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Biomedical subjects

D Porte

Publications and source records attributed to D Porte.

At least 145 records · Page 8Linked to original sources
PubMed1982

The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes.

In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P less than 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3-6 mo. During therapy, FPG was lower (133 +/- 9 vs. 216 +/- 20 mg/dl, mean +/- SEM; P less than 0.001), glucose production was lower (59.5 +/- 2.0 vs 77.6 +/- 4.9 mg/m2/min; P less than 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P less than 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 +/- 2, treated 21 +/- 2 muU/ml; P= NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P less than 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 +/- 8.1 vs. 7.8 +/- 2.4 mg/m2/min; P less than 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.

Adult↗
PubMed1982

Quantitative evaluation of cardiac parasympathetic activity in normal and diabetic man.

Heart rate and RR variation (the standard deviation of the mean RR interval for a 5-min period) were evaluated as measurements of cardiac parasympathetic nervous system activity in fasting supine diabetic (N = 22) and comparable age normal (N = 22) subjects. The rate of breathing did not effect heart rate, but was inversely related to the RR variation (r = 0.89, P less than 0.01). Heart rate was increased (P less than 0.0001) and RR variation decreased (P less than 0.05) during beta-adrenergic stimulation with isoproterenol and during parasympathetic blockade with atropine (both P less than 0.0001). Hence, the cardiac effects of beta-adrenergic stimulation may mimic the effects of diminished parasympathetic function. To evaluate parasympathetic control of RR variation, independently of possible effects of increased sympathetic activities, studies were performed during beta-adrenergic blockade with propranolol. RR variation during propranolol was less both in 14 diabetic subjects without clinical symptoms of autonomic neuropathy (P less than 0.005) and in 8 diabetics with clinical symptoms of autonomic neuropathy (P less than 0.001) when compared with 22 age-comparable normal subjects. The measurement of RR variation was very reproducible with a day-to-day coefficient of variation of 9.7 +/- 2.8% (x +/- SEM) in diabetic subjects with stable hyperglycemia. It is concluded that supine RR variation during a deep respiratory rate and during beta-adrenergic blockade is a sensitive, quantitative, and reproducible method to evaluate parasympathetic nervous activity in normal and diabetic subjects. Furthermore, cardiac parasympathetic activity may be diminished in diabetic subjects before clinical symptoms of autonomic neuropathy are evident.

Adult↗
PubMed1981

The regulation of glucose-induced insulin secretion by pre-stimulus glucose level and tolbutamide in normal man.

The relationship between the pre-stimulus glucose level and immunoreactive insulin responses to a glucose challenge (20-g IV) was studied in normal subjects. When the steady-state pre-stimulus glucose concentration was lowered by a 0.33 mU.kg-1.min-1 insulin infusion or raised by a 900 mg/min glucose infusion, no effect on first phase insulin secretion (mean delta 3-5 min insulin level) was observed. In contrast, the second phase response (10-60 min insulin area after glucose pulse) to intravenous glucose fell during insulin infusion and increased during the glucose infusion. Overall, a linear relationship was found between the change of pre-stimulus glucose or level from the control to that during the insulin or glucose infusion and the change in second phase response (r = 0.65, n = 14, p less than 0.02). The effect of tolbutamide infusion (7 mg.m-2.min-1) when compared with saline control was to increase both first phase (+54 +/- 13 mU/l, n = 8, p less than 0.001, mean +/- SEM) and second phase (+972 +/- 256 mU. min-1.l-1, p less than 0.01) insulin secretion. It is concluded that the first phase response to a glucose pulse is independent of the steady-state pre-stimulus glucose concentration and is directly enhanced by tolbutamide; in contrast, second phase is related to both the steady-state pre-stimulus glucose level and tolbutamide. These findings suggest that changes in basal or pre-stimulus plasma glucose during therapy with sulphonylurea drugs may be expected to influence the second phase insulin responses to glucose challenge.

Adult↗
PubMed1981

Diabetic neuropathy and plasma glucose control.

Diabetic neuropathy is defined, and theories of its pathogenesis are reviewed. Recent studies designed to investigate the influence of plasma glucose on nerve function in noninsulin-dependent diabetic patients are summarized. Motor nerve conduction velocities in the median and peroneal nerves were measured using a double-stimulus technique, and sensory conduction velocity was measured by conventional methods before and after therapy with oral agents or insulin. The degree of hyperglycemia was assessed by measurement of fasting plasma glucose and glycosylated hemoglobin concentrations. The degree of slowing in motor nerve conduction velocity in untreated patients was found to correlate with the fasting plasma glucose and glycosylated hemoglobin concentrations, but sensory nerve function, although abnormal, did not show such correlation. Reduction of hyperglycemia was associated with improvement in motor nerve conduction velocity in the peroneal and median motor nerves of these patients, but sensory nerve conduction velocity showed no such improvement. Improvement in median motor nerve conduction velocity was directly related to the degree of reduction in fasting plasma glucose concentration. These findings suggest that metabolic factors related to hyperglycemia are important in the impaired motor nerve function seen in noninsulin-dependent patients with maturity-onset diabetes.

