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In normal humans, infusion of epinephrine for 4 h increased plasma epinephrine to 411 +/- 38 pg/ml but had no significant effect on palsma insulin or glucagon levels. Epinephrine produced a prompt 45% rise in glucose output (P less than 0.01) and a 120% rise in FFA (P less than 0.001), both of which declined to basal levels by 60-90 min. Glucose clearance decreased by 25% (P less than 0.005) and remained suppressed for 4 h. The binding of [125I]hydroxybenzylpindolol to lymphocytes was unchanged after epinephrine infusion. We conclude that in normal humans 1) physiological increments in epinephrine have a persistent effect in decreasing glucose clearance but only transiently increase hepatic glucose output and FFA levels and 2) this refractoriness of liver and adipose tissue to epinephrine occurs without a concomitant decrease in beta-adrenergic binding to lymphocytes.

To evaluate the effect of strict glycemie control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2–6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 ± 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 ± 4 mg/dl) than in normal control subjects (56 ± 1 mg/dl, P < .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50–60 mg/dl. After intensive therapy (HbA, 7.1 ± 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 ± 2 mg/dl) below normal (P < .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemie level, and a greater hypoglycemie stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemie control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.

The plasma growth hormone, epinephrine, and norephinephrine responses to cycle ergometer exercise (15 min at 1 W/kg) were examined in 10 juvenile-onset, insulin-dependent diabetics (ages 10–32 yr) during conventional insulin treatment and after 7 and 14 days of treatment with a portable subcutaneous insulin infusion system that normalizes plasma glucose. During conventional insulin treatment (mean plasma glucose, 205 ± 22 mg/dl), the growth hormone response to exercise was sevenfold greater than in normal controls (P < 0.01). After 1 wk of insulin pump treatment (mean plasma glucose, 89 ± 3), the growth hormone response fell 62% (P < 0.001); by 2 wk the growth hormone response had fallen 83% (P < 0.001) to values comparable to those of controls. Exercise resulted in a two- to threefold rise in plasma epinephrine in diabetics (P < 0.001) during conventional treatment but failed to elicit a consistent increment in epinephrine in normal control subjects or in the diabetic patients after 14 days of pump treatment. The rise in plasma norepiriephrine after exercise in conventionally treated diabetic patients was 12-fold greater than in healthy control subjects (P < 0.025) but fell 82% (P < 0.001) after 7 days and 88% (P < 0.001) after 14 days of pump treatment to values similar to those of controls. These data indicate that treatment of insulin-dependent diabetics with a subcutaneous portable insulin infusion system that normalizes plasma glucose results in normalization of the growth hormone and catecholamine response to exercise within 7 to 14 days of institution of treatment.

Hypoglucagonemia (induced by somatostatin) and hyperglucagonemia (induced by infusion of physiologic amounts of glucagon) have only evanescent effects on blood glucose regulation. Despite on-going glucagon suppression by somatostatin, fasting hyperglycemia develops within 4-6 hr of insulin suppression, indicating that (1) basal glucagon secretion is not essential for the development of the diabetic state; and (2) insulin-deficiency (rather than altered glucagon secretion) is the dominant long-term factor determining glucose homeostasis in the diabetic. With respect to hyperglucagonemia, only a transient increase in splanchnic glucose output is observed in normal and diabetic subjects in response to physiologic increments in this hormone. The exaggerated hyperglycemic effect of glucagon observed in diabetics1 is thus a consequence of the failure to metabolize the glucose traniently released into the systemic circulation in response to the glucagon rather than a result of persistent stimulation of hepatic glucose production. These observations thus further underscore the essentiality of insulin deficiency in the diabetogenic action of glucagon.

To evaluate the effect of physiologic hyperglucagonemia on nitrogen and glucose metabolism and on urinary electrolyte excretion, pancreatic glucagon was administered as a continuous 3-day infusion to three adult-onset non-insulin-dependent diabetics and two insulin-treated juvenile diabetics while on a constant dietary intake. The glucagon infusion resulted in increases in plasma glucagon which were 4-6 fold greater than control values. Despite prolonged hyperglucagonemia, urinary glucose excretion was unchanged. Similarly, urinary urea nitrogen and total nitrogen excretion were not altered by glucagon administration. Urinary sodium tended to rise, albeit not significantly (p less than .01), on the first infusion day, but later declined to control values despite increasing plasma glucagon concentrations. Urinary chloride, potassium, calcium, phosphorus excretion remained unchanged. We conclude that continuous physiologic increments in plasma glucagon do not enhance glycosuria or increase protein catabolism and ureagenesis in diabetes when insulin is available. The augmented protein catabolism and glucogenesis that accompany diabetic ketoacidosis cannot be explained primarily on the basis of hyperglucagonemia.

