Important role of glucagon during exercise in diabetic dogs

To define the role of immunoreactive glucagon (IRG) during exercise in diabetes, 12 insulin-deprived alloxan-diabetic (A-D) dogs were run for 90 min (100 m/min, 12 degrees) with or without somatostatin (St 0.5 microgram . kg-1 . min-1). Compared with normal dogs, A-D dogs were characterized by similar hepatic glucose production (Ra), lower glucose metabolic clearance, and higher plasma glucose and free fatty acid levels during rest and exercise. In A-D dogs IRG was greater at rest and exhibited a threefold greater exercise increment than controls, whereas immunoreactive insulin (IRI) was reduced by 68% at rest but had similar values to controls during exercise. Basal norepinephrine, epinephrine, cortisol, and lactate levels were similar in normal and A-D dogs. However, exercise increments in norepinephrine, cortisol, and lactate were higher in A-D dogs. When St was infused during exercise in the A-D dogs, IRG was suppressed by 432 +/- 146 pg/ml below basal and far below the exercise response in A-D controls (delta = 645 +/- 153 pg/ml). IRI was reduced by 1.8 +/- 0.2 microU/ml with St. With IRG suppression the increase in Ra seen in exercising A-D controls (delta = 4.8 +/- 1.6 mg . kg-1 . min-1) was virtually abolished, and glycemia fell by 104 to 133 +/- 37 mg/dl. Owing to this decrease in glycemia, the increase in glucose disappearance was attenuated. Despite the large fall in glucose during IRG suppression, counterregulatory increases were not excessive compared with A-D controls. In fact, as glucose levels approached euglycemia, the increments in norepinephrine and cortisol were reduced to levels similar to those seen in normal exercising dogs. In conclusion, IRG suppression during exercise in A-D dogs almost completely obviated the increase in Ra, resulting in a large decrease in plasma glucose. Despite this large fall in glucose, there was no excess counterregulation, since glucose concentrations never reached the hypoglycemic range.     

Role of carotid bodies in control of the neuroendocrine response to exercise

This study was aimed at assessing the role of carotid body function in neuroendocrine and glucoregulatory responses to exercise. The carotid bodies and associated nerves were removed (CBR, n = 6) or left intact (Sham, n = 6) in anesthetized dogs >16 days before experiments, and infusion and sampling catheters were implanted. Conscious dogs were studied at rest and during 150 min of exercise. Isotopic dilution was used to assess glucose production (R(a)) and disappearance (R(d)). Arterial glucagon was reduced in CBR compared with Sham at rest (29 +/- 3 vs. 47 +/- 3 pg/ml). During exercise, glucagon increased more in Sham than in CBR (47 +/- 9 vs. 15 +/- 2 pg/ml). Cortisol and epinephrine levels were similar in the two groups at rest and during exercise. Basal norepinephrine was similar in CBR and Sham. During exercise, norepinephrine increased by 432 +/- 124 pg/ml in Sham, but by only 201 +/- 28 pg/ml in CBR. Basal arterial plasma glucose was 108 +/- 2 and 105 +/- 2 mg/dl in CBR and Sham, respectively. Arterial glucose dropped by 10 +/- 3 mg/dl at onset of exercise in CBR (P < 0.01) but was unchanged in Sham (decrease of 3 +/- 2 mg/dl, not significant). Basal glucose kinetics were equal in Sham and CBR. At onset of exercise, R(a) and R(d) were transiently uncoupled in CBR (i.e., R(d) > R(a)) but were closely matched in Sham. In steady-state exercise, R(a) and R(d) were closely matched in both groups. Insulin was equal in the basal period and decreased similarly during exercise. These studies suggest that input from the carotid bodies, or receptors anatomically close to them, 1) is important in control of basal glucagon and the exercise-induced increment in glucagon, 2) is involved in the sympathetic response to exercise, and 3) participates in the non-steady-state coupling of R(a) to R(d), but 4) is not essential to glucoregulation during sustained exercise.     

