Glucagon Excess Research Articles

In vivo assessment of the metabolic alterations in glucagonoma syndrome

Stable-isotope methodology and indirect calorimetry were used to evaluate metabolic abnormalities in a patient with glucagonoma syndrome manifested by 17% body weight loss, hypoaminoacidemia, and hyperglycemia. Energy expenditure (26 kcal/kg) was the same as that predicted by the Harris-Benedict equation. The rate of appearance (Ra) of intracellular leucine (2.70 μmol/kg/min), an index of protein breakdown, was normal, although the percentage of leucine flux oxidized (31%), an index of amino acid catabolism, was 50% greater than the normal mean value. Glucose Ra in plasma (12.9 μmol/kg/min), representing hepatic glucose production, and glycerol Ra in plasma (3.04 μmol/kg/min), a measurement of whole-body lipolysis, were 15% and 25% greater, respectively, than mean values found in normal volunteers. These results suggest that long-term alterations in energy, leucine, glucose, and lipid metabolism in patients with glucagonoma are minimal. However, small long-term metabolic alterations caused by glucagon excess, in conjunction with chronic negative energy balance, could be responsible for the weight loss, hypoaminoacidemia, and hyperglycemia observed in this patient population.

Morphological changes in the human endocrine pancreas induced by chronic excess of endogenous glucagon

The non-tumoral endocrine pancreas from a patient with elevated plasma levels of glucagon due to a malignant glucagonoma was studied immunocytochemically, ultrastructurally and morphometrically. Compared with normal pancreatic islets from control subjects, those of the pancreas from the patient with a glucagonoma showed an almost complete disappearance of A cells, a decrease in immunoreactive insulin in B cells associated with cytological features indicating enhanced synthesis and secretion of this hormone, and an increase in immunoreactive somatostatin and pancreatic polypeptide (PP) accompanied by unusually high numbers of D and PP cells. In addition, numerous B cells were found outside the islets, either forming micro-islets or scattered in the exocrine tissue (nesidioblastosis). The possible mechanisms involved in determining the changes in the secretory activity of B cells and the alterations in the cell composition of the islets are discussed.

Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic Alpha cells

An excessive glucagon secretion to intravenous arginine infusion was found in obese hyperinsulinaemic patients with glucose intolerance. This study was designed to determine whether the glucagon hyperresponsiveness to arginine in these patients would improve by insulin infused at a high enough dose to overcome insulin resistance. By infusing high dose insulin during arginine infusion, the previously exaggerated glucagon response to arginine could be normalized. To normalize the abnormal glucagon response, insulin doses of 4.2 +/- 0.7 and 3.8 +/- 0.5 IU were required during arginine infusion in obese hyperinsulinaemic patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus, respectively. This achieved plasma peak insulin levels 3 to 4 times higher than those observed in non-obese healthy subjects. Furthermore, we clarified whether or not the effect of normalizing insulin action and/or glycaemic excursions contributed to normalizing the exaggerated glucagon response to arginine in these patients. Blood glucose was clamped while high dose insulin was infused at the same levels as observed during the arginine infusion test with no insulin infusion. As a result, normalization of the exaggerated plasma glucagon response was achieved, whether hyperglycaemia existed or not. These results clearly demonstrate that, similar to non-obese hypoinsulinaemic Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, the exaggerated Alpha-cell response to arginine infusion in obese hyperinsulinaemic patients with glucose intolerance is secondary to the reduction of insulin action on the pancreatic Alpha cell, and that the expression of insulin action plays an important part in normalizing these abnormalities.

Effect of hyperglucagonemia on hepatic glycogenolysis and gluconeogenesis after a prolonged fast

The aim of this study was to determine if glucagon can stimulate hepatic glucose production in prolonged fasted (7 days) animals. Two protocols were used; in one ("hormone replacement"; n = 4), intraportal basal replacement amounts of insulin and glucagon were given during a somatostatin infusion, whereas, in the other ("glucagon excess"; n = 5) basal insulin was given along with somatostatin and excess glucagon. Plasma insulin levels were similar and constant throughout both protocols (6 +/- 1 microU/ml). The plasma glucagon was basal in the hormone-replacement protocol (49 +/- 9 pg/ml) but rose from 46 +/- 7 to 448 +/- 35 pg/ml (P less than 0.05) in the other protocol. Plasma glucose levels and the rates of glucose production were unchanged during hormone replacement but rose from 100 +/- 5 to 199 +/- 28 mg/dl and from 1.5 +/- 0.1 to a peak of 5.6 +/- 0.2 mg.kg-1.min-1 at 15 min (P less than 0.05) and an eventual plateau of 2.7 +/- 0.2 mg.kg-1.min-1 (P less than 0.05) in response to glucagon excess. Because of the sluggish increase in gluconeogenic parameters, the early marked rise in glucose production was attributable to increased glycogenolysis. Eventually, however, the gluconeogenic rate rose, with net hepatic uptake of alanine increasing 50% and fractional alanine extraction doubling. Gluconeogenic efficiency and conversion increased in response to glucagon excess by 0.30 +/- 0.05 and 159 +/- 48%, respectively, although it should be noted that these parameters rose 0.15 +/- 0.06 and 150 +/- 49% in the hormone-replacement protocol. In conclusion, even after a prolonged fast physiological glucagon can cause hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma amino acid kinetics during acute states of glucagon deficiency and excess in healthy adults