We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset diabetic patients that delivers insulin via the subcutaneous route with a portable pump at constant basal rates with pulse dose increments before meals. Studies in the hospital in 15 diabetic patients for 2–14 days indicated rapid restoration of normal glucose homeostasis. Mean plasma glucose levels on pump therapy averaged 85–90 mg/dl, maximal fluctuations in plasma glucose fell by 50–75%, and glycosuria was eliminated. Minimal plasma glucose values varied between 45 and 67 mg/dl. Cholesterol, triglycerides, and free fatty acids as well as fasting and postprandial branched chain amino acid levels were elevated on conventional treatment but fell to normal after 7 days of pump therapy. Pump treatment also restored to normal increased basal growth hormone levels and excessive exercise-induced rises in growth hormone and catecholamines. Normalization of body fuel metabolism occurred, although the total dose of insulin administered by the pump was no greater than the usual insulin dose given by conventional means. We have treated seven insulin-dependent diabetic patients (aged 13–32 yr) for 3–8 mo outside of the hospital. Patients pursued their usual work or school activities. Mean blood glucose (237 ± 28 mg/dl during conventional therapy) fell to 105 ± 5 mg/dl after 4 wk of pump treatment and was maintained between 80 and 104 mg/dl beyond 8 wk. Total glycosylated hemoglobulin was normalized in all patients within 8 wk, as were cholesterol and triglyceride levels. Symptoms of hypoglycemia and overinsulinization and underinsulinization due to human error was relatively uncommon. No episode of mechanical pump failure occurred in 1110 patient-days of use. We conclude that normalization or near normalization of blood glucose levels and correction of abnormal lipid and amino acid metabolism can be achieved with a portable subcutaneous insulin infusion system when continuously used to treat juvenile-onset diabetic patients. Long-term use of this system may provide a feasible means for determining whether metabolic changes resulting from insulin lack cause the complications of diabetes.

l-Leucine was administered as a primed continuous 3-4-h infusion in nonobese and obese subjects in the postabsorptive state and for 12 h in obese subjects after a 3-day and 4-wk fast. In nonobese and obese subjects studied in the post-absorptive state, the leucine infusion resulted in a 150-200% rise in plasma leucine above preinfusion levels, a small decrease in plasma glucose, and unchanged levels of plasma insulin and glucagon and blood ketones. Plasma isoleucine (60-70%) and valine (35-40%) declined to a greater extent than other amino acids (P < 0.001). After 3 days and 4 wk of fasting, equimolar infusions of leucine resulted in two- to threefold greater increments in plasma leucine as compared to post-absorptive subjects, a 30-40% decline in other plasma amino acids, and a 25-30% decrease in negative nitrogen balance. Urinary excretion of 3-methylhistidine was however, unchanged. Plasma glucose which declined in 3-day fasted subjects after leucine administration, surprisingly rose by 20 mg/100 ml after 4 wk of fasting. The rise in blood glucose occurred in the absence of changes in plasma glucagon and insulin and in the face of a 15% decline in endogenous glucose production (as measured by infusion of [3-3H]glucose). On the other hand, fractional glucose utilization fell by 30% (P < 0.001), thereby accounting for hyperglycemia. The estimated metabolic clearance rate of leucine fell by 48% after 3 days of fasting whereas the plasma delivery rate of leucine was unchanged, thereby accounting for a 40% rise in plasma leucine during early starvation. After a 4-wk fast, the estimated metabolic clearance rate of leucine declined further to 59% below base line. Plasma leucine nevertheless fell to postabsorptive levels as the plasma delivery rate of leucine decreased 65% below postabsorptive values. Conclusions: (a) Infusion of exogenous leucine in prolonged fasting results in a decline in plasma levels of other amino acids, improvement in nitrogen balance and unchanged excretion of 3-methylhistidine, thus suggesting stimulation of muscle protein synthesis, (b) leucine infusion also reduces glucose production and to an even greater extent, glucose consumption, thereby raising blood glucose concentration; and (c) the rise in plasma leucine in early starvation results primarily from a decrease in leucine clearance which drops progressively during starvation.

The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model. The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma. The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization. We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.

Seven patients with juvenile-onset, insulin-dependent diabetes (aged 13 to 32 years) were continuously treated for 12 to 32 weeks while out of the hospital in their usual environment with a portable, battery-powered infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse dose increments before meals. Mean blood glucose levels (237 +/- 28 mg/dl during conventional insulin therapy) fell to 105 +/- 5 mg/dl after four weeks of pump treatment (p less than 0.01) and were maintained at 80 to 104 mg/dl as pump treatment was continued beyond eight weeks. Glycosylated hemoglobin levels (16.0 +/- 1.5 per cent before pump therapy) also fell within two weeks (p less than 0.01) reaching normal values (9.9 +/- 0.3) after eight weeks of pump therapy. Mean plasma cholesterol and triglyceride levels were elevated during conventional therapy and fell to normal after pump treatment. After the first month of pump treatment, only minor adjustments in insulin dose (less than 5 per cent of total daily dose) were made. No episode of mechanical pump failure occurred during the 1,110 patient-days of treatment. Overinsulinization and underinsulinization due to human error were relatively rare (four and six episodes, respectively) and failed to result in symptoms of hypo- or hyperglycemia. All patients performed their usual home, work or school activities during pump treatment. We conclude that normalization or near normalization of blood glucose levels can be achieved with a portable subcutaneous insulin infusion system when continuously used to treat patients with juvenile-onset, insulin-dependent diabetes outside the hospital for three to eight months.

