Induction of defective insulin secretion and impaired glucose tolerance by clonidine. Selective stimulation of metabolic alpha-adrenergic pathways.
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Adult↗
Biomedical subjects
J B Halter
Publications and source records attributed to J B Halter.
Glycosylated hemoglobin in normal subjects and subjects with maturity-onset diabetes. Evidence for a saturable system in man.
Concentrations of glycosylated hemoglobin (GHb) are elevated in diabetes mellitus and are believed to reflect previous metabolic control. To better define possible determinants of GHb in man, we investigated the relationship between GHb and both fasting plasma glucose (FPG) and basal insulin (IRI) in 42 normal subjects and 29 patients with maturity-onset diabetes. Concentrations of GHb in diabetic subjects (12.7 +/- 3.4, x +/- S.D., per cent total hemoglobin) were significantly higher than in normal subjects (8.2 +/- 1.2, p less than 0.001). In normal subjects, FPG (r = 0.52) and GHb (r = 0.58) (both p less than 0.001) correlated with age. GHb did not correlate with IRI in either group. However, GHb was closely associated with FPG in both normal (r = 0.60, p less than 0.001) and diabetic (r = 0.85, p less than 0.001) subjects. Linear regression analysis of the data for the two groups combined was highly significant (r = 0.91, p less than 0.001). However, the slope of the regression line for GHb versus FPG seen in normal subjects was significantly steeper than that of diabetic patients (p less than 0.005). A curve describing a nonenzymatic saturable model was also found to fit the data of the two groups combined (r = 0.85, p less than 0.001), suggesting the possible existence of a saturable system for glycosylation in man.
Adult↗
Autonomic epilepsy: clonidine blockade of paroxysmal catecholamine release and flushing.
We studied a 59-year-old man with transient paroxysms of hypertension, tachycardia, and flushing in whom pheochromocytoma was excluded. Although catecholamine excretion was normal, plasma catecholamine levels rose from normal basal levels (282 +/- 14 pg/ml) to increased levels (585 +/- 67 pg/ml; x +/- SEM; n = 4) at the peak of spells. Other hormones or substrates expected to rise with nonspecific "stress" did not increase after paroxysms. Therapy with clonidine (0.2 to 0.4 mg/day) suppressed basal catecholamines to undetectable levels and markedly reduced peak levels during spells (80 pg/ml). An epileptic pathogenesis was suggested by stereotypic olfactory and epigastric prodromata before spells, and abolition of paroxysms with the anticonvulsant carbamazepine. This patient represents a rare case of autonomic epilepsy with the seizure focus in the temporal lobe.
Autonomic Nervous System↗
Comparison of double- and single-isotope enzymatic derivative methods for measuring catecholamines in human plasma.
We directly compared the reliability of a single-isotope enzymatic derivative technique for measurement of plasma catecholamines with that of the well-established double-isotope method. A significant (p less than 0.001) correlation was observed between measurements (n = 52) in the two assays, both for norepinephrine (r = 0.97) and epinephrine (r = 0.80). Means and coefficients of variation for the two analytes in a pooled specimen of plasma, measured repeatedly during six months, were virtually identical by each assay method. Basal plasma catecholamine concentrations in two different groups of apparently healthy subjects were also similar by each method. Dopamine concentrations in plasma were consistently below the limits measurable by either technique. The single-isotope assay requires half the assay time and 1/200th the sample as the double-isotope method. We conclude that this assay is just as reliable as the double-isotope technique and gives virtually identical values for norepinephrine and epinephrine concentrations in the physiological range.
Adult↗
Selective osmoreceptor dysfunction in the syndrome of chronic hypernatremia.
