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Biomedical subjects

S R Heller

Publications and source records attributed to S R Heller.

At least 19 recordsLinked to original sources

Increased symptoms of hypoglycaemia in the standing position in insulin-dependent diabetes mellitus.

1. To test the hypothesis that patients with insulin-dependent diabetes mellitus perceive the symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position, we assessed symptoms of hypoglycaemia, as well as heart rate and plasma noradrenaline and adrenaline concentrations, in both positions during hyperinsulinaemic glucose clamps on three occasions in seven patients. 2. Plasma glucose concentrations were clamped at 5.0 mmol/l (90 mg/dl) and 5.0 mmol/l on one occasion, at 5.0 mmol/l and 3.9 mmol/l (70 mg/dl) on another occasion, and at 5.0 mmol/l and 2.8 mmol/l (50 mg/dl) on yet another occasion. 3. During euglycaemia there was no effect of position on the symptom panels used to assess the symptomatic response to hypoglycaemia. However, at the plasma glucose concentration of 2.8 mmol/l, total (P less than 0.003) and neurogenic (P less than 0.005), but not neuroglycopenic, hypoglycaemic symptom scores were higher with the patients in the standing than in the lying position. Increments in total hypoglycaemic symptom scores, over those during the corresponding euglycaemic phase, were 5 +/- 2 in the lying position and 11 +/- 2 in the standing position (means +/- SEM, P less than 0.01). 4. Thus patients with insulin-dependent diabetes mellitus perceive symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position because of enhanced neurogenic symptoms.

Adult

Physiological disturbances in hypoglycaemia: effect on subjective awareness.

Deficiencies in the release of glucagon and adrenaline during hypoglycaemia in diabetic patients are associated with a high frequency of severe hypoglycaemic episodes. These have been attributed to a resulting inability to increase hepatic glucose output acutely. A more important consequence may be reduced awareness of impending hypoglycaemia. Such hypoglycaemia unawareness is related to, but not entirely explained by, diminished sympathetic activity, perhaps due to failure to activate the sympathoadrenal system until a lower blood glucose level is achieved. The patient's subsequent failure to act appropriately would then be due to impaired cerebral function preventing the perception of sympathoadrenal activation during the more severe hypoglycaemia. Unawareness of moderate hypoglycaemia is common in diabetic patients. Autonomic neuropathy probably accounts for only a few cases of hypoglycaemia unawareness and other factors which are potentially important include duration of diabetes, glycaemic control, insulin species, and the degree and frequency of hypoglycaemia. Further research is required to discover both the pathophysiological mechanisms of, and the treatment needed to reverse or prevent, the abnormality.

Awareness

Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans.

To test the hypothesis that glucose recovery from hypoglycemia can occur in the absence of decrements in insulin below baseline, we studied nine normal humans on six occasions. In a control study, saline was infused. In five experimental studies, insulin (0.6 mU.kg-1.min-1) was infused from 0 to 80 min, to produce hypoglycemia (approximately 3.3 mM). Then, from 80 to 180 min, insulin was not infused or was infused in four different doses 0.1, 0.2, 0.4, and 0.6 mU.kg-1.min-1), and glucose recovery was assessed. In the recovery periods, approximately fourfold peripheral with approximately twofold portal insulin elevations prevented glucose recovery (glucose = 3.6 +/- 0.1 mM, counter-regulatory hormone levels elevated throughout). However, biological glucose recovery, documented by increments to 4.3 +/- 0.1 mM and decrements in all counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) to control levels, occurred despite nearly twofold peripheral hyperinsulinemia (54 +/- 4 vs. 32 +/- 4 pM, P less than 0.01) in the absence of portal hypoinsulinemia (58 +/- 4 vs. 68 +/- 8 pM). Thus we conclude that, although dissipation of insulin normally plays an important role in the correction of hypoglycemia, biological glucose recovery from hypoglycemia to glucose levels more than sufficient to disengage glucose counterregulatory systems and well above those required to produce symptoms of hypoglycemia can occur in the absence of decrements in portal insulin below baseline and despite mild peripheral hyperinsulinemia.

3-Hydroxybutyric Acid

Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans.

To test the hypothesis that hypoglycemia itself causes reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia, we measured those responses during clamped hypoglycemia (2.8 mM) on consecutive mornings on two occasions, with interval afternoon (1400-1600) hypoglycemia (3 mM) on one occasion and interval afternoon euglycemia (5 mM) on the other, in nine nondiabetic humans. None of the measured responses were reduced by interval euglycemia. In contrast, plasma epinephrine (P less than 0.005), glucagon (P less than 0.005), pancreatic polypeptide (P less than 0.01), cortisol (P less than 0.02), and total (P less than 0.001), neurogenic (P less than 0.001) and neuroglycopenic (P less than 0.05) symptom responses to morning hypoglycemia were reduced after interval afternoon hypoglycemia. Thus, a single episode of hypoglycemia caused a generalized reduction of the neuroendocrine and symptomatic responses to subsequent hypoglycemia, a finding that may be important to the pathogenesis of iatrogenic hypoglycemia in insulin-dependent diabetes mellitus.

