Attenuation of vasopressin-induced antidiuresis in poorly controlled type 2 diabetes

Renal resistance to vasopressin has been demonstrated in type 1 diabetes and in type 2 diabetes with nephropathy. However, renal response to vasopressin in type 2 diabetes without nephropathy has not been studied. We studied 10 subjects with poorly controlled type 2 diabetes (PCDS; Hb A(1c) >9%), 10 subjects with well-controlled type 2 diabetes (WCDS; Hb A(1c) <7%), and 10 matched nondiabetic control subjects (NDCS) during a euglycemic 8-h water deprivation test. None of the subjects had nephropathy. Water deprivation caused similar rises in plasma vasopressin concentrations in all three groups, but the rise in urine osmolality in PCDS (280.3 +/- 49.7 to 594.4 +/- 88.5 mosmol/kgH(2)O) was lower than in WCDS (360.7 +/- 142.8 to 794.1 +/- 77.3 mosmol/kgH(2)O, P < 0.001) or NDCS (336.0 +/- 123.3 to 786.5 +/- 63.3 mosmol/kgH(2)O, P = 0.019). Total urine output was higher in the PCDS than in WCDS and NDCS (P < 0.05). Linear regression analysis showed that, in PCDS, the osmotic thresholds for thirst (291.9 +/- 4.6 mosmol/kgH(2)O) and vasopressin release (291.1 +/- 2.9 mosmol/kgH(2)O) were higher compared with WCDS (286.6 +/- 1.8 and 286.0 +/- 3.6 mosmol/kgH(2)O, respectively) and NDCS (286.0 +/- 2.4 and 284.1 +/- 4.7 mosmol/kgH(2)O, respectively) (between groups P < 0.001 for both variables). Under conditions of euglycemia, PCDS have impaired renal response to vasopressin and elevated osmotic threshold for thirst and vasopressin release in response to dehydration. Under conditions of chronic hyperglycemia, these abnormalities may significantly contribute to the development of dehydration in PCDS.     

Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs.

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4-5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of approximately 300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the approximately 15-h-fasted dog underwent a primed continuous 150-min infusion of [3-(3)H]glucose, followed by a 30-min treadmill exercise test (approximately 65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rd(tissue)) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rd(tissue), and plasma-derived GF were severely blunted by approximately 30-50% in the NGD state, but increments in MCRg remained markedly reduced by approximately 70-75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rd(tissue) during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rd(tissue) during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rd(tissue) and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.     

Effect of beta-adrenergic blockade on thermoregulation during exercise

To resolve conflicting reports concerning the effects of beta-blockade (BB) on thermoregulatory reflexes during exercise, we studied six fit men during 40 min of cycle ergometer exercise at 60% maximum O2 consumption at ambient temperatures of 22 and 32 degrees C. Two hours before exercise, each subject ingested a capsule containing either 80 mg of propranolol or placebo in single-blind fashion. Heart rate at 40 min of exercise was reduced (P less than 0.01) from 125 to 103 beats min at 22 degrees C and 137 to 104 beats min at 32 degrees C, demonstrating effective BB. After 40 min of exercise, esophageal temperature (Tes) was elevated with BB (P less than 0.05) from 37.66 +/- 0.04 to 38.14 +/- 0.03 and 38.13 +/- 0.04 to 38.41 +/- 0.04 degrees C at 22 and 32 degrees C, respectively. The elevated Tes resulted from a reduced core-to-skin heat flux at both temperatures, indicated by a reduction in the slope of the forearm blood flow (FBF)-Tes relationship, and a decrease in maximal FBF. Systolic blood pressure was decreased 20 mmHg with BB (P less than 0.01), whereas diastolic blood pressure was unchanged, reducing arterial pulse pressure (PP). Because PP was decreased and cardiac filling pressure was presumably not reduced (since cardiac stroke volume was elevated), we suggest that at least a part of the relative increase in peripheral vasomotor tone during BB was the consequence of reduced sinoaortic baroreceptor stimulation.     

Renal resistance to vasopressin in poorly controlled type 1 diabetes mellitus

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P<0.001) rise in urine osmolality in controls (67.6+/-10.7 to 720+/-31.1 mosmol/kg, P<0.001) than in IDDM patients (64.3+/-21.6 to 516.7+/-89.3 mosmol/kg, P<0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8+/-105.6 fmol/mg creatinine) than in IDDM (462.0+/-94.9 fmol/mg creatinine, P = 0. 003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A(Ic) (r = -0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A(Ic) >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8+/-49.0; A, 640.0+/-137.2 mosmol/kg, P<0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 +/-69 to 375+/-280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.     

