Biomedical subjects

S N Davis

Publications and source records attributed to S N Davis.

At least 19 recordsLinked to original sources

PubMed1997

Prevention of an increase in plasma cortisol during hypoglycemia preserves subsequent counterregulatory responses.

The aim of this study was to determine whether preventing increases in plasma cortisol during antecedent hypoglycemia preserves autonomic nervous system counterregulatory responses during subsequent hypoglycemia. Experiments were carried out on 15 (8 male/7 female) healthy, overnight-fasted subjects and 8 (4 male/4 female) age- and weight-matched patients with primary adrenocortical failure. 5 d before a study, patients had their usual glucocorticoid therapy replaced with a continuous subcutaneous infusion of cortisol programmed to produce normal daily circadian levels. Both groups underwent identical 2-d experiments. On day 1, insulin was infused at a rate of 1.5 mU/kg per min, and 2-h clamped hypoglycemia (53+/-2 mg/dl) was obtained during the morning and afternoon. The next morning, subjects underwent an additional 2-h hypoglycemic (53+/-2 mg/ dl) hyperinsulinemic clamp. In controls, day 2 steady state epinephrine, norepinephrine, pancreatic polypeptide, glucagon, growth hormone, and muscle sympathetic nerve activity were significantly blunted (P < 0.01) compared with day 1 hypoglycemia. In marked contrast, when increases of plasma cortisol were prevented in the patient group, day 2 neuroendocrine, muscle sympathetic nerve activity, hypoglycemic symptoms, and metabolic counterregulatory responses were equivalent with day 1 results. We conclude that (a) prevention of increases of cortisol during antecedent hypoglycemia preserves many critical autonomic nervous system counterregulatory responses to subsequent hypoglycemia; (b) hypoglycemia-induced increases in plasma cortisol levels are a major mechanism responsible for causing subsequent hypoglycemic counterregulatory failure; and (c) our results suggest that other mechanisms, apart from cortisol, do not play a major role in causing hypoglycemia-associated autonomic failure.

Addison Disease↗

PubMed1997

Brain of the conscious dog is sensitive to physiological changes in circulating insulin.

The aim of this study was to determine whether a selective, physiologically relevant increase in blood-borne insulin perfusing the brain has an impact on the counterregulatory response to hypoglycemia. Experiments were carried out on 12 conscious 18-h-fasted dogs. Insulin was infused (1 mU x kg(-1) x min(-1)) in separate, randomized studies into a peripheral vein (n = 6) or both carotid and vertebral arteries (n = 6). This resulted in equivalent systemic insulinemia (38 +/- 2 vs. 35 +/- 5 microU/ml) but differing head insulin levels (38 +/- 2 microU/ml during peripheral infusion and an estimated 90 microU/ml during head insulin infusion). Glucose was infused during peripheral insulin infusion to equate the level of hypoglycemia (58 +/- 2 mg/dl) to that obtained during head insulin infusion (57 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and hypoglycemia, incremental area under the curve responses for epinephrine, glucagon and cortisol were increased during head insulin infusion (P < 0.05). Net hepatic glucose output, gluconeogenesis, and lipolysis were increased 50-100% (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog 1) physiologically relevant increases of blood-borne insulin to the head can amplify neuroendocrine and metabolic counterregulatory responses and 2) glucagon secretion can be regulated, in part, by neural efferent activity.

Alanine↗

PubMed1996

Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans.