This study was undertaken to examine glucose turnover during a 30-min recovery period following an acute bout of intensive exercise (85% VO2 max) performed to exhaustion (11.7 ± 1.4 min). Plasma glucose (basal 85 ± 2 mg/dl) rose by 10 mg/dl at exhaustion and increased further during the initial phase of recovery, reaching a peak value of 35 mg/dl above basal at 5 min of recovery. Thereafter, there was a gradual decline, but the values remained 15–20 mg/dl above basal at 30 min. The early rise in plasma glucose during recovery was due to an imbalance between glucose production and utilization caused by a more rapid decline in utilization than production. At 5 min of recovery, glucose production was fivefold greater than in the basal state and comparable to peak values observed at exhaustion, while glucose utilization was 33% lower than observed at exhaustion and only 75% higher than in the basal state. Beyond 5 min of recovery glucose utilization and production again differed in the direction of response. Glucose production fell to basal values while glucose utilization remained 70–80% above baseline. The maintenance of basal rates of glucose production and increased rates of glucose utilization occurred in a setting in which plasma insulin levels were increased by 25–50%. Plasma catechol-amines, which rose 5–10-fold during exercise, fell rapidly during the initial 3 min of recovery. We conclude that recovery from exhaustive exercise is characterized by a biphasic imbalance between glucose production and utilization in which production exceeds utilization for the initial 5 min and utilization exceeds production at 10–30 min. The hormone-substrate milieu (modest increments in plasma insulin and glucose) accompanying the changes in glucose kinetics observed beyond 5 min suggests that the recovery period from acute exercise may be characterized by an increase in peripheral sensitivity to insulin, which could provide a mechanism for facilitating muscle glycogen repletion during recovery from intensive exercise.

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.

To determine whether children with insulin-dependent diabetes mellitus (IDDM) might have exaggerated hormonal responses to hypoglycemia, the euglycemic-hypoglycemic glucose clamp procedure was used to provide a uniform hypoglycemic stimulus (plasma glucose kept at 90 mg/dL for 2 hours, then reduced to 50 to 55 mg/dL for 1 hour) in children and adults with and without IDDM. The chidren with IDDM showed an exaggerated rise in plasma epinephrine levels (625 +/- 112 pg/mL) compared with adults with IDDM (259 +/- 57 pg/mL, P less than 0.02); the same was true for children and adults without IDDM (811 +/- 100 vs 458 +/- 85 pg/mL, P less than 0.05). Among the children, the increase in epinephrine during hypoglycemia was similar in prepubertal and pubertal patients. Children with IDDM showed a greater rise in plasma norepinephrine than did adults with IDDM (P less than 0.001), and both diabetic groups failed to mount a glucagon response. Growth hormone and cortisol responses were unaffected by either childhood or diabetes. Enhanced secretion of epinephrine, induced by mild reductions in plasma glucose, may contribute to the management difficulties characteristically observed in the young patient with diabetes.

To evaluate the importance of the raised levels of growth hormone that characterize poor diabetic control, we gave growth hormone for 21 to 45 hours in the form of hourly 100-micrograms pulses to 14 diabetics being treated by insulin pump. Insulin-pump settings and meals were kept constant. Mean 24-hour levels of growth hormone (+/- S.E.M.) rose from 8 +/- 1 to 16 +/- 2 ng per milliliter--values identical to those observed in 12 other patients with poorly controlled diabetes (17 +/- 3 ng per milliliter). Plasma glucose concentrations doubled within 8 to 10 hours and remained elevated until growth hormone was discontinued (fasting glucose level rose from 86 +/- 11 to 204 +/- 17 mg per deciliter at 18 hours and to 240 +/- 20 mg per deciliter at 42 hours). The hyperglycemia was due mainly to a marked stimulation of hepatic glucose production that occurred without changes in levels of free insulin or glucagon. Levels of circulating free fatty acids, ketones, and branched-chain amino acids were also increased. The moderate elevations in growth hormone levels that occur in poorly controlled diabetes can themselves reproduce the whole spectrum of abnormal metabolic fuel concentrations that are associated with poor diabetic control, despite optimized insulin treatment. Thus, hypersecretion of growth hormone may be the cause as much as the consequence of poor diabetic control.

We evaluated insulin secretion and insulin action with the hyperglycemic (125 mg/dl above basal) and euglycemic insulin (40 mU · m2 · min−1) clamps in seven moderately obese subjects before and after a 6-wk exercise training program. Thirty-nine normalweight, age-matched subjects served as controls. Both fasting plasma insulin concentration and glucosestimulated (hyperglycemic clamp) insulin secretion were significantly (P < .001) increased in the obese subjects. After the training program fasting insulin levels decreased by 26% (P < .01). Insulin secretion in response to hyperglycemia decreased by a similar percentage (P < .01). Nonetheless, total-body glucose metabolism increased significantly (P < .05) during the hyperglycemic clamp. With the euglycemic insulin clamp, obese subjects were shown to be significantly (P < .001) insulin resistant compared with controls. The decrease in total-body glucose uptake resulted from defects in both peripheral glucose disposal and suppression of hepatic glucose production. After the 6-wk training program, insulin-mediated total-body glucose metabolism increased due to significant improvements in peripheral glucose uptake (P < .01) and more effective suppression of hepatic glucose production (P < .05). These results indicate that a moderate-intensity physical conditioning program is capable of ameliorating the insulin resistance and reducing glucose-stimulated hyperinsulinemia observed in obese subjects with normal glucose tolerance.

Excerpt Recent studies in rats indicate that somatostatin inhibits jejunal fluid secretion induced by prostaglandin E1and theophylline in vivo (1) and the effect of vasoactive intestinal polypeptid...

