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Biomedical subjects

G Perriello

Publications and source records attributed to G Perriello.

At least 55 records · Page 3Linked to original sources
PubMed1993

Nocturnal blood glucose control in type I diabetes mellitus.

A major problem in replacing insulin in type I diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. Because all of the currently available intermediate- or long-acting insulin preparations have a peaked-action profile, excess insulin action at midnight and insulin waning at dawn occur whenever such an insulin preparation is given at supper time. If the target fasting plasma glucose is the ambitious near-normoglycemia of intensive insulin therapy, intermediate-acting insulin at suppertime easily results in hypoglycemia in the early evening hours and hyperglycemia in the fasting state. The problems of overnight glycemia in type I diabetes are further complicated by the dawn phenomenon and the Somogyi phenomenon. The dawn phenomenon is the combination of an initial decrease in insulin requirements between approximately 2400 and approximately 0300, followed by an increase in the insulin needs between approximately 0500 and approximately 0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients. Its contribution to fasting hyperglycemia correlates with diabetes duration (inversely) and the HbA1c percentage (directly). Overall, it is estimated that the specific contribution of the dawn phenomenon to fasting hyperglycemia is approximately 2 mM (approximately 35 mg/dl), but it may be much greater because of the warning of the depot-insulin preparation injected the previous evening. The Somogyi phenomenon, strictly speaking, refers to fasting hyperglycemia that occurs after inducement of nocturnal hypoglycemia by regular insulin. Because the present therapeutic regimens of NPH/Lente insulin given at suppertime cause overnight hyperinsulinemia, excessive fasting hyperglycemia rarely follows nocturnal hypoglycemia, except when excessive glucose is ingested to correct hypoglycemia. However, nocturnal hypoglycemia may easily deteriorate glycemic control later in the day, because it induces prolonged posthypoglycemic insulin resistance, which results in postbreakfast and late-morning hyperglycemia. With nocturnal insulin therapy, it is important to consider the problems of insulin pharmacokinetics, the dawn phenomenon, and the Somogyi phenomenon to prevent both nocturnal hypoglycemia and excessive fasting hyperglycemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Glucose↗
PubMed1992

Effect of cigarette smoking and of a transdermal nicotine delivery system on glucoregulation in type 2 diabetes mellitus.

The effect of nicotine absorbed transdermally from a patch (TNS) and from cigarette smoking on insulin secretion and action in Type 2 diabetes has been compared. Twelve Type 2 diabetic smoking patients, aged 51 y, with diabetes for 9 y, treated either with diet and/or oral hypoglycaemic agents, were studied on three occasions, according to a double-blind, placebo-controlled, cross-over design. The subjects were investigated 12 h after their last cigarette or application of one patch of TNS 30 cm2 or TNS placebo, or whilst smoking their usual cigarette. Insulin secretion was assessed by a glucagon (1 mg IV) stimulation test. On a second occasion, insulin action was assessed by a hyperglycaemic-hyperinsulinaemic clamp, the spontaneous hyperglycaemia of the fasting state (8.61 mmol.l-1) being maintained during a 4 h insulin infusion (at 0.1 mU.kg-1.min-1 for the initial 2 h, and 1 mU.kg-1.min-1 during the last 2 h). TNS and the cigarette did not affect endogenous insulin secretion as compared to placebo. During the initial 2 h of the clamp study, plasma insulin increased from 88 to 155 pmol.l-1, hepatic glucose production (3-3H-glucose) was less suppressed after TNS (4.31 mumol.kg-1.min-1) than after placebo (2.5 mumol.kg-1.min-1), but was more suppressed than after cigarette smoking (5.61 mumol.kg-1.min-1). In the last 2 h of the clamp (plasma insulin 646 pmol.l-1), glucose utilization was less stimulated after TNS (36.1 mumol.kg-1.min-1) vs placebo (39.8 mumol.kg-1.min-1), but more than after cigarette smoking (33.6 mumol.kg-1.min-1), primarily because of a decrease in glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1992

Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis.