Animals↗
PubMed1981

Insulin secretion in diabetes mellitus.

A brief review of the normal physiology of insulin secretion is given. The dual role of glucose to directly stimulate insulin release and to potentiate insulin secretion to other islet regulators is emphasized. The B cell of the pancreatic islet is discussed as a metabolic integrator for nutrients, modulated by neural and hormonal input. A feedback model for the normal regulation of glucose concentrations is also described. This model is based on a closed loop between the islet, the liver and peripheral tissues for the production and utilization of glucose. Diabetes mellitus with overt hyperglycemia is characterized by impaired pancreatic B-cell function; however, in noninsulin-dependent diabetic subjects, many aspects of insulin secretion are maintained by a compensatory increase in plasma glucose concentration. The model shows why this increase in plasma glucose occurs and the importance of this hyperglycemia to the restoration of insulin responses to nonglucose secretagogues, second-phase insulin secretion to glucose and basal insulin. The model can account for the usual stability of plasma glucose in noninsulin-dependent diabetes mellitus and the very high glucose levels and lack of glucose stability in insulin-dependent diabetes mellitus. Sulfonylurea drugs increase insulin secretion, but this increase is dependent on the glucose level. Thus, the augmented B-cell function can be masked by a decrease in plasma glucose concentrations. During long-term therapy, the insulin level and responses are unchanged despite lower concentrations of glucose. Therefore, it is hypothesized that sulfonylureas still act by enhancement of B-cell function.

Blood Glucose↗
PubMed1981

Voltage dependence of rhythmic plateau potentials of pancreatic islet cells.

The origin and control of glucose-induced rhythmic plateau potentials of pancreatic islet cells have been studied with intracellular microelectrodes in isolated mouse islets. Rapid changes of extracellular potassium concentration and direct electrical stimulation via a suction electrode were used to perturb islet cell membrane potentials. We show that brief depolarizing stimuli trigger permature plateau potentials, and brief hyperpolarizing currents abort endogenous plateaus. Both responses occur in an all-or-none manner, show a reciprocal relationship between stimulus strength and stimulus duration, have stimulus thresholds that approach zero at the time of the endogenous event, and completely reset the endogenous plateau rhythm. These results indicate that the plateau potentials are due to voltage-dependent regenerative mechanisms as in other electrically excitable tissues and implicate membrane potential or membrane ionic fluxes in the glucose-dependent pacemaker system that triggers their onset and offset.

Action Potentials↗
PubMed1981

Endogenous hyperglycemia restores insulin release impaired by somatostatin analogue.

These studies assessed the ability of des-Asn5-[D-Trp8-D-Ser13]-somatostatin (d-ATS-SS) to selectively inhibit insulin release and produce a hyperglycemia sufficient to compensate for the original impairment. d-ATS-SS at 0.017 micrograms/min inhibited basal insulin output (delta = -38 +/- 6%, P less than 0.005) and increased basal pancreatic glucagon output (delta - +21 +/- 6%, P less than 0.05, n = 5). d-ATS-SS at 0.17 micrograms/min markedly inhibited insulin output (delta = -84 +/- 4%, P less than 0.0005) and slightly inhibited glucagon output (delta = -14 +/- 6%, P less than 0.05, n = 5). d-ATS-SS at 0.055 micrograms/min decreased basal and stimulated insulin release but not basal nor stimulated glucagon release. By 3.5 of analogue infusion, plasma glucose had risen by 116 +/- 13 mg/dl, and base-line insulin levels and the insulin responses to both isoproterenol and arginine, but not glucose, increased toward control values. We conclude that d-ATS-SS produces selective insulinopenia resulting in hyperglycemia which in turn compensates for the original impairment. Thus, the hyperglycemia observed in other states of selective insulin deficiency (e.g., noninsulin-dependent diabetes mellitus) may compensate for defects in beta-cell function.

Animals↗
PubMed1981

Morphine: dual effects on plasma catecholamines.

The present studies demonstrate that morphine can increase, decrease, or not affect plasma catecholamines depending on the dose and on the experimental conditions under which it is given. In the conscious dog, morphine (30 mg s.c.) produces a marked elevation of plasma epinephrine but not norepinephrine. In contrast, morphine (15 mg i.v.) prevents the rise of both plasma epinephrine and norepinephrine in the anesthetized, laparotomized dog. Since neither dose of morphine changes plasma catecholamines significantly in the non-laparotomized, anesthetized dog, we suggest (a) that the catechol-lowering effect is due to the analgesic properties of morphine, and (b) that the catechol-raising effect is due to activation of separate central nervous system pathways which are suppressed by barbiturate anesthesia.