Continuous, low dose, insulin infusion in conscious dogs produced moderate hypoglycemia but only a transient fall in glucose production that rose towards preinfusion levels 20 to 30 min before any detectable increase in plasma counterregulatory hormones. Addition of epinephrine or glucagon to the insulin infusion prevented the fall in glucose production throughout the experiment but only partially diminished the hypoglycemic response. When hypoglycemia was prevented by a variable glucose infusion, neither epinephrine nor glucagon was able to counteract the suppressive effect of insulin on glucose output. These findings suggest that a fall in blood glucose per se may reverse insulin-induced inhibition of glucose production independent of a rise in counterregulatory hormones and that the insulin antagonist effect of counterregulatory hormones is modulated, at least in part, by blood glucose concentration.

To investigate the mechanism of growth hormone-induced hyperglycemia in diabetes, two studies were done in insulin-dependent diabetic patients receiving intensive insulin therapy with the insulin pump. First, the metabolic response to a standard breakfast following a subcutaneous insulin bolus was examined before and after 20 hourly boluses of intravenous growth hormone in eight patients. Despite unchanged insulin therapy, growth hormone administration produced a marked rise in fasting glucose concentrations (197 +/- 21 v 96 +/- 11 mg/dL), as well as increases in fasting levels of free fatty acids and branched chain amino acids. Nevertheless, postprandial blood glucose increments were only slightly greater after growth hormone (36 +/- 14 v 20 +/- 12 mgdL). Moreover, the increased levels of other insulin-sensitive fuels induced by growth hormone fell to normal following the meal. In a second study, six patients received a low-dose insulin clamp (designed to reproduce the mean postprandial concentrations of glucose and insulin observed in the meal study) before and after growth hormone administration. Despite endogenous glucose overproduction after growth hormone, modest elevations in free insulin (40 to 50 microU/mL) were sufficient to suppress glucose production to an extent comparable to the control day (from 2.8 +/- 0.2 to 0.6 +/- 0.3 mg/kg min after growth hormone v 1.6 +/- 0.1 to 0.4 +/- 0.2 mg/kg min on the control day). However, the normal stimulation of glucose uptake by insulin was abolished by growth hormone. We conclude that in diabetic patients growth hormone-stimulated hepatic glucose overproduction (and the increases in other insulin-sensitive fuels) can be relatively easily overcome with extra insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that variations in rate of glucose fall influence counterregulatory hormone responses to hypoglycemia, we have modified the glucose-clamp technique to provide a reproducible hypoglycemic stimulus in normal and type I diabetic subjects that varied only in the rate of glucose fall. Responsive elevations in plasma epinephrine and norepinephrine and in growth hormone, glucagon, and cortisol were not significantly affected by a ninefold change in the rate at which plasma glucose was lowered from 83 ± 1 to 50 ± 1 mg/dl in normal subjects. Similarly, wide variation in the rate of fall produced no substantive differences in counterregulatory hormone responses to hypoglycemia in diabetic subjects. The plasma glucose threshold at which epinephrine release began, determined from the slow-fall studies, was 63 ± 3 mg/dl in normal subjects but exhibited a wide range (48-74 mg/dl). Similar values were found in the diabetics. Thresholds for growth hormone, cortisol, and glucagon were slightly lower, ranging from 45 to 68 mg/dl in the normals. Our data suggest that counterregulatory hormone responses to hypoglycemia are triggered by the glucose level per se and not by its rate of fall. Furthermore, individual differences in glucose thresholds for epinephrine release may contribute to variations in the glucose level associated with hypoglycemic symptoms.

Hypocaloric diets cause a fall in resting metabolic rate that interferes with weight loss. To evaluate the mechanisms underlying this phenomenon, resting metabolic rate was measured sequentially in six healthy obese women on a weight maintenance diet (more than 2,300 kilocalories), after 15 days of an 800 kilocalories carbohydrate-free diet, and after isocaloric sucrose replacement for an additional 15 days. The carbohydrate-free diet produced a 21 percent decline in resting metabolic rate (p less than 0.005) as well as a decrease in circulating triiodothyronine (41 percent, p less than 0.02) and insulin (38 percent, p less than 0.005) concentrations. Plasma norepinephrine levels also tended to decline (10 percent, 0.05 greater than p less than 0.1). However, when sucrose was substituted, resting metabolic rate rose toward baseline values even though total caloric intake was unchanged and weight loss continued. The sucrose-induced rise in resting metabolic rate was accompanied by a rise in serum triiodothyronine values, but not plasma insulin or norepinephrine concentrations. Throughout, changes in resting metabolic rate correlated with changes in serum triiodothyronine levels (r = 0.701, p less than 0.01). In four obese women, a hypocaloric sucrose diet was given at the outset for 15 days. The fall in both resting metabolic rate and triiodothyronine concentration was markedly reduced as compared with values during the carbohydrate-free diet. It is concluded that carbohydrate restriction plays an important role in mediating the fall in resting metabolic rate during hypocaloric feeding. This effect may, at least in part, be related to changes in circulating triiodothyronine levels. Incorporation of carbohydrate in diet regimens may, therefore, minimize the thermic adaptation to weight loss.

