On the origin of non-insulin-dependent diabetes.
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Adrenal Glands↗
Biomedical subjects
W A Stubbs
Publications and source records attributed to W A Stubbs.
Hyperglycaemia: imitating Claude Bernard's piqûre with drugs.
Hyperglycaemia lasting for hours, has been produced in unanesthetized cats, rabbits and rats by injection into the cerebral ventricles or the cisterna magna of a variety of drugs (morphine, etorphine, pethidine, beta-endorphin, enkephalin, bombesin, TRH, cholecystokinin, naloxone, propranolol, phentolamine, chloralose, magnesium chloride and GABA). These drugs probably act at the ventral surface of the brainstem and initiate a sympathetic discharge to the adrenals which results in a prolonged release of relatively small amounts of adrenaline. When adrenaline is released in this way hyperglycaemia may be the only effect. The mechanism of the piqûre hyperglycaemia of Claude Bernard may be the same, although Bernard assumed that it resulted from an effect on the floor of the fourth ventricle, i.e. on the dorsal surface of the brainstem. However, it is clear from his description that his trochar not only pricked the floor of the fourth ventricle but penetrated to the ventral surface of the brainstem. Release of adrenaline from the adrenals is usually regarded as a stress response, as in fight, flight, fear or rage when it is suddenly released in large amounts and produces its typical cardiovascular and ocular reactions. The results now obtained with drugs injected intraventricularly or intracisternally suggest an additional physiological role for adrenaline when it is released over prolonged periods and in relatively small amounts producing only hyperglycaemia. Such a release may play a role in the day-to-day control of blood glucose, and its disturbance might underlie non-insulin-dependent diabetes.
Adrenergic beta-Antagonists↗
Metabolic studies in chlorpropamide-alcohol flush positive and negative Type 2 (non-insulin dependent) diabetic patients with and without retinopathy.
Serum insulin and blood metabolite responses to oral glucose with and without intravenous naloxone were measured in 24 chlorpropamide-alcohol flush positive and negative Type 2 (non-insulin dependent) diabetic patients with and without retinopathy. In the chlorpropamide-alcohol flush positive patients with retinopathy, fasting blood glucose was increased greater than 40% and the serum triglycerides were increased over twofold compared with each of the other three groups. Following oral glucose (50 g), the chlorpropamide-alcohol flush positive diabetic patients with complications had a lower serum insulin and higher blood glycerol than the other three groups. Thus, chlorpropamide-alcohol flush positive subjects with retinopathy showed distinct metabolic differences from the other three groups. There was no evidence that opiate-receptors influenced the metabolic response to oral glucose in the Type 2 diabetic patients since the infusion of intravenous naloxone produced no effect on the serum insulin or blood metabolites.
Aged↗
The endocrine and metabolic effects of cimetidine.
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Administration, Oral↗
Hyperglycaemia, a morphine-like effect produced by naloxone in the cat.
In unanaesthetized cats the pronounced hyperglycaemia produced by intravenous morphine (5 mg/kg) was inhibited by naloxone. However, naloxone itself produced hyperglycaemia when given in doses slightly larger than those required to produce inhibition. These two effects of naloxone were obtained when it was injected intravenously, into a lateral cerebral ventricle, or into the cisterna magna. The hyperglycaemia produced when naloxone or morphine was injected into a lateral cerebral ventricle or into the cisterna magna was not inhibited by intravenous naloxone. Hyperglycaemia was not the only morphine-like effect of naloxone. It also reproduced some of the behavioural effects of morphine.
Animals↗
Muscle capillary basement membrane in identical twins discordant for insulin-dependent diabetes.
Although hereditary factors clearly modulate susceptibility to develop diabetes, their role as determinants of vascular complications associated with diabetes remains unclear. These studies were undertaken to further assess the extent to which capillary basement membrane thickening (CBMT) is governed by metabolic derangements associated with relative or absolute insulin deficiency versus genetic determinants of vascular disease closely linked to but independent of those modulating susceptibility to develop relative or absolute insulin deficiency. Quadriceps muscle capillary basement membranes obtained by needle biopsy were examined in eight pairs of identical twins discordant for insulin-dependent diabetes (IDD) for 11-29 yr. Biopsy material from one of the diabetic twins was technically unsuitable for study. The average CBM width of the IDD twins was found to be significantly thicker than that of their nondiabetic (ND) twin mates (t = 2.50, P less than 0.025). Three IDD, but none of the ND twins, had basement membrane width values in excess of 95% upper tolerance intervals for age- and sex-matched controls with no family history of diabetes. The absence of CBMT in all of the ND twins and in four of the IDD twins with diabetes of 15-24 yr duration argues against the existence, in this group of subjects, of hereditary determinants of diabetic vascular disease linked to those governing susceptibility to develop diabetes. In addition, the absence of CBMT in four subjects with IDD of 15-24 yr duration is consistent with evidence from other studies indicating that diabetic microangiopathy is not an inevitable consequence of the diabetic milieu.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Insulin clearance by perfused rat lung.
