Somatostatin enhances insulin-mediated glucose disposal in elderly subjects

Somatostatin (SRIH) infusion has been widely used in metabolic studies of carbohydrate metabolism. While the effects of SRIH itself on various aspects of carbohydrate economy have been assessed in young adults, such studies have not been conducted in the elderly, which represent an increasingly important study group. To examine the effect of SRIH on insulin-mediated glucose disposal in the elderly, we studied 12 (7 men and 5 women) healthy nonobese subjects, aged 65-80 yr. Paired 3-h euglycemic insulin clamp studies were performed in random order employing insulin alone (22 mU/m2.min) or insulin with SRIH (250 micrograms/h) and glucagon (0.4 ng/kg.min) to maintain normal basal plasma glucagon levels. Basal plasma insulin, glucose, glucagon, GH, and glucose production and disappearance were similar on each occasion. Steady state (10-180 min) mean plasma insulin [insulin alone, 298 +/- 12 (+/- SE); insulin; glucagon, and SRIH, 304 +/- 15 pmol/L] and glucagon (insulin alone, 85 +/- 7; insulin, glucagon, and SRIH, 96 +/- 9 ng/L) concentrations were similar. At steady state (150-180 min) glucose production was suppressed to similar levels (insulin alone, 26 +/- 7; insulin, glucagon, and SRIH, 36 +/- 13 mumol/kg.min). However, steady state glucose disposal was significantly higher during the SRIH infusion (insulin alone, 295 +/- 26; insulin, glucagon, and SRIH, 346 +/- 32 mumol/kg.min; P less than 0.02). We conclude that SRIH augments insulin-mediated glucose disposal in healthy older subjects at physiological levels of insulin.     

Somatostatin infusion enhances hepatic glucose production during hyperglucagonemia

Somatostatin (SRIH) is widely employed in metabolic studies to permit quantitation of glucose production and disposal rates while the endocrine pancreas is suppressed and the hormonal milieu is under the investigator's control. In these studies it is assumed that if peripheral levels of insulin and glucagon are the same during SRIH infusion as during control studies, the effects of these hormones on glucose metabolism are equivalent. If the effect of glucagon is influenced by SRIH infusion, then these techniques may be unsuitable for the study of the regulation of hepatic glucose output. To assess the influence of SRIH on glucagon-stimulated hepatic glucose production (Ra), we determined Ra during paired studies in ten healthy (five younger and five older) subjects. In each study an insulin infusion designed to yield physiologic systemic insulin levels of 20 to 30 microU/mL was given from 0 to 210 minutes. In addition, from 60 to 210 minutes either glucagon alone (3.5 ng/kg/min) (I + IRG) or glucagon (3.5 ng/kg/min) and SRIH (250 micrograms/h) (I + IRG + SRIH) was infused. Since results for plasma levels of insulin, C-peptide, glucagon, and Ra were similar in young and old subjects, the two age groups were combined for analysis. Basal plasma insulin, glucagon, C-peptide, glucose, and Ra were similar in each arm of the study. Insulin values were nearly identical from 60 to 210 minutes (I + IRG, 23.8 +/- 1.1; I + IRG + SRIH, 24.0 +/- 1.0 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in glucagon do not play an essential role in the glucoregulatory responses to mild hyperinsulinemia in dogs