The aim of this study was to determine the role of increased plasma cortisol levels in the pathogenesis of hypoglycemia-associated autonomic failure. Experiments were carried out on 16 lean, healthy, overnight fasted male subjects. One group (n = 8) underwent two separate, 2-d randomized experiments separated by at least 2 mo. On day 1 insulin was infused at a rate of 1.5 mU/kg per min and 2 h clamped hypoglycemia (53 +/- 2 mg/dl) or euglycemia (93 +/- 3 mg/dl) was obtained during morning and afternoon. The next morning subjects underwent a 2-h hyperinsulinemic (1.5 mU/kg per min) hypoglycemic (53 +/- 2 mg/dl) clamp study. In the other group (n = 8), day 1 consisted of morning and afternoon 2-h clamped hyperinsulinemic euglycemia with cortisol infused to stimulate levels of plasma cortisol occurring during clamped hypoglycemia (53 mg/dl). The next morning (day 2) subjects underwent a 2-h hyperinsulinemic hypoglycemic clamp identical to the first group. Despite equivalent day 2 plasma glucose and insulin levels, steady state epinephrine, norepinephrine, pancreatic polypeptide, glucagon, ACTH and muscle sympathetic nerve activity (MSNA) values were significantly (R < 0.01) blunted after day 1 cortisol infusion compared to antecedent euglycemia. Compared to day 1 cortisol, antecedent hypoglycemia produced similar blunted day 2 responses of epinephrine, norepinephrine, pancreatic polypeptide and MSNA compared to day 1 cortisol. Antecedent hypoglycemia, however, produced a more pronounced blunting of plasma glucagon, ACTH, and hepatic glucose production compared to day 1 cortisol. We conclude that in healthy overnight fasted men (a) antecedent physiologic increases of plasma cortisol can significantly blunt epinephrine, norepinephrine, glucagon, and MSNA responses to subsequent hypoglycemia and (b) these data suggest that increased plasma cortisol is the mechanism responsible for antecedent hypoglycemia causing hypoglycemia associated autonomic failure.

Adrenocorticotropic Hormone↗

PubMed1996

Effects of an acute decrease in non-esterified fatty acid levels on muscle glucose utilization and forearm indirect calorimetry in lean NIDDM patients.

The aim of the study was to evaluate an acute decrease in NEFA levels during an oral glucose tolerance test and its effects on glucose tolerance, muscle glucose uptake and muscle indirect calorimetry in ten lean non-insulin-dependent diabetic subjects. Two 75-g oral glucose tolerance tests were performed in random order. Placebo or 250 mg acipimox (to inhibit lipolysis) were administered orally 2 h before the start of the oral glucose tolerance test. Two hours after acipimox administration (time 0), non-esterified fatty acid, glycerol and 3-hydroxybutyrate levels decreased by 84, 68 and 77% respectively, compared to basal levels. Concomitantly, muscle lipid oxidation and non-oxidative glycolysis also decreased significantly. After placebo administration, non-esterified fatty acids, glycerol and 3-hydroxybutyrate and lipid oxidation increased by 29, 28, 106 and 33%, respectively (NS vs basal levels; p < 0.001 vs acipimox). There was a negative rate of net glucose storage (interpreted as glycogenolysis) during post-absorptive conditions and at time 0 after administration of both drugs. After oral glucose tolerance test, the incremental areas of blood glucose and insulin were significantly decreased by 18 and 19% after acipimox compared to placebo. In addition, the ratio between the incremental area of forearm muscle glucose uptake and the insulin levels was significantly increased by 45% during acipimox compared to placebo administration. Glucose oxidation and non-oxidative glycolysis were significantly higher while lipid oxidation was significantly lower after acipimox than after placebo. In conclusion, our study found that in lean non-insulin-dependent diabetic subjects, an acute decrease in non-esterified fatty acid levels improves glucose tolerance, muscle glucose uptake, glucose oxidation and non-oxidative glycolysis, but is unable to normalize glucose storage.

3-Hydroxybutyric Acid↗

PubMed1995

Compartmental modeling of glucagon kinetics in the conscious dog.

The aim of the present study was to examine glucagon metabolism and distribution using both compartmental-modeling approaches and steady-state organ-balance techniques in conscious, overnight-fasted dogs. Arterial plasma glucose concentrations were clamped at 14 mmol/L with a variable exogenous glucose infusion. Somatostatin was infused to block endogenous secretion of insulin and glucagon. Insulin was replaced intraportally at 2.4 pmol.kg-1.min-1 to maintain basal insulin concentrations in the range from 70 +/- 4 to 95 +/- 12 pmol/L. Glucagon was not given during the control period, but was subsequently infused peripherally in four 1-hour steps of 1.0, 3.0, 6.0, and 3.0 ng.kg-1.min-1. Glucagon levels increased from 0 to 68 +/- 6, 195 +/- 19, 378 +/- 47, and 181 +/- 20 ng/mL. Compartmental analysis of glucagon concentrations showed that glucagon was distributed in one compartment with a volume approximately equal to the plasma volume. The metabolic clearance rate of glucagon was 17.6 mL.kg-1.min-1. The liver cleared 24% of glucagon, and the kidneys, 17%.

Animals↗

PubMed1995

Paradoxical insulin-induced increase in gluconeogenesis in response to prolonged hypoglycemia in conscious dogs.