Animals↗
PubMed1981

Differential effects of tolbutamide on first and second phase insulin secretion in noninsulin-dependent diabetes mellitus.

Immunoreactive insulin responses to a 20-g iv glucose challenge during a 7.5 mg/m2/min tolbutamide infusion were studied in 21 untreated noninsulin-dependent male diabetics. All data were analyzed by paired t tests. During the tolbutamide infusion, compared to the saline control period in the same subjects, glucose levels were lowered [217 +/- 17 vs. 196 +/- 16 mg/dl (mean +/- SEM); P less than 0.005], and there was an increase in both first phase (2 +/- 1 vs. 16 +/- 4 micro U/ml; P less than 0.005) and second phase insulin responses (296 +/- 71 vs. 499 +/- 101 micro U. min/ml; P less than 0.05; n = 21). However, when the prestimulus glucose level was lowered by an insulin infusion (214 +/- 20 vs. 145 +/- 17 mg/dl; P less than 0.001), no effect on first phase insulin secretion was observed, and the second phase response decreased (290 +/- 78 vs. 124 +/ 55 micro U. min/ml; P less than 0.005; n = 11; saline control vs. insulin infusion). In 8 subjects, the plasma glucose level during the tolbutamide infusion was kept constant by a concurrent variable glucose infusion. First phase insulin secretion was still increased, though no more than in studies were plasma glucose was not kept constant. However, there was further augmentation of the second phase response (tolbutamide alone, 443 +/- 142 micro U. min/ml; tolbutamide plus glucose, 802 +/- 232 micro U. min/ml; P less than 0.05). These findings indicate that tolbutamide augments first phase insulin secretion in untreated diabetics independently of the prestimulus glucose level. However, changes in the glucose level significantly modulate the sulfonylurea influence on the second phase insulin response to glucose. This effect of glucose level is an important consideration when evaluating the insulinotropic effects of a sulfonylurea.

Adult↗
PubMed1981

Glucose disposal is not proportional to plasma glucose level in man.

Metabolic clearance rate (MCR) of glucose has been defined as the rate of glucose utilization divided by the glucose concentration. This model of glucose transport has been widely used as a measure of hormonally regulated glucose disposal, on the assumption that glucose disposal rate is proportional to glucose concentration. To test this assumption, the relationship between glucose concentration and disposal rate was studied in man during infusion of somatostatin +/- exogenous insulin to achieve fixed plasma insulin levels of 1, 18, and 46 microM/ml on separate days. When glucose concentration was increased to more than twice basal fasting levels, the glucose disposal rate increased significantly at all three insulin levels. However, the increase was not proportional to the rise in glucose concentration, and MCR fell by 38%, 16%, and 11% at the low, medium, and high insulin levels, respectively. These results are explained by an alternative model of glucose transport in which insulin-independent tissues such as brain have a relatively fixed glucose uptake, while other tissues have glucose transport systems which take up glucose at a rate proportional to its plasma concentration. We conclude that MCR of glucose is not a good measure of hormonally regulated glucose disposal because it is partially dependent on the glucose concentration, particularly at low insulin levels.

Adult↗
PubMed1981

Glucose and acetylcholine have different effects on the plateau pacemaker of pancreatic islet cells.

Pancreatic islet cell membrane electrical activity has been studied with intracellular microelectrodes in perifused, isolated mouse islets of Langerhans. The dose-response effects of glucose and of acetylcholine on the pattern of electrical activity are compared and are shown to be qualitatively different. Electrical activity in the presence of glucose consists of periodic alterations between a polarized silent phase potential and depolarized plateau phase with superimposed rapid spiking activity. Increasing glucose concentration prolongs the plateau phase, at the expense of the silent phase, and thus increases the the plateau fraction (the fraction of time in each electrical cycle spent in the plateau phase). By contrast, graded doses of acetylcholine, in the presence of stimulatory levels of glucose, had no effect on plateau fraction. Increasing glucose concentration also slightly reduced the frequency of plateaus, whereas increasing acetylcholine markedly increased plateau frequency. Furthermore, changes of glucose concentration had no effect on the potential levels during the plateau and silent phases, while addition of acetylcholine depolarized the silent phase until, at high concentrations of acetylcholine, the combination of increased plateau frequency and silent phase depolarization produced continuous spiking. Addition of acetylcholine to a slightly substimulatory level of glucose depolarized the membrane without, however, inducing periodic spiking activity. The results suggest aht the effects of acetylcholine and glucose are due to different effects on the plateau pacemaker system involved in the regulation of insulin release.

Acetylcholine↗
PubMed1981

Glycemic control and nerve conduction abnormalities in non-insulin-dependent diabetic subjects.