To examine whether an increase in the glucagon concentration is essential for restoring hepatic glucose output following moderate decrements in blood glucose, we used isotope dilution techniques in trained conscious dogs (n = 5) to measure glucose production (Ra) and glucose utilization (Rd) during mild hyperinsulinemia (19 +/- 1 mU/l). In Study A, when insulin was infused to raise plasma insulin (IRI) from 13 +/- 2 to 19 +/- 1 mU/l, basal glucose (93 +/- 3 mg/dl) fell at a rate of 0.37 +/- 0.06 mg/dl/min over 30 min. Ra fell from 2.8 +/- 0.4 mg/kg/min by 0.5 +/- 0.1 mg/kg/min at 20 min (P less than 0.05), but recovered to baseline by 30 min; glucagon (IRG) fell transiently but returned to baseline by 45 min. In Study B, endogenous secretion of IRI and IRG was suppressed by infusion of somatostatin (0.2 microgram/kg/min), while peripheral concentrations were maintained constant by replacing glucagon (0.65 ng/kg/min) and insulin (0.225 mU/kg/min). Steady-state baseline plasma IRI, IRG, glucose and glucose turnover rates were similar to Study A; hyperinsulinemia was then induced as in Study A. Glucose fell by 0.78 +/- 0.19 mg/dl/min over 30 min and, as in Study A, Ra decreased transiently, but recovered to baseline by 30 min. The restoration of Ra occurred in study B despite constant IRG, and preceded later increments in cortisol and catecholamines at 60-90 min. Thus, in both studies A and B, Ra recovered to baseline without an increase in IRG and before the onset of significant hypoglycemia (glucose 83 +/- 1 and 70 +/- 1 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency

The physiological significance of the hyperglucagonemia that occurs in patients with many catabolic conditions is unclear. The effect of hyperglucagonemia on resting metabolic rate (RMR) was studied in six normal subjects. Infusion of somatostatin (SRIH; 500 micrograms/h for 210 min) resulted in a 5-fold decrease in plasma C-peptide and a 2-fold decrease in plasma insulin and glucagon concentrations, but did not change RMR significantly. When glucagon (0.2 micrograms/kg X h), was infused with SRIH (500 micrograms/h for 210 min), the decreases in plasma C-peptide and insulin were similar to that during the infusion of SRIH alone, but plasma glucagon increased from 160 +/- 24 (+/- SEM) to 560 +/- 80 pg/mL (P less than 0.001). There was a significant increase in RMR during the entire period (210 min) of glucagon infusion (P less than 0.01). During the last hour of the glucagon plus SRIH infusion, the RMR was 1.38 +/- 0.10 Cal/min, which was 15% higher than the preinfusion RMR (1.19 +/- 0.10 Cal/min; P less than 0.01) and 14% higher than the RMR during the same period when SRIH alone was infused (1.21 +/- 0.11 Cal/min; P less than 0.01). When SRIH and glucagon were infused, protein oxidation (calculated from urinary nitrogen loss) was 52 +/- 5 mg/min, 29% higher than when SRIH alone was infused (40 +/- 5 mg/min; P less than 0.05). These results indicate that hyperglucagonemia during insulin deficiency results in an increase in energy expenditure, which may contribute to the catabolic state in many conditions.     

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.

AIMS: Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans. METHODS: Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2). RESULTS: Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2). CONCLUSIONS: Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.     

Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes. METHODS: Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 +/- 1 years; body mass index, 28 +/- 1 kg/m(2)). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/m(2)/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol x kg(-1) x min(-1) from 30 to 180 minutes. RESULTS: Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 +/- 63 pmol/l; GLP-1, 1140 +/- 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 +/- 35 pmol/l; GLP-1, 781 +/- 41 pmol/l; p = NS). Basal (control, 2.08 +/- 0.05 mg/kg/min; GLP-1, 2.13 +/- 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 +/- 0.18 mg/kg/min; GLP-1, 0.45 +/- 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 +/- 0.39 mg/kg/min; GLP-1, 5.52 +/- 0.43 mg/kg/min; p <.01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 +/- 0.32 mg/kg/min; GLP-1, 6.05 +/- 0.37 mg/kg/min; p <.05). CONCLUSIONS: We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.     