The effects of glucagon deficiency and excess on plasma leucine, lysine, and alanine were examined in six healthy young adult men, with primed continuous infusions of L-[1-13C]- or L-[5,5,5-2H3]leucine, L-[alpha-15N]-lysine, and L-[3-13C]alanine for 150 min before and during 210 min of either a glucagon-deficient euglycemic state (experiment 1), a basal glucagon state (experiment 2), or a glucagon-excess state (experiment 3). Steady-state plasma hormone levels were achieved by infusion of somatostatin (250 micrograms/h) and insulin (0.07 mU.kg-1.min-1), without (experiment 1) or with an infusion of glucagon at 0.7 ng.kg-1.min-1 (experiment 2) or 2.5 ng.kg-1.min-1 (experiment 3). Plasma branched-chain amino acid (AA) concentrations did not change with altered glucagon status, whereas significant differences were observed for plasma lysine, alanine, glycine, serine, threonine, proline, tyrosine, citrulline, and ornithine levels (0.05 greater than P greater than 0.001). Plasma leucine, lysine, and alanine fluxes and the rate of de novo alanine synthesis showed no significant changes with either glucagon deficiency or excess. These findings lead to the conclusion that glucagon-induced alterations in plasma AA profiles are not due to changes in the rate of appearance of AA from peripheral tissues but rather a consequence of changes in the fate of AA within the splanchnic region.

Glucagon and glucose tolerance in liver cirrhosis.

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

Binding and degradation of 125I-glucagon by highly purified rat liver plasma membranes

125I-glucagon binding and degradation were studied in highly purified plasma membranes from rat livers. Specific 125I-glucagon binding increased rapidly with time at 30°C and reached a maximum between 30 and 120 min. At 120 min the labelled material present in the supernatants from incubation mixtures had extensively lost its ability to rebind to fresh membranes whatever the glucagon concentration. This impairment was not due to the release of a degradative activity into the incubation mixture, suggesting a membrane-mediated process. The presence of proteinase inhibitors (bacitracin/aprotinin) resulted both in an increase in specific 125I-glucagon binding to membranes and an improvement in the ability of the labelled material from the supernatant to rebind to fresh membranes. When analysed by Bio-Gel P-10 chromatography the loss in the ability of the labelled material in the supernatants to rebind to fresh membranes correlated with a decrease in the labelled material which eluted as 125I-glucagon from the column. Chromatographic analysis overestimated 125I-glucagon when compared to the radioreceptor assay. The labelled material extracted from membranes by Triton X-100 solubilization or dissociated from membranes after exposure to an excess of unlabelled glucagon mainly eluted as 125I-glucagon. However, a significant amount (20–30%) of the labelled material eluted in the low molecular weight region.

Mechanism of the blunted glucagon response to insulin-induced hypoglycemia in diabetics

It has been widely reported that dysfunctions of pancreatic A-cell occur in diabetics. Since these pancreatic A-cell dysfunctions are not normalized by conventional insulin injection treatment, they were thought to be a primary defect of diabetes mellitus. Recently it was found that paradoxic glucagon secretion to oral glucose and excessive glucagon response to i.v. arginine could be perfectly normalized if strict blood glucose regulations were achieved with appropriate insulin treatment. However, there has been no report on the perfect normalization of glucagon secretion in response to insulin-induced hypoglycemia in diabetics. In this report, to elucidate the precise significance of A-cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations and the importance of intact autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. In experiments on hypoglycemia-induced glucagon secretion in diabetics, 0.2 to 0.3 U/kg of regular insulin injection were usually employed to overcome the hyperglycemia and insulin resistance. However, hyperinsulinemia has been demonstrated to suppress A-cell function in experiments using the euglycemic clamp technique. Therefore, the effect of plasma insulin concentrations after insulin injections was first studied in 7 healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. In this experiment with 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to that with 0.1 U/kg of insulin by using glucose clamp technique with artificial endocrine pancreas. The plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin. From these experiments, it was concluded that not only hypoglycemic stimuli but also plasma insulin concentrations are important factors for demonstrating significant glucagon secretion in response to insulin-induced hypoglycemia. Second, the effects of strict glycemic control and autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. Regular insulin at a dose of 0.1 U/kg was injected in an i.v. bolus form into 21 insulin-dependent (IDDM) and 22 noninsulin-dependent (NIDDM) diabetics before and one to three months after strict glycemic control with multiple insulin injection therapy or continuous subcutaneous insulin infusion therapy. To reduce fasting blood glucose level and to obtain the same hypoglycemic stimuli, overnight insulin infusion at a basal dose was undertaken in IDDM who showed hyperglycemia before strict glycemic regulations.(ABSTRACT TRUNCATED AT 400 WORDS)