The aim of this study was to determine the effects of differing insulin concentrations on the gluconeogenic response to equivalent prolonged hypoglycemia. Insulin was infused intraportally, for 3 h, into normal 18-h fasted conscious dogs at 2 (lower, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during high dose to maintain the hypoglycemic plateau (50 +/- 1 mg/dl) equivalent to lower. Epinephrine (806 +/- 180 vs. 2,589 +/- 260 pg/ml), norepinephrine (303 +/- 55 vs. 535 +/- 60 pg/ml), cortisol (5.8 +/- 1.2 vs. 12.1 +/- 1.5 micrograms/dl), and pancreatic polypeptide (598 +/- 250 vs. 1,198 +/- 150 pg/ml) were all increased (P < 0.05) in the presence of high-dose insulin. Net hepatic glucose production increased significantly from 2.2 +/- 0.3 to 3.8 +/- 0.5 mg.kg-1.min-1 (P < 0.05) during high-dose infusion but remained at basal levels (2.3 +/- 0.4 mg.kg-1.min-1) during lower-dose insulin. During the 3rd h of hypoglycemia, gluconeogenesis accounted for between 42 and 100% of glucose production during high-dose infusion but only 22-52% during lower-dose insulin. Intrahepatic gluconeogenic efficiency, however, increased similarly during both protocols. Lipolysis, as indicated by arterial blood glycerol levels, increased by a greater amount during high- compared with lower-dose insulin infusion. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. Gluconeogenesis remained similar to basal levels, but lipolysis was significantly suppressed during both series of hyperinsulinemic euglycemic studies. In summary, these data suggest that 1) the important counterregulatory processes of gluconeogenesis and lipolysis can be significantly increased during prolonged hypoglycemia despite an eightfold increase in circulating insulin levels and 2) the amplified gluconeogenic rate present during the hypoglycemic high-dose insulin infusions was caused by enhanced substrate delivery to the liver rather than an increase in intrahepatic gluconeogenic efficiency.

Animals↗

PubMed1995

Evidence that the brain of the conscious dog is insulin sensitive.

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84 +/- 6 vs. 86 +/- 6 microU/ml) but differing insulin levels in the head (84 +/- 6 vs. 195 +/- 5 microU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56 +/- 2 mg/dl) at a value similar to that seen during head insulin infusion (58 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792 +/- 198 vs. 2394 +/- 312 pg/ml), norepinephrine (404 +/- 33 vs. 778 +/- 93 pg/ml), cortisol (6.8 +/- 1.8 vs. 9.8 +/- 1.6 micrograms/dl) and pancreatic polypeptide (722 +/- 273 vs. 1061 +/- 255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6 +/- 0.2 to 4.3 +/- 0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6 +/- 0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes.

3-Hydroxybutyric Acid↗

PubMed1994

Exaggerated epinephrine response to hypoglycemia in a physically fit, well-controlled IDDM subject.

Metabolically well controlled insulin-dependent diabetic subjects (IDDM) have deficient autonomic adrenomedullary responses to hypoglycemia. This defect, coupled with the characteristic deficient glucagon response to hypoglycemia, predisposes well-controlled IDDM subjects to an increased incidence of severe hypoglycemic episodes. In this report we describe a physically trained subject with long-duration IDDM (9 years) who was rigorously well-controlled (normal HBA1c), yet had exaggerated epinephrine responses to hypoglycemia compared with normal controls. Steady state epinephrine levels during a low-dose insulin (9 pM/kg/min) hypoglycemic clamp (2.9 +/- 0.1 mM) were approximately 2-fold higher compared with normal controls (10.6 vs. 5.5 +/- 0.7 nM). Epinephrine levels during a high-dose insulin (30 pM/kg/min) hypoglycemic clamp (2.8 +/- 0.1 mM) were also increased compared with normal controls (13.1 vs. 8.8 +/- 0.6 nM). We conclude that physical training in this metabolically well-controlled IDDM subject was associated with an augmented autonomic adrenomedullary response to hypoglycemia.

3-Hydroxybutyric Acid↗

PubMed1994

Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity.