The clearance of insulin has been demonstrated in the perfused in situ rat lung. Porcine insulin added to the perfusion medium at 50 microunits/l was cleared at 6.3 U/h in lungs from fed animals, 6.1 U/h in fasted animals and 15.7 U/h in diabetic rat lungs. At a higher concentration of insulin (500 microunits/l) increased clearance was observed in lungs from both fed, fasted and diabetic animals, 33.0, 36.0 and 56.5 U/h respectively. It is suggested that the clearance of insulin by the lung is dependent on metabolic state of the animal.
Animal Nutritional Physiological Phenomena↗
Opiate receptors and the metabolic response to intravenous glucose.
The role of opiate receptors in the metabolic response to an intravenous glucose load was determined in eight non-diabetic subjects (four of whom showed a positive chlorpropamide alcohol flush response and four who did not). Subjects were studied in a double blind randomised fashion receiving either a saline control or the specific opiate receptor antagonist, naloxone (0.4 mg/min), as an infusion for 5 minutes before and 20 minutes after an intravenous bolus of glucose (0.5 g/kg body weight). Naloxone decreased the early plasma glucose peak in all subjects by increasing the distribution volume but did not alter the fractional glucose clearance. Insulin and glucagon responses to glucose were not altered by naloxone. Naloxone delayed the normal post-glucose rise in the levels of the gluconeogenic precursors alanine, lactate, pyruvate and glycerol suggesting a delay in the usual inhibition in gluconeogenesis following a glucose load. There was no difference in the metabolic response between those subjects who were liable to chlorpropamide alcohol flushing and those who were not either with or without naloxone. We conclude that opiate receptors may influence distribution volume and gluconeogenesis but do not play a major role in either insulin or glucagon secretion or in glucose disposal following an intravenous glucose load.
Alanine↗
Metabolic studies in unaffected co-twins of non-insulin-dependent diabetics.
Forty-eight out of 53 non-insulin-dependent diabetic identical twin pairs were concordant for diabetes. In the five discordant pairs the diabetic twin had only recently been diagnosed. Oral glucose tolerance tests were carried out on the unaffected twins of the five pairs and on matched controls. Fasting concentrations of blood glucose (5.5 +/- 0.6 v 3.7 +/- 0.3 mmol/l; 99.1 +/- 10.8 v 66.6 +/- 5.4 mg/100 ml), haemoglobin A1 (mean 9.1%, range 8.8-9.2% v mean 7.9%, range 7.4-8.4%), lactate, alanine, and glycerol (0.090 +/- 0.017 v 0.045 +/- 0.008 mmol/l); and the lactate: pyruvate ratio were significantly higher in the twins than controls. After glucose challenge blood glucose, lactate, alanine, and glycerol concentrations and lactate: pyruvate ratio were increased in the twins. Insulin response was severely impaired, being almost absent in four of the five twins. The non-diabetic members of the discordant non-insulin-dependent diabetic pairs showed noticeable metabolic abnormalities which would later presumably deteriorate to frank diabetes. These findings, taken with the high concordance rate for non-insulin-dependent diabetic twins, suggest that non-insulin-dependent diabetes is predominantly, possibly entirely, inherited.
Adult↗
Studies off the opiate control of prolactin, GH and TSH.
Opiate peptides are known to influence the secretion of several anterior pituitary hormones under basal conditions. Further studies on prolactin, GH and TSH have therefore been performed in normal subjects, under basal and stimulated conditions, using an opiate agonist and antagonist. Sixteen mg naloxone had no effect on the basal release of prolactin or GH, but lowered TSH. An infusion of the met-enkephalin analogue DAMME (1 mg) increased GH, and produced an exaggerated response of both prolactin and TSH to 200 micrograms TRH i.v. The peak responses of both prolactin and GH to hypoglycaemia were unaffected by pretreatment with either low-dose (0.4 mg) or high-dose (25 mg) naloxone, or DAMME (0.25 mg). These results suggest that opiate peptides are unlikely to play a major role in the tonic or hypoglycaemia-stimulated release of prolactin and GH, although they may be of importance in the control of TSH.
Adolescent↗
[Opiates and carbohydrate metabolism].
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Blood Glucose↗
Management of the pregnant diabetic: home or hospital, with or without glucose meters?
Thirteen pregnant insulin-dependent diabetic patients were allocated to blood-glucose self-monitoring (meter) or conventionally treated (non-meter) groups at 30--31 weeks. A day-profile of blood-glucose and intermediary metabolite levels was obtained 2 weeks later at home and after routine admission to hospital at 35--36 weeks. Metabolic profiles were also obtained in eight normal pregnant women of equivalent gestational ages admitted to hospital for study. The mean blood-glucose and metabolite concentrations in both the meter and non-meter groups were similar to those obtained in the non-diabetic pregnant women (mean diurnal blood-glucose 4.6 +/- 1.1 mmol/l, meter group; 5.3 +/- 1.5 non-meter group; 4.8 +/- 0.8 controls). The diabetic control achieved at home was not improved by the use of a meter or admission to hospital (mean glucose at home 5.0 +/- 1.3 and 6.3 +/- 1.6 mmol/l in hospital). Both the use of a meter and admission to hospital may be valuable in some patients. Neither, however, is essential for the good control of blood-glucose in all pregnant diabetics.