Three studies were performed on nine normal volunteers to assess whether catecholamine-mediated lipolysis contributes to counterregulation to hypoglycemia. In these three studies, insulin was intravenously infused for 8 h (0.30 mU.kg-1.min-1 from 0 to 180 min, and 0.40 mU.kg-1.min-1 until 480 min). In study I (control study), only insulin was infused; in study II (direct + indirect effects of catecholamines), propranolol and phentolamine were superimposed to insulin and exogenous glucose was infused to reproduce the same plasma glucose (PG) concentration of study I. Study III (indirect effect of catecholamines) was the same as study II, except heparin (0.2 U.kg-1.min-1 after 80 min), 10% Intralipid (1 ml.min-1 after 160 min) and variable glucose to match PG of study II, were also infused. Glucose production (HGO), glucose utilization (Rd) [3-3H]glucose, and glucose oxidation and lipid oxidation (LO) (indirect calorimetry) were determined. In all three studies, PG decreased from approximately 4.8 to approximately 2.9 mmol/liter (P = NS between studies), and plasma glycerol and FFA decreased to a nadir at 120 min. Afterwards, in study I plasma glycerol and FFA increased by approximately 75% at 480 min, but in study II they remained approximately 40% lower than in study I, whereas in study III they rebounded as in study I (P = NS). In study II, LO was lower than in study I (1.69 +/- 0.13 vs. 3.53 +/- 0.19 mumol.kg-1.min-1, P less than 0.05); HGO was also lower between 60 and 480 min (7.48 +/- 0.57 vs. 11.6 +/- 0.35 mumol.kg-1.min-1, P less than 0.05), whereas Rd was greater between 210 and 480 min (19 +/- 0.38 vs. 11.4 +/- 0.34 mumol.kg-1.min-1, respectively, P less than 0.05). In study III, LO increased to the values of study I; between 4 and 8 h, HGO increased by approximately 2.5 mumol.kg-1.min-1, and Rd decreased by approximately 7 mumol.kg-1.min-1 vs. study II. We conclude that, in a late phase of hypoglycemia, the indirect effects of catecholamines (lipolysis mediated) account for at least approximately 50% of the adrenergic contribution to increased HGO, and approximately 85% of suppressed Rd.

Adult↗
PubMed1991

The dawn phenomenon in type 1 (insulin-dependent) diabetes mellitus: magnitude, frequency, variability, and dependency on glucose counterregulation and insulin sensitivity.

In 114 subjects with Type 1 (insulin-dependent) diabetes mellitus the nocturnal insulin requirements to maintain euglycaemia were assessed by means of i.v. insulin infusion by a Harvard pump. The insulin requirements decreased after midnight to a nadir of 0.102 +/- 0.03 mU.kg-1.min-1 at 02.40 hours. Thereafter, the insulin requirements increased to a peak of 0.135 +/- 0.06 mU.kg-1.min-1 at 06.40 hours (p less than 0.05). The dawn phenomenon (increase in insulin requirements by more than 20% after 02.40 hours lasting for at least 90 min) was present in 101 out of the 114 diabetic subjects, and its magnitude (% increase in insulin requirements between 05.00-07.00 hours vs that between 01.00-03.00 hours) was 19.4 +/- 0.54% and correlated inversely with the duration of diabetes (r = -0.72, p less than 0.001), but not with age. The nocturnal insulin requirements and the dawn phenomenon were highly reproducible on three separate nights. In addition, glycaemic control, state of counterregulation to hypoglycaemia and insulin sensitivity all influenced the magnitude of the dawn phenomenon as follows. In a subgroup of 84 subjects with Type 1 diabetes, the multiple correlation analysis showed that not only duration of diabetes (t = -9.76, p less than 0.0001), but also % HbA1 significantly influenced the magnitude of the dawn phenomenon (t = 2.03, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension.