Glucose turnover in insulinoma--a case report

To define glucose flux in a state of chronic endogenous insulin excess, a patient with an insulinoma was studied. Plasma glucose, insulin (IRI), glucagon (IRG) and glucose turnover ([3-3H]glucose infusion) were measured before and after insulinoma resection in the postabsorptive state (PA), during a glucose infusion adjusted to attain euglycemia (before insulinoma resection only) and following an intravenous glucagon bolus (1 mg). Before insulinoma resection, plasma glucose was 55 mg/dl, glucose production (Ra) and disappearance (Rd) were equal (1.6 mg/kg/min) and glucose clearance was elevated (2.8 ml/kg/min) in PA. When glycemia was raised with a glucose infusion to 77 mg/dl, Rd did not change; in contrast Ra dropped to zero. Plasma IRI and IRG concentrations were 0.7 ng/ml and 110 pg/ml respectively before glucose infusion and remained constant throughout. After resection of the insulinoma, glycemia in PA was 103 mg/dl, Ra and Rd were increased slightly to 1.9 mg/kg/min while the metabolic clearance of glucose was decreased by 25% (2.1 ml/kg/min). Glucagon stimulation pre- and postinsulinoma resection resulted in significant increases in glycemia and IRI. We conclude that hypoglycemia with insulinoma is a consequence of decreased glucose production and increased glucose clearance. Hepatic sensitivity to small increments in glycemia is markedly enhanced so as to fully suppress endogenous glucose production at euglycemic levels in the absence of any change in IRI and IRG. The mechanisms controlling hepatic Ra in insulinoma appear different from normal.     

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.     

Lack of effect of sodium nitroprusside on insulin-mediated blood flow and glucose disposal in the elderly

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging, a state characterized by reduced endothelial production of NO, an attenuated effect of insulin on skeletal muscle blood flow, and resistance to insulin-mediated glucose uptake (IMGU). We tested the hypothesis that the NO donor sodium nitroprusside (SNP) would augment insulin-mediated vasodilation and thus increase IMGU in healthy elderly subjects. Experiments were performed with young (n = 9; age, 25 +/- 1 years; body mass index [BMI], 24 +/- 1 kg/m2) and old (n = 10; age, 78 +/- 2 years; BMI, 25 +/- 1 kg/m2) healthy subjects. Each group underwent two studies in random order. In one study (control), insulin was infused using the euglycemic clamp protocol for 240 minutes at a rate of 40 mU/m2/min (young) and 34 mU/m2/min (old). In the other study (SNP), SNP was coinfused with insulin from 120 to 240 minutes. At regular intervals in each study, blood samples were obtained and calf blood flow was measured using venous occlusion plethysmography. Glucose and insulin values were similar in control and SNP studies in both age groups. In the young, SNP had no effect on blood flow to the calf, but its action in calf resistance vessels augmented insulin-mediated vasodilation, since incremental calf vascular conductance was greater during SNP infusion (control v SNP, 0.027 +/- 0.002 v 0.040 +/- 0.008 mL/100 mL/min/mm Hg, P< .0001). However, SNP had no effect on insulin-mediated glucose disposal. In the elderly, SNP reduced the blood flow to the calf, but this was countered by its effect on calf resistance vessels such that vascular conductance was unaffected (control v SNP, 0.012 +/- 0.003 v 0.011 +/- 0.003 mL/100 mL/min/mm Hg, P = nonsignificant [NS]). Steady-state (180 to 240 minutes) glucose disposal (control v SNP, 7.47 +/- 0.47 v 6.54 +/- 0.56 mg/kg/min, P < .01) rates were significantly lower during SNP infusion. In summary, systemic infusion of SNP did not increase insulin-mediated glucose disposal in either young or old subjects. Thus, the present findings do not support the concept that increasing NO availability will enhance glucose disposal in either age group. However, because the incremental increases in IMGU during SNP infusion paralleled the changes in blood supply to the calf rather than calf vascular conductance, any potential benefits on NO delivery in elderly subjects may have been offset by the direct or reflex effects of systemic hypotension. Other stimuli to NO production that do not cause hypotension must be tested before this therapeutic strategy can be considered as a potential means for enhancing the metabolic actions of insulin in the elderly.     