To ascertain whether small elevations of epinephrine alter glucose tolerance, we infused epinephrine or saline into seven healthy volunteers for 5 hours. Two hours after starting the infusions, subjects ingested 100 g of glucose. Plasma epinephrine (basal 23 +/- 4 pg/mL) rose during epinephrine infusion to levels (75 to 80 pg/mL) similar to those observed in nine outpatients presenting with mild viral illnesses (66 +/- 8 pg/mL). Although epinephrine produced only a small (5 mg/dL) increase n plasma glucose before glucose ingestion, after oral glucose the levels of glucose increased by 30 to 60 mg/dL above saline control values (163 +/- 14 mg/dL versus 108 +/- 15 at 2 h, p0.005). This diabetogenic effect occurred despite two-fold higher insulin levels and normal suppression of plasma glucagon. We conclude that small physiologic increments of epinephrine, which cause minimal changes in fasting plasma glucose, produce a marked reduction in glucose tolerance. Our data suggest marked sensitivity to the insulin antagonistic effects of epinephrine and may provide a mechanism for stress-induced glucose intolerance.

Glucagon was infused to maintain plasma concentrations three to six times the basal level (300 to 600 pg per milliliter) into 16 normal and seven non-diabetic obese subjects. Hyperglucagonemia caused only a transient rise of 5 to 10 mg per 100 ml in basal glucose levels and had no effect on oral glucose tolerance or plasma insulin. In three patients with adult and two with juvenile-onset diabetes on maintenance insulin, hyperglucagonemia maintained for two to four days caused no change in plasma glucose of ketone concentration. In contrast, in nine insulin-withdrawn patients the glycemic response to hyperglucagonemia was five to 15 times greater (P less then 0.05) than in normal controls. Hyperglucagonemia does not cause glucose intolerance in normal subjects or bring about deterioration of diabetic control when insulin is available. Glucagon in the insulin-deprived patient can worsen the diabetic state. These findings suggest the primary role of insulin deficiency in the diabetogenic action of glucagon.

The disposal of ingested glucose was quantitated in dogs during individual and combined infusion of glucagon, epinephrine, and cortisol. Initial splanchnic extraction of ingested glucose, endogenous glucose production, and glucose uptake were quantitated using a double-tracer technique. Glucagon or cortisol individually had no effect on the kinetic response to glucose ingestion, whereas epinephrine increased glucose levels by 50–100 mg/dl. Epinephrine caused a reduced suppression of glucose production and a marked inhibition of the initial rise in glucose uptake. Initial splanchnic glucose extraction, plasma insulin, and glucagon were not significantly altered. The addition of glucagon and cortisol to epinephrine did not accentuate hyperglycemia, except after 150 min when glucose production increased. We conclude that a) epinephrine produces glucose intolerance when infused individually, b) this effect is primarily dependent on inhibition of glucose uptake and, to a lesser extent, on a reduction in suppression of endogenous glucose output, and c) addition of glucagon and cortisol has only a minor effect on epinephrine-induced changes in glucose disposal. Our data suggest an important role of epinephrine in stress-induced glucose intolerance.

In a group of 55 insulin-dependent diabetic patients with early diabetic retinopathy, microaneurysm counts from fluorescein angiograms were related to the level and severity of retinopathy derived by grading eight standard stereo color photographs as used in the Early Treatment of Retinopathy Study (ETDRS). All patients were studied at 0, 8, and 24 months. Significant correlations were present between both "definite" and "possible" microaneurysm count and retinopathy level of the eye studied and the mean retinopathy level of the two eyes, at all three time intervals, (P less than 0.05-less than 0.001). Similarly, there were significant correlations between microaneurysm counts and severity of the following lesions: microaneurysms and haemorrhages, cotton-wool spots (P less than 0.05-less than 0.001); to a lesser degree, severity of hard exudates (P less than 0.1-less than 0.001) and intraretinal microvascular abnormalities (P not significant-less than 0.001). There was no correlation between microaneurysm count and venous abnormalities (as at no time were there more than 11 eyes with any venous abnormality). We conclude that microaneurysm counts from fluorescein angiograms accurately reflect the severity of important signs in early diabetic retinopathy.

Counterregulatory hormone responses to hypoglycemia were examined in six healthy controls and in six patients with type I diabetes before and after 4 to 8 months of insulin pump treatment. The insulin clamp technique was used to provide an identical hypoglycemic stimulus (about 50 mg/dL) in each study group. Before pump treatment, the release of counterregulatory hormones (except glucagon) during the hypoglycemic period was not significantly different in diabetics from that in normal controls. However, when values before and after pump treatment in diabetics were compared, there were significant reductions in epinephrine (304 +/- 70 and 127 +/- 43 pg/mL; p less than 0.01), growth hormone (45 +/- 12 and 18 +/- 5 ng/mL; p less than 0.05), and cortisol (20 +/- 3 and 10 +/- 2 micrograms/dL; p less than 0.01) levels during hypoglycemia. Defective glucagon release during hypoglycemia in the diabetics was not corrected by pump treatment. Intensive insulin treatment of patients with type I diabetes causes a generalized reduction in counterregulatory hormone release after a moderate fall in blood glucose levels. This reduction may impair glucose counterregulation and diminish perception of hypoglycemia, thereby increasing the risk of hypoglycemic episodes.

We measured 14 C-alanine conversion to 14 C-glucose (an index of gluconeogenesis) and glucose production in six healthy volunteers during low-dose insulin infusion (0.3 mU/kg · min for four hours). Insulin rose from 7 ± 2 to 20 ± 2 μU/mL, and plasma glucose fell to a plateau of 65 to 70 mg/dL after 60 minutes. Glucagon and catecholamines increased after 60 minutes, whereas C-peptide decreased immediately. Glucose production decreased transiently by 43% and then returned to baseline after 45 minutes. In contrast, 14 C-alanine conversion to 14 C-glucose was unchanged for 120 minutes, but then rose twofold above baseline by 240 minutes. Our data suggest that early recovery of glucose production during mild hyperinsulinemia occurs independent of changes in gluconeogenesis. However, gluconeogenesis plays an increasingly more important role in maintaining glucose production when mild hypoglycemia is prolonged.

