Human insulin.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
A W Patrick
Publications and source records attributed to A W Patrick.
Human insulin and hypoglycaemia: burning issue or hot air?
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Awareness↗
Changes in renal function during acute insulin-induced hypoglycaemia in patients with type 1 diabetes.
The effect of acute hypoglycaemia on renal function was examined in eight male patients with Type 1 diabetes who had normal urinary albumin excretion. Insulin was given as a bolus intravenous injection (0.125 U kg-1) and plasma glucose fell to a nadir of 1.6 (SE 0.2) mmol l-1, with all patients experiencing an acute autonomic reaction. Renal plasma flow fell from 674 (106) to 540 (198) ml min-1 during hypoglycaemia (p less than 0.01) and returned to 655 (181) ml min-1 (NS vs baseline). Glomerular filtration rate (GFR) declined from 143 (23) to 110 (36) ml min-1 during hypoglycaemia (p less than 0.02), rising to 150 (44) ml min-1 in the recovery period (NS vs baseline). The urinary flow rate and urinary albumin excretion rate both fell significantly in response to hypoglycaemia (10.6 (1.2) to 4.7 (1.1) ml min-1; p less than 0.002, and 46.2 (10.6) to 26.0 (10.5) micrograms min-1, respectively). Urinary dopamine excretion also declined, from 322 (37) to 211 (29) mumol min-1 (p less than 0.005) but sodium excretion was unchanged. Plasma adrenaline concentration (0.2 (0.03) to 1.7 (0.4) nmol l-1; p less than 0.01) and plasma renin activity (0.49 (0.13) to 1.08 (0.17) ng-Ang 1 l-1 h-1; p less than 0.01) increased during hypoglycaemia, but changes in plasma noradrenaline and angiotensin II levels did not attain significance. These acute changes in renal function, observed during hypoglycaemia in diabetic patients, may result from direct stimulation of the efferent sympathetic nerves to the kidney, complemented by the hormonal changes induced by hypoglycaemia.
Adult↗
Are some animals more equal than others?
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Animals↗
Hospital in-patient statistics underestimate the morbidity associated with diabetes mellitus.
Hospital in-patient statistics are an important outcome measurement in the assessment of the morbidity associated with diabetes mellitus. A prospective study of 157 consecutive admissions over a 28-day period compared diagnoses obtained from the clinical records with the ICD9 coding of the same admissions recorded at the Information and Statistics Division of the Scottish Health Service. Sixty-one percent of all discharge summaries omitted the diagnosis of diabetes. Even when admission was principally related to diabetes complications, 47% of medical and 88% of surgical discharge summaries omitted diabetes as a diagnostic category. ICD9 coding underestimated the percentage of admissions accounted for by diabetic patients by 100% (2.8 vs 5.6%) and as a result underestimated bed occupancy by over 200% (4.3 vs 13.7%), and is thus failing to fulfil its potential as a demographic and epidemiological record of resource use by disease classification.
Adolescent↗
The Liverpool Symposium on Human Insulin and Hypoglycemia.
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Diabetes Mellitus, Type 1↗
Exaggerated sensitivity to NE-induced vasoconstriction in IDDM patients with microalbuminuria. Possible etiology and diagnostic implications.
Increased urinary albumin excretion rate (AER) in the microalbuminuric phase of diabetic nephropathy has been attributed to intraglomerular hypertension. This could be caused by constriction of efferent glomerular arterioles, which carry alpha-adrenoceptors. We tested the hypothesis that insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria are hypersensitive to vasoconstriction induced by norepinephrine (NE). We studied 15 IDDM patients with microalbuminuria (AER 32-295 mg/24 h), 13 IDDM patients with normal AER (5-24 mg/24 h), and 9 nondiabetic subjects (AER 8-22 mg/24 h). All were normotensive. NE-induced vasoconstriction was measured in dorsal hand veins, which carry alpha-receptors similar to those of glomerular efferent arterioles. Vein diameter was measured with a linear displacement probe during a stepped NE infusion (1-32 ng/min) into the vein, and venoconstriction was expressed as a percentage of the maximum passively distended venous diameter. Microalbuminuric IDDM patients exhibited significantly greater vasoconstriction (P less than 0.005) at all NE infusion rates than both other groups. The NE infusion rate producing 50% of maximal venoconstriction (ED50) in the microalbuminuric IDDM group (median 1.1 ng/min, range 0.2-25.2 ng/min) was significantly less than in both the normoalbuminuric IDDM group (median 12.5 ng/min, range 4.9-40.5 ng/min, P = 0.00007) and the nondiabetic group (median 17.7 ng/min, range 5.9-42.2 ng/min, P = 0.0003). Dose-response curves and ED50 did not differ significantly between normalbuminuric IDDM and nondiabetic groups. IDDM patients with microalbuminuria are hypersensitive to NE-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes.