Insulin antagonism is not a primary abnormality of amyotrophic lateral sclerois but is related to disease severity

Sensitivity to insulin was studied in 13 patients with amyotrophic lateral sclerosis (ALS) and 10 age- and weight-matched normal subjects by performing euglycemic clamp studies at low (1.5 mU/kg X min) and high (10 mU/kg X min) insulin infusion rates. Mean glucose disposal rates were similar in the ALS patients and normal subjects at both the low [4.8 +/- 0.6 (+/- SEM) vs. 5.2 +/- 0.6 mg/kg X min] and high (9.2 +/- 1.3 vs. 9.8 +/- 0.5 mg/kg X min) insulin infusion rates, respectively. Binding of [125I] iodoinsulin to monocytes was also similar in seven patients with ALS (3.8 +/- 1.0%/10(7) cells) and 10 normal subjects (3.9 +/- 0.9). However, glucose disposal rates correlated inversely with disease severity in the ALS patients, at both the low (r = -0.76; P less than 0.01) and high (r = -0.83; P less than 0.001) insulin infusion rates. We conclude that insulin antagonism is not a primary abnormality of ALS, but may be related to the inactivity associated with disease progression.     

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.     

Glucagon and glucose tolerance in liver cirrhosis

The present study was undertaken in order to establish the significance of glucagon in glucose intolerance in liver cirrhosis. The plasma glucose response to an oral glucose load (75 g) was determined in 10 control subjects and in 10 cirrhotic patients, after infusions of: glucagon (3 ng.kg-1.min-1) or saline (154 mmol/l); somatostatin (SRIH) (500 micrograms/h); and SRIH plus glucagon (3 ng.kg-1.min-1). Glucagon infusion did not impair glucose tolerance, neither in normal subjects nor in patients with cirrhosis. On the other hand, in both groups glucose tolerance was impaired by SRIH infusion, presumably owing to an absolute insulin deficiency. Both in normal subjects and in cirrhotic patients, SRIH plus glucagon infusion further impaired glucose tolerance, presumably as a result of excess glucagon and concomitant insulin deficiency. In conclusion, our data show that hyperglucagonemia is not an important factor in the development of the glucose intolerance in patients with hepatic cirrhosis.     

Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs

Previous studies in anesthetized dogs demonstrated that basal hepatic extraction of insulin and glucagon are approximately 50 and 10-20%, respectively. Because of the stress of anesthesia and surgery, these values may not be relevant to normal physiology. In this study, hepatic extraction of insulin and glucagon were compared in conscious and anesthetized dogs. The conscious dogs had chronically implanted catheters in the portal and hepatic vein and the carotid artery and Doppler flow probes on the portal vein and hepatic artery. The mean basal portal vein insulin (42 +/- 10 and 44 +/- 7 microU/ml, respectively) and glucagon (247 +/- 37 and 219 +/- 20 pg/ml, respectively) concentrations were similar in conscious and anesthetized animals. The mean basal portal vein, but not hepatic artery, plasma flow was significantly increased in conscious dogs (462 +/- 62 vs. 294 +/- 35 ml/min, respectively). Despite the increased portal vein plasma flow in conscious animals, the basal hepatic extractions of insulin (42 +/- 6 vs. 39 +/- 6%, respectively) and glucagon (12 +/- 7 vs. 7 +/- 7%, respectively) were similar in both types of animals. Arginine and cholecystokinin-pancreozymin (CCK-PZ) infusion, which increased the amount of insulin and glucagon presented to the liver in conscious and anesthetized dogs, significantly decreased the hepatic extraction of insulin. Hepatic extraction of glucagon did not change in either group of animals. In contrast, infusion of insulin (1.0 mU/kg X min) and glucagon (4 ng/kg X min) into the portal system did not alter hepatic extraction of insulin even though the amounts of insulin and glucagon presented to that organ were similar to those obtained with arginine and CCK-PZ. The basal arterial glucose level was significantly lower in the conscious dogs but the basal hepatic glucose output was similar in the two groups. The glucose response to the infusion of arginine and CCK-PZ and exogenous hormones was significantly greater in the anesthetized animals.     