Tocopherol mobilization during dynamic exercise after beta-adrenergic blockade.

This study addresses the question of whether tocopherol mobilization during exercise could be explained by a lipolysis effect. Nine healthy male subjects were submitted to dynamic exercise of graded intensity (45, 60, 75% VO2max) on a cycle ergometer after ingestion of either a placebo or 40 mg propranolol as beta-blocker. Plasma tocopherol concentration increased toward a peak value reached during or at the end of exercise. The magnitude of this increase did not differ in the two experimental conditions while plasma free fatty acids concentration was lowered under beta-adrenergic blockade by propranolol. From these results, we conclude that tocopherol mobilization during dynamic exercise does not depend on lipolysis.     

Thermoregulation during prolonged exercise in heat: alterations with beta-adrenergic blockade

Thermoregulation and cardiovascular drift were studied under conditions of prolonged exercise in a warm environment (dry bulb temperature 31.7 +/- 0.3 degrees C, rh 44.7 +/- 4.7%) during beta-adrenergic blockade. Fourteen subjects performed 90-min rides on a cycle ergometer at a work rate equivalent to 40% of their control maximal O2 uptake under each of three treatments provided in a randomized double-blind manner: atenolol (100 mg/day), propranolol (160 mg/day), and a placebo. Exercise during the propranolol trial resulted in significantly higher forearm vascular resistance values and significantly lower forearm blood flows (FBF) compared with the placebo trial. However, the significantly lower FBF during propranolol did not significantly alter the rectal temperature (Tre) response to prolonged exercise. In addition, both beta-blockers produced lower FBF for any given Tre, suggesting that beta-adrenergic blockade affects FBF through nonthermal factors. The slight differences in Tre, despite the large differences in FBF between the various treatments, are apparently the result of an enhanced sweat loss and a lower mean skin temperature during exercise with beta-blockade. The uncoupling of FBF and sweat loss provides evidence of independent regulation. The reduction in FBF at any given Tre was concomitant to lower blood pressure values during beta-blockade and suggests that baroreflexes provide significant input to the control of skin blood flow when both pressure and temperature maintenance are simultaneously challenged.     

beta-adrenergic blockade augments glucose utilization in horses during graded exercise.

To examine the role of beta-adrenergic mechanisms in the regulation of endogenous glucose (Glu) production [rate of appearance (R(a))] and utilization [rate of disappearance (R(d))] and carbohydrate (CHO) metabolism, six horses completed consecutive 30-min bouts of exercise at approximately 30% (Lo) and approximately 60% (Hi) of estimated maximum O(2) uptake with (P) and without (C) prior administration of the beta-blocker propranolol (0.22 mg/kg iv). All horses completed exercise in C; exercise duration in P was 49.9 +/- 1.2 (SE) min. Plasma Glu was unchanged in C during Lo but increased progressively in Hi. In P, plasma Glu rose steadily during Lo and Hi and was higher (P < 0.05) than in C throughout exercise. Plasma insulin declined during exercise in P but not in C; beta-blockade attenuated (P < 0.05) the rise in plasma glucagon and free fatty acids and exaggerated the increases in epinephrine and norepinephrine. Glu R(a) was 8.1 +/- 0.8 and 8.4 +/- 1.0 micromol. kg(-1). min(-1) at rest and 30.5 +/- 3.6 and 42.8 +/- 4.1 micromol. kg(-1). min(-1) at the end of Lo in C and P, respectively. During Hi, Glu R(a) increased to 54.4 +/- 4.4 and 73.8 +/- 4.7 micromol. kg(-1). min(-1) in C and P, respectively. Similarly, Glu R(d) was approximately 40% higher in P than in C during Lo (27.3 +/- 2.0 and 39.5 +/- 3.3 micromol. kg(-1). min(-1) in C and P, respectively) and Hi (37.4 +/- 2.6 and 61.5 +/- 5.3 micromol. kg(-1). min(-1) in C and P, respectively). beta-Blockade augmented CHO oxidation (CHO(ox)) with a concomitant reduction in fat oxidation. Inasmuch as estimated muscle glycogen utilization was similar between trials, the increase in CHO(ox) in P was due to increased use of plasma Glu. We conclude that beta-blockade increases Glu R(a) and R(d) and CHO(ox) in horses during exercise. The increase in Glu R(d) under beta-blockade suggests that beta-adrenergic mechanisms restrain Glu R(d) during exercise.     

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.     