Role of beta-adrenergic mechanisms during exercise in poorly controlled diabetes

To examine the beta-adrenergic effects of the catecholamines in poorly controlled diabetes, we have studied insulin-deprived alloxan-diabetic (A-D) dogs during 90 min of moderate exercise (100 m/min, 10-12 degrees) alone (C) or with propranolol (5 micrograms . kg-1 . min-1) (P) or combined P and somatostatin infusion (0.5 microgram . kg-1 . min-1) (P + St). In P, in contrast to C, immunoreactive glucagon (IRG) rose only after 50 min of exercise. However, hepatic glucose production (Ra) rose normally. In P + St, IRG fell 50% below basal, and the Ra response to exercise was abolished. Interestingly, in P and P + St, glucose metabolic clearance rate (MCR) rose by 400% above the inadequate MCR response to exercise in C, despite 30% lower insulin levels. Compared with C, free fatty acids (FFA) and lactate were sharply reduced during P and P + St. Plasma glucose (G) did not change in C, but due to elevated glucose uptake, G fell over 120 mg/dl in P, and due to diminished Ra, G fell 170 mg/dl in P + St. Norepinephrine was similar in all groups. Epinephrine and cortisol were higher in P + St by 90 min of exercise, perhaps as a result of hypoglycemia. In summary, during exercise in poorly controlled A-D dogs, beta-blockade does not appear to affect Ra; beta-blockade leads to diminished mobilization of extrahepatic substrate as evidenced by reduced FFA and lactate levels; beta-blockade increases MCR to levels seen in normal dogs during exercise alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute anemia increases lactate production and decreases clearance during exercise

We evaluated whether elevated blood lactate concentration during exercise in anemia is the result of elevated production or reduced clearance. Female Sprague-Dawley rats were made acutely anemic by exchange transfusion of plasma for whole blood. Hemoglobin and hematocrit were reduced 33%, to 8.6 +/- 0.4 mg/dl and 26.5 +/- 1.1%, respectively. Blood lactate kinetics were studied by primed continuous infusion of [U-14C]lactate. Blood flow distribution during rest and exercise was determined from injection of 153Gd- and 113Sn-labeled microspheres. Resting blood glucose (5.1 +/- 0.2 mM) and lactate (1.9 +/- 0.02 mM) concentrations were not different in anemic animals. However, during exercise blood glucose was lower in anemic animals (4.0 +/- 0.2 vs. 4.6 +/- 0.1 mM) and lactate was higher (6.1 +/- 0.4 vs. 2.3 +/- 0.5 mM). Blood lactate disposal rates (turnover measured with recyclable tracer, Ri) were not different at rest and averaged 136 +/- 5.8 mumol.kg-1.min-1. Ri was significantly elevated in both control (260.9 +/- 7.1 mumol.kg-1.min-1) and anemic animals (372.6 +/- 8.6) during exercise. Metabolic clearance rate (MCR = Ri/[lactate]) did not differ during rest (151 +/- 8.2 ml.kg-1.min-1); MCR was reduced more by exercise in anemic animals (64.3 +/- 3.8) than in controls (129.2 +/- 4.1). Plasma catecholamine levels were not different in resting rats, with pooled mean values of 0.45 +/- 0.1 and 0.48 +/- 0.1 ng/ml for epinephrine (E) and norepinephrine (NE), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice

Hypoglycemia-induced counterregulatory failure is a dangerous complication of insulin use in diabetes mellitus. Controlled hypoglycemia studies in gene knockout models, which require the use of mice, would aid in identifying causes of defective counterregulation. Because stress can influence counterregulatory hormones and glucose homeostasis, we developed glucose clamps with remote blood sampling in conscious, unrestrained mice. Male C57BL/6 mice implanted with indwelling carotid artery and jugular vein catheters were subjected to 2 h of hyperinsulinemic glucose clamps 24 h apart, with a 6-h fast before each clamp. On day 1, blood glucose was maintained (euglycemia, 178 +/- 4 mg/dl) or decreased to 62 +/- 1 mg/dl (hypoglycemia) by insulin (20 mU x kg(-1) x min(-1)) and variable glucose infusion. Donor blood was continuously infused to replace blood sample volume. Baseline plasma epinephrine (32 +/- 8 pg/ml), corticosterone (16.1 +/- 1.8 microg/dl), and glucagon (35 +/- 3 pg/ml) were unchanged during euglycemia but increased significantly during hypoglycemia, with a glycemic threshold of approximately 80 mg/dl. On day 2, all mice underwent a hypoglycemic clamp (blood glucose, 64 +/- 1 mg/dl). Compared with mice that were euglycemic on day 1, previously hypoglycemic mice had significantly higher glucose requirements and significantly lower plasma glucagon and corticosterone (n = 6/group) on day 2. Epinephrine tended to decrease, although not significantly, in repeatedly hypoglycemic mice. Pre- and post-clamp insulin levels were similar between groups. We conclude that counterregulatory responses to acute and repeated hypoglycemia in unrestrained, chronically cannulated mice reproduce aspects of counterregulation in humans, and that repeated hypoglycemia in mice is a useful model of counterregulatory failure.     

Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia

We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of alpha-(1-24)-ACTH (100 microg/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to approximately 45 microg/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P = 0.004, final plasma epinephrine levels of 489 +/-64 vs. 816 +/-113 pg/ml), sympathetic neural (P = 0.0022, final plasma norepinephrine levels of 244 +/-15 vs. 342 +/-22 pg/ml), parasympathetic neural (P = 0.0434, final plasma pancreatic polypeptide levels of 312 +/- 37 vs. 424 +/- 56 pg/ml), and neurogenic (autonomic) symptom (P = 0.0097, final symptom score of 7.1 +/-1.5 vs. 10.6 +/- 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus.     

Pharmacokinetics and effects of intravenous infusion of somatostatin in normal subjects--a two-compartment open model

A direct radioimmunoassay of plasma somatostatin-like immunoreactivity (SRIF-LI) was developed and validated. The sensitivity was 16.0 pg/ml, and the specificity was good. The recovery of plasma SRIF-LI was 98.8 +/- 6.3%. The Scatchard plot of the antiserum binding data revealed a straight line, with a binding affinity of 3.52 X 10(-12) M and a binding capacity 4.06 X 10(-10) M. Synthetic SRIF (Stilamin), 250 micrograms, was infused intravenously over a 30-min period in 9 healthy volunteers. Plasma glucose, insulin (IRI), glucagon (IRG) and SRIF-LI were measured. A two-compartment open model was adopted to analyze the pharmacokinetic data of SRIF-LI. The results showed that plasma SRIF-LI rose from 192.2 +/- 16.2 pg/ml to a plateau of 2,129.8 +/- 288.2 pg/ml within 5-10 min after starting the infusion. The half disappearance time from plasma (Ta1/2) was 1.36 +/- 0.18 min, the half disappearance time from the 'remote' compartment (Tb1/2) was 49.6 +/- 10.9 min and the net half disappearance time from the two compartments together (Tn1/2) was 9.19 +/- 1.49 min. The metabolic clearance rate was 50.3 +/- 7.0 ml/kg/min. The plasma IRI, IRG and the IRI/IRG molar ratio were all suppressed during the infusion period. The recovery time of plasma IRG was mildly delayed in comparison to that of IRI. This indicates that there are dissociations between IRI and IRG in the extent and the duration of suppression caused by somatostatin infusion.     

Hepatic alpha- and beta-adrenergic receptors are not essential for the increase in R(a) during exercise in diabetes