To assess the effects of ACE-inhibition on insulin action in Type 2 (non-insulin-dependent) diabetes mellitus associated with essential hypertension, 12 patients with Type 2 diabetes (on diet and oral hypoglycaemic agents) and arterial hypertension were examined on two occasions, in a single blind, cross-over study after two days of treatment with either captopril or a placebo. The study consisted of a euglycaemic-hyperinsulinaemic clamp (two sequential steps of insulin infusion at the rates of 0.25 mU.kg-1.min-1 and 1 mU.kg-1.min-1, 2 h each step), combined with an infusion of 3-3H-glucose to measure the rate of hepatic glucose production and that of peripheral glucose utilization. The results show that blood pressure was lower after captopril (sitting, systolic 148 +/- 5 mm Hg, diastolic 89 +/- 2 mm Hg) compared to placebo (155 +/- 6 and 94 +/- 2 mm Hg) (p less than 0.05). Captopril treatment resulted in a more suppressed hepatic glucose production (2.7 +/- 0.4 vs 4.94 +/- 0.55 mumol.kg-1.min-1), and a lower plasma non-esterified fatty acid concentration (0.143 +/- 0.05 vs 0.200 +/- 0.05 mmol/l) (captopril vs placebo, p less than 0.05) at the end of the first step of insulin infusion (estimated portal plasma insulin concentration 305 +/- 28 pmol/l); and in a greater glucose utilization (36.5 +/- 5.1 vs 28 +/- 3.6 mumol.kg-1.min-1, p less than 0.001) at the end of the second step of insulin infusion (arterial plasma insulin concentration of 604 +/- 33 pmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Evidence against important catecholamine compensation for absent glucagon counterregulation.

To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon's effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.

3-Hydroxybutyric Acid↗
PubMed1991

Contribution of adrenergic mechanisms to glucose counterregulation in humans.

To assess the role of adrenergic mechanisms during prolonged hypoglycemia, eight normal subjects were studied on six occasions. In study 1, insulin was infused subcutaneously (15 mU.m-2.min-1 for 12 h), and plasma glucose concentration (PG) decreased from 89 +/- 2 to 50 +/- 1 mg/dl. In study 2 (insulin as in study 1 + propranolol and phentolamine + variable glucose to maintain PG as in study 1), the rate of hepatic glucose production (HGO, [3-3H]glucose) was approximately 30% lower after 1.5 h, and the rate of peripheral glucose utilization (GU) was approximately 15% greater after 5 h. To quantitate the effects of adrenergic mechanisms on glucose counterregulation, in a control study (study 3), glucoregulatory hormone secretion was blocked, and the hormones were reinfused to reproduce study 1. When alpha- and beta-blockade plus variable glucose were superimposed to study 3 (study 4), HGO was approximately 25% lower (after 2 h), and GU was approximately 10% greater (after 6 h) vs. study 3. When glucose was not infused to match PG of study 3 (study 5), severe hypoglycemia developed (PG at 7 h 36 +/- 2 vs. 62 +/- 3 mg/dl). Finally, when glucose was not infused during alpha- and beta-blockade of study 2 (study 6), PG was 49 +/- 3 mg/dl at 7 h vs. 65 +/- 3 mg/dl of the control study (study 1), despite greater secretion of glucagon, growth hormone, and cortisol. It is concluded that adrenergic mechanisms play a key counterregulatory role, even in the presence of appropriate responses of glucagon and that greater increases in glucagon (and other counterregulatory hormones) cannot compensate fully for absent contribution of adrenergic mechanisms to counterregulation.

Adipose Tissue↗
PubMed1990

Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in type 1 (insulin-dependent) diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning.

The aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (approximately 25 mU/l, n = 7; approximately 80 mU/l, n = 5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (approximately 30% increase in the rate of hepatic glucose production, approximately 25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Impact of activated glucose counterregulation on insulin requirements in insulin-dependent diabetes mellitus.