A patient with the syndrome of chronic hypernatremia (serum Na+: mean = 154, range 139-184 mEq/l, n = 30) and hypodipsia due to a hypothalamic injury was studied to evaluate osmolar and baroreceptor control of arginine vasopressin (AVP) secretion. Resting plasma AVP levels measured by radioimmunoassay were inappropriately low for the degree of plasma hyperosmolality: range = less than 0.5-2.1 pg/ml, n = 10, with corresponding levels of plasma osmolality (P osM) greater than 300 m osmol/kg, suggesting either direct damage to the AVP synthesis and storage area or impaired afferent osmoreceptor function. Direct pituitary damage seemed unlikely, since anterior pituitary function was normal by standard testing. The existence of adequate neurohypophyseal stores of AVP was demonstrated by baroreceptor stimulation with the hypotensive agent trimethaphan (Arfonad): plasma AVP rising to 50.0 pg/ml during transient hypotension (BP = 70/0). Osmoreceptor function was evaluated during acute water loading followed by hypertonic saline infusion. During hypertonic saline infusion plasma AVP levels correlated with P osM (R = .87, P less than .01, n = 8), suggesting some residual osmotic regulation of AVP release. The osmotic threshold for AVP release (the x-axis intercept of the plasma AVP-P osM regression line) was not higher than normal. However, the AVP levels throughout this study remained markedly subnormal for the degree of plasma hyperosmolality (maximum plasma AVP = 1.9 PG/ML when P os M = 327 M OSMOL/KG). Since a substantial amount of AVP was released with baroreceptor stimulation, the inadequate rise in plasma AVP level with hyperosmolality indicates that afferent input from the osmoreceptor/thirst area of the hypothalamus is selectively impaired in this patient. These findings directly demonstrate a dissociation of osmoreceptor function from the AVP secretory apparatus in man.
Arginine Vasopressin↗
Mechanism of plasma catecholamine increases during surgical stress in man.
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Adult↗
A role for alpha-adrenergic receptors in abnormal insulin secretion in diabetes mellitus.
To determine whether endogenous alpha-adrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, diabetic patients, alpha-adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P less than 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P less than 0.05) and diabetics (P less than 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta-adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha-adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alpha-adrenergic activity might be related to elevated circulating catecholamines, total plasma-catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P less than 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P less than 0.02 and less than 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha-adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.
Autonomic Agents↗
[Insulin release from fetal and newborn rat pancreas in vitro: role of the adenyl cyclase system].
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Animals↗
The effect of oral and intravenous D-ribose on plasma insulin levels in unanesthetized dogs.
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Animals↗
Changes in regional myocardial metabolism during partial stenosis in the presence of coronary vasodilators.
The relation of regional myocardial metabolism to coronary blood flow during pharmacologic flow elevation with dipyridamole was studied in four unsedated dogs. Chronic catheters were implanted in the aorta, left atrium, and coronary sinus at the anterior cardiac vein for determination across the left anterior descending coronary vascular bed of arteriovenous O2 content, glucose, free fatty acids, and lactate. A flowmeter and inflatable occluder were placed on the left anterior descending coronary artery, and mean aortic pressure and heart rate were recorded. Flow was increased with dipyridamole (0.4 mg/kg i.v.) and subsequently lowered by a partial stenosis in order to examine effects of relative flow decrease on metabolism without reducing flow below resting control or producing ischemia. Regional metabolism was compared at maximum flow and at submaximal flow with partial stenosis. Resting flow, maximal flow, and submaximal flow values were 72 +/- 3, 231 +/- 12, and 121 +/- 10 ml/min/100 g, respectively. When flow was lowered from maximal to submaximal levels, there was a significant decrease in both MVO2, from 8.2 +/- 0.7 to 6.4 +/- 0.5 ml/min/100 g, and free fatty acid uptake, from 23.9 +/- 5.5 to 6.8 +/- 1.0 muEq/min/100 g, p less than 0.01. There was no significant change in glucose uptake, lactate uptake, or external work (heart rate-pressure product). These results demonstrate that coronary blood flow and/or distal coronary pressure is a primary determinant of myocardial metabolism in the absence of changes in external metabolic demand, ischemia, or shifts in substrate utilization. We suggest that this phenomena accounts for the relative infrequency of anginal pain in the presence of perfusion defects during diagnostic imaging.
Animals↗
Sensitivity of R-R variation and Valsalva ratio in assessment of cardiovascular diabetic autonomic neuropathy.