BACKGROUND AND OBJECTIVES: The hepatic 6-hydroxylation of chlorzoxazone in vitro is mediated primarily by CYP2E1, and measurement of this metabolic pathway may provide an in vivo probe of the enzyme. In animals, such as the rat, levels of CYP2E1 are induced by both fasting and obesity. This study investigated whether these two physiologic factors are determinants of the metabolism and disposition of chlorzoxazone in humans. METHODS: The plasma concentration-time profiles of chlorzoxazone and its 6-hydroxy metabolite were determined after oral administration of parent drug (250 mg). The urinary excretion of the metabolite was also determined. In one study, the disposition profiles were obtained in six healthy white men, first after an overnight fast, and on a separate occasion after a 38-hour fast. The second study investigated the disposition of chlorzoxazone in nine obese women and in nine age-matched women. RESULTS: Prolonged fasting produced a significant increase in circulating ketone bodies. This was associated with a reduction in the oral clearance of chlorzoxazone (mean +/- SD, 5.79 +/- 1.04 to 3.69 +/- 1.54 ml.min-1.kg-1; p < 0.03). The 0- to 24-hour urinary recovery of the 6-hydroxy metabolite was extensive (50% to 80%), and the reduced clearance reflected a lower 6-hydroxylating ability after fasting. The elimination half-life of the drug was increased by a similar extent to clearance (1.00 +/- 0.09 versus 1.50 +/- 0.42 hours; p < 0.004), whereas its apparent volume of distribution was unaffected by fasting. By contrast, obesity resulted in significant increases in the oral clearance and distribution of chlorzoxazone on both an absolute and weight-normalized basis; for example, 4.15 +/- 0.81 versus 6.23 +/- 1.72 ml.min-1.kg-1 and 0.50 +/- 0.28 versus 0.82 +/- 0.19 L.kg-1. Half-life of elimination was similar in both groups of subjects. Estimation of the fractional clearance of 6-hydroxychlorzoxazone showed that obesity increased this parameter to a similar extent as oral clearance. The difference in the oral clearance and 6-hydroxylating ability of nonobese men and women was also statistically different. CONCLUSIONS: A discordancy was observed between the reported effect of fasting in rodents and that observed in humans. This may reflect an interspecies difference in CYP2E1 regulation or, more likely, destruction of the enzyme by lipid peroxidation resulting from the prolonged period of fasting. However, serious to morbid obesity in humans is associated with increased 6-hydroxylation of chlorzoxazone, consistent with induction of CYP2E1. Accordingly, such individuals may be at increased risk of CYP2E1-mediated toxicities and adverse effects caused by the formation of CYP2E1-mediated metabolites of environmental agents. In addition, the efficacy of an active drug that is a CYP2E1 substrate may be reduced in obese patients.

Adult↗

PubMed1994

Pulsatility does not alter the response to a physiological increment in glucagon in the conscious dog.

The present study was designed to investigate if pulsatile hyperglucagonemia of physiological magnitude has greater efficacy in stimulating hepatic glucose production than constant glucagon. Paired studies were performed in conscious dogs. After insulin and glucagon were clamped at basal concentrations for 2 h, glucagon was elevated for 4 h with either a continuous infusion or pulses having physiological frequency and amplitude. With continuous infusion, plasma glucagon concentrations increased from 56 +/- 7 to 194 +/- 27 ng/l. With pulsatile infusion, glucagon concentrations started at 53 +/- 6 ng/l and then oscillated between 157 +/- 15 and 253 +/- 28 ng/l. Plasma insulin concentrations remained constant at basal levels. Glucose production was determined using a time-varying two-compartment model for glucose kinetics and deconvolution. After 15 min, glucose production had risen from 13.6 +/- 1.1 to 53.8 +/- 3.9 mumol.kg-1.min-1 with continuous infusion and from 12.9 +/- 0.6 to 50.6 +/- 2.9 mumol.kg-1.min-1 with pulsatile infusion. After 4 h, the production had fallen to 16.1 +/- 1.2 and 17.1 +/- 0.7 mumol.kg-1.min-1. In the present animal model with insulin held constant, no difference was noted between the response to continuous or pulsatile glucagon infusion.

Animals↗

PubMed1994

Effects of physiological hyperinsulinemia on counterregulatory response to prolonged hypoglycemia in normal humans.

To test the hypothesis that differing physiological insulin levels can modify the counter-regulatory response to prolonged hypoglycemia, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mumol.kg-1.min-1) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mumol/l, P < 0.02) were increased in high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mumol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mumol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Assessment of proinsulin's effects on intermediary metabolism using the forearm technique in normal man.