The glucose counterregulatory system is one of the most important homeostatic systems in physiology, since it normally prevents hypoglycaemia or, should it occur for any reason such as insulin administration, limits the severity of hypoglycaemia and ultimately may restore normoglycaemia. In normal nondiabetic subjects, activation of counterregulation does not result in overt hyperglycaemia in the post-absorptive state, because the pancreatic beta-cell increases insulin secretion. On the contrary, in subjects with insulin-dependent diabetes mellitus (IDDM) whose pancreatic B-cell cannot respond to an increase in plasma glucose, activated counterregulation may easily result in overt hyperglycaemia. There are two different circumstances under which counterregulation may contribute to excessive hyperglycaemia in IDDM, namely nonhypoglycaemic nocturnal activation of counterregulation (dawn phenomenon), and hypoglycaemic activation of counterregulation (Somogyi phenomenon). The dawn phenomenon is an increase in insulin requirements which occurs between 04.00 and 08.00 h in the absence of preceding hypoglycaemia and concomitant hypoinsulinemia. It is caused by a decrease in hepatic and extrahepatic sensitivity to insulin induced by the nocturnal secretion of growth hormone. The dawn phenomenon may contribute importantly to fasting hyperglycaemia in IDDM, because usually plasma insulin concentration following the pre-supper insulin injection decreases after 04.00 h, i.e. a time at which plasma insulin concentration should instead increase to maintain normoglycaemia. The Somogyi phenomenon is best defined as hyperglycaemia following hypoglycaemia and is caused by the insulin resistance induced by hypoglycaemic-activation of counterregulation. Although insulin resistance following hypoglycaemia is a constant event in IDDM, post-hypoglycaemic hyperglycaemia is not the rule. For example, if the responses of counterregulatory hormones to nocturnal hypoglycaemia are blunted, or plasma insulin concentration following hypoglycaemia is inappropriately high, post-hypoglycaemic insulin resistance is not powerful enough to result in overt hyperglycaemia in the fasting state. However, post-breakfast plasma glucose may be exaggerately elevated following nocturnal hypoglycaemia even in the case that fasting plasma glucose is only modestly increased. It is important to prevent nocturnal hypoglycaemia, not only to protect brain function, but also to prevent insulin resistance which may easily result in exaggerated hyperglycaemia and initiate the vicious circle "hypoglycaemia-hyperglycaemia-increase in insulin dose-risk for subsequent hypoglycaemia", and so on.

Blood Glucose↗
PubMed1989

Demonstration of a role for growth hormone in glucose counterregulation.

To test the hypothesis that growth hormone secretion plays a counterregulatory role in prolonged hypoglycemia in humans, four studies were performed in nine normal subjects. Insulin (15 mU.M-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 2 microU/ml), and plasma glucose decreased from 88 +/- 2 to 53 +/- 1 mg/dl for 12 h. In study 1, plasma glucose, glucose fluxes (D-[3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored. In study 2 (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretions (except for catecholamines) were prevented by somatostatin (0.5 mg/h iv) and metyrapone (0.5 g/4 h po), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of growth hormone increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma growth hormone at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of a growth hormone response caused a decrease in hepatic glucose production and an increase in glucose utilization that resulted in an approximately 25% greater hypoglycemia despite compensatory increases in plasma catecholamines. Plasma free fatty acid, 3-beta-hydroxybutyrate, and glycerol concentrations were reduced approximately 50%. It is concluded that growth hormone normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.

Adult↗
PubMed1989

Contribution of cortisol to glucose counterregulation in humans.

To test the hypothesis that cortisol secretion plays a counterregulatory role in hypoglycemia in humans, four studies were performed in eight normal subjects. In all studies, insulin (15 mU.m-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 1 microU/ml). In study 1, plasma glucose concentration and glucose fluxes [( 3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored, and plasma glucose decreased from 89 +/- 2 to 52 +/- 2 mg/dl for 12 h. In study 2, (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretion (except for catecholamines) was prevented by somatostatin (0.5 mg/h, iv) and metyrapone (0.5 g/4 h, per os), and glucagon, cortisol, and growth hormone were infused to reproduce the concentrations of study 1. In study 3 (lack of cortisol increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma cortisol at basal levels, and glucose was infused, whenever needed, to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of cortisol increase caused a approximately 22% decrease in hepatic glucose production (P less than 0.01) and a approximately 15% increase in peripheral glucose utilization (P less than 0.01), which resulted in greater hypoglycemia (37 +/- 2 vs. 52 +/- 2 mg/dl, P less than 0.01) despite compensatory increases in plasma epinephrine. Lack of cortisol response also reduced plasma free fatty acid, beta-hydroxybutyrate, and glycerol concentrations approximately 50%. We conclude that cortisol normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.