The purpose of this study was to determine the role of direct hepatic adrenergic stimulation in the control of endogenous glucose production (R(a)) during moderate exercise in poorly controlled alloxan-diabetic dogs. Chronically catheterized and instrumented (flow probes on hepatic artery and portal vein) dogs were made diabetic by administration of alloxan. Each study consisted of a 120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min recovery, and 30-min blockade test period. Either vehicle (control; n = 6) or alpha (phentolamine)- and beta (propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create suprapharmacological levels at the liver. Isotopic ([3-(3)H]glucose, [U-(14)C]alanine) and arteriovenous difference methods were used to assess hepatic function. Arterial plasma glucose was similar in controls (345 +/- 24 mg/dl) and HAB (336 +/- 23 mg/dl) and was unchanged by exercise. Basal arterial insulin was 5 +/- 1 mU/ml in controls and 4 +/- 1 mU/ml in HAB and fell by approximately 50% during exercise in both groups. Basal arterial glucagon was similar in controls (56 +/- 10 pg/ml) and HAB (55 +/- 7 pg/ml) and rose similarly, by approximately 1.4-fold, with exercise in both groups. Despite greater arterial Epi and NE levels in HAB compared with controls during the basal and exercise periods, exercise-induced increases in catecholamines from basal were similar in both groups. Gluconeogenic conversion from alanine and lactate and the intrahepatic efficiency of this process were increased by twofold during exercise in both groups. R(a) rose similarly by 2.9 +/- 0.7 and 2.7 +/- 1.0 mg. kg(-1). min(-1) at time = 150 min during exercise in controls and HAB. During the blockade test period, arterial plasma glucose and R(a) rose to 454 +/- 43 mg/dl and 11.3 mg. kg(-1). min(-1) in controls, respectively, but were essentially unchanged in HAB. The attenuated response to the blockade test in HAB substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results demonstrate that direct hepatic adrenergic stimulation does not play a role in the stimulation of R(a) during exercise in poorly controlled diabetes.     

Changes in plasma glucagon, pancreatic polypeptide and insulin during development of alloxan diabetes mellitus in dog

Changes in canine plasma glucose, immunoreactive glucagon (IRG), pancreatic polypeptide (PP) and insulin (IRI) were studied during the acute development of diabetes mellitus after iv alloxan injection. 100 mg or 75 mg/kg body weight of alloxan was injected iv and blood was taken successively till one or two days later. Plasma glucose showed four phases: first immediate and moderate decrease appeared 30 min after injection, second initial hyperglycemic phase, third hypoglycemic and fourth diabetic ones. Plasma IRI had already increased to 182 +/- 60 microU/ml 10 min after injection and again began to increase after about 6 h, peaking to 134 +/- 49 microU/ml at 18 h. Plasma IRG began increasing gradually soon after alloxan injection. The initial value was 196 +/- 26 pg/ml and it increased to 534 +/- 144 pg/ml at 4 h during the initial hyperglycemic phase, then reached a higher level through the hypoglycemic and diabetic phases. The change in plasma PP was similar to that in IRG. The initial value was 256 +/- 95 pg/ml at 12 h after injection, peaking to 840 +/- 100 pg/ml in the hypoglycemic phase. Similar blunted values were obtained following 75 mg/kg alloxan injection. Thus not only plasma IRI but also plasma IRG and PP varied greatly during the acute development of alloxan diabetes and some contribution of IRG to the initial hyperglycemic phase was suggested.     

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake

The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake (VO(2 max))] comprises a marked increment in glucose production (R(a)) and a lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a) correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate R(a), this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40 min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))] from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a) increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(-1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) = 0.923, P 相似文献   

Influence of endogenous opioids on the response of selected hormones to exercise in humans

To examine the influence of endogenous opioids on the hormonal response to isotonic exercise, eight males were studied 2 h after oral administration of placebo or 50 mg naltrexone, a long-lasting opioid antagonist. Venous blood samples were obtained before, during, and after 30 min of bicycle exercise at 70% VO2max. Naltrexone had no effect on resting cardiovascular, endocrine, or serum variables. During exercise epinephrine was higher [mean 433 +/- 100 (SE) pg/ml] at 30 min with naltrexone than during placebo (207 +/- 26 pg/ml, P less than 0.05). Plasma norepinephrine showed the same trend but the difference (2,012 +/- 340 pg/ml with naltrexone and 1,562 +/- 241 pg/ml with placebo) was not significant. Plasma glucose was higher at all times with naltrexone. However, the difference was significant only 10 min into recovery from exercise (104.7 +/- 4.7 vs. 94.5 +/- 2.8 mg/dl). Plasma growth hormone and cortisol increased during recovery and these elevations were significantly (P less than 0.05) augmented by naltrexone. Plasma vasopressin and prolactin increased with exercise as did heart rate, blood pressure, lactic acid, and several serum components; these increases were not affected by naltrexone. Psychological tension or anxiety was lower after exercise compared with before and this improved psychological state was not influenced by the naltrexone treatment. These data suggest that exercise-induced activation of the endogenous opioid system may serve to regulate the secretion of several important hormones (i.e., epinephrine) during and after exercise.     