We have compared the effects of human proinsulin and insulin on forearm metabolism. Seven normal, non-obese subjects were infused with 386 pmol/kg per hour of proinsulin and 180 pmol/kg per hour of insulin using the euglycaemic clamp technique. Glucose appearance and utilization rates were quantified using a primed continuous infusion of [6',6'-2H2]glucose. Mean blood glucose was 4.1 +/- 0.1 and 4.1 +/- 0.2 mmol/l during proinsulin and insulin infusions respectively. Basal insulin concentrations increased from 0.02 +/- 0.01 to 0.25 +/- 0.03 nmol/l. The proinsulin infusion was chosen to give steady-state levels approximately 20-fold higher on a molar basis than those of insulin, based on previous findings that proinsulin has only 5% the biological potency of insulin. Basal proinsulin concentrations increased from 0.003 to 5.4 +/- 0.3 nmol/l. Hepatic glucose production was suppressed similarly during the last hour of each hormone infusion: 0.07 +/- 0.16 (proinsulin, P), and 0.01 +/- 0.13 (insulin, I) mg/kg per minute. Glucose disposal, however, was significantly increased during the final hour of the insulin infusion: 4.7 +/- 0.4 (I) and 3.4 +/- 0.2 (P) mg/kg per minute (P = 0.025). Net forearm glucose uptake (FGU) increased by a greater amount during insulin compared with proinsulin infusion: 1.44 +/- 0.02 (I) and 0.71 +/- 0.01 (P) mumol/100 ml forearm per minute (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Proinsulin and insulin concentrations following intravenous glucose challenges in normal, obese, and non-insulin-dependent diabetic subjects.

We investigated the effects of different intravenous (IV) glucose challenges on insulin and proinsulin secretion. On separate occasions, seven normal controls and five obese and five non-insulin-dependent diabetic (NIDDM) subjects each received an IV glucose tolerance test (IVGTT), a hyperglycemic clamp (HY), and a 60-minute, standardized, low-dose, continuous infusion of glucose (CIG) in a randomized fashion. Basal proinsulin concentrations in NIDDM subjects (8.4 +/- 5.0 pmol/L) were significantly higher compared with those of normal (1.1 +/- 0.2) and obese subjects (1.5 +/- 0.4; both P < .05). Basal molar proinsulin:insulin ratio (P:I) was also significantly higher in NIDDM subjects (22% +/- 12%) compared with normal (1.0%) and obese subjects (1.6% +/- 0.8%; both P < .01). Proinsulin concentrations did not increase significantly in any group during the first 10 minutes of the IV glucose challenges. However, during HY, significant increases in proinsulin concentration occurred after 60 minutes in each group. In normal and obese subjects, IV glucose administration resulted in significant acute increases in insulin concentrations compared with the characteristic blunted response in NIDDM subjects. The P:I ratio in normal and obese subjects did not change in the first 10 minutes after IV glucose administration. However, by the end of HY, the P:I ratio had increased significantly in normal subjects by 1% to 5% +/- 2% (P < .05), and in obese subjects by 1% to 5% +/- 1% (P < .02). In NIDDM subjects, both HY (19% +/- 10% to 27% +/- 12%) and IVGTT (18% +/- 9% to 43% +/- 16%) resulted in a transient increase in the basal P:I ratio by 5 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

The effects of subcutaneous human proinsulin on the production of 64/65 split proinsulin, glucose turnover and intermediary metabolism in non-insulin-dependent diabetic man.

We have compared the effects of subcutaneously injected human proinsulin, insulin zinc suspension and inactive diluent (control) on glucose turnover, intermediary carbohydrate and lipid metabolism in non-insulin-dependent diabetic man. Six weight-matched (24.8 +/- 1.6 kg M-2) non-insulin-dependent diabetic subjects underwent 3 separate, randomized, 10 h isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6'6'2H2] glucose. Each subject received 0.35 U/kg of hormone or control made up to isovolumetric amounts. The mean blood glucose level of 7.3 +/- 0.8 mmol/l was similar at the start of each isoglycemic clamp. Incremental area under the curve proinsulin levels (1195 +/- 146 nmol/l) were about 21-fold higher, on a molar basis, than insulin (62.4 +/- 10 nmol/l). Des 64/65 split proinsulin increased in a parallel manner to intact proinsulin (r = 0.99, P < 0.0001) and comprised approximately 13% of the intact proinsulin concentration. Hepatic glucose production was suppressed similarly following proinsulin and insulin zinc injection. However, both proinsulin and insulin zinc had a significantly greater effect on suppression of hepatic glucose production compared to control (P = 0.01, P = 0.009, respectively). Metabolic clearance rate of glucose fell significantly during the control studies compared to insulin zinc or proinsulin injections (P < 0.05). Blood lactate, pyruvate and alanine concentrations were similar following control or hormone injections. However blood glycerol, 3-hydroxybutyrate and plasma-non-esterified fatty acids were suppressed significantly by proinsulin and insulin zinc compared to control injections. The conclusions were: (1) In overnight fasted hyperglycemic non-insulin-dependent subjects s.c. injections of proinsulin and insulin zinc can produce similar effects on glucose turnover, intermediary lipid and carbohydrate metabolism. (2) Similar carbohydrate intermediary metabolism profiles can be obtained following insulin zinc, proinsulin or control injections. (3) However lipolysis and ketogenesis were significantly suppressed by both hormones compared to control. (4) Subcutaneous proinsulin injection resulted in approximately 13% conversion to des 64/65 split proinsulin.