3-Hydroxybutyric Acid↗
PubMed1988

The effect of asymptomatic nocturnal hypoglycemia on glycemic control in diabetes mellitus.

To assess the effect of asymptomatic nocturnal hypoglycemia on glycemic control in insulin-dependent diabetes mellitus, we studied, on three nights, 10 patients receiving their usual regimens of continuous subcutaneous insulin infusion. During a control night, the patients' mean (+/- SE) plasma glucose level reached a nadir of 4.5 +/- 0.2 mmol per liter at 3 a.m.; the fasting glucose level was 5.9 +/- 0.3 mmol per liter at 7:30 a.m., and a peak glucose level of 8.6 +/- 0.3 mmol per liter was reached at 10 a.m., after breakfast. During nights two and three, supplemental insulin was infused intravenously from 10 p.m. to 2 a.m. to simulate a clinical overdose of insulin. On these nights, either hypoglycemia (2.4 +/- 0.2 mmol per liter) was permitted to occur or a nearly normal glucose level (5.5 mmol per liter) was maintained by infusion of glucose. The subjects were asymptomatic on all three nights. Despite comparable plasma free insulin levels from 4 to 11 a.m., both fasting (7.3 +/- 0.2 mmol per liter) and postbreakfast (12.5 +/- 0.4 mmol per liter) plasma glucose levels were significantly higher after hypoglycemia than when hypoglycemia was prevented (6.2 +/- 0.2 mmol per liter and 8.7 +/- 0.4 mmol per liter, respectively; P less than 0.001 in both cases). Fasting levels of plasma glucose correlated directly with overnight plasma levels of epinephrine (r = 0.78, P less than 0.001), growth hormone (r = 0.57, P less than 0.009), and cortisol (r = 0.52, P less than 0.02) but correlated inversely with the overnight nadir of plasma glucose (r = -0.62, P less than 0.005). We conclude that asymptomatic nocturnal hypoglycemia can cause clinically important deterioration in glycemic control (the Somogyi phenomenon) in patients receiving intensive insulin therapy, and should therefore be considered in the differential diagnosis of unexplained morning hyperglycemia.

Adult↗
PubMed1988

Effect of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with type 1 (insulin-dependent) diabetes mellitus.

These studies were undertaken to assess the influence of storage temperature of insulin vials on pharmacokinetics and pharmacodynamics of a mixture of lente insulin (Monotard HM) and regular insulin (Actrapid HM) injected subcutaneously. Seven subjects with Type 1 (insulin-dependent) diabetes mellitus were studied twice after overnight normalization of plasma glucose. A mixture of lente insulin (0.22 U/kg) and regular insulin (0.11 U/kg) was prepared from insulin vials kept either refrigerated (approximately 4 degrees C) or at room temperature (approximately 18 degrees C) and injected subcutaneously (abdomen). Euglycaemia was maintained for the following 16 h by glucose infusion at variable rate. With refrigerated insulin, the plasma free insulin peak was greater (53 +/- 5 versus 45 +/- 6 mU/l) and occurred earlier (2.5 +/- 0.2 versus 6 +/- 0.3 h), and the glucose infusion rate showed a greater (16.5 +/- 1.2 versus 14.5 +/- 0.9 mumol.kg-1.min-1) and earlier peak (3.2 +/- 0.2 versus 6 +/- 0.4 h) as compared to that occurring with the non-refrigerated insulin (p less than 0.05). However, 6 h after insulin injection, both plasma free insulin and glucose infusion rate were 30% lower with the mixture of refrigerated as compared to that of non-refrigerated insulin (p less than 0.05). In contrast, when NPH-insulin (Protaphane HM) was mixed with regular insulin and injected in 4 out of the 7 diabetic patients, the storage temperature of insulin vials had no effect on the pharmacokinetics and pharmacodynamics of the mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man.