R-R variation and the Valsalva ratio are commonly used to quantitatively assess diabetic autonomic neuropathy (DAN). To assess the sensitivity of these two measures to parasympathetic ablation, 12 nondiabetic subjects were tested before and after graded doses (0.3-4.0 mg i.v.) of atropine. R-R variation was significantly reduced at 0.7 mg, whereas Valsalva ratio was not significantly smaller until the 2.0-mg dose of atropine. R-R variation continued to become progressively smaller during the 0.85-, 1.0-, and 2.0-mg doses. Valsalva ratio, but not R-R variation, was further reduced by the 4.0-mg dose. To further compare these two measures, two groups of diabetic subjects were compared with a group of nondiabetic subjects (n = 22). One group of diabetic subjects had symptoms of DAN (n = 22), and the other diabetic group had no symptoms of DAN (n = 19). In DAN subjects, both R-R variation (nondiabetic 33.2 +/- 4.3 vs. DAN 9.8 +/- 1.2, P less than .001) and the Valsalva ratio (nondiabetic 1.98 +/- 0.07 vs. DAN 1.55 +/- 0.07, P less than .001) were reduced. However, in asymptomatic subjects, R-R variation (23.2 +/- 3.9, P less than .05), but not Valsalva ratio (1.94 +/- 0.13, NS), was less than nondiabetic subjects. Even after beta-blockade, R-R variation was still less in both groups of diabetic subjects (nondiabetic 34.4 +/- 4.2 vs. DAN 7.4 +/- 1.3, P less than .001; asymptomatic 21.8 +/- 3.3, P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Quantitative evaluation of sympathetic and parasympathetic control of iris function.
The use of quantitative measurements of pupil size as an index of autonomic nervous system (ANS) activity in normal and diabetic subjects is described. The dual innervation of the iris by the parasympathetic (PNS) and sympathetic (SNS) nervous system was demonstrated by measurement of steady-state pupil size before and after changes in ANS activity by pharmacologic agents. In the presence of total PNS blockade, dark-adapted pupil size was a reliable index of SNS activity to the iris. Latency time (time from light stimulation to initial pupil response) appeared to be a good index of PNS activity. However, increased SNS activity may also prolong the latency time. Thus, consideration of SNS activity is necessary when evaluating the latency time. In 25 diabetic subjects, there was evidence of impaired SNS activity (smaller dark-adapted pupil size during total PNS blockade) and PNS activity (prolonged latency time). In a subgroup of diabetic subjects without clinical manifestations of autonomic neuropathy and normal subjects, both dark-adapted pupil size during PNS blockade (SNS index) and latency time (PNS index) were abnormal. The coefficient of variation for these two indices was less than 5% in glycemic stable diabetic subjects. Thus, these two indices are reliable and sensitive measures of the SNS and PNS activity to the iris in normal and diabetic subjects.
Adult↗
Autonomic neural dysfunction in recently diagnosed diabetic subjects.
Because onset of autonomic neural dysfunction in the diabetic syndrome has not been well established, sensitive and quantitative measures of autonomic nervous system (ANS) function were made in 19 non-insulin-dependent (NIDD) and 14 insulin-dependent (IDD) recent-onset diabetic subjects. The known duration of diabetes mellitus in the NIDD subjects was less than or equal to 12 mo. The duration in the IDD subjects was less than or equal to 24 mo. RR-variation during beta adrenergic blockade (an index of an ANS reflex involving the cardiac parasympathetic nervous system [PNS] pathway) was smaller than that of control subjects in both NIDD (P less than 0.001) and IDD subjects (P less than 0.01). This PNS abnormality was not likely to be due to volume depletion since acute volume depletion induced by furosemide in six normal subjects (1608 +/- 105 ml, mean +/- SEM) did not change RR-variation. Dark-adapted pupil size after topical PNS blockade (an index of iris sympathetic nervous system [SNS] activity) was also smaller in both groups of diabetic subjects (NIDD, P less than 0.01; IDD, P less than 0.05). Pupillary latency time (an index of an ANS reflex involving iris PNS pathway) was prolonged in the NIDD subjects (P less than 0.005) but was not significantly altered in the IDD subjects. Thus, it would appear that the ANS is impaired soon after the diagnosis of diabetes mellitus. We hypothesize that early impairment of the ANS is common in IDD and NIDD subjects. This finding is consistent with the hypothesis that abnormal carbohydrate metabolism is an important factor in the etiology of diabetic autonomic neuropathy.