Adolescent↗
The lung, whole-body metabolism and disease.
It is well recognized that the lung has its own hormonally responsive endogenous metabolism. Less well recognized is the potential of the lung to influence and, in turn, be influenced by the homeostatic mechanisms of the body. It is suggested that the lung could modulate concentrations of circulating hormones and thereby play an indirect exogenous metabolic role in whole-body metabolism. Investigations of patients undergoing cardiopulmonary bypass as well as studies with the perfused rat lung suggest that the lung could make an important direct contribution to whole-body lactate and perhaps alanine production. The control of the endogenous and exogenous metabolism of the lung may be exerted through circulating hormones, substrates, blood gases and lung movement. Disorders of the lung or the whole body may disturb these relationships. In patients with chronic lung disease circulating blood metabolites are affected and conversely in diabetes there are effects on lung metabolism. The unified concept of lung/whole-body metabolism is discussed in relation to therapeutic approaches for the prevention and investigation of neonatal and adult respiratory distress syndromes.
Animals↗
Substrate utilization by the lung.
Intermediary metabolism of the lung and its regulation have received relatively little attention in the past, partly because of difficulty in producing suitable models for study. An in situ perfused rat lung preparation is described which remains viable for four hours or more. Concentration-dependent glucose utilization has been found with this model, associated with marked lactate production. More than half the glucose used appears as lactate, despite the high PO2 and maintenance of normal ATP concentrations. The high rates of glycolysis may be related to glycerol-3-phosphate requirements for lipid synthesis. Glucose clearance from the perfusion medium is dependent on nutritional status, clearance by lungs from 48-hour starved animals being decreased by comparison with lungs of fed controls. Lactate is taken up actively at concentrations of 2 mmol/l or above but is produced at an initial lactate concentration of 0.4 mmol/l. Non-esterified fatty acids (1 mmol/l in the perfusate) are also cleared by lung and may be important as an energy source even though 80% is used for synthetic reactions. Alanine, glycerol and 3-hydroxybutyrate are unimportant as substrates. The lung responds to metabolically important hormones. Insulin and adrenaline cause an acute increase in glucose utilization whereas corticosterone and noradrenaline are inhibitory. Utilization of glucose is also diminished in lungs from diabetic ketoacidotic rats. Further work is required to establish the relative importance of oxidative and synthetic routes for added substrates and the mechanisms of hormonal regulation.
Adenosine Triphosphate↗
Airway and metabolic resistance to intravenous salbutamol: a study in normal man.
1. The airway and metabolic responses to an intravenous beta 2-agonist salbutamol have been investigated in normal subjects before and after chronic administration of inhaled salbutamol, 1600 micrograms daily for 2 weeks. 2. Before chronic inhalation of salbutamol there was a dose-dependent increase in specific airway conductance after intravenous salbutamol in cumulative doses from 25 to 300 micrograms. 3. Measurement of concentrations of blood glucose, lactate, pyruvate, glycerol, ketone bodies, non-esterified fatty acids, insulin, plasma cyclic AMP and cyclic GMP were made after each increment of salbutamol and all showed an increase apart from cyclic GMP. 4. After chronic inhalation of salbutamol there was a decrease in the airway, metabolic and insulin response to intravenous salbutamol. The cyclic AMP response showed little change. 5. This study confirms the development of adrenergic resistance in the airways of normal subjects after large does of inhaled salbutamol and shows that this is associated with widespread metabolic adrenergic resistance.
Adult↗
Chlorpromazine, haloperidol, metoclopramide and domperidone release prolactin through dopamine antagonism at low concentrations but paradoxically inhibit prolactin release at high concentrations.
1. The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied. 2. Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine-mediated inhibition of prolactin release at low concentrations. 3. Each dopamine antagonist displaced the dose-response curve for dopamine-induced suppression of prolactin release to the right in a parallel manner. 4. At higher concentrations, the four drugs became less effective as dopamine antagonists. 5. At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism.
Animals↗
Effect of serotonin on prolactin secretion in vitro.
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Animals↗
Sensitivity to enkephalin as a cause of non-insulin dependent diabetes.
Non-insulin-dependent diabetes is associated with facial flushing after alcohol in patients on chlorpropamide (chlorpropamide alcohol flushing, C.P.A.F.) especially when there is a family history of diabetes. C.P.A.F. in three subjects (two diabetics, one non-diabetic) was blocked by the specific opiate antagonist naloxone. In nine subjects (six diabetics) C.P.A.F. was reproduced by the enkephalin analogue with opiate-like activity [D-Ala2, MePhe4, Met (O)-ol] enkephalin (DAMME). C.P.A.F. thus may be due to increased sensitivity to endogenous opiates. DAMME and other substances with opiate-like activity, such as morphine and beta-endorphin, affect carbohydrate metabolism and insulin secretion. Increased sensitivity to endogenous opiates such as enkephalin may thus give rise to non-insulin-dependent diabetes associated with C.P.A.F.
Alcoholic Beverages↗