298 ALTERED PERINATAL GLUCAGON-PHOSPHOENOLPYRUVATE CAR BOXYKINASE (PEPCK) RELATIONS IN THE GROWTH RETARDED RAT

Since diminished gluconeogenic enzyme activity is a cause of hypoglycemia in the growth retarded neonate, we characterized the relation of glucagon, an inducer of gluconeogenic enzymes, to the appearance of hepatic PEPCK, a key gluconeogenic enzyme. Fetal and neonatal rat pups were rendered growth retarded by maternal bilateral uterine artery ligation (L) on day 18.5 (term 21.5). Pups of L, sham (S), and nonoperated (N) mothers had significantly different body and placental mass on days 19.5 - 21.5 (L < S < N). Glucose availability was limited in L on day 19.5 since fetal glucose (L 37±5; S 65±6; N 72±5 mg/dl; p < .01) and fetal/maternal glucose ratios differed (L < S < N). Despite this, glucagon and PEPCK were not stimulated in L fetuses. Glucagon (516-552 pg/ml), insulin, and hepatic PEPCK (.078-.096 μmoles PEP/g liver/min) did not differ between L, S, and N fetuses. At birth, L pups had significantly greater glucagon surge than S and N, but did not increase PEPCK as S and N did (120 min: L .147±.019; S .223±.031; N .201±.019 μmoles PEP/g liver/min; p < .01). Exogenous glucagon induced PEPCK equivalently in L, S, and N (day 20.5) fetuses and newborns but not in day 19.5 fetuses. Little PEPCK induction occurs during late fetal life, and exogenous glucagon can induce PEPCK on day 20.5 and at birth. L newborns, despite excessive glucagon surge, cannot induce PEPCK due to either limited secretory capability or relative insensitivity to glucagon.

Insulin and glucagon response of the diabetic Chinese hamster in the Asahikawa colony

The relationship between pancreatic hormone content and pattern of hormone release has not been completely elucidated because of heterogeneity in diabetes. Accordingly, this study was performed to establish the relationship, using spontaneously diabetic Chinese hamsters in the Asahikawa colony, a newly discovered experimental model resembling insulin-deficient diabetes in humans. As a result of investigations of insulin and glucagon responses to glucose or arginine in vivo and in vitro using isolated islets obtained by the collagenase procedure, a decreased insulin response and paradoxical glucagon response to glucose, and an excessive glucagon response to arginine were found in the diabetic animals. While the yield of isolated islets tended to decrease, a decreased pancreatic insulin content and increased pancreatic glucagon content were found as the diabetic state advanced. It may be suggested, therefore, that the relationship between pancreatic hormone content and pattern of hormone release in diabetic animals in the Asahikawa colony is based on the disruption of islets, disruption or dysfunction of B-cells and hyperplasia or hypertrophy of A-cells by some cause genetically determined.

Effects of glucagon on plasma amino acids.

The effects of glucagon deficiency and excess on plasma concentrations of 21 amino acids were studied in six normal human subjects for 8 h. During glucagon deficiency, produced by intravenous infusion of somatostatin (0.5 mg/h) and insulin (5 mU/kg per h), amino acid concentration (sum of 21 amino acids) rose from 2,607 +/- 76 to 2,922 +/- 133 microM after 4 h (P less than 0.025). The largest increases occurred in lysine (+26%), glycine (+24%), alanine (+23%), and arginine (+23%) concentrations. During glucagon excess produced by intravenous infusion of somatostatin (0.5 mg/h), insulin (5 mU/kg per h), and glucagon (60 ng/kg per h), amino acid concentration decreased from 2,774 +/- 166 to 2,388 +/- 102 microM at 8 h (P less than 0.01). The largest decreases occurred in citrulline (-37%), proline