Plasma glucagon-immunoreactive components in early life in dogs

High plasma concentrations of C-terminal immunoreactive glucagon (IRG) have been found during early life in several mammalian species. We have analyzed the plasma IRG of 12 h to 60 day-old dogs in terms of the 4 peaks (IRG greater than 20,000, IRG9000, IRG3500 and IRG2000) obtained by gel filtration on Bio-Gel P-30. Significant changes with age and in response to administered agents were confined to IRG9000 and IRG3500. IRG9000 was 9-fold higher in 12-36 h old dogs than in adults (108 +/- 24 pg/ml pancreatic glucagon equivalents v. 12 +/- 3 pg/ml, mean +/- SEM) and showed a decline to 2-fold higher (27 +/- 5 pg/ml) at 31-60 days. IRG3500 was higher than in the adult only during the first 36 h of life (36 +/- 5 pg/ml v. 15 +/- 3 pg/ml). Arginine infusion (0.5 g/kg over 15 min) caused an increase in plasma levels of both IRG9000 and IRG3500 in the newborn, whereas in adult dogs only IRG3500 was increased. Insulin injection (0.2 U/kg intravenously) causing a marked hypoglycemia had no significant effect on the plasma level of any IRG component in newborn dogs. Dihydrosomatostatin infusion (10 micrograms/kg bolus +/- 90 micrograms/kg over 30 min) caused a decrease in both IRG9000 and IRG3500. The increased basal level and secretory response to arginine of IRG9000 in newborn dogs may reflect an immaturity of the A cells, whereby more of this component, which may represent a precursor of pancreatic glucagon, is secreted than in the adult. The immature A cells also appear to have an impaired secretory response to hypoglycemia.     

Glucose turnover and hormonal changes during insulin-induced hypoglycemia in trained humans

Eight athletes (T), studied the third morning after the last exercise session, and seven sedentary males (C) (maximal O2 consumption 65 +/- 4 vs. 49 +/- 4 (SE) ml X kg-1 X min-1, for T and C men, respectively) had insulin infused until plasma glucose, at an insulin level of 1,600 pmol X l-1, was 1.9 mmol X l-1. Glucose turnover was determined by primed constant rate infusion of 3-[3H]glucose. Basal C-peptide (0.46 +/- 0.04 vs. 0.73 +/- 0.06 pmol X ml-1) and glucagon (4 +/- 0.4 vs. 10 +/- 2 pmol X l-1) were lower (P less than 0.05) and epinephrine higher (0.30 +/- 0.06 vs. 0.09 +/- 0.03 nmol X l-1) in T than in C subjects. During and after insulin infusion production, disappearance and clearance of glucose changed identically in T and C subjects. However, in spite of identical plasma glucose concentrations, epinephrine (7.88 +/- 0.99 vs. 3.97 +/- 0.40 nmol X l-1), growth hormone (97 +/- 17 vs. 64 +/- 6 mU X l-1), and pancreatic polypeptide (361 +/- 84 vs. 180 +/- 29 pmol X l-1) reached higher levels (P less than 0.05) and glucagon (28 +/- 3 vs. 47 +/- 10 pmol X l-1) lower levels in T than in C subjects. Blood pressures changed earlier in athletes during insulin infusion, and early recovery of heart rate, free fatty acid, and glycerol was faster. Responses of norepinephrine, cortisol, C-peptide, and lactate were similar in the two groups. Training radically changes hormonal responses but not glucose kinetics in insulin hypoglycemia.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Acute anemia results in an increased glucose dependence during sustained exercise