Adult

Double-blind evaluation of efficacy and tolerability of metformin in NIDDM.

OBJECTIVE: To test the efficacy and tolerability of metformin. RESEARCH DESIGN AND METHODS: An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily. RESULTS: Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly, and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated. CONCLUSIONS: Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects.

Body Weight

Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes.

Both hypoglycaemia and alcohol consumption affect cognitive function but it is unclear whether moderate drinking alters awareness of hypoglycaemia. We have examined this in a single blind randomised hyperinsulinaemic clamp study in eight non-diabetic subjects and seven Type 1 (insulin-dependent) diabetic patients. After 30 min of euglycaemia (blood glucose 4.5 mmol/l) subjects drank either 0.75 g/kg ethanol or a placebo drink after which blood glucose was lowered to 2.5 mmol/l for 40 min. Awareness of hypoglycaemia, reaction time and physiological responses were measured before and after ethanol. At a blood glucose concentration of 4.5 mmol/l, ethanol (producing peak blood levels of 20-25 mmol/l) caused a transient increase in systolic blood pressure (p less than 0.05), a sustained increase in heart rate (p less than 0.01) and a slowing of reaction time in both normal subjects and diabetic patients. During hypoglycaemia in both groups, the slowing of reaction time and increase in sweating were more marked after ethanol than placebo (both p less than 0.05), while the increase in finger tremor (p less than 0.05) was blunted after ethanol, in both groups. Counter regulatory hormone secretion was not affected by ethanol. Despite increases in symptoms during hypoglycaemia, only 2 of 15 individuals "felt hypoglycaemic" after ethanol compared to 11 out of 15 after placebo. We conclude that after moderate drinking non-diabetic subjects and Type 1 diabetic patients are less aware of hypoglycaemia despite exaggerated physiological changes.

Adult

Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross-over design in 12 healthy volunteers. 2. All three beta-adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m-2 min-1) clamp conditions, at a blood glucose of 2.5 mmol l-1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre-treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta-adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter-regulatory hormones during hypoglycaemia was enhanced by beta-adrenoceptor blockade. 6. We conclude that beta-adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.

Adrenergic beta-Antagonists

Human antibody responses to bacteriophage phi X 174: sequential induction of IgM and IgG subclass antibody.

We studied the appearance of antigen-specific immunoglobulin classes and IgG subclasses in normal adult human subjects in response to primary, secondary, and tertiary immunization with the T-cell-dependent neo-antigen bacteriophage phi X 174. To complete the study we developed a sensitive, specific, and reproducible ELISA assay which was closely comparable to the widely used neutralization assay for total antibody (r = +0.97) and for IgG antibody (r = +0.93), and reasonably comparable for IgM antibody (r = +0.76). We confirmed that the initial response to primary immunization was predominantly, but not exclusively, IgM antibody. The secondary and tertiary responses demonstrated memory, amplification, and switch from IgM to IgG antibody. There was an orderly appearance of phage-specific IgG subclasses. IgG3 and IgG1 antibodies appeared 2 to 6 weeks after primary immunization. In all subjects there was a marked increase in IgG1 and IgG3 antibody after secondary immunization, and IgG2 antibody followed closely; IgG4 antibody appeared in some subjects. IgM antibody persisted in significant amounts (approx 50%) throughout the secondary response period. Following tertiary immunization, IgG1, IgG2, and IgG3 antibody consistently increased, and IgG4 antibody appeared in all subjects; IgG1 antibody predominated. Low levels of IgM antibody (approx 1% of total) persisted during the tertiary response. The persisting antibody on long-term follow-up (median 4 years after immunization) was virtually all (greater than 90%) IgG1.

Adult

Lymphocyte alterations in zinc-deficient calves with lethal trait A46.