Some insulin-dependent diabetic patients who have clear symptoms of hypoglycaemia during animal insulin treatment have reported loss of these symptoms when human insulin preparations are introduced. A survey of Mersey Region, UK, identified eleven patients whose awareness of hypoglycaemia was lost after introduction of human insulin but returned with animal insulin treatment; seven took part in the study. Acute hypoglycaemia was induced in these patients on two occasions by intravenous infusion of porcine or human soluble insulin (2.5 mU.kg-1, min-1) in random order. There was no significant difference between porcine and soluble insulin in the plasma glucose profile; mean (SEM) plasma glucose fell from 7.1 (0.4) mmol/l to a nadir of 1.5 (0.1) mmol/l with porcine insulin and from 7.1 (0.5) mmol/l to 1.6 (0.2) mmol/l with human insulin. An acute autonomic reaction occurred in all seven patients, at a similar plasma glucose concentration (1.9 [0.1] mmol/l with porcine insulin; 2.0 [0.2] mmol/l with human insulin). There were no significant differences in the frequency of symptoms or signs of hypoglycaemia between the two insulin species, nor any consistent differences in plasma glucagon, cortisol, growth hormone, adrenaline, or noradrenaline responses to hypoglycaemia. Symptomatic and hormonal responses to acute hypoglycaemia induced by porcine and human soluble insulins therefore seem to be almost indistinguishable, even in patients carefully selected for their apparent loss of hypoglycaemia awareness with human insulin.
Acute Disease↗
Association between connective tissue changes and smoking habit in type 2 diabetes and in non-diabetic humans.
Two hundred type 2 (non-insulin-dependent) diabetic patients and 170 non-diabetic age- and sex-matched normotensive controls were examined for limited joint mobility (LJM) and Dupuytren's contracture (DC), and their smoking history was documented. The prevalences of LJM and DC were not significantly different in diabetic and control subjects (LJM: odds ratio 1.58, 95% CI 0.99 to 2.50; DC: odds ratio 1.34, CI 0.81 to 2.23). Cigarette smoking was positively associated with both LJM and DC in the diabetic patients (LJM: relative risk (R) = 1.96, 95% CI 1.10 to 3.49; DC: R = 2.88, CI 1.29 to 6.43) and in the control group (LJM: R = 2.22, CI 1.70 to 5.86; DC: R = 2.71, CI 1.23 to 5.89). Limited joint mobility and Dupuytren's contracture are both associated with cigarette smoking in type 2 diabetic patients and in age-matched non-diabetic subjects. This suggests that type 2 diabetes is only one of a number of factors which promote the development of these connective tissue changes.
Connective Tissue↗
Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation.
To investigate the relationship between awareness of symptoms and the autonomic reaction of hypoglycaemia, acute hypoglycaemia was induced with intravenous insulin (2.5 mU kg-1 min-1) in diabetic and non-diabetic subjects, all of whom had normal cardiovascular autonomic function tests. Three groups were studied: (1) nine patients with Type 1 diabetes with loss of awareness of hypoglycaemia; (2) eight patients who had normal awareness of hypoglycemia, matched for duration of diabetes and blood glucose control; (3) eleven non-diabetic volunteers. The onset of the acute autonomic reaction was identified objectively by the sudden and rapid responses of heart rate and sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia. In the 'unaware' diabetic patients, onset of the reaction occurred at a significantly lower plasma glucose (1.0 +/- 0.1 mmol l-1) than in the 'aware' diabetic patients (1.6 +/- 0.2 mmol l-1) (p less than 0.05) or in the non-diabetic control group (1.4 +/- 0.1 mmol l-1) (p less than 0.05). Obvious neuroglycopenia was observed only in the 'unaware' diabetic group and developed when plasma glucose had declined to approximately 1.4 +/- 0.1 mmol l-1, and thus preceded the reaction (p less than 0.02 vs the autonomic threshold). The maximal rise in plasma adrenaline was of similar magnitude in all three groups but a lower plasma glucose was required to stimulate this hormonal response in the 'unaware' patients, in whom the plasma adrenaline concentration was lower at the time of the reaction. Thus, the plasma glucose at which activation of the autonomic reaction was observed was lower in the diabetic patients with unawareness of hypoglycaemia.
Adrenal Glands↗
Alterations in monocyte receptor function in type 1 diabetic patients with ketoacidosis.