Adult↗
Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus.
The pathogenesis of the abnormal metabolic state in patients with non-insulin-dependent diabetes (NIDDM) is controversial. Even the term NIDDM stirs controversy because of the easily drawn inference that individuals with this form of diabetes do not need insulin treatment. Yet many patients with NIDDM are treated with insulin; some even develop hyperosmolar coma if not given insulin. Ketoacidosis, however, is very infrequent in this syndrome, implying that these patients are not dependent on insulin treatment to prevent mass mobilization of fatty acids and ketone bodies. The phrase noninsulin-dependent is therefore appropriate when used in this restricted fashion but inappropriate when used to imply adequacy of insulin secretion. The evaluation of the adequacy of islet function in this syndrome has been complex, since there is no standard of insulin output that can be defined for normal islets without specifying the physiologic setting under which the assessment has been made. For example, individuals with normal glucose levels but variable degrees of obesity have widely varying insulin secretion rates. Thus, the choice of controls is critical when comparing islet function in NIDDM to normal. In addition, the efficiency of the B-cell response to a challenge (e.g., oral glucose tolerance test) can markedly influence the magnitude of the stimulatory glucose level during the period of testing. For example, a subject with some impairment of insulin output will tend to become more hyperglycemic during the test. The hyperglycemia may then stimulate more insulin secretion so that the overall insulin output may appear equal to or even greater than that of a normal individual. In such a closed-loop system, strict control of input variables is necessary to evaluate whether or not insulin secretion is normal. As will be discussed, control of glucose level and other variables is seldom accomplished in dynamic glucose tolerance tests. As will be presented in this review, the development of appropriately controlled studies of islet function has provided convincing evidence that islet B-cell function is abnormal in patients with NIDDM. Since these studies are based on an understanding of normal islet function, normal islet B-cell physiology is discussed before pathophysiology. Finally, the implications of this analysis for the treatment of NIDDM with diet, hypoglycemic sulfonylureas, and insulin will be discussed.
Administration, Oral↗
Attitudes of diabetic men after implantation of a semi-rigid penile prosthesis.
Erectile impotence is a common and distressing problem in diabetic men. In order to examine the impact of a penile prosthesis on the quality of life of the recipients, we mailed a questionnaire to all patients (N = 49) who received a semi-rigid (Small-Carrion) prosthesis at the Seattle VAMC from 1976 to 1981. Fourteen patients with diabetes and 23 without diabetes returned the questionnaire. Direct comparisons showed no statistically significant differences between the responses of the two groups. Based on a scale of 1-7 (1 = worst, 4 = no change, 7 = best), the general effect of the operation on the quality of life of the recipients was 5.7 +/- 0.3 (Mean +/- SEM); the quality of intercourse was 5.1 +/- 0.3; the patient's perception of his partner's response to the prosthesis was 5.2 +/- 0.3; and the patient's perception of postoperative changes in his relationship with his partner was 5.6 +/- 0.3. Eighty-three percent of the patients were satisfied with the performance of the prosthesis. Most of the patients (86%) felt that their preoperative expectations had been fulfilled and would elect to have the procedure if they had it to do over again. However, five patients (14%) stated that they would not elect the operation again because their partners did not appreciate the operation (N = 2); the operation produced severe, prolonged pain (N = 1); or the patient's expectations had not been fulfilled (N = 2). Preoperative counseling should be used to foster realistic patient and partner expectations. This operation, which appears to improve the quality of life for most diabetic patients with erectile impotence, should be considered a part of standard care and not as a cosmetic procedure or extraordinary care.
Coitus↗
Correlations among autonomic, sensory, and motor neural function tests in untreated non-insulin-dependent diabetic individuals.
