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Biomedical subjects

S A Amiel

Publications and source records attributed to S A Amiel.

16 recordsLinked to original sources
PubMed1992

Evidence for reversibility of defective counterregulation in a patient with insulinoma.

To investigate her unheralded neuroglycopenia, a 45-year-old woman was studied before and 3 months after removal of her insulinoma. Hypoglycaemia was induced and reversed by glucose infusion during 4-h insulin infusions (1.5 mU kg-1 min-1). Postoperatively, the low preoperative adrenaline, noradrenaline, growth hormone, and cortisol responses increased by 490, 152, 64, and 178%, respectively, and started at higher glucose levels (2.7 vs 1.9 mmol l-1 for adrenaline), with a four-fold increase in autonomic symptoms and more profound psychomotor dysfunction. We conclude that the syndrome of recurrent severe hypoglycaemia with defective warning symptoms and hormonal responses, in this case induced by an insulin-secreting tumour, is reversible, perhaps by the removal of the hypoglycaemia, a finding which may be relevant to other patients with recurrent severe hypoglycaemia.

Blood Glucose↗
PubMed1992

Hypoglycemia in the treated diabetic patient. A risk of intensive insulin therapy.

With more physiologic insulin replacement and more accurate glucose monitoring, it was believed that very strict glycemic control of IDDM could be achieved without increasing the risks of hypoglycemia. No one anticipated that intensive treatment itself would lead to physiologic adaptations that would impair protective responses and contribute to the two- to threefold increase in risk of hypoglycemia. The influence of diabetes and its control on the recognition of and response to hypoglycemia are explored in this section as well as steps that can be taken by the patient and clinician to reduce these risks.

Blood Glucose↗
PubMed1991

"Brittle" diabetes.

Explore the source record for details and available documents.

Diabetes Mellitus, Type 1↗
PubMed1991

Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel.

1. The effect of hyperketonaemia on counter-regulatory hormone responses to hypoglycaemia has been examined in six healthy subjects. 2. A controlled, step-wise reduction in blood glucose concentration was achieved by adjusting the rate of glucose infusion during a primed-continuous infusion of soluble insulin (1.5 m-units min-1 kg-1 body weight, plasma insulin concentration approximately 90 m-units/l). Simultaneous infusion of either saline or beta-hydroxybutyrate (3 mg min-1 kg-1 body weight) was administered in a single-blind fashion, in random order. Despite a need for 40% more glucose during the ketone infusion, an identical fall in blood glucose concentration was achieved in each study. 3. The glycaemic threshold for stimulating an adrenaline response of 0.41 nmol/l was reduced from 3.1 to 2.8 mmol/l (P less than 0.05) during ketone infusion, and that for stimulating a response of more than 50% of basal from 3.6 to 3.1 mmol/l (P less than 0.001). The peak adrenaline response fell from 7.97 to 2.6 nmol/l (P less than 0.04). Peak noradrenaline, cortisol and growth hormone responses were also significantly lower during ketone infusion (P = 0.04, 0.001 and 0.006, respectively). Glucagon responses alone were unaffected by hyperketonaemia. 4. The provision of an alternate metabolic fuel thus produced immediate changes in the neurohumoral responses to hypoglycaemia. This is consistent with the hypothesis that human nervous tissue can metabolize ketones acutely.

3-Hydroxybutyric Acid↗
PubMed1991

Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism.

To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2.min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P less than 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P less than 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.

3-Hydroxybutyric Acid↗
PubMed1991

Effect of antecedent glucose control on cerebral function during hypoglycemia.

OBJECTIVE: The incidence of both severe and asymptomatic hypoglycemia is increased threefold in intensively treated diabetic patients. To examine whether this reflects cerebral adaptation to low blood glucose levels, we investigated the effect of preceding glycemic experience on hormonal, EEG, and evoked potential responses to experimentally induced hypoglycemia with the slow-fall clamp. RESEARCH DESIGN AND METHODS: Three groups were examined: well-controlled diabetic patients and patients with insulinoma (group 1), poorly controlled diabetic patients (group 2), and nondiabetic subjects (group 3). RESULTS: The glucose threshold for epinephrine release was lower in group 1 (2.3 +/- 0.1 vs. 3.0 +/- 0.3 and 3.1 +/- 0.1 mM, P less than 0.02), and the peak epinephrine response was reduced (1.29 +/- 0.36 vs. 5.48 +/- 1 and 5.62 +/- 1.2 nM, P less than 0.01) compared with groups 2 and 3, whereas symptoms were not perceived until a lower blood glucose level had been reached (2.0 +/- 0.2 vs. 3.3 +/- 0.4 and 2.6 +/- 0.2 mM, P less than 0.01). Other counterregulatory responses were similarly delayed and diminished. In contrast, EEG changes that were compatible with hypoglycemia were detected in all subjects in group 1 (blood glucose 1.9 +/- 0.1 mM) but in only two in group 2 and none in group 3, despite similar blood glucose nadirs. CONCLUSIONS: The glycemic threshold for hormonal responses to hypoglycemia falls in individuals with intensively treated diabetes or insulinomas, but these patients are more likely to develop EEG abnormalities during hypoglycemia. This disparity helps explain the increased vulnerability of intensively treated patients to severe hypoglycemia.