Alanine↗

PubMed1993

Effects of hyperinsulinemia on the subsequent hormonal response to hypoglycemia in conscious dogs.

The aim of this study was to determine if differing periods of prior hyperinsulinemic nonhypoglycemia can modify the subsequent counterregulatory response to hypoglycemia. Experiments were carried out on 19 normal 18-h fasted conscious dogs. Insulin was infused intraportally at 8 mU.kg-1.min-1 for 3 h on two occasions and 3.5 h on a third separate occasion. This resulted in similar steady-state arterial insulin levels during each protocol (4,370 +/- 433 pmol/l). Each animal was maintained at a similar plasma glucose nadir (2.8 +/- 0.6 mmol/l) for 2 or 2.5h, depending on the protocol. In protocol I (n = 7) plasma glucose was allowed to fall to the desired hypoglycemic plateau by 30 min. In a second group of dogs (protocol II, n = 5) there was a 30-min period of euglycemic hyperinsulinemia followed by a 30-min fall (similar to protocol I) in plasma glucose. In a third group of dogs (protocol III, n = 7), there was an initial 15-min period of euglycemic hyperinsulinemia followed by a 45-min fall in plasma glucose. Differing periods of euglycemic hyperinsulinemia had distinct effects on subsequent counterregulation. During the final 2 h of hypoglycemia the incremental area under the curve (AUC) for glucagon was significantly greater in protocol I vs. II (3.0 +/- 1.0, -0.5 +/- 0.2 micrograms.l-1.min-1, P < 0.02, respectively). Conversely, catecholamine levels were increased in protocol II (30 min prior hyperinsulinemic euglycemia) compared with protocol I (epinephrine 1,448 +/- 268, 855 +/- 119 nmol.l-1.min-1; norepinephrine 244 +/- 30, 166 +/- 23 nmol.l-1.min-1, respectively, P < 0.05). During protocol III, glucagon and catecholamine levels were intermediate between protocols I (no euglycemic hyperinsulinemia) and II (30 min euglycemic hyperinsulinemia).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females.

The aim of this study was to determine if insulin could augment the counterregulatory response to equivalent hypoglycemia in normal females similarly to males. Experiments were carried out in nine normal lean overnight-fasted female subjects. Insulin was infused in two separate randomized protocols so that steady-state levels of 794 +/- 62 (low) and 3,620 +/- 476 pM (high) were obtained. Despite an identical plasma glucose level (2.8 +/- 0.1 mM), epinephrine (5.7 +/- 0.9 vs. 3.9 +/- 0.6 nM), norepinephrine (2.7 +/- 0.4 vs. 1.8 +/- 0.3 nM), cortisol (918 +/- 55 vs. 826 nM), and growth hormone (35.8 +/- 3.7 vs. 28.4 +/- 2.7 micrograms/l) were increased (P < 0.05) during high compared with low insulin infusion, respectively. Glucagon and pancreatic polypeptide levels increased significantly but were not different during the two insulin infusions. Hepatic glucose production was increased during the high-compared with low-dose infusions (9.5 +/- 1.1 vs. 5.1 +/- 2.2 mumol.kg-1 x min-1; P < 0.05). Lipolysis, as indicated by the blood glycerol level, increased significantly during high- compared with low-dose insulin infusions (121 +/- 29 vs. 65 +/- 13 microM; P < 0.05). The hormonal and metabolic responses to hypoglycemia were significantly different in females compared with previous results in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

The effects of insulin on the counterregulatory response to equivalent hypoglycemia in patients with insulin-dependent diabetes mellitus.

We previously demonstrated that hyperinsulinemia can amplify the counterregulatory response to hypoglycemia in normal subjects. The aim of the present study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent fixed hypoglycemia in insulin-dependent-diabetic subjects (IDDM). Experiments were carried out in seven lean, overnight-fasted, moderately controlled (hemoglobin A1c, 10.9%; normal range, 5-9) IDDM subjects with a disease duration of 13 +/- 3 yr. All were maintained normoglycemic overnight so that basal plasma glucose (5.6 +/- 0.2 and 5.4 +/- 0.2 mmol/L) and insulinemia (63 +/- 18 and 48 +/- 10 pmol/L) were similar at the start of each study. Insulin was infused for 120 min in two separate randomized protocols, so that steady state levels (mean +/- SE) of 742 +/- 212 pmol/L (low) and 3360 +/- 710 pmol/L (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.09 mmol/L.min) and the hypoglycemic plateau (2.8 +/- 0.1 mmol/L) were similar. In response to hypoglycemia, plasma levels of epinephrine, norepinephrine, cortisol, GH, and pancreatic polypeptide increased similarly during both insulin infusions. During the final 30 min, despite similar levels of counterregulatory hormones, hepatic glucose production was significantly reduced in the presence of high compared to low insulin levels (1.7 +/- 2.8 vs. 8.3 +/- 1.7 mumol/kg.min; P < 0.05). Similarly, plasma nonesterified fatty acids (472 +/- 94 vs. 787 +/- 105 mumol/L) and blood 3-hydroxybutyrate levels (30 +/- 12 vs. 106 +/- 29 mumol/L) were significantly reduced (P < 0.05) during high compared to low dose infusions. Cardiovascular parameters (heart rate and systolic, diastolic, and mean arterial pressures) responded similarly during both infusions. We conclude that 1) insulin per se does not amplify the counterregulatory response to equivalent hypoglycemia in individuals with moderately controlled, long duration IDDM; and 2) there may be a relative autonomic adrenomedullary deficit in some IDDM subjects that prevents the amplified epinephrine response to hyperinsulinemia during hypoglycemia.

Adult↗

PubMed1993

The effects of differing insulin levels on the hormonal and metabolic response to equivalent hypoglycemia in normal humans.

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia in normal humans. Experiments were conducted in 9 normal, lean men, who had fasted overnight. Insulin was infused in two separate, randomized protocols so that steady-state levels of 486 +/- 33 (low) and 3056 +/- 236 pM (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.07 mM/min) and hypoglycemic plateau (2.8 +/- 0.1 mM) were similar. Despite similar plasma glucose levels, EPI (8.7 +/- 0.7 vs. 5.5 +/- 0.7 nM), NE (3.3 +/- 0.3 vs. 2.3 +/- 0.2 nM), and cortisol (811 +/- 36 vs. 611 +/- 72 nM) significantly increased during high compared with low insulin infusion, respectively (P < 0.05). Glucagon, growth hormone, and pancreatic polypeptide levels increased briskly and significantly but were not different during the two insulin infusions. HGP rose significantly from 12.1 +/- 0.3 to 18.1 +/- 1.1 mumol.kg-1 x min-1 in response to the high insulin level (P < 0.05) but remained unchanged (12.1 +/- 0.4 and 11.7 +/- 1.4 mumol.kg-1 x min-1) in the presence of th low insulin level. GRa increased significantly during high insulin levels (3.4 +/- 0.3 to 4.8 +/- 0.7 mumol.kg-1 x min-1, P < 0.05) but remained at a basal rate (3.0 +/- 0.3 to 2.7 +/- 0.6 mumol.kg-1 x min-1) in the presence of low insulin levels. sBP and heart rate increased more during high insulin infusion (18 +/- 5 vs. 6 +/- 5 mmHg and 18 +/- 4 vs. 7 +/- 2 beats/min, respectively, P < 0.05). In summary, the 6-fold higher insulin level resulted in significantly greater increases in catecholamine and cortisol secretion, HGP, lipolysis, heart rate, and sBP despite equivalent hypoglycemia. We conclude that at moderate hypoglycemia, high doses of insulin can augment certain aspects of the counterregulatory response in normal humans.

Adult↗