We evaluated whether acute anemia results in altered blood glucose utilization during sustained exercise at 26.8 m/min on 0% grade, which elicited approximately 60-70% maximal O2 consumption. Acute anemia was induced in female Sprague-Dawley rats by isovolumic plasma exchange transfusion. Hemoglobin and hematocrit were reduced 33% by exchange transfusion to 8.6 +/- 0.4 g/dl and 26.5 +/- 1%, respectively. Glucose kinetics were determined by primed continuous infusion of [6-3H]glucose. Rates of O2 consumption were similar during rest (pooled means 25.1 +/- 1.8 ml.kg-1.min-1) and exercise (pooled means 46.8 +/- 3.0 ml.kg-1.min-1). Resting blood glucose and lactate concentrations were not different in anemic animals (pooled means 5.1 +/- 0.2 and 0.9 +/- 0.02 mM, respectively). Exercise resulted in significantly decreased blood glucose (4.0 +/- 0.2 vs. 4.6 +/- 0.1 mM) and elevated lactate (6.1 +/- 0.4 vs. 2.3 +/- 0.5 mM) concentrations in anemic animals. Glucose turnover rates (Rt) were not different between anemic and control animals at rest and averaged 58.8 +/- 3.6 mumol.kg-1.min-1. Exercise resulted in a 30% greater increase in Rt in anemic (141.7 +/- 3.2 mumol.kg-1.min-1) than in control animals (111.2 +/- 5.2 mumol.kg-1.min-1). Metabolic clearance rates (MCR = Rt/[glucose]) were not different at rest (11.6 +/- 7.4) but were significantly greater in anemic (55.2 +/- 5.7 ml.kg-1.min-1) than in control animals (24.3 +/- 1.4 ml.kg-1.min-1) during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased dependence on blood glucose after acclimatization to 4,300 m

To evaluate the hypothesis that altitude exposure and acclimatization result in increased dependency on blood glucose as a fuel, seven healthy males (23 +/- 2 yr, 72.2 +/- 1.6 kg, mean +/- SE) on a controlled diet were studied in the postabsorptive condition at sea level (SL), on acute altitude exposure to 4,300 m (AA), and after 3 wk of chronic altitude exposure to 4,300 m (CA). Subjects received a primed continuous infusion of [6,6-2D]glucose and rested for a minimum of 90 min, followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the SL maximal O2 consumption (VO2 max; 65 +/- 2% of altitude VO2 max). At SL, resting arterial glucose concentration was 82.4 +/- 3.2 mg/dl and rose significantly to 91.2 +/- 3.2 mg/dl during exercise. Resting glucose appearance rate (Ra) was 1.79 +/- 0.02 mg.kg-1.min-1; this increased significantly during exercise at SL to 3.71 +/- 0.08 mg.kg-1.min-1. On AA, resting arterial glucose concentration (85.8 +/- 4.1 mg/dl) was not different from sea level, but Ra (2.11 +/- 0.14 mg.kg-1.min-1) rose significantly. During exercise on AA, glucose concentration rose to levels seen at SL (91.4 +/- 3.0 mg/dl), but Ra increased more than at SL (to 4.85 +/- 0.15 mg.kg-1.min-1; P less than 0.05). Resting arterial glucose was significantly depressed with CA (70.8 +/- 3.8 mg/dl), but resting Ra increased to 3.59 +/- 0.08 mg.kg-1.min-1, significantly exceeding SL and AA values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Type 2 diabetes mellitus in a non-obese mouse model induced by Meg1/Grb10 overexpression

We assessed the possibility of C57BL/6-Tg (Meg1/Grb10)isn(Meg1 Tg) mice as a non-obese type 2 diabetes (2DM) animal model. Meg1 Tg mice were born normal, but their weight did not increase as much as normal after weaning and showed about 85% of normal size at 20 weeks of age. Body mass index of Meg1 Tg mice was also smaller than that of control mice. The glucose tolerance test and insulin tolerance test showed that Meg1 Tg mice had reduced ability to normalize the blood glucose level. Blood urea nitrogen (BUN) in Meg1 Tg mice (19.6 +/- 1.2 mg/dl) was significantly lower than in controls (22.0 +/- 0.8 mg/dl), while plasma triglyceride, insulin, adiponectin, and resistin levels were significantly higher (202.0 +/- 23.4 mg/dl vs 146.3 +/- 23.4 mg/dl, 152.4 +/- 16.3 pg/ml vs 88.1 +/- 16.9 pg/ml, 74.4 +/- 10.9 microg/ml vs 48.3 +/- 7.0 microg/ml, and 4.0 +/- 0.2 ng/ml vs 3.6 +/- 0.2 ng/ml, respectively). Body, visceral fat weight and liver weights were significantly lower (19.6 +/- 0.4 g vs 24.3 +/- 0.3 g, 376.7 +/- 29.6 mg to 507.5 +/- 23.0 mg, and 906.0 +/- 41.8 mg to 1,001.0 +/- 15.1 mg, respectively). Thus, hyperinsulinemia observed in Meg1 Tg mice indicates that their insulin signaling pathway is somehow inhibited. With high fat diet, the diabetes onset rate of Meg1 Tg mice increased up to 60%. These results suggest that Meg1 Tg mice resemble human 2DM.     