Isolated case reports have suggested short-term beneficial effects of subcutaneous insulin infusion pump treatment on background and proliferative diabetic retinopathy. To evaluate this question further, 30 eyes of 15 Type I diabetic patients were evaluated prospectively before and after 11--23 months (mean 18.1 months) of pump treatment. In each patient plasma glucose and total glycosylated hemoglobin fell to normal or near normal levels. The ten eyes without diabetic retinopathy at entry remained without. Four of 20 eyes with diabetic retinopathy at entry advanced by modified Early Treatment Diabetic Retinopathy Study (ETDRS) classification, including one eye that progressed from background to proliferative diabetic retinopathy. No eyes with diabetic retinopathy improved their modified ETDRS classification. One eye progressed to blindness; no other eye lost vision. Six eyes had laser treatment prior to insulin pump treatment; four of these and two more required laser during pump treatment. Two eyes had vitreous hemorrhages prior to pump treatment; one of these and four others hemorrhaged during pump treatment. No eyes with diabetic retinopathy showed regression of microvascular changes. The data suggest prolonged restoration of near normal glucose metabolism with the insulin pump does not reverse established diabetic retinopathy. Whether pump treatment slows the progression, or prevents the development, of diabetic retinopathy remains to be established.

Although patients with thyrotoxicosis improve clinically after treatment with beta-adrenergic blocking drugs, it has never been established whether the hypermetabolism and body protein wasting caused by thyroid hormone excess are actually mediated by adrenergic mechanisms. To evaluate this issue, we measured basal energy expenditure, epinephrine-stimulated calorigenesis, and leucine kinetics (an index of body protein catabolism) in six normal volunteers before and after triiodothyronine (T3) administration (150 micrograms/d for 1 week). Serum T3 rose nearly threefold (P less than 0.001) during T3 administration, producing significant increases in basal metabolic rate (21%, P less than 0.001), nitrogen excretion (45%, P less than 0.001), and leucine flux (45%, P less than 0.01). In response to epinephrine infusion, the absolute rise in metabolic rate above basal was 57% greater in the thyrotoxic condition (P less than 0.02). Although beta-adrenergic blockade with intravenous propranolol totally abolished the calorigenic response to epinephrine, it had no detectable effect on either the accelerated basal metabolic rate or the augmented body protein catabolism caused by thyroid horomone excess. Our data suggest that in the basal, resting state, the increased metabolic rate and accelerated protein breakdown caused by thyroid hormone are not adrenergically mediated. However, under nonbasal conditions (when sympathetic activity is stimulated), enhanced responsiveness to catecholamine calorigenesis may exaggerate the hypermetabolic state and thereby contribute to weight loss and other clinical manifestations of thyrotoxicosis. This mechanism may explain the clinical efficacy of beta-adrenergic blocking agents in the treatment of thyrotoxicosis.

Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice.

Although impaired growth is a well-recognized complication of uncontrolled diabetes, it has not been established whether less severe metabolic derangements commonly seen with conventional treatment adversely affected growth potential. To examine this question, growth velocity was measured in nine type 1 diabetic patients (age 14 +/- 3 years) before and after six months of intensive insulin treatment either with the insulin pump or with multiple injections, which lowered mean plasma glucose concentration from 270 +/- 96 to 105 +/- 55 mg/dl and total glycosylated hemoglobin from 12.4 +/- 3.0 to 8.4 +/- 1.5% (mean +/- SD). During conventional treatment, growth velocity (5.3 +/- 2.2 cm/year) was within the range of normal despite elevations in plasma glucose concentrations. However, growth velocity increased sharply during intensive treatment (to 9.4 +/- 3.9 cm/year, P less than 0.005), reaching values in excess of normal in seven patients. The increase in growth velocity observed during intensive treatment was associated with a twofold rise in plasma somatomedin-C values. Skeletal maturation, previously normal or slightly delayed, did not advance excessively. These data indicate that the metabolic changes accompanying intensive treatment may enhance growth in diabetic children, even in those with apparently normal growth velocity during conventional therapy.

The metabolic response to acute exercise in diabetics is largely determined by the availability of insulin. In nonketotic, insulin-dependent diabetics, acute exercise lowers the level of plasma glucose, whereas in insulin-deficient, ketotic patients, blood glucose may increase during exercise. Exercise accelerates insulin absorption from the exercising limb. Thus, by injecting insulin into a nonexercising area (eg, into the abdomen before leg exercise), the degree of exercise-induced hypoglycemia can be reduced in diabetic patients. Also, elevation in the level of antiinsulin hormones caused by exercise is exaggerated in diabetics if insulin treatment is less than optimal. This abnormal hormonal response may be restored to normal by improved methods of insulin delivery. In normal subjects, regular exercise or training results in enhanced body sensitivity to insulin. This rise in sensitivity may be mediated by augmented insulin binding to receptors. Furthermore, regular exercise may decrease levels of serum triglycerides and low-density lipoprotein cholesterol and increase those of high-density lipoprotein cholesterol. These beneficial effects of training on carbohydrate and lipid metabolism observed in normal subjects may extend to diabetic patients as well.

