress, methods for measurement of sympathetic nervous myocardial infarction and burns, for example, are activity (SNA). Much work has been done to develop known to induce a diabetes-like change in metabo- a radioimmunoassay for determining the enzyme lism that will be discussed later. dopamine-beta-hydroxylase in serum, which unfor- In a number of studies, Carlstr6m [21, 22] has tunately has turned out to be a poor index of SNA shown that exercise induced greater lipid mobilisa- [90]. The development of enzymatic isotope-deriva- tion in untreated juvenile diabetics in comparison tive techniques [53, 54] enabled reliable measure- with normal subjects. Concentrations of plasma free ments of plasma noradrenaline (NA) and adrenaline fatty acids were normalised after insulin treatment, (A). Studies in man have shown that plasma NA is an while plasma glycerol was nearly normalised. Hansen index of SNA [34, 41]. [72, 73] has shown that there was a greater rise in The present survey deals mostly with the function growth hormone during exercise in untreated of the sympathetic nervous system in various clinical juvenile diabetics which was nearly normalised after situations occurring in diabetic patients, particularly insulin treatment. Both the exercise induced lipid mobilisation and the rise in plasma growth hormone Abbreviations: NA = noradrenaline; A = adrenaline; SNA = during exercise are probably mediated through the sympathetic nervous activity sympathetic nervous system. 0012-186X/79/0016/0211 / $02.80 212 N.J. Christensen: Catecholamines and Diabetes Mellitus Plasma catecholamines plasma catecholamine concentration (the sum of NA ng ' ml and A, but mainly NA) in two juvenile diabetics studied at rest and during exercise. During ketosis 3.0 the diabetics demonstrated elevated resting values and the peak plasma concentration in response to exercise was approximately eight times higher than in the controls. The pulse rate was also higher in the 2.0 untreated diabetics than in the controls. After treat- ment with insulin, the catecholamine values at rest and during exercise were similar to those obtained in the controls. 1.0 In a later study [32] plasma NA and plasma A T were measured in 10 diabetics hospitalised in keto- 0.5 acidosis and again after treatment with insulin. All Exercise the untreated diabetics had plasma NA values 0 0 10 20 0 la 20 exceeding the upper 95 per cent limit of the values Min obtained in the controls. The large variation among Fig. 1. Plasma catecholamines in subjects at rest, during, and after individual patients, 0.36 ng/ml to 4.19 ng/ml, could exercise in the supine position. Left: two diabetics, O--O--O un- be explained by the different degrees of metabolic treated, 0--0--0 treated. Right: average values of five controls derangement upon hospitalisation. Plasma NA was _+ SD. (Reproduced with permission from: Scand. J. Clin. Lab. Invest. [25]) correlated to the total carbon dioxide in plasma (Figure 2), to the pulse rate and to the blood glucose concentration. Plasma adrenaline was elevated in 4 Plasma noradrenaline of the 10 patients. After treatment with insulin, ng / ml plasma NA and A concentrations were similar to 10.0 those obtained in the controls. Studies in diabetic patients after withdrawal of insulin [4] showed that plasma NA and A were nor- mal in the early stage after withdrawal of treatment. 1.0 It is uncertain, of course, to what extent such experi- ments mimic patients developing keto-acidosis out- side the hospital. In a significant number of patients Total plasma CO 2 with keto-acidosis, omission of the insulin is the 0.1 5 15 25 mM / I causal factor. Elevated catecholamines probably con- Fig. 2. Correlation obtained in ten diabetics between plasma nor- stitute an important compensation to volume deple- adrenaline and total carbon dioxide in plasma. (Reproduced with tion and disturbed cell function, thus maintaining permission from: Diabetes [32]) vital body functions at the expense of an aggravated metabolic disturbance. Schade & Eaton [132] have recently emphasised the role of anti-insulin hor- Porte [119] has presented some experiments sug- mones in the development of keto-acidosis. gesting that the adrenergic response to dehydration It is mentioned above that the metabolic changes in diabetics may aggravate their metabolic status, observed in diabetes mellitus are similar to those pro- while Havel [76] has suggested that autonomic duced by infusion of catecholamines. Glucose-stimu- neuropathy in diabetics may protect them from the lated insulin secretion is reduced under both condi- development of keto-acidosis. tions. It must be emphasised, however, that basal Baker, Kaye & Haque [9] observed an increase in insulin secretion differs in these two conditions. ketone body responsiveness to adrenaline infusions While juvenile diabetic patients have normal or in diabetic children while the rises in glucose and free reduced insulin values in comparison with control fatty acids were comparable to those obtained in nor- subjects, basal insulin secretion is elevated during mal children. Gerich et al. [67] and Benson et el. [14] prolonged infusions of catecholamines and in reported that the glucagon response to adrenaline patients with myocardial infarction [39, 125]. infusion was greater in juvenile diabetics than in nor- There is some evidence indicating that the defec- mal subjects. tive insulin secretion in diabetics is not caused by the Plasma catecholamine concentration is elevated catecholamines; insulin secretion in response to iso- in untreated diabetics [25]. Figure 1 shows the total proterenol (a beta-adrenergic receptor agonist) was N. J. Christensen: Catecholamines and Diabetes Mellitus 213 Table 1. Acute effects of insulin on the cardiovascular system Parameter Change Mechanism Comments Heart rate Increases Non-adrenergic Arterial blood pressure Unchanged or ? Decreases in patients with neuro- decreases pathy Plasma noradrenaline Increases Compensatory to hypovolaemiaor Plasma adrenaline is unchanged antagonising effects of insulin on some actions of NA? Forearm blood flow Decreases ? Plasma volume Decreases ? Haematocrit Increases .9 Changes smaller than in plasma volume Urinary albumin excretion Increases Glomerular Beta-2-microglobulinexcretion de- creases Glomerular filtration rate and renal Decreases ? Due to the fall in blood glucose con- plasma flow centration? Micropinocytoticvesicles in capillaryen- Increases ? Free vesicles dothelial cells often preserved in diabetics in whom glucose had no may aggravate the metabolic status they are probably effect [45, 126]. This provides evidence not only that important in the maintenance of vital body functions the glucose receptor is distinct from the beta- in the more seriously ill patients. On the other hand, adrenergic receptor, but also indicates that the beta- it seems unlikely that catecholamines are responsible adrenergic receptor, is unlikely to be responsible for for the defective insulin response to glucose which is the defective insulin secretion to glucose in diabetes observed in most patients with diabetes mellitus. mellitus. Linde & Deckert [96] observed that administration of phentolamine during an intrave- nous glucose tolerance test increased glucose-stimu- Acute Cardiovascular Effects of Insulin lated insulin secretion to about the same extent in diabetics and in controls. Robertson et al. [124] have It is now known that insulin apart from its effects on reported that diabetics have a greater increase in metabolism and on ion fluxes has a marked acute basal