The influence of therapy of hyperglycemia on the progression of diabetic neuropathy is unclear. We studied variables of glycemia and motor and sensory nerve conduction velocity in a group of 18 non-insulin-dependent diabetic subjects before and after institution of diabetes therapy. Diabetes therapy significantly reduced variables of glycemia after 1, 3, 6, and 12 months. Conduction velocity of the median motor nerve was improved from baseline at each time tested during treatment. In addition, peroneal and tibial motor nerve conduction velocities improved in patients whose levels of hyperglycemia were lowered. Moreover, extent of improvement of conduction velocity of some motor nerves was related to the degree of reduction of hyperglycemia. Sensory nerve conduction velocity was not altered by diabetes therapy. These findings support the hypothesis of a metabolic component to diabetic neuropathy and suggest that optimal glycemic control may be beneficial to patients with this disorder.

Adult↗
PubMed1981

Regulation of food intake and body weight in insulin.

A feedback system for the regulation of food intake and body weight, consisting of two elements is proposed. One is related to the quantity and quality of the food ingested. It consists of neural afferents, psychosocial conditioning factors, and peptide signals from the gastrointestinal tract released by specific nutrient intake. The other is also sensitive to nutrient intake, but importantly modulated by relative adiposity. We present evidence to suggest that insulin serves as the key feedback signal to the central nervous system to serve this second function (body adiposity signal). Insulin has been found in cerebrospinal fluid where it concentration is increased by systemic infusions of glucose or insulin and is proportional to its concentration in plasma. When insulin (10 and 10 micro U/kg/day) is infused into the lateral cerebral ventricles of free feeding baboons a dose dependent suppression of food intake and body weight is found. Intravenous infusion of 25% and 50% of total calories as glucose elevates endogenous insulin concentrations and suppresses food intake. These findings suggest that the amount of insulin secreted per day and more modulates food intake to maintain a constant body weight.

Adipose Tissue↗
PubMed1981

Peptides and the control of meal size.

There are now a large number of experiments demonstrating that peripheral administration of exogenous cholecystokinin or its synthetic analogue, CCK-8, reduces meal size in a number of species. The peptide interacts with other factors which influence satiety, and treatments thought to be effective in eliciting secretion of cholecystokinin have predictable effects on meal size. Cholecystokinin is effective in the genetically obese Zucker rat, obese rats with lesions of the ventromedial hypothalamus, and subdiaphragmatically vagotomized rats. Somatostatin and bombesin are also reasonable candidates for satiety factors. Intraperitoneal naloxone reduces meal size in rats, and beta-endorphin injected intraventricularly causes an increase in meal size of 50% over 30 minutes. We conclude that cholecystokinin and bombesin may interact in weight regulation and control of meal time food intake.

Appetite↗
PubMed1980

Stress hyperglycemia and the adrenergic regulation of pancreatic hormones in hypoxia.

Stress hyperglycemia occurs in normal and chronically hypoxemic dogs when PaO2's are acutely lowered below 30 torr. Several factors are thought to contribute to the rise in blood glucose. The initial fall in PaO2 activates the sympathetic nervous system, stimulating alpha and beta adrenergic receptors. Because of reduced beta receptor function, alpha receptor effects predominate, promoting glucagon and inhibiting insulin release. The changes in pancreatic hormones in conjunction with the direct effects of hypoxemia and alpha receptor stimulation increase hepatic glycogenolysis. Meanwhile, glucose clearance is decreased because of elevated circulating levels of catecholamines and low insulin concentrations. This combination of events plays a major role in the development of hyperglycemia. Since high blood glucose levels seems to protect the brain and other vital organs at low oxygen tensions, the development of hyperglycemia may represent an important protective mechanism in severely hypoxemic animals, including humans.

Animals↗
PubMed1980

Ventromedial hypothalamic lesions increase pancreatic sensitivity to streptozotocin in rats.

Rats with electroytic lesions of the ventromedial hypothalamus (VMX rats) and sham-operated controls (SHAM rats) were injected with streptozotocin (STZ) at a dose of 50 mg/kg 48 h after the lesions were made. VMX rats were significantly more sensitive to STZ in that over 70% died within 6 wk, shereas none of the SHAM rats dies. When smaller doses of STZ were given to VMX rats (30--35 mg/kg), a large percentage still died, although the survivors appeared equally as diabetic (in terms of hyperglycemia and hypoinsulinemia) as SHAM rats given a larger dose of STZ. At 25 mg/kg, the surviving VMX rats were more hyperglycemic than matched controls. We suggest that the increased B-cell activity known to occur in VMX animals might be the important factor in the increased sensitivity to STZ observed. We speculate that similar variation in pancreatic B-cell response to an environmental injury may be an important determinant of diabetes susceptibility in man.

Animals↗