To evaluate the effect of caloric restriction and dietary composition on circulating T3 and rT3 obese subjects were studied after 7-18 days of total fasting and while on randomized hypocaloric diets (800 kcal) in which carbohydrate content was varied to provide from 0 to 100% calories. As anticipated, total fasting resulted in a 53% reduction in serum T3 in association with reciprocal 58% increase in rT3. Subjects receiving the no-carbohydrate hypocaloric diets for two weeks demonstrated a similar 47% decline in serum T3 but there was no significant change in rT3 with time. In contrast, the same subjects receiving isocaloric diets containing at least 50 g of carbohydrate showed no significant changes in either T3 or rT3 concentration. The decline in serum T3 during the no-carbohydrate diet correlated significantly with blood glucose and ketones but there was no correlation with insulin or glucagon. We conclude that dietary carbohydrate is an important regulatory factor in T3 production in man. In contrast, rT3 concentration is not significantly affected by changes in dietary carbohydrate. Our data suggest that the rise in serum rT3 during starvation may be related to more severe caloric restriction than that caused by the 800 kcal diet.

To evaluate the mechanism underlying raised growth hormone levels in diabetes, we compared the response to growth hormone–releasing factor (GRF) in type I diabetic and healthy control subjects. In 12 poorly controlled diabetic subjects (fasting plasma glucose 276 ± 27 mg/dl) basal serum growth hormone levels were elevated by 200–300% (P < 0.02), yet the incremental increase in growth hormone after GRF injection was no greater than in control subjects. Furthermore, five additional diabetic subjects with normal growth hormone levels after long-term insulin pump treatment also showed an identical response to GRF. Thus, raised basal growth hormone levels in diabetes and the fall that follows intensive insulin treatment may reflect changes in hypothalamic regulation of, rather than in pituitary responsiveness to, GRF. However, when five normal subjects were restudied during glucose infusion, even quite modest hyperglycemie (plasma glucose ∼150 mg/dl) caused marked suppression of the response to GRF (P < 0.005). Thus, the “normal” response to GRF in poorly controlled diabetes is actually inappropriate. Failure of the pituitary to suppress in response to hyperglycemie in diabetes implies a second abnormality that may further aggravate disordered growth hormone secretion.

Recent studies have suggested that insulin action is reduced during puberty in normal children. To determine whether such resistance leads to excessive insulin secretion, we used the hyperglycemic clamp technique to produce a standard hyperglycemic stimulus (125 mg/dl above fasting levels for 120 minutes) in 9 preadolescent and 14 adolescent healthy children and in 14 normal adults. Fasting plasma insulin and C-peptide concentrations were higher in adolescents than in preadolescents and adults (p less than or equal to 0.02). Despite identical glucose increments during the glucose clamp procedure, both first- and second-phase plasma insulin and C-peptide responses were also markedly greater in adolescents than in preadolescents or adults (p less than 0.01 vs. other groups). Despite sharply increased insulin responses in adolescents, the amount of exogenous glucose required to maintain hyperglycemia was similar in all three groups. Insulin responses in the children were directly correlated with fasting plasma levels of insulin-like growth factor I (r = 0.60 to 0.70, p less than 0.01). We conclude that glucose-stimulated insulin secretion is normally increased during puberty, a response that may compensate for puberty-induced defects in insulin sensitivity.

Excerpt The central role of insulin in the pathogenesis of diabetes has been recognized since the classical experiments of Banting and Best in 1921. Subsequent studies, however, have clearly shown ...

To examine the effects of prolonged infusions of somatostatin in maturity-onset diabetes, we administered five-hour infusions to eight patients. This infusion resulted in a 45 to 55 per cent decline in plasma insulin and glucagon. Plasma glucose initially fell by 20 to 25 mg per 100 ml, but later rose despite continuing hypoglucagonemia. After five hours, plasma glucose concentration was 40 to 50 mg per 100 ml higher than that observed with saline infusion (P less than 0.001). The degree of hyperglycemia and plasma insulin levels correlated inversely at completion of the infusion (P less than 0.01). In addition, somatostatin resulted in a fivefold increase in beta-hydroxybutyrate and a 40 to 45 per cent rise in branched-chain amino acids (P less than 0.005). Our findings suggest that glucagon is not essential for the development and maintenance of fasting hyperglycemia. Furthermore, accentuation by somatostatin of hyperglycemia, hyperketonemia and hyperaminoacidemia in maturity-onset diabetes argues against its use in patients with residual insulin secretion.

We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.

Publisher Summary This chapter discusses hormonal interactions in the regulation of blood glucose. The regulation of the blood glucose concentration is a well-recognized function of the endocrine system. The efficacy of the various control mechanisms is reflected by the very limited excursions in blood glucose observed in normal humans. In normal man, the bursts of glucagon secretion precipitated by feeding pure protein prevent the inhibition in glucose production and the hypoglycemia that would otherwise accompany protein-stimulated insulin secretion. In contrast, sustained hyperglucagonemia fails to cause glucose intolerance or worsening of preexisting diabetes so long as endogenous or exogenous insulin is available. In the case of insulin, the down regulation of the insulin receptor has been observed to occur in hyperinsulinemic states. The glucagon infusion fails to alter specific binding of insulin or growth hormone, indicating the specificity of the effect of hyperglucagonemia on glucagon binding. Glucagon-induced hyperglycemia can, however, be observed either in circumstances of absolute insulin deficiency or when tissue sensitivity to this hormone is increased. The synergistic nature of these hormone–hormone interactions with respect to raising circulating plasma glucose levels may constitute the mechanism for stress hyperglycemia.