The level of expression of three monocyte cell surface receptors was studied in seven patients with Type 1 (insulin-dependent) diabetes admitted to hospital with ketoacidosis. After recovery of metabolic control the monocyte carbohydrate-binding ('lectin-like') receptors that recognize bacterial cell wall sugars and receptors for complement components were reduced in the patients compared with normal control subjects. This was in contrast to the expression of the receptor for the Fc portion of immunoglobulin which remained unaltered. Compared with the control subjects the level of 'lectin-like' receptors was reduced by 22.8 +/- 6.5% (p less than 0.05) on admission to hospital and 12.1 +/- 1.7% (p less than 0.001) 6 weeks later when metabolic control had been established. The expression of complement receptors was 33.8 +/- 8.1% (p less than 0.01) lower than normal subjects when the diabetic patients suffered from ketoacidosis and 8.6 +/- 1.6% (p less than 0.01) lower than control subjects when patients had recovered metabolic control. The increased susceptibility to infection seen in diabetic patients, and the high incidence of infection in patients with ketoacidosis, may be partially the result of these changes in monocyte recognition mechanisms.
Adult↗
Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach.
OBJECTIVE: This study allocated the symptoms identified during acute hypoglycemia objectively to the autonomic or neuroglycopenic groups of symptoms by the use of factor analysis. RESEARCH DESIGN AND METHODS: Twenty-five nondiabetic subjects, 14 newly diagnosed insulin-dependent diabetic patients, and 16 insulin-dependent diabetic patients with diabetes greater than 4 yr duration were studied. Acute hypoglycemia was induced with insulin (2.5 mU.kg-1 body wt.min-1 i.v.), and symptoms of hypoglycemia were recorded with a seven-point scale at regular time points throughout the studies. Factor analysis of the symptom scores at the time of the acute autonomic reaction with principal component analysis followed by Varimax rotation was used to separate those symptoms that might belong to neuroglycopenic and autonomic groups. RESULTS: Hypoglycemia was induced to a mean +/- SE plasma glucose nadir of 1.3 +/- 0.1 mM in nondiabetic subjects, to 2.0 +/- 0.3 mM in newly diagnosed diabetic patients, and 1.4 +/- 0.2 mM in patients with diabetes of greater than 4 yr duration. The most frequently reported autonomic symptoms were sweating, trembling, and warmness, and the most frequently reported neuroglycopenic symptoms were inability to concentrate, weakness, and drowsiness. Neuroglycopenic symptoms were reported more commonly at the onset of hypoglycemia, which was identified by the development of symptoms. Factor analysis grouped trembling, anxiety, sweating, warmness, and nausea together, and this grouping was labeled an autonomic factor. A second factor was identified that included dizziness, confusion, tiredness, difficulty in speaking, shivering, drowsiness, and inability to concentrate, which was labeled a neuroglycopenic factor. CONCLUSIONS: This study demonstrated the high frequency with which neuroglycopenic symptoms occur at the onset of hypoglycemia and the symptoms that could be used by an individual patient as a warning of the development of acute hypoglycemia, although the rapid reduction of plasma glucose is faster than experienced by the ambulant diabetic patient. Factor analysis assisted with the allocation of symptoms to either the autonomic or neuroglycopenic groupings, but the allocation of some symptoms remained undefined, and care must be taken when assessing symptoms such as hunger, weakness, blurred vision, and drowsiness when comparing the frequency of autonomic versus neuroglycopenic symptoms. To reduce the confusion resulting from the use of different symptom questionnaires in studies of hypoglycemia, a sample questionnaire is presented, the development of which was assisted by our analysis.
Adult↗
Relationship between urinary excretion of sodium and dopamine in type 1 diabetic patients with an without microalbuminuria.
The relationship between urinary sodium and dopamine excretion was investigated in 40 normal males and in 48 normotensive, Type 1 diabetic males, 11 with microalbuminuria and 37 with normal albumin excretion. In all three groups a significant correlation was demonstrated and the regression lines were similar. Thus, no evidence was found that a defect in dopamine mobilization contributes to the early renal pathophysiological changes of Type 1 diabetes.
Adult↗
The natural history and associations of microalbuminuria in type 2 diabetes during the first year after diagnosis.
The prevalence of microalbuminuria was assessed in 149 consecutive, newly-diagnosed and untreated patients with Type 2 diabetes, 129 of whom were followed up for 1 year, with at least three urine specimens being obtained during this period. At initial presentation, 39 (26%) patients had a urinary albumin to creatinine ratio (ACR) of greater than 2.5 mg mmol-1 and compared with patients who had a normal ACR, they were older (64 (11) (SD) vs 58 (11) yr, p less than 0.002), with higher random blood glucose (14.4 (4.5) vs 12.3 (4.4) mmol l-1, p less than 0.02) and glycosylated haemoglobin (13.0 (3.1) vs 11.3 (2.7)%, p less than 0.01) concentrations. An elevated ACR was also associated with a higher systolic blood pressure (149 (22) vs 140 (22), p less than 0.05) and the presence of macrovascular disease, particularly peripheral vascular disease (p less than 0.001), with this association persisting after adjustment for the effect of age. Ten patients reverted to normal albumin excretion on improving blood glucose control, this group having a significantly higher glycosylated haemoglobin concentration at initial presentation than the group with a persistently elevated ACR (14.4 (2.5) vs 12.0 (3.0)%, p less than 0.05). The 21 (16%) patients with a persistently elevated ACR from diagnosis of Type 2 diabetes were older than those with normal albumin excretion throughout (64 (7) vs 58 (10) yr, p less than 0.02) and it is probable that these patients have abnormal albumin excretion secondary to established renal pathology.