Adult↗
PubMed1988

Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion.

Diabetes mellitus in patients receiving hypertransfusion for thalassemia major is usually attributed to damage to beta cells. To determine whether iron overload leads to insulin resistance before the development of insulin deficiency, insulin was infused (by euglycemic insulin-clamp technique) into 12 children with thalassemia (4 of whom were prepubertal, and 8 pubertal) who had normal or only moderately impaired glucose tolerance and who were receiving chelation therapy. Although insulin-stimulated glucose metabolism in the prepubertal children with thalassemia was similar to that in controls (normal prepubertal children) (319 +/- 23 vs. 314 +/- 41 mg per square meter of body-surface area per minute, P not significant), the response to insulin was markedly impaired in the pubertal children with thalassemia (155 +/- 18 vs. 224 +/- 15 mg per square meter per minute in normal pubertal controls, P less than 0.01). Plasma insulin levels rose excessively after oral glucose administration in the pubertal subjects with thalassemia, but not in the prepubertal patients (P less than 0.001). Furthermore, in response to a standard hyperglycemic stimulus, insulin levels in the pubertal patients rose to two to three times greater than normal and C-peptide levels became significantly elevated. Our data suggest that insulin resistance and increased insulin secretion develop in older children with thalassemia treated with long-term hypertransfusion therapy before the development of diabetes.

Adolescent↗
PubMed1988

Circadian variation of GH-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?

Evidence is accumulating that a non-GH dependent insulin-like growth factor-binding protein (IGF-BP) is not only a carrier protein but also has an active role in the growth process. We have measured levels of this IGF-BP, using a specific RIA, over 12 or 24-h periods in 11 adolescents with diabetes mellitus and five normal adults. In each of the normal the IGF-BP was undetectable for most of the day but with a broad nocturnal peak observed, with levels up to 50 micrograms/l. The levels of IGF-BP were unrelated to the secretory pattern for GH but correlated inversely with the concentration of circulating insulin. In the diabetics a very similar pattern was observed, but with detectable levels throughout the day and much higher peak levels seen at night. Peak levels were up to 120 micrograms/l if a long-acting insulin preparation was administered in the evening but were 400-500 micrograms/l if the long-acting preparation was administered in the morning. The IGF-BP was strongly correlated with plasma glucose in this latter group. In a further group of diabetics overnight profiles were obtained on two separate nights, a normal night and a night with euglycaemia maintained with a glucose clamp technique. Euglycaemia failed to affect peak levels of the binding protein, although the shape of the nocturnal peak was altered consistent with the altered pattern of circulating free insulin. In this group a strong inverse correlation was obtained between the IGF-BP and free insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

The role of growth hormone in diabetes mellitus.

The insulin and growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis are two endocrine systems that are interlinked at many levels. GH is one of the glucose counter-regulatory hormones, rising in response to hypoglycaemia, it has both intrinsic hyperglycaemic actions and causes insulin resistance. Both IGF-I and its receptor have high structural and functional homology to insulin and its receptor. Insulin can regulate IGF-I production, acting on the GH receptor or at a post-receptor site. Conversely IGF-I is thought to have a permissive effect on the pancreatic insulin response to glucose. Growth is compromised in poorly controlled diabetic children; however, a causal link with altered GH/IGF-I levels has not been proven. Insulin-dependent diabetes clearly causes derangements in the GH/IGF-I axis. In poorly controlled diabetics GH levels are invariably raised whilst normal or low levels of IGF-I are found, indicating a dissociation between the two factors. Altered IGF-binding protein levels are also found, with high levels of small binding protein and low levels of large binding protein. These derangements are probably the result of interactions at many levels although the exact mechanisms are not fully understood. Raised GH levels could result from altered hypothalamic/pituitary control or reduced feedback inhibition. The latter could, in turn, result from low IGF-I levels, reduced availability of IGF-I to relevant receptors or increased levels of inhibitors (possibly the small binding protein). Low IGF-I levels could be directly due to deficient insulin levels or simply to lack of available circulating binding protein. Alternative or altered molecular forms of circulating GH in diabetes seem unlikely on present evidence. That GH has an effect on glycaemic control is most evident from the abnormal glucose tolerance seen in acromegalics, but is also seen with physiological GH variations such as during the pubertal growth spurt. In diabetics the derangements to the GH/IGF-I axis, caused by poor metabolic control, leads to aggravation of the metabolic problems. Altered GH/IGF-I levels have been implicated in the long-term complications associated with diabetes, and whilst GH/IGF-I are not essential for the early changes involved in these complications they may still play an important role in their development, especially proliferative retinopathy.

