Biagio Ungaro

Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man.

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg(-1) min(-1)) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg(-1) min(-1); (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg(-1) min(-1)); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg(-1) min(-1)). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls ( approximately 170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 muU/ml at 90 min. NSGB switched from a net output of 1.71+/-0.13 to a net uptake of 1.5-1.6 mg kg(-1) min(-1) due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78+/-0.13 to 1.6-1.8 mg kg(-1) min(-1); P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 muU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 muU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 muU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg(-1) min(-1)). Peripheral glucose uptake rose to the same extent as in controls. IT IS CONCLUDED THAT: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

Mechanisms of epinephrine-induced glucose intolerance in normal humans.

To evaluate the role of the splanchnic bed in epinephrine-induced glucose intolerance, we selectively assessed the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose production, and peripheral glucose uptake by combining infusion of [3-(3)H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg(-1) per min(-1)) or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg(-1) per min(-1)); and (b) in amounts identical to the control study. During infusion of glucose alone, blood glucose rose twofold, insulin levels and net posthepatic insulin release increased three- to fourfold, and net splanchnic glucose output switched from a net output (1.65+/-0.12 mg/kg(-1) per min(-1)) to a net uptake (1.56+/-0.18). This was due to a 90-95% fall (P < 0.001) in hepatic glucose production and a 100% rise (P < 0.001) in splanchnic glucose uptake (from 0.86+/-0.14 to 1.71+/-0.12 mg/kg(-1) per min(-1)), which in the basal state amounted to 30-35% of total glucose uptake. Peripheral glucose uptake rose by 170-185% (P < 0.001). When epinephrine was combined with the lower glucose dose, blood glucose, insulin release, and hepatic blood flow were no different from values observed with glucose alone. However, hepatic glucose production fell only 40-45% (P < 0.05 vs. glucose alone) and, most importantly, the rise in splanchnic glucose uptake was totally blocked. As a result, splanchnic glucose clearance fell by 50% (P < 0.05), and net splanchnic glucose uptake did not occur. The rise in peripheral glucose uptake was also reduced by 50-60% (P < 0.001). When epinephrine was added to the same dose of glucose used in the control study, blood glucose rose twofold higher (P < 0.001). The initial rise in splanchnic glucose uptake was totally prevented; however, beyond 30 min, splanchnic glucose uptake increased, reaching levels seen in the control study when severe hyperglycemia occurred. Splanchnic glucose clearance, nevertheless, remained suppressed throughout the entire study (40%-50%, P < 0.01). It is concluded that (a) the splanchnic bed accounts for one-third of total body glucose uptake in the basal state in normal humans; (b) epinephrine markedly inhibits the rise in splanchnic glucose uptake induced by infusion of glucose; and (c) this effect does not require a fall in insulin and is modulated by the level of hyperglycemia. Our data indicate that the splanchnic bed is an important site of glucose uptake in post-absorptive humans and that epinephrine impairs glucose tolerance by suppressing glucose uptake by both splanchnic and peripheral tissues, as well as by its well known stimulatory effect on endogenous glucose production.

Inverted response of arginine vasopressin to postural change in patients with essential hypertension

This study was designed to compare the response of plasma arginine vasopressin (AVP) to head‐up tilt in hypertensive patients and in normals.

The glucoregulatory response to intravenous glucose infusion in normal man: Roles of insulin and glucose

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg-1 min-1) or glucose (3 mg kg-1 min-1) in conjunction with somatostatin (500 microgram hr-1), insulin (0.15 mU kg-1 min-1) and glucagon (1 ng kg-1 min-1). Glucose kinetics were measured by the primed-constant infusion of 3-3H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45--50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%--90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose to three-fourfold while plasma glucagon fell by 25%--30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p less than 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%--30%; p less than 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.

Renal Function in Borderline Hypertensive First-Degree Relatives of Essential Hypertensives

Renal function in the basal state and after sodium load has been investigated in 21 borderline, hypertensive, first-degree relatives of established hypertensives and in 21 age- and sex-matched, normal subjects with no family history of hypertension. During intravenous infusion of inulin and p-aminohippurate in saline, both groups showed a decrease in plasma aldosterone levels (p less than 0.05) but renal plasma flow (595 +/- 48 vs. 750 +/- 59 ml/min, p less than 0.05), diuresis (1.4 +/- 0.2 vs. 2.2 +/- 0.5 ml/min, p less than 0.05), natriuresis (0.21 +/- 0.02 vs. 0.3 +/- 0.02 mEq/min, p less than 0.05) and sodium clearance (1.05 +/- 0.1 vs. 2.4 +/- 0.4 ml/min, p less than 0.05) in borderline hypertensives were higher than in the control group. After the salt load (NaCl, 1.35% i.v., 5 ml/min for 2 h) there was an increase in blood pressure and a decrease in plasma aldosterone and potassium levels in both groups. However, borderline hypertensives showed higher diuresis, natriuresis, sodium clearance and also kaliuresis compared to normotensives. These results suggest that borderline hypertensives already present the changes in renal function which are characteristics of established hypertensives.