Lymphocyte numbers and activities were evaluated at 2, 4, 8 and 12 weeks of age in two calves with lethal trait A46 (A46), a genetic disorder affecting intestinal zinc absorption. Plasma zinc concentrations declined to subnormal by 3 weeks of age, after which anorexia, diarrhea, alopecia and hyperkeratosis occurred. Lymphocyte response to phytohemagglutinin-P (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) stimulation was variably reduced. CD4+ T-lymphocytes were subnormal on at least one observation period following onset of zinc deficiency, and relative numbers of B lymphocytes were decreased at 8 weeks. Secondary antibody responses to bacteriophage phi X 174 were significantly reduced. The results demonstrate that calves homozygous for the A46 trait have normal numbers of functional lymphocyte subpopulations at birth, and that the activity of their lymphocytes is altered once the calves become zinc deficient.

Animals

Role of C3 in humoral immunity. Defective antibody production in C3-deficient dogs.

Previous studies have shown that animals pharmacologically depleted of C3 have impaired antibody responses. However, such C depletion is neither complete nor sustained, and the C3 cleavage products generated by C3 depletion can both enhance and inhibit the immune response. To clarify the role of C3 in humoral immunity, the antibody response of dogs with genetically determined total deficiency of C3 (C3D) was examined. Serum IgG levels of the C3D animals were within the normal range, but were significantly lower than levels seen in normal controls or C3D heterozygotes. Specific antibody production was defective: the antibody titers of C3D dogs in response to primary intravenous immunization with two different T cell-dependent Ag (sheep E and bacteriophage phi X-174) were markedly reduced when compared to either normal controls or C3D heterozygotes. After secondary immunization with T-dependent Ag, the total antibody titers were normal, but the C3D dogs made proportionately more IgM and less IgG antibody than did either control group. After i.v. immunization with a T cell-independent Ag (DNP-Ficoll), the C3D dogs had reduced levels of IgM and IgG antibody after primary and secondary immunization. Neither i.m. immunization nor the use of a 20-fold increase in Ag dose i.v. could correct the defect seen in the antibody response of C3D dogs. The results herein demonstrate that C3 plays a critical role in the generation of a normal humoral immune response.

Agammaglobulinemia

Group education for obese patients with type 2 diabetes: greater success at less cost.

It has been suggested that much effort expended in teaching diabetic diets is ineffective and wasteful. We have tested a different system by randomly allocating 75 newly diagnosed obese Type 2 diabetic patients to usual 'unstructured' clinic care or to group education by diabetes specialist nurses and a dietitian. Patients allocated to group education attended five 90-min group sessions during the first 6 months. Six months after diagnosis they had lost more weight (median (95% Cl), 7 (5.5-9) vs 2(1-5)kg, p less than 0.002) and were better controlled (HbA1:7.5 (7.0-8.1) vs 9.5 (8.7-10.4)%, p less than 0.001) than those randomized to the usual clinic system. At 1 year (after no further visits) the difference in weight loss was less (5.5 (4-6.5) vs 3 (2-4) kg, p less than 0.05) and diabetic control was similar (HbA1:9.0(8.2-9.8) vs 9.9(8.9-10.9)%. At 1 year only 14(39%) of the education group and 9(23%) of those attending the clinic had a fasting blood glucose less than 7.0 mmol l-1.

Blood Glucose

Influence of sympathetic nervous system on hypoglycaemic warning symptoms.

The effect of mild insulin-induced hypoglycaemia on symptoms, physiological changes, and adrenaline responses was assessed in 10 normal subjects and 15 insulin-dependent diabetic patients (5 with reduced awareness of hypoglycaemic symptoms). When blood glucose was maintained at 3.2 mmol/l, reaction time was prolonged in both normal and diabetic subjects and plasma adrenaline levels increased in the normals and some diabetics; there were no other physiological responses. 2 normals and 1 diabetic were aware that their blood glucose was low. When blood glucose was maintained at 2.5 mmol/l for 30 min, 9/10 normals but only 4/15 diabetics recognised hypoglycaemia. Increases in hypoglycaemic symptom score, tremor, and sweating, and falls in diastolic blood pressure were significant only in the normal subjects and the 4 "aware" patients. Adrenaline levels increased in all cases, but were more pronounced in the normals and aware diabetics. Reaction time remained prolonged in all groups. All measurements returned to baseline when blood glucose was raised to 4.5 mmol/l. Impairments in adrenaline response may be common, even in diabetic patients without autonomic neuropathy and in those who do not complain of hypoglycaemic unawareness; consequent failure to recognise a falling blood glucose may predispose to a risk of severe hypoglycaemia.

Adult

Counterregulation in type 2 (non-insulin-dependent) diabetes mellitus. Normal endocrine and glycaemic responses, up to ten years after diagnosis.