A well-defined group of untreated non-insulin-dependent (NIDD) subjects were evaluated to determine whether involvement of neural function measurements is generalized and symmetrical and to compare the autonomic, sensory, and motor neural measurements. After age adjustment, the sensory and motor neural function measurements were significantly slower in the diabetic group than in normal subjects (P less than 0.01). Similarly, the autonomic nervous system function measurements were also abnormal in the NIDD group (P less than 0.01). Further analysis revealed that each of the specific measurements--median motor nerve conduction velocity (NCV,P less than 0.005), peroneal motor NCV (P less than 0.005), median sensory NCV (P less than 0.005), dark-adapted pupil size after muscarinic blockade (P less than 0.02), pupillary latency time (P less than 0.02), and RR-variation after beta adrenergic blockade (P less than 0.001)--was significantly less by analysis of covariance after age adjustment in the NIDD group than in normal subjects. Thus, there was evidence of motor and sensory neural impairment in the upper and lower extremities as well as evidence of impairment of the reflex arcs involving the parasympathetic nerves to the heart and eye and the sympathetic nerves to the iris. Further analysis revealed that right and left NCV were correlated (P less than 0.01), as were the median motor and median sensory NCV (P less than 0.01), the median motor and peroneal motor NCV (P less than 0.001), and the peroneal motor and median sensory NCV (P less than 0.001). Thus, there was evidence of symmetrical upper and lower limb, as well as motor and sensory proportional involvement of large nerve fiber NCV in this group of NIDD subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Decreased numbers of platelet alpha-adrenergic binding sites in diabetes mellitus.
Eleven men with diabetes mellitus were compared with 45 male controls for platelet alpha-adrenergic binding sites by using [3H]dihydroergocryptine (DHE) as the radioligand antagonist. There was no difference between the two for binding affinity, but the number of sites was 430 +/- 30 (means +/- SEM) for diabetic subjects and 574 +/- 29 for controls (P = .005). Decreased sites were related to increased glycosylated hemoglobin levels (P = .002). There was no relationship between the decreased sites and catecholamine levels, duration of disease, body weight, or fasting blood sugar. Hence, binding sites were inversely related to control, but further studies are needed to define the pathophysiologic significance of this.
Adult↗
Acute and chronic effects of sulfonylurea drugs on pancreatic islet function in man.
The pancreatic islet can be viewed as an integrator of nutrient, neural, and hormonal signals. In normal people, glucose directly stimulates insulin release and also plays a key role as a potentiator of nonglucose stimulants of the B-cells. In patients with non-insulin-dependent diabetes mellitus (NIDDM), the direct effect of glucose on insulin secretion is markedly impaired. However, as hyperglycemia develops, basal insulin levels and insulin responses to nonglucose signals are maintained in many NIDD patients by the potentiating effect of hyperglycemia. Both acute and chronic administration of sulfonylurea drugs results in enhanced B-cell sensitivity to the potentiating effect of glucose. During sulfonylurea therapy this effect initially causes an increase in insulin level. However, as the glucose level falls during therapy the insulin level may tend to return toward pretreatment values, thereby masking the improvement of B-cell function. In NIDD patients with mild to moderate hyperglycemia (fasting plasma glucose less than 200 mg/dl), chronic sulfonylurea therapy results in the maintenance of near-normal insulin levels, but at a lower plasma glucose level. In patients with more severely impaired B-cell function, whose insulin levels before therapy are subnormal despite marked hyperglycemia, there is a net absolute increase in insulin levels during chronic sulfonylurea administration. Thus, some NIDD patients may show an increase in basal insulin levels during chronic sulfonylurea therapy while others may not; however, all patients who respond to sulfonylureas demonstrate increased B-cell sensitivity to glucose. Acute and chronic sulfonylurea treatment also results in a suppression of glucagon levels, an effect that may be secondary to the enhancement of B-cell function. The fall of plasma glucose during chronic sulfonylurea therapy is associated with a decrease in hepatic glucose production in NIDD patients. The magnitude of this effect is correlated with the degree of enhancement of basal insulin secretion. Thus, chronic sulfonylurea therapy clearly enhances pancreatic islet function in patients with NIDDM. We postulate that the major antihyperglycemic action of sulfonylurea therapy is mediated by this pancreatic effect.
Chlorpropamide↗