In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by epinephrine

In vivo glucose uptake (Rd) occurs via two mechanisms: 1) insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and 2) noninsulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and insulin-insensitive tissues. Thus, in the postabsorptive (basal) state Rd = IMGU + NIMGU. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of epinephrine (EPI) on IMGU and NIMGU in seven normal men after an overnight fast. To study NIMGU, somatostatin (600 micrograms/hr) was infused to suppress endogenous insulin secretion, and glucose turnover was measured isotopically while the serum glucose level was clamped at about 200 mg/dL for 240 min. Separate studies were done during the infusion of saline or EPI (0.2 microgram/kg X min). The final 120 min of each study were used for data analysis. Under these conditions insulin action is absent and Rd = NIMGU. NIMGU was 210 +/- 15 (+/- SEM) and 200 +/- 17 mg/min during saline and EPI treatment, respectively (P = NS). Therefore, EPI has no ability to modulate NIMGU. To measure the effect of EPI on Rd, hyperglycemic (200 mg/dL) hyperinsulinemic clamp (30 mU/M2 X min) studies were performed during the infusion of saline and EPI. EPI decreased Rd by 46 +/- 6% (751 +/- 85 to 405 +/- 43 mg/min; P less than 0.01). When the effect of EPI on IMGU (Rd - NIMGU) was considered separately, the inhibitory effect of EPI was more potent, as indicated by a 61 +/- 12% decrease in IMGU. In conclusion, 1) EPI inhibits IMGU, but has no effect on NIMGU; 2) when NIMGU is taken into account, EPI has a more potent ability to inhibit IMGU than previously found; and 3) the systems responsible for NIMGU and IMGU are independently regulated.     

Persistent effect of sustained hyperglucagonemia on glucose production in man.

In man prolonged infusions of glucagon cause a transient increase in glucose production. To determine whether this represents complete loss of effect of hyperglucagonemia on the liver or merely decreased hepatic responsiveness, glucagon (3 ng/kg/min) was infused in six normal subjects to produce sustained hyperglucagonemia for 180 min; at this time glucagon infusions were stopped for 60 min, then restarted at the same rate for 60 min and finally increased to 7.5 ng/kg/min for 30 min. Glucose production (Ra) and utilization (Rd) were measured isotopically. Initially glucagon infusion increased Ra transiently from 1.8 +/- 0.1 mg/kg/min to a maximum at 15 min of 2.5 +/- 0.2 mg/kg/min (p less than .01); Ra returned to basal values by 60 min and remained there until the glucagon infusion was stopped, whereupon it abruptly declined to a nadir of 1.4 +/- 0.1 mg/kg/min, a value significantly below baseline levels, p less than .005. Upon restarting the glucagon infusion, Ra increased to a similar extent as observed with the initial infusion and then returned to basal levels; when the glucagon infusion rate was increased to 7.5 ng/kg/min, Ra again increased. These results indicate that sustained hyperglucagonemia, despite apparent waning of its effect, continues to modulate hepatic glucose production.     

Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans

The analysis of mass isotopomers in blood glucose and lactate can be used to estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction, nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone, growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The elevation in GP was due to a near doubling of nongluconeogenic glucose release compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01). High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8 +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P < .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of nongluconeogenic glucose release. High-dose glucagon increases GP by an increase in both Gneo and nongluconeogenic glucose release.     

Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment.We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.     

Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp

A group of 22 newly diagnosed noninsulin-dependent diabetic subjects and seven nondiabetic subjects underwent a glucose clamp at plasma glucose 100 mg/dL with insulin infusion rates of 1.0 and 10 mU/kg/min. During both insulin infusion rates, there was a sustained rise in plasma growth hormone (GH) above basal in 18 of the 22 diabetic subjects. Basal GH values were 2.37 +/- 0.67 ng/mL, rising above basal during the lower insulin infusion (6.1 +/- 3.3 ng/mL, P = 0.05) with a further rise at the higher insulin level (8.58 +/- 2.0 ng/mL, P less than 0.001). There was no rise in GH in any of the nondiabetic subjects. In neither group was there any rise above basal in cortisol, prolactin, glucagon, or somatostatin (SRIH). In a group of three nondiabetic subjects, a rise in GH similar to that seen in the diabetic group was induced by elevating the plasma glucose to 200 mg/dL for 60 minutes prior to the euglycemic clamp procedure. However, it is unlikely that changes in plasma glucose account totally for the changes in plasma GH described in the diabetic subjects since a rise in plasma GH was also seen in four diabetic subjects clamped at their fasting plasma glucose. We conclude that in newly diagnosed noninsulin-dependent diabetic subjects there is a rise in plasma GH during the euglycemic clamp procedure, which may be due to both the prior lowering of plasma glucose and the high plasma insulin levels.     

