Substrate metabolism during modest hyperinsulinemia in response to isolated hyperketonemia in insulin-dependent diabetic subjects

To assess the metabolic effects of moderate hyperketonemia, six young male type 1 diabetic patients received a 200-minute intravenous (IV) infusion of (1) 0.9 mmol 3-hydroxybutyrate (3-OHB)/kg/h, and (2) saline. To ensure comparable metabolic conditions, a low-dose hyperinsulinemic euglycemic glucose clamp was performed from 5 hours before and throughout 3-OHB/saline infusions. The forearm technique was employed to estimate substrate fluxes in muscle. Infusion of 3-OHB caused: (1) increases (P less than .05) in circulating levels of 3-OHB (from 112 +/- 73 mumol/L to 825 +/- 111 mumol/L) and forearm arteriovenous differences of 3-OHB (from 19 +/- 10 mumol/L to 145 +/- 46 mumol/L), as well as an eightfold increase of plasma acetoacetate. (2) Decreased (P less than .05) levels of nonesterified fatty acids (NEFA; from 466 +/- 85 mumol/L to 201 +/- 14 mumol/L) and glycerol (from 39 +/- 7 mumol/L to 11 +/- 4 mumol/L) and decreased (P less than .05) arteriovenous differences of glycerol (from -16 +/- 8 mumol/L to -3 +/- 2 mumol/L). (3) Increased (P less than .05) levels of serum growth hormone (GH; from 4.1 +/- 1.5 micrograms/L to 15.9 +/- 8.0 micrograms/L). No change was recorded in circulating concentrations of free insulin, glucagon, glucose, lactate, or alanine. Nor were arteriovenous balances of these intermediary metabolites, isotopically determined glucose turnover or amounts of exogenously administered glucose affected. In conclusion, in type 1 diabetic man, the main regulatory effect of isolated hyperketonemia appears to be a direct negative feedback inhibition of lipolysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-response studies on the metabolic effects of a growth hormone pulse in humans.

Whereas the lipolytic and diabetogenic consequences of sustained growth hormone (GH) exposure are well described, the metabolic effects of a short-lived physiological GH pulse have only recently been reported. To assess the possible dose-response of such short-term bolus administration of GH, six healthy, male subjects were each studied thrice for 4 1/2 hours after an intravenous (IV) bolus of either 70, 140, or 350 micrograms GH, resulting in peak GH concentrations of 10, 15, and 34 micrograms/L. Observed results include: (1) Time- (but not dose-) dependent changes (P less than .05) in plasma glucose and an acute (from 10 minutes onward), persistent, 40% decrease in forearm glucose uptake. Total glucose turnover decreased steadily with time on all occasions. (2) Time- and dose-dependent increases (P less than .05) in the concentrations of circulating lipid intermediates, with an increase of 3-hydroxybutyrate (3-OHB) from a basal of 35 mumol/L to peak values of 108 +/- 34 (70 micrograms), 176 +/- 46 (140 micrograms), and 232 +/- 51 mumol/L (350 micrograms), forearm uptake of 3-OHB changed in parallel. (3) Respiratory exchange ratio decreased (P less than .05) with increasing GH doses (indicating increased lipid and decreased glucose oxidation), and energy expenditure remained unaffected. (4) Concentrations of insulin, C-peptide, and glucagon were unchanged throughout all studies. We conclude that the stimulating effects of a modest GH bolus on circulating lipid intermediates and lipid oxidation are dose-dependent. This finding underlines the potential role of GH as a principal physiological regulator of fuel consumption in the maintenance of metabolic homeostasis.     

Role of growth hormone in the pathogenesis of dawn phenomenon in IDDM]

The early morning hyperglycemia of diabetic patients has been commonly referred to as the "dawn phenomenon". Recently the nocturnal surges of growth hormone (GH) have been suggested as an important factor in the pathogenesis of the dawn phenomenon. In order to reassess the role of the nocturnal GH secretion in the dawn phenomenon, seven C-peptide negative diabetic patients were studied during 48hr-feedback control using a closed-loop insulin infusion device (Biostator). They received oral sleeping medication only on the first night (control) and sleeping medication with anticholinergic agent (pirenzepine 75mg) on the second night, and blood glucose, insulin requirements, GH and cortisol concentrations during 0000hr and 0700hr were measured. The peak of sleep-induced GH secretions was markedly suppressed by pirenzepine in comparison with the control night (19.8 +/- 3.7 vs. 3.0 +/- 1.2ng/ml; p less than 0.05). Insulin requirements during 0500hr and 0700hr were suppressed significantly by pirenzepine (3.0 +/- 0.2 vs. 2.0 +/- 0.2U/2hr; p less than 0.05). Insulin infusion ratio, i.e. insulin requirements during 0500hr and 0700hr divided by those during 0000hr and 0200hr, was decreased by pirenzepine (2.2 +/- 0.3 vs. 1.5 +/- 0.2; p less than 0.05). There were no significant differences in blood glucose and cortisol concentrations whether or not the anticholinergic agent was given. In conclusion, these results have shown that an anticholinergic agent may be useful in the management of insulin-treated patients with marked dawn phenomenon.     

Epinephrine directly antagonizes insulin-mediated activation of glucose uptake and inhibition of free fatty acid release in forearm tissues.

To determine whether the anti-insulin effect of epinephrine is due to a direct antagonism on target tissues or is mediated by indirect mechanisms (systemic substrate and/or hormone changes), insulin and epinephrine were infused intrabrachially in five normal volunteers using the forearm perfusion technique. Insulin (2.5 mU/min) was infused alone for 90 minutes and in combination with epinephrine (25 ng/min) for an additional 90 minutes, so as to increase the local concentrations of these hormones to physiological levels (60 to 75 microU/mL and 200 to 250 pg/mL for insulin and epinephrine, respectively). Systemic plasma glucose and free fatty acids (FFA) concentrations remained stable at their basal values during local hormone infusion. Forearm glucose uptake (FGU) increased in response to insulin alone from 0.8 +/- 0.2 mg.L-1.min-1 to 4.3 +/- 0.8. Addition of epinephrine completely abolished the insulin effect on FGU, which returned to its preinfusion value (0.7 +/- 0.2). Forearm lactate release was slightly increased by insulin alone, but rose markedly on addition of epinephrine (from 5.2 +/- 0.8 mumol.L-1.min-1 to 17 +/- 2; P less than .02). During infusion of insulin alone, forearm FFA release (FFR) decreased significantly from the postabsorptive value of 1.76 +/- 0.25 mumol.L-1.min-1 to 1.05 +/- 0.11 (P less than .01). Epinephrine addition reverted insulin suppression of FFR, which returned to values slightly above baseline (2.06 +/- 0.47 mumol.L-1.min-1; P less than .05 v insulin alone). The data demonstrate that epinephrine is able to antagonize directly insulin action on forearm tissues with respect to both stimulation of glucose uptake and inhibition of FFA mobilization.     

Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance

This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.     

The dawn phenomenon does not occur in normal elderly subjects

To determine whether the dawn phenomenon occurs in normal elderly subjects and thus contributes to the progressive mild fasting hyperglycemia of aging, we examined the effect of physiological insulin levels on glucose disposal and hepatic glucose production (HGO) between 0530 and 0800 h, and 0930 and 1200 h. Paired euglycemic insulin clamp studies (8 mU/m2 X min) were performed on healthy old subjects (n = 5), employing [3H]glucose methodology to measure glucose production and disposal rates. Basal plasma insulin, GH, glucagon, and cortisol levels, and HGO and glucose disposal rates were similar before each study. Steady state plasma insulin values were slightly, but not significantly, lower during the dawn study [dawn: 20.3 +/- 1.1 (SE); control: 23.5 +/- 2.1 microU/ml, P = 0.08]. Insulin clearance rates were higher during the dawn study (dawn: 523 +/- 16; control: 430 +/- 19 ml/m2 X min, P less than 0.01). Maximum glucose disposal rates (dawn: 3.10 +/- 0.24; control: 3.03 +/- 0.23 mg/kg X min) and minimum HGO levels (dawn: 0.83 +/- 0.09; control: 0.62 +/- 0.03 mg/kg X min) were not significantly different in each part of the study. There was a significant decrease in plasma GH during the dawn (P less than 0.01, analysis of variance) but not the control studies. There was no difference in cortisol levels during the euglycemic clamp between the dawn and control studies. The mean decrement in glucagon during the insulin infusion was similar in each part of the study. We conclude that the dawn phenomenon does not occur in healthy elderly subjects despite an increase in insulin clearance during the dawn period.     

Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation

We tested whether FFAs influence glucose uptake by human peripheral tissues in vivo. Whole body glucose uptake, FFA turnover, energy expenditure and substrate oxidation rates, forearm glucose and FFA uptake, and nonoxidative glycolysis (net release of alanine and lactate) were measured in 14 normal male subjects in the basal state (0-240 min; serum insulin, approximately 5 microU/mL) and during euglycemic hyperinsulinemia (240-360 min; approximately 75 microU/mL) on 2 separate occasions, once during elevation of plasma FFA by infusions of Intralipid and heparin (plasma FFA, 4.6 +/- 0.1 vs. 4.2 +/- 0.4 mmol/L; 180-240 vs. 300-360 min) and once during infusion of saline (plasma FFA, 0.50 +/- 0.07 vs. 0.02 +/- 0.07 mmol/L, respectively). In the basal state, whole body glucose disposal remained unchanged, but the fate of glucose was significantly altered toward diminished oxidation (7.3 +/- 0.8 vs. 5.6 +/- 0.5 mumol/kg.min; P less than 0.05, saline vs. Intralipid) and increased nonoxidative glycolysis (P less than 0.05). Elevation of plasma FFA significantly increased forearm glucose uptake (1.0 +/- 0.6 vs. 2.4 +/- 0.7 mumol/kg.min; P less than 0.01) and nonoxidative glycolysis (net release of alanine and lactate, 0.4 +/- 0.5 vs. 1.2 +/- 0.4 mumol glucose equivalents/kg.min; P less than 0.05). During hyperinsulinemia, FFA decreased whole body glucose disposal (38 +/- 2 vs. 30 +/- 3 mumol/kg.min; P less than 0.001) due to a decrease in glucose oxidation (13 +/- 1 vs. 7 +/- 1 mumol/kg.min; P less than 0.01, saline vs. Intralipid), and forearm glucose uptake (31 +/- 4 vs. 24 +/- 6 mumol/kg.min; P less than 0.01, saline vs. Intralipid). Under these conditions, 7 +/- 2% and 3 +/- 1% (P less than 0.05) of forearm glucose uptake could be accounted for by nonoxidative glycolysis in the Intralipid and saline studies, respectively. In summary, 1) elevation of plasma FFA concentrations suppresses the rate of carbohydrate oxidation to a rate that, both basally and during hyperinsulinemia, is similar to that reported for insulin-independent glucose oxidation in the brain; 2) basally, forearm glucose uptake is increased by FFA; and 3) during hyperinsulinemia, FFA inhibit glucose uptake by forearm tissues. We conclude that the interaction between glucose and FFA fuels in human forearm tissues is dependent upon the ambient insulin concentration; the increase in basal glucose uptake would be compatible with the increase need of glucose for FFA reesterification; the decrease in insulin-stimulated glucose uptake supports operation of the glucose-FFA cycle in human forearm tissues.     

Influence of growth hormone on glucose-induced glucose uptake in normal men as assessed by the hyperglycemic clamp technique

To determine whether physiological increments in circulating GH concentrations influence glucose-induced glucose uptake (GIGU), two-step sequential hyperglycemic clamp (plasma glucose, 6 and 14 mmol/L) studies were performed in six normal subjects with and without GH infusion (40 ng/kg.min). The latter resulted in serum GH levels of 15 +/- 1 (+/- SE) microgram/L. Infusion of somatostatin (250 micrograms/h during step 1 and 750 micrograms/h during step 2) together with a replacement dose of insulin (1.1 pmol/kg.min) resulted in serum insulin levels comparable to basal levels in both studies. The GIGU ([3-3H]glucose), assessed as the difference between steps 2 and 1 glucose utilization during the final 60 min of each step (150 min) was markedly impaired during GH infusion (with GH, 1.1 +/- 0.2 mg/kg.min; without GH, 3.1 +/- 0.3 mg/kg.min; P less than 0.001). Moreover, the percent increase in glucose uptake was considerably reduced during hypersomatotropinemia (with GH, 44 +/- 9%; without GH, 97 +/- 11%; P less than 0.01). In the GH infusion as well as control studies, endogenous glucose production (EGP) was similar at the two levels of glycemia, whereas GH infusion approximately doubled EGP [2.3 +/- 0.2 vs. 1.1 +/- 0.3 mg/kg.min and 2.0 +/- 0.4 vs. 1.1 +/- 0.4 mg/kg.min (step 1 and 2, respectively)]. We conclude that moderate hypersomatotropinemia for several hours is characterized by impaired GIGU as well as augmented EGP.     

Short-term effects of growth hormone on fuel oxidation and regional substrate metabolism in normal man

Primarily by increasing the availability of lipid intermediates, GH is likely to have profound effects on substrate consumption rates. To examine the short term actions of GH on glucose turnover, fuel oxidation and regional forearm metabolism, six normal volunteers were each studied twice for 5.5 h after having received a 4-h infusion of GH (20 ng/kg.min) or saline. GH induced slightly falling plasma glucose levels, acute 40-50% decreases in forearm glucose uptake, and no change in glucose turnover. Furthermore, substantial increases in circulating concentrations and forearm uptake of nonesterified fatty acids and 3-hydroxybutyrate were recorded. Although GH infusion was followed by a 50% reduction of forearm alanine release hepatic nitrogen excretion seemed unaffected. Energy expenditure was not influenced by GH, but the non-protein respiratory exchange ratio decreased from a basal value of 0.778 +/- 0.008 to 0.732 +/- 0.007 after GH treatment (P less than 0.05). Correspondingly, lipid oxidation increased from 1.20 +/- 0.06 to 1.48 +/- 0.09 mg/kg.min, and glucose oxidation decreased from 0.97 +/- 0.12 to 0.39 +/- 0.06 mg/kg.min (P less than 0.05). Nonoxidative glucose utilization tended to increase. These data indicate that GH, by promoting lipid utilization and decreasing glucose oxidation, diminishes the need for gluconeogenesis and, therefore, could be protein preserving in the long term. Overall, we found no evidence of GH having acute insulin-like effects on glucose metabolism. GH appears to increase glucose storage, leaving total energy expenditure unaffected.     

Impairment of noninsulin-mediated glucose disposal in the elderly

While normal aging is characterized by resistance to insulin-mediated glucose disposal (IMGU), the effect of age on noninsulin-mediated glucose disposal (NIMGU), which is responsible for the majority of basal glucose uptake, has not been completely evaluated. These studies were conducted on healthy nonobese young (n = 10; age, 20-30 yr) and old (n = 10; age, 62-80 yr) men. Each subject underwent two paired studies in random order. In all studies a [3H]glucose infusion was used to measure glucose uptake and production rates, and somatostatin (500 micrograms/h) was infused to suppress endogenous insulin release. In study A, plasma glucose was kept close to fasting levels (approximately 5.6 mmol/L) using an euglycemic clamp protocol for 4 h. Plasma insulin decreased to less than 20 pmol/L within 15 min and remained suppressed thereafter in all studies. Steady state (15-240 min) plasma glucagon levels were slightly greater in the elderly [young, 86 +/- 5 (+/- SE); old, 98 +/- 2 ng/L; P less than .05]. Basal glucose uptake was similar in both groups (young, 877 +/- 21; old, 901 +/- 24 mumol/min). Glucose uptake during the last hour of the study (180-240 min) was used to represent NIMGU, because insulin action was assumed to be absent by this time. NIMGU was less in the elderly (young, 744 +/- 18; old, 632 +/- 32 mumol/min; P less than 0.01). In study B, plasma glucose was kept at about 11 mmol/L for 4 h using a hyperglycemic clamp protocol. Plasma insulin decreased to less than 20 pmol/L within 15 min and remained suppressed thereafter in all studies. Steady state plasma glucagon levels were slightly but not significantly higher in the elderly (young, 88 +/- 6; old, 100 +/- 4 ng/L). Basal glucose uptake (young, 910 +/- 27; old, 883 +/- 25 mumol/min) and NIMGU (young, 933 +/- 36; old, 890 +/- 16 mumol/min; P = NS) were similar in both young and old subjects. We conclude that aging is associated with impairment in NIMGU only in the basal state, which may explain in part the increase in fasting glucose with age.     

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.     

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.     

Growth hormone, insulin, glucose, cortisol, luteinizing hormone, and diabetes in beagle bitches treated with medroxyprogesterone acetate

Adult beagle bitches (20 to 101 months old) received medroxyprogesterone acetate (MPA; 75 mg/kg, im) or control vehicle at 3 month intervals. Changes in serum concentrations of GH, insulin and glucose were determined in 18 MPA-treated and 6 of 12 control bitches at 0, 2, 4, 8, 16 and 17-24 months of treatment (Exp. I). GH, LH and cortisol responsiveness to combined im injection of TRH (10 micrograms/kg), GnRH (10 micrograms/kg), and ACTH (5 micrograms/kg) was determined in 9 MPA-treated and 9 control bitches at 17 months of treatment (Exp. II). In Exp. I, serum concentrations of GH at month 2 (2.6 +/- 0.3 micrograms/l), 4 (3.0 +/- 0.3 micrograms/l), 8 (4.0 +/- 1.2 micrograms/l), 16 (8.5 +/- 1.7 micrograms/l), and 17-24 (21.2 +/- 4.1 micrograms/l) of treatment were greater (P less than 0.05) than pretreatment (1.4 +/- 0.07 micrograms/l) and control (1.5 +/- 0.1 microgram/l) levels. The increase in GH at 2 months preceded (N = 4) or coincided (N = 2) with the development of hyperinsulinaemia and insulin resistance in 6 of the 18 treated bitches, two of which became diabetic by 17 months of MPA treatment. GH (24.6 +/- 5.0 vs 11.4 +/- 2.1 micrograms/l) and insulin (308 +/- 77 vs 119 +/- 9 pmol/l) concentrations were greater (P less than 0.05) in older (49 +/- 4 months; N = 12) than in the younger (26 +/- 2 months; N = 6) treated bitches at 17-24 months of MPA treatment. In Exp. II, pretreatment concentrations of GH were increased (9.8 +/- 3.0 vs 1.4 +/- 0.1 micrograms/l, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1-44)

To determine whether the short-term administration of growth hormone inhibits pituitary responsiveness to h-GHRH we measured the somatotroph response to h-GHRH-44 (0.3 micrograms/kg) stimulation in ten normal subjects from the third to the fifth hour of an infusion of met-hGH (2 micrograms/kg/h) or saline. Insulin, insulin-like growth factors (IGF), somatomedins, free fatty acids (FFA), glycerol, and glucose levels also were assessed during the first 3 hours of infusion. Steady-state GH levels of 5 to 20 ng/mL were achieved during met-hGH infusion. No significant changes in IGF, insulin, or glucose levels measured at the beginning and again after three hours of infusion occurred within or between conditions. Infusion of met-hGH was associated with a significantly greater increase in FFA levels (69 +/- 50 mumol/L following saline v 433 +/- 57 mumol/L following three hours of met-hGH infusion (P less than .001)). The somatotroph response to h-GHRH-44 was significantly blunted during met-hGH infusion (incremental area under the GH/time curve decreasing from 1,196 +/- 183 (ng/mL) X min to 380 +/- 139 (ng/mL) X min (P less than .005)). These data demonstrate that this blunting can occur following short-term exogenous GH administration and at serum GH levels comparable to those achieved during naturally occurring bursts of GH secretion. They also suggest that acute mediation of GH release must occur, at least in part, at the pituitary somatotroph level and that IGFs and/or insulin may not be the primary inhibitors. This phenomenon may be directly or indirectly due to GH-dependent metabolic factors such as FFA or glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Skeletal muscle is a major site of lactate uptake and release during hyperinsulinemia.

During conditions of increased glucose disposal, plasma lactate concentrations increase due to an increase in plasma lactate appearance. The tissue sites of the elevated lactate production are controversial. Although skeletal muscle would be a logical source of this lactate, studies using the limb net balance technique have failed to demonstrate a major change in net lactate output when plasma glucose disposal is increased. Because the limb balance technique underestimates production of a substrate when the limb not only produces but also consumes that substrate, we infused 3-14C-lactate basally and during a hyperinsulinemic euglycemic clamp in seven normal volunteers to determine plasma lactate appearance, forearm lactate fractional extraction, and forearm lactate uptake and release. After 3 hours of hyperinsulinemia, glucose and lactate turnovers increased from basal values of 11.8 +/- 0.13 and 12.2 +/- 0.59 to 32.6 +/- 3.4 and 16.5 +/- 1.07 mumol/(min.kg), accompanied by an increase in plasma lactate from 0.88 +/- 0.07 to 1.16 +/- 0.09 mmol/L (P less than .05). Forearm lactate extraction increased from 27% +/- 2% to 38% +/- 2% (P less than .001), resulting in an increase in forearm lactate uptake from 0.65 +/- 0.09 to 1.18 +/- 0.08 mumol/(min.100 mL tissue) (P less than .001). Although forearm lactate net output decreased during hyperinsulinemia, forearm lactate production increased from 1.04 +/- 0.12 basally to 1.69 +/- 0.13 mumol/(min.100 mL). When forearm data was extrapolated to whole body, muscle could account for 41% +/- 4% of systemic lactate appearance basally and 45% +/- 4% during hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The dawn phenomenon is related to overnight growth hormone release in adolescent diabetics

We have investigated the relation between nocturnal insulin requirements and nocturnal growth hormone (GH) release in 26 diabetic adolescents at various puberty stages and have examined the effect of nocturnal GH suppression on pre-breakfast insulin requirement. In all the studies, euglycaemia was maintained overnight using a computer-calculated variable-rate insulin infusion, and 15-min blood samples were collected for GH assay. During initial clamp studies, insulin infusion rates were greater from 0500-0800 h (15.22 +/- 0.95 mU/kg/h, mean +/- SEM) than from 0100-0400 h (12.42 +/- 0.84 mU/kg/h, P less than 0.001). The increase in insulin infusion rate correlated with mean overnight GH concentration (r = 0.68, P less than 0.001), and was maximal at puberty stage 3 in both sexes. In seven of the subjects, a second identical clamp was performed following administration of 100 mg oral pirenzepine. During these studies, mean overnight GH levels were reduced by 11-85%, from 17.6 +/- 1.6 to 7.5 +/- 2.2 mU/l; P less than 0.01. Insulin requirements were not significantly different between the periods 0100-0400 and 0500-0800 h during these studies, and the reduction in pre-breakfast (0500-0800 h) insulin requirement when compared with the baseline studies correlated with the fall in GH secretion (rs = 0.82, P less than 0.01). The dawn increase in insulin requirement in adolescents with IDDM is related to the overnight GH secretion during puberty, and pre-breakfast insulin requirement can be reduced by suppressing nocturnal GH release.     

Interactions of galanin and arginine on growth hormone, prolactin, and insulin secretion in man.

Galanin (GAL), a 29 amino acid neuropeptide, is known to increase both basal and growth hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion while not significantly increasing prolactin (PRL) secretion in man. GAL is also endowed with an inhibiting effect on glucose-stimulated insulin release in animals, but not in man. We studied the effect of GAL (80 pmol/kg/min infused over 60 minutes) on the arginine- (ARG, 30 g infused over 30 minutes) stimulated GH, PRL, insulin, and C-peptide secretion in eight healthy volunteers (age, 20 to 30 years). GAL induced an increase of GH (GAL v saline, area under curve [AUC], mean +/- SEM: 316.5 +/- 73.9 v 93.2 +/- 20.9 micrograms/L/h, P less than .05), but failed to modify both PRL and insulin secretion. GAL enhanced the ARG-induced stimulation of both GH (1,634.1 +/- 293.1 v 566.9 +/- 144.0 micrograms/L/h, P less than .02) and PRL secretion (1,541.9 +/- 248.8 v 1,023.8 +/- 158.7 micrograms/L/h, P less than .02). On the contrary, GAL blunted the ARG-stimulated insulin (816.3 +/- 87.7 v 1,322.7 +/- 240.9 mU/L/h, P less than .05), as well as C-peptide secretion (105.1 +/- 9.8 v 132.8 +/- 17.3 micrograms/L/h, P less than .02). ARG administration induced a transient increase of glucose levels (P less than .01 v baseline) followed by a significant decrease (P less than .05 v baseline). This latter effect was prevented by the coadministration of GAL. In conclusion, these results show that in man GAL potentiates the GH response to ARG, suggesting that these drugs act at the hypothalamic level, at least in part, via different mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose utilization in Type 1 (insulin-dependent) diabetes: Evidence for a defect not reversible by acute elevations of insulin

It has long been assumed that replacement of insulin in insulin-deficient diabetic patients will normalise glucose utilization. In this study, glucose utilization was measured in nine long-standing, poorly controlled diabetic patients and five control subjects, matched for age (33 +/- 3 versus 33 +/- 2 years) and ponderal index (22.9 +/- 1.3 versus 21.7 +/- 1.0). Glucose uptake was measured during steady state insulinaemia in the diabetic patients and control subjects, at euglycaemia (5.5 +/- 0.5 versus 5.4 +/- 0.3 mmol/l, respectively) and moderate hyperglycaemia (11.8 +/- 0.9 versus 10.2 +/- 0.7 mmol/l, respectively). At euglycaemia with similar free insulin levels (50 +/- 19 versus 43 +/- 9 mU/l; p greater than 0.6), the diabetic patients utilized less glucose than the control subjects (27.8 +/- 4.2 versus 56.4 +/- 5.7 mumol.kg-1.min-1;.p less than 0.005). During hyperglycaemia, the diabetic patients utilized almost as much glucose as the control subjects did at euglycaemia (49.9 +/- 6.4 versus 56.4 +/- 5.7 mumol.kg-1.min-1, respectively). In the control subjects, a 1-mmol/l rise in glucose concentration (with insulin remaining constant) resulted in a 12.3 +/- 1.3 mumol.kg-1.min-1 rise in glucose utilization. In contrast, in the diabetic patients, a 1-mmol/l rise in blood glucose resulted in a rise in glucose utilization of only 3.8 +/- 0.8 mumol.kg-1.min-1 (p less than 0.001), in the presence of similar concentrations of plasma insulin. This defect of glucose utilization in Type1 diabetic patients could not be reversed by acutely raising insulin to 247 +/- 23 mU/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic hyperinsulinemia stimulates lactate extraction by heart muscle in the conscious dog

The effect of physiologic hyperinsulinemia on the net balance of lactate, glucose, and free fatty acids across the heart was studied in eight normal postabsorptive conscious dogs. After obtaining basal measurements of myocardial substrate balance, arterial plasma insulin was increased from 8 +/- 1 to 68 +/- 14 microU/mL while blood glucose was maintained constant (64 +/- 1 mg/dL) using the hyperinsulinemic euglycemic clamp. Myocardial lactate uptake increased nearly fourfold, from 5.8 +/- 1.8 to 22.4 +/- 2.9 mumol/min (P less than .005). Despite a small increase in arterial lactate concentration from 0.46 +/- 0.08 to 0.79 +/- 0.11 mmol/L (P less than .02), the lactate extraction fraction increased from 23% +/- 7% to 54% +/- 2% (P less than .001) indicating an increased efficiency of lactate extraction. Euglycemic hyperinsulinemia led to a comparable increase in myocardial glucose uptake (6.7 +/- 2.3 to 18.2 +/- 3.7 mumol/min, P less than .05). Arterial free fatty acid concentrations fell from 1.06 +/- 0.13 to 0.35 +/- 0.06 mmol/L (P less than .001) with a concomitant decline in the myocardial uptake of free fatty acids from 18.5 +/- 5.3 to 5.8 +/- 2.9 mumol/min (P less than .05). These results indicate that physiologic hyperinsulinemia increases lactate as well as glucose uptake in normal heart muscle.     

Glucose turnover and recycling in diabetes secondary to total pancreatectomy: effect of glucagon infusion

This study was designed to evaluate whether chronic deficiency of pancreatic glucagon in patients with diabetes secondary to total pancreatectomy (PX) is responsible for the commonly observed increase in blood concentrations of gluconeogenic precursors (alanine, lactate, and pyruvate). Seven PX patients were studied on two different occasions: 1) after an overnight insulin infusion (0.15 mU/kg.min) and 2) after an overnight insulin/glucagon infusion (2 ng/kg.min). Five type 1 diabetic individuals were also studied after a similar overnight insulin infusion. In the morning of each study day, [6-3H]glucose and [1-14C]glucose were rapidly injected for determination of total glucose turnover rate [( 6-3H]glucose) and glucose recycling (difference between [6-3H]glucose and [1-14C]glucose turnover rate). Basal concentrations of hormones, glucose, and intermediary metabolites were measured. After overnight insulin infusion, plasma glucose concentration (3.8 +/- 0.4 vs. 6.8 +/- 1.4 mmol/L), turnover rate (8.4 +/- 1.0 vs. 13.7 +/- 1.9 mumol/kg.min), and percent glucose recycling (5.6 +/- 3.9% vs. 19.0 +/- 3.8%) were significantly lower in PX patients than in type 1 diabetic individuals (P less than 0.05-0.01). On the contrary, blood alanine (459 +/- 93 vs. 263 +/- 28 mumol/L), lactate (1157 +/- 109 vs. 818 +/- 116 mumol/L), and pyruvate (71 +/- 8 vs. 42 +/- 3 mumol/L) were significantly higher than those values in type 1 diabetic patients (P less than 0.05-0.01). Insulin/glucagon infusion increased plasma glucose concentration (8.7 +/- 1.5 mmol/L), total turnover (18.1 +/- 1.7 mumol/kg.min), and percent recycling (20.4 +/- 6.6%) to values similar to those in type 1 diabetic subjects. The change in glucose metabolism was associated with a significant drop in blood concentrations of alanine (179 +/- 24 mumol/L), lactate (611 +/- 25 mumol/L), and pyruvate (30 +/- 3 mumol/L; all P less than 0.05-0.01 vs. insulin infusion alone). In PX patients, the glucose turnover rate was inversely correlated with blood concentrations of both alanine (r = 0.67) and lactate (r = 0.71; P less than 0.01). In conclusion, chronic deficiency of pancreatic glucagon in PX patients 1) is associated with a decreased rate of glucose turnover, 2) causes a marked impairment in glucose recycling (an index of the activity of hepatic gluconeogenesis), and 3) increases blood concentrations of alanine, lactate, and pyruvate. All abnormalities are reversed by glucagon.