Glucose kinetics differ between women and men, during and after exercise.

As exercise can improve the regulation of glucose and carbohydrate metabolism, it is important to establish biological factors, such as sex, that may influence these outcomes. Glucose kinetics, therefore, were compared between women and men at rest, during exercise, and postexercise. It was hypothesized that glucose flux would be significantly lower in women than men during both the exercise and postexercise periods. Subjects included normal weight, healthy, eumenorrehic women and men, matched for habitual activity level and maximal oxygen uptake per kilogram lean body mass. Testing occurred following 3 days of diet control, with no exercise the day before. Subjects were tested in the overnight-fasted condition with women studied in the midluteal phase of the menstrual cycle. Resting (120 min), exercise (85% lactate threshold, 90 min), and postexercise (180 min) measurements of glucose flux and substrate metabolism were made. During exercise, women had a significantly lower rate of glucose appearance (Ra) (P<0.001) and disappearance (Rd) (P<0.002) compared with men. Maximal values were achieved at 90 min of exercise for both glucose Ra (mean+/-SE: 22.8+/-1.12 micromol.kg body wt-1.min-1 women and 33.6+/-1.79 micromol.kg body wt-1.min-1 men) and glucose Rd (23.2+/-1.26 and 34.1+/-1.71 micromol.kg body wt-1.min-1, respectively). Exercise epinephrine concentration was significantly lower in women compared with men (P<0.02), as was the increment in glucagon from rest to exercise (P<0.04). During the postexercise period, glucose Ra and Rd were also significantly lower in women vs. men (P<0.001), with differences diminishing over time. In conclusion, circulating blood glucose flux was significantly lower during 90 min of moderate exercise, and immediately postexercise, in women compared with men. Sex differences in the glucagon increase to exercise, and/or the epinephrine levels during exercise, may play a role in determining these sex differences in exercise glucose turnover.     

Pancreatic B-cell function in non-insulin-dependent diabetes mellitus during successive periods of sulfonylurea and insulin treatment: serum C-peptide response to glucagon and urine C-peptide excretion

Serum C-peptide responses to glucagon and daily urine C-peptide excretion in successive periods of different treatment in two groups of patients with non-insulin-dependent diabetes mellitus (NIDDM) (mean interval between two tests less than 1 month) were compared. In group A patients (n = 8), the glycemic control was improved after transferring the treatment from sulfonylurea (SU) to insulin (fasting plasma glucose: SU: 192 +/- 47, insulin: 127 +/- 21 mg/dl, mean +/- S.D., p less than 0.01). Fasting serum C-peptide immunoreactivity (CPR) was significantly lower at the period of insulin treatment (SU: 1.93 +/- 1.01, insulin: 1.47 +/- 0.79 ng/ml, p less than 0.05), but there was no difference in the increase in serum CPR (maximal--fasting) (delta serum CPR) during glucagon stimulation in the two periods of treatment (SU: 1.70 +/- 0.72, insulin: 1.47 +/- 0.98 ng/ml). In group B patients (n = 7), there was no significant difference in glycemic control after transferring the treatment from insulin to SU (fasting plasma glucose: insulin: 127 +/- 24, SU: 103 +/- 13 mg/dl). Fasting serum CPR was significantly lower during the period of insulin treatment (insulin: 1.39 +/- 0.64, SU: 2.21 +/- 0.86 ng/ml, p less than 0.025), but delta serum CPR during glucagon stimulation still showed no significant difference between the two periods (insulin: 1.97 +/- 1.16, SU: 2.33 +/- 1.57 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)