Albuminuria↗
Fatal hypoglycaemia in insulin-treated diabetes mellitus: clinical features and neuropathological changes.
Four insulin-treated diabetic patients presented over a 2-year period in hypoglycaemic coma and died secondary to this. At autopsy, there were widespread neuropathological changes, in all four cases consistent with hypoglycaemic damage. Abnormalities were also found in areas regarded as generally being spared in hypoglycaemic brain injury, particularly the brain stem, thalamus, globus pallidus, and cerebellum, and these lesions may relate to seizure activity and cardio-respiratory depression secondary to the hypoglycaemia. Although more than one aetiological factor may be contributing, it is concluded that the neuropathological changes in diabetic patients dying in hypoglycaemic coma are extremely diverse.
Adult↗
Leucocyte mobilization and release of neutrophil elastase following acute insulin-induced hypoglycaemia in normal humans.
Insulin-induced hypoglycaemia in humans is associated with the rapid mobilization of leucocytes in peripheral blood. The aim of the present study was to determine whether neutrophil activation, manifested in plasma by neutrophil elastase concentration, occurs in response to insulin-induced hypoglycaemia. Acute hypoglycaemia (mean blood glucose 1.3 +/- 0.2 mmol l-1; mean +/- SD) was induced with intravenous insulin in 15 normal human subjects, and provoked an increase in the neutrophil count from 3.4 (range 1.9-6.5) to 10.7 (9.4-16.3) X 10(9) l-1 (p less than 0.001), and in the total leucocyte counts from 5.7 (4.1-8.1) to 12.8 (11.3-18.6) X 10(9) l-1 (p less than 0.001), with associated elevations in plasma neutrophil elastase concentration from 21 (12-34) to 29 (14-70) micrograms l-1 (p less than 0.05), and in total neutrophil elastase concentration from 5.90 (3.13-8.20) to 25.20 (23.00-52.00) mg l-1 (p less than 0.001). As neutrophil elastase is implicated in the development of vascular disease, this rise in response to hypoglycaemia may be of pathological importance in insulin-treated diabetic patients.
Adult↗
Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department.
Hypoglycaemia remains a serious and much feared complication of insulin therapy. In this study, patients attending an accident and emergency department in hypoglycaemic coma were randomized to treatment with either intravenous dextrose (25g) or intramuscular glucagon (1mg), administered into the right thigh. Restoration of normal conscious level was slower after glucagon than dextrose (9.0 vs 3.0 min, P less than 0.01), although the average duration of hypoglycaemic coma was 120 min. Two patients in the glucagon-treated group, who failed to show satisfactory recovery after 15 min, required additional treatment with intravenous dextrose. On questioning following recovery, all except two patients reported loss of awareness of the onset of hypoglycaemia Intramuscular glucagon is valuable in the treatment of severe hypoglycaemia outwith hospital and, although the slightly slower and less predictable recovery may appear to make it a less attractive option than intravenous dextrose in the accident and emergency department, this must be balanced against the advantages of ease of administration and a lower incidence of serious adverse effects.
Diabetes Mellitus, Type 1↗
Plasma hepatic glutathione S-transferase concentrations after insulin-induced hypoglycaemia in normal subjects and diabetic patients.
Plasma glutathione S-transferase basic isoenzyme (GST B1) concentrations have been measured by specific radioimmunoassay in Type 1 diabetic patients and in normal subjects, before and after controlled insulin-induced hypoglycaemia, and in a further group of Type 1 diabetic patients in hypoglycaemic coma. The activities of alanine aminotransferase (ALT), aspartate amino-transferase (AST), and gamma-glutamyl transferase (gamma GT) were also measured. GST B1 concentrations were significantly increased 3 h after controlled insulin-induced hypoglycaemia, both in the diabetic patients (p less than 0.02) and in the normal group (p less than 0.05), but the magnitude of the rise did not differ between these two groups. Four of the 9 patients presenting in hypoglycaemic coma had a GST B1 concentration above the reference range. ALT, AST, and gamma GT activities did not rise following hypoglycaemia in any of the groups.
Adolescent↗