We have examined hormonal and metabolic responses to insulin-induced hypoglycaemia in 10 Type 2 (non-insulin-dependent) diabetic patients treated with tablets and 10 age, sex and weight matched control subjects. Diabetic patients were under 110% ideal body weight, had no autonomic neuropathy and were well controlled (HbA1, 7.1 +/- 0.2%). After the diabetic patients were kept euglycaemic by an overnight insulin infusion, hypoglycaemia was induced in both groups by intravenous insulin at 30 mU.m-2.min-1 for 60 min and counterregulatory responses measured for 150 min. There were no significant differences between diabetic patients and control subjects in the rate of fall (3.3 +/- 0.3 vs 4.0 +/- 0.3 mmol.l-1.h-1), nadir (2.4 +/- 0.2 vs 2.3 +/- 0.1 mmol/l) and rate of recovery (0.027 +/- 0.002 vs 0.030 +/- 0.003 mmol.l-1.min-1) of blood glucose. Increments of glucagon (60.5 +/- 5.7 vs 70 +/- 9.2 ng/l) and adrenaline (1.22 +/- 0.31 vs 1.45 +/- 0.31 nmol/l) were similar in both groups. When tested using this model, patients with Type 2 diabetes, without microvascular complications and taking oral hypoglycaemic agents show no impairment of the endocrine response and blood glucose recovery following hypoglycaemia.

Adult

Starting insulin treatment as an outpatient. Report of 100 consecutive patients followed up for at least one year.

Most textbooks advise that newly diagnosed insulin-dependent diabetics be admitted to the hospital. Nevertheless, if they are not acutely ill, we start insulin treatment on an outpatient basis. We report herein the logistics, efficacy, and safety of our system. Over two years, 115 newly diagnosed insulin-dependent diabetics were seen in our hospital. Fifteen (66% of them ketoacidotic) were admitted. The other 100 were treated as outpatients by a nurse specialist with a starting dosage of 6 to 10 units of intermediate-acting insulin twice daily. Hemoglobin A1 concentration at diagnosis was 15.2% +/- 2.7% (mean +/- SD); at six months, 10.9% +/- 2.9%; and at one year, 10.6% +/- 2.8%. Only three outpatient starters were hospitalized in the first year, one for hypoglycemia and two with respiratory tract infections. Our findings suggest that outpatient stabilization is both safe and cost-effective.

Adolescent

Renal handling of calcium and sodium in metastatic and non-metastatic malignancy.

Investigation of the renal handling of calcium and sodium in rehydrated patients with hypercalcaemia associated with malignancy showed enhanced reabsorption of calcium in most cases. This was a feature of both metastatic and non-metastatic malignancy, and in this respect the patients were indistinguishable from patients with primary hyperparathyroidism. As the increased calcium reabsorption was inversely correlated with the rate of excretion of sodium modest salt loading can be used to inhibit this process. This is an important practical aspect of the treatment of patients with this type of hypercalcaemia.

Absorption

Quantitation of the renal effect of calcitonin in the hypercalcaemia of malignancy.

The renal effect of calcitonin (independent of changes due to variations in sodium excretion) was quantitated in malignancy associated hypercalcaemia. There was considerable inter- and intra-patient variability in response but this was unaffected by tumour type. Humoral hypercalcaemia tended to be resistant to control. In responsive patients the renal effects of calcitonin unlike those described in bone did not diminish with time.

Calcitonin

Complement, membrane glycoproteins, and complement receptors: their role in regulation of the immune response.

To determine the effect of complement on the normal antibody response we studied seven patients with genetically determined complement component deficiencies, guinea pigs deficient of C4 and C2, respectively, and two patients whose neutrophils and monocytes lack the C3bi receptor. Patients deficient of early complement components (C4, C2, C3) have abnormal antibody responses to the T-cell-dependent antigen, bacteriophage phi X 174. Complement-deficient guinea pigs (C4, C2) produce less antibody than normal guinea pigs and are unable to maintain measurable antibody levels; during secondary immunization they fail to develop amplification and to switch from IgM to IgG. This defect can be overcome by increasing the antigen dose or by injecting normal guinea pig serum at the time of the primary (but not the secondary) immunization. Patients with deficiency of the C3bi receptor were shown to have a significantly depressed antibody response to T-dependent antigens. We postulate that the contribution of complement to the mature humoral immune response is related to activation of C3. The initial production of IgM following antigen injection leads to antigen-antibody complexes which interact with complement, to be nonspecifically trapped by C3b and C3bi receptors on B cells or macrophages. Thus antigen is selectively accumulated within the lymphoid organs and in turn may entrap antigen-specific B cells by interaction of the trapped antigen with surface immunoglobulin. As a result, close approximation between antigen, antibody, and a network of specific and nonspecific lymphoid cells is initiated, allowing generation of specific memory cells and initiation of a prompt mature antibody response on subsequent exposure to antigen.

Animals