To establish the glycemic threshold for onset of neuroglycopenia (impaired cognitive function, measured by the latency of the P300 wave), activation of hormonal counterregulation and hypoglycemic symptoms, 12 normal subjects were studied either under conditions of insulin-induced, glucose-controlled plasma glucose decrements, or during maintenance of euglycemia. A decrement in plasma glucose concentration from 88 +/- 3 to 80 +/- 1 mg/dl for 150 min did not result in changes in the latency of the P300 wave nor in an activation of counterregulatory hormonal response. In contrast, a greater decrement in plasma glucose concentration from 87 +/- 3 to 72 +/- 1 mg/dl for 120 min caused an increase in the latency of the P300 wave (from 301 +/- 12 to 348 +/- 20 ms, P less than 0.01), a subsequent increase in all counterregulatory hormones but no hypoglycemic symptoms. Finally, when plasma glucose concentration was decreased in a stepwise manner from 88 +/- 2 to 50 +/- 1 mg/dl within 75 min, the increase in the latency of the P300 wave was correlated with the corresponding plasma glucose concentration (r = -0.76, P less than 0.001). The glycemic threshold for hypoglycemic symptoms was 49 +/- 2 mg/dl. Thus, in normal man the glycemic threshold for neuroglycopenia (72 +/- 1 mg/dl) is greater than currently thought; the hormonal counterregulation follows the onset of neuroglycopenia; the hypoglycemic symptoms are a late indicator of advanced neuroglycopenia.

3-Hydroxybutyric Acid↗
PubMed1987

The pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans.

The present experiments were undertaken to develop an approach to analyze the contribution of individual glucose counterregulatory hormones in humans. For this purpose, 24 normal subjects were studied twice: once (control experiments) hypoglycemia was induced by subcutaneous infusion of insulin; and once [pancreatic-adrenocortical-pituitary (PAP) clamp technique] the spontaneous responses of plasma glucagon, growth hormone, and cortisol to hypoglycemia were prevented by intravenous somatostatin and oral metyrapone, respectively, and each hormone was infused at variable rates, which reproduced spontaneous changes in their circulating concentrations in the control experiments. Plasma glucose rate of decrease (0.052 +/- 0.003 vs. 0.06 +/- 0.003 mg X dl-1 X min-1), plasma glucose nadir (49.8 +/- 1.2 vs. 50 +/- 1.0 mg/dl), initial suppression of glucose production (0.22 +/- 0.01 vs. 0.23 +/- 0.01 mg X kg-1 X min-1), subsequent compensatory increase in glucose production (0.54 +/- 0.05 vs. 0.48 +/- 0.04 mg X kg-1 X min-1), and the increase in glucose utilization (0.45 +/- 0.05 vs. 0.42 +/- 0.05 mg X kg-1 X min-1) in PAP clamp and control experiments, respectively, were not significantly different and were significantly correlated. Changes in plasma alanine, lactate, free fatty acids, 3-beta-hydroxybutyrate concentrations were also virtually identical in the PAP clamp experiments and in control experiments. We conclude that the PAP clamp technique can faithfully reproduce the spontaneous hormonal and substrate responses to hypoglycemia and should be useful to assess the contribution of individual hormones during counterregulation by creating an isolated (total or partial) deficiency of a particular hormone without confounding compensatory changes in secretion of other counterregulatory hormones.

3-Hydroxybutyric Acid↗
PubMed1986

Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon.

In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 +/- 0.014 mU X kg-1 X min-1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 +/- 0.012 mU X kg-1 X min-1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00-02.30 hours and from 04.00-08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU X kg-1 X min-1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00-02.30 hours (12.6 +/- 0.17 ml X kg-1 X min-1) was no different from that of the interval 04.00-08.30 hours (12.5 +/- 0.19 ml X kg-1 X min-1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU X kg-1 X min-1) were infused from 22.00-02.30 hours on one occasion, and from 04.00-08.30 hours on the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