Techniques have been developed for examining the binding of insulin to its target cells and for evaluating the in vivo action of insulin, rekindling interest in the possible role of insulin resistance in adult-onset diabetes. A host of new data have accumulated regarding the contribution of glucagon to the syndrome.

The effects of continuous infusions of insulin in physiologic doses on glucose kinetics and circulating counterregulatory hormones (epinephrine, norepinephrine, glucagon, cortisol, and growth hormone) were determined in normal subjects and diabetics. The normals received insulin at two dose levels (0.4 and 0.25 mU/kg per min) and the diabetics received the higher dose (0.4 mU/kg per min) only. In all three groups of studies, continuous infusion of insulin resulted in an initial decline in plasma glucose followed by stabilization after 60-180 min. In the normal subjects, with the higher insulin dose there was a fivefold rise in plasma insulin. Plasma glucose fell at a rate of 0.73+/-0.12 mg/min for 45 min and then stabilized at 55+/-3 mg/dl after 60 min. The initial decline in plasma glucose was a result of a rapid, 27% fall in glucose output and a 33% rise in glucose uptake. Subsequent stabilization was a result of a return of glucose output and uptake to basal levels. The rebound increment in glucose output was significant (P < 0.05) by 30 min after initiation of the insulin infusion and preceded, by 30-45 min, a significant rise in circulating counterregulatory hormones. With the lower insulin infusion dose, plasma insulin rose two- to threefold, plasma glucose initially fell at a rate of 0.37+/-0.04 mg/min for 75 min and stabilized at 67+/-3 mg/dl after 75 min. The changes in plasma glucose were entirely a result of a fall in glucose output and subsequent return to base line, whereas glucose uptake remained unchanged. Plasma levels of counterregulatory hormones showed no change from basal throughout the insulin infusion. In the diabetic group (plasma glucose levels 227+/-7 mg/dl in the basal state), the initial rate of decline in plasma glucose (1.01+/-0.15 mg/dl) and the plateau concentration of plasma glucose (59+/-5 mg/dl) were comparable to controls receiving the same insulin dose. However, the initial fall in plasma glucose was almost entirely a result of suppression of glucose output, which showed a twofold greater decline (60+/-6%) than in controls (27+/-5%, P

Serum stimulates the production of prostaglandins by transformed mouse fibroblasts. Hydrocortisone (cortisol) inhibits this stimulation. The half-maximal inhibition occurs at 6x10-9 M. Studies with cells labeled with [3H]arachidonic acid in their lipids show that the stimulation by serum results in the release of arachidonic acid from the cellular lipids, mostly phospholipids. Hydrocortisone inhibits this release but does not inhibit the production of prostaglandins from exogenously supplied arachidonic acid. This inhibition of arachidonic acid release from phospholipids may be the mechanism for the anti-inflammatory action of corticosteroids.

Elevations of plasma epinephrine comparable to those observed in physiologic stress, cause a sustained 20--35 mg/dl elevation of plasma glucose in normal humans. This hyperglycemic action is due to a transient increase in hepatic glucose output as well as a reduction in the rate of glucose disposal which accounts for the persistence of hyperglycemia. The latter results from epinephrine-induced suppression of endogenous insulin secretion and, more importantly from a direct inhibitory effect on insulin-stimulated glucose utilization. In diabetes, the hyperglycemic effect of epinephrine is markedly accentuated. The enhanced rise in plasma glucose is due to an alternation in response of the liver to epinephrine. Despite infusion of insulin, epinephrine produces a sustained rather than transient elevation in hepatic glucose output in diabetic subjects. In contrast, the inhibitory effect of epinephrine on glucose utilization is unchanged by the diabetic state. In normal subjects, the hyperglycemic action of epinephrine is enhanced by simultaneous elevations of glucagon and cortisol. The former increases the magnitude, but not the duration, of the rise in hepatic glucose output induced by epinephrine. The latter, converts epinephrine's hepatic action from a transient to a sustained response. Our data thus suggest that marked hyperglycemia in normal subjects requires the concomitant elevation of multiple anti-insulin hormones, whereas such changes may occur in diabetes if any member of this group of hormones is increased. These findings may account for long-standing clinical observation that stress adversely affects blood glucose regulation to a much greater extent in diabetics as compared to normal subjects.

Plasma pancreatic glucagon concentrations were determined in 18 cirrhotic patients in the basal state and after the infusion of alanine, 0.15 g per kilogram of body weight in two to four minutes. In the cirrhotic patients, basal concentrations of glucagon were two to five times normal, and the glucagon response to alanine administration was three to 13 times greater than in 11 control subjects. Glucagon levels were highest in four patients with portacaval anastomosis, were less elevated in 10 cirrhotic patients with spontaneous portal-systemic shunting and were normal in four cirrhotic patients without portal-systemic shunting. Glucagon concentrations correlated closely in all three groups with the degree of ammonia intolerance. Elevations of plasma tyrosine, methionine and phenylalanine were observed in the cirrhotic group, whereas the levels of branched chain amino acids (valine, leucine and isoleucine) were reduced. Hyperglucagonemia may contribute to the glucose intolerance observed in cirrho...