Alteration in myocardial oxygen balance during exercise after beta-adrenergic blockade in dogs

The effects of beta-adrenergic blockade upon myocardial blood flow and oxygen balance during exercise were evaluated in eight conscious dogs, instrumented for chronic measurements of coronary blood flow, left ventricular pressure, aortic blood pressure, heart rate, and sampling of arterial and coronary sinus venous blood. The administration of propranolol (1.5 mg/kg iv) produced a decrease in heart rate, peak left ventricular (LV) dP/dt, LV (dP/dt/P, and an increase in LV end-diastolic pressure during exercise. Mean coronary blood flow and myocardial oxygen consumption were lower after propranolol than at the same exercise intensity in control conditions. The oxygen delivery-to-oxygen consumption ratio and the coronary sinus oxygen content were also significantly lower. It is concluded that the relationship between myocardial oxygen supply and demand is modified during exercise after propranolol, so that a given level of myocardial oxygen consumption is achieved with a proportionally lower myocardial blood flow and a higher oxygen extraction.     

Heat regulation during exercise with controlled cooling

During heavy sustained exercise, when sweating is usually needed to dissipate the extra metabolic heat, controlled cooling caused heat loss to match total heat production with little sweating. The total heat produced and metabolic rate were varied independently by having subjects walk uphill and down. Heat loss was measured directly with a suit calorimeter; other measurements included metabolic energy from respiratory gas exchange and body temperatures. Thermoregulatory sweating was minimized by adjusting cooling in the calorimeter suit. Heat loss rose to match total heat, not metabolic rate, and there was a slow rise in rectal temperature. In the absence of major thermoregulatory response rectal temperature correlated most closely with total heat; it also correlated with the relative oxygen cost of exercise. Heat flow or heat content appeared to be the controlled variable and body temperature rise a secondary event resulting from thermal transport lag.     

Effect of beta-adrenergic blockade during exercise on ventilation and gas exchange.

The ventilatory effects of beta-adrenergic blockade during steady-state exercise were studied in eight normal subjects using intravenous propranolol hydrochloride (0.2 mg/kg). Heart rate decreased in all subjects by an average of 17%. Coincident with the phase of decreasing heart rate was a significant decrease in both minute ventilation (VE) and CO2 output (VCO2), averaging 9.6 and 9.2%, respectively. Both functions returned to prepropranolol levels after heart rate had reached its reduced steady-state value. The change in VE was significantly correlated with the change in VCO2 (r = 0.85, P less than 0.005), and was associated with negligible changes in endtidal CO2 tensions and ventilatory equivalents for CO2. We interpret these studies as showing that the transient isocapnic hypopnea concomitant with an acute reduction in cardiac output was secondary to a transient decrease in CO2 flux (cardiac output x mixed venous CO2 content). This decrease in VE appears to be induced by the acute decrease in cardiac output ("cardiodynamic hypopnea"), in fashion similar to the previously described cardiodynamic hyperpnea.     

Role of cardiopulmonary baroreflexes during dynamic exercise

To examine the role of cardiopulmonary (CP) mechanoreceptors in the regulation of arterial blood pressure during dynamic exercise in humans, we measured mean arterial pressure (MAP), cardiac output (Q), and forearm blood flow (FBF) during mild cycle ergometer exercise (77 W) in 14 volunteers in the supine position with and without lower-body negative pressure (LBNP). During exercise, MAP averaged 103 +/- 2 mmHg and was not altered by LBNP (-10, -20, or -40 mmHg). Steady-state Q during exercise was reduced from 10.2 +/- 0.5 to 9.2 +/- 0.5 l/min (P less than 0.05) by application of -10 mmHg LBNP, whereas heart rate (97 +/- 3 beats/min) was unchanged. MAP was maintained during -10 mmHg LBNP by an increase in total systemic vascular resistance (TSVR) from 10.3 +/- 0.5 to 11.4 +/- 0.6 U and forearm vascular resistance (FVR) from 17.5 +/- 1.9 to 23.3 +/- 2.6 U. The absence of a reflex tachycardia or reduction in arterial pulse pressure during -10 mmHg LBNP supports the hypothesis that the increase in TSVR and FVR results primarily from the unloading of CP mechanoreceptors. Because CP mechanoreceptor unloading during exercise stimulates reflex circulatory adjustments that act to defend the elevated MAP, we conclude that the elevation in MAP during exercise is regulated and not merely the consequence of differential changes in Q and TSVR. In addition, a major portion of the reduction in FBF in our experimental conditions occurs in the cutaneous circulation. As such, these data support the hypothesis that CP baroreflex control of cutaneous vasomotor tone is preserved during mild dynamic exercise.