Diabetes Complications↗
PubMed1988

Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release.

To evaluate the effect of strict glycemic control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2-6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 +/- 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 +/- 4 mg/dl) than in normal control subjects (56 +/- 1 mg/dl, P less than .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50-60 mg/dl. After intensive therapy (HbA1 7.1 +/- 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 +/- 2 mg/dl) below normal (P less than .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemic level, and a greater hypoglycemic stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemic control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.

Adolescent↗
PubMed1987

Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus.

We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.

Adult↗
PubMed1987

Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children.

To determine whether children with insulin-dependent diabetes mellitus (IDDM) might have exaggerated hormonal responses to hypoglycemia, the euglycemic-hypoglycemic glucose clamp procedure was used to provide a uniform hypoglycemic stimulus (plasma glucose kept at 90 mg/dL for 2 hours, then reduced to 50 to 55 mg/dL for 1 hour) in children and adults with and without IDDM. The chidren with IDDM showed an exaggerated rise in plasma epinephrine levels (625 +/- 112 pg/mL) compared with adults with IDDM (259 +/- 57 pg/mL, P less than 0.02); the same was true for children and adults without IDDM (811 +/- 100 vs 458 +/- 85 pg/mL, P less than 0.05). Among the children, the increase in epinephrine during hypoglycemia was similar in prepubertal and pubertal patients. Children with IDDM showed a greater rise in plasma norepinephrine than did adults with IDDM (P less than 0.001), and both diabetic groups failed to mount a glucagon response. Growth hormone and cortisol responses were unaffected by either childhood or diabetes. Enhanced secretion of epinephrine, induced by mild reductions in plasma glucose, may contribute to the management difficulties characteristically observed in the young patient with diabetes.

Adult↗
PubMed1987

Rate of glucose fall does not affect counterregulatory hormone responses to hypoglycemia in normal and diabetic humans.

To test the hypothesis that variations in rate of glucose fall influence counterregulatory hormone responses to hypoglycemia, we have modified the glucose-clamp technique to provide a reproducible hypoglycemic stimulus in normal and type I diabetic subjects that varied only in the rate of glucose fall. Responsive elevations in plasma epinephrine and norepinephrine and in growth hormone, glucagon, and cortisol were not significantly affected by a ninefold change in the rate at which plasma glucose was lowered from 83 +/- 1 to 50 +/- 1 mg/dl in normal subjects. Similarly, wide variation in the rate of fall produced no substantive differences in counterregulatory hormone responses to hypoglycemia in diabetic subjects. The plasma glucose threshold at which epinephrine release began, determined from the slow-fall studies, was 63 +/- 3 mg/dl in normal subjects but exhibited a wide range (48-74 mg/dl). Similar values were found in the diabetics. Thresholds for growth hormone, cortisol, and glucagon were slightly lower, ranging from 45 to 68 mg/dl in the normals. Our data suggest that counterregulatory hormone responses to hypoglycemia are triggered by the glucose level per se and not by its rate of fall. Furthermore, individual differences in glucose thresholds for epinephrine release may contribute to variations in the glucose level associated with hypoglycemic symptoms.

Adult↗
PubMed1986

Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes.

Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201 +/- 12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316 +/- 34 and 290 +/- 21 mg per square meter, respectively; P less than 0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 microU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P less than 0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P less than 0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P less than 0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients.

Adolescent↗
PubMed1976

The effects of Bordetella pertussis vaccine on cerebral vascular permeability.

The effect of Bordetella pertussis vaccine on the cerebral vascular permeability in the mouse was studied by a radio-isotope method (131I-labelled HSA). Intravenous injection of 4 x 1010 heat-killed pertussis organisms caused a measurable increase in permeability in normal mice. Cryoinjury to the cerebral hemispheres resulted in a striking increase in vascular permeability at 24 h. This declined within 48 h and stabilized at a level fractionally higher than normal at 7 days ("healed lesion"). When pertussis organisms were injected into mice bearing ("healed lesion"). When pertussis organisms were injected into mice bearing "healed lesions" the increase in permeability was similar in magnitude to that in uninjured brain. The effect was increased by a second administration of pertussis 24 h after the first. The action of pertussis on a newly inflicted cryoinjury was protective. It is suggested that permeability changes in the cerebral vessels may be involved in the evolution of the encephalopathy attributed to the use of Bordetella pertussis vaccine in man.

Animals↗