Metabolic control during total parenteral nutrition: use of an artificial endocrine pancreas

The metabolic impact of total parenteral nutrition (TPN) was evaluated in nine subjects who underwent esophagogastroplasty for esophageal carcinoma. On the second day after operation all subjects were connected to an artificial endocrine pancreas. In four patients only glucose was infused (5.5 mg/kg X min). The remaining five subjects received glucose (4.0 mg/kg X min), amino acid (0.5 mg/kg X min), and lipid emulsion (0.6 mg/kg X min). Plasma glucose concentration was kept constant over 24 hours. However, both insulin requirement (111 +/- 15 v 70 +/- 2 mU/kg X h) and plasma insulin level (99 +/- 15 v 30 +/- 7 microU/mL; P less than .01) were higher during combined TPN. Blood lactate concentration was higher during glucose infusion (P less than .05). No difference was found in blood concentrations of pyruvate, alanine, and ketone bodies. Both glycerol and FFA were higher during combined TPN. The ratio between glucose infusion rate and the average plasma insulin level was calculated as an index of insulin-mediated glucose metabolism; G/I X 100 was markedly reduced during combined TPN (4.5 +/- 0.8 v 20.7 +/- 3.7; P less than .05). Plasma FFA levels were positively correlated with plasma insulin concentration (r = .76) and inversely correlated to G/I X 100 (r = -.73; both P less than .05). In conclusion, during combined TPN a state of insulin resistance is induced and more insulin is required to achieve a normal glucose utilization.     

Contrasting effects of L-arginine on insulin-mediated blood flow and glucose disposal in the elderly

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging. We tested the hypothesis that L-arginine, the endogenous precursor for NO synthesis, would augment insulin-mediated vasodilation and in so doing increase insulin-mediated glucose uptake (IMGU) in healthy elderly subjects. Experiments were conducted on healthy young (n = 9; age, 24 +/- 1 years; body mass index, 24 +/- 1 kg/m2) and old (n = 9; age, 77 +/- 2 years; BMI, 25 +/- 1 kg/m2) subjects. Each underwent two euglycemic clamp studies. On both occasions, insulin was infused from 0 to 120 minutes (young, 40 mU/m2/min; old, 34 mU/m2/min). On 1 day, insulin was continued and L-arginine (7.5 mg/kg/min) was coinfused from 120 to 240 minutes. On the second study day, the insulin infusion from 120 minutes onward was adjusted in each subject to match corresponding plasma concentrations during the L-arginine infusion. Calf blood flow was measured bilaterally using venous occlusion plethysmography. Mean arterial blood pressure decreased in response to L-arginine in both young (77 +/- 1 v 73 +/- 1 mm Hg; P < .05) and old (103 +/- 2 v 94 +/- 2 mm Hg; P < .01). Calf vascular conductance increased in young (from 0.094 +/- 0.009 to 0.113 +/- 0.012 mL/100 mL/min/mm Hg; P < .01) and old (from 0.035 +/- 0.003 to 0.050 +/- 0.003 mL/100 mL/min/mm Hg; P < .01), consistent with the concept that the addition of substrate can augment skeletal muscle endothelial NO production in both age groups. Calf blood flow increased in both young (control, 7.04 +/- 0.73; L-arginine, 8.02 +/- 0.78 mL/100 mL/min; P < .05) and old (control, 3.60 +/- 0.27: L-arginine, 4.65 +/- 0.23 mL/100 mL/min; P < .0001) subjects, yet L-arginine had no impact on glucose disposal in either age group. In conclusion, L-arginine caused skeletal muscle vasodilation in the elderly, indicating that this endothelially mediated response is not attenuated with age. However, this increase in blood flow had no impact on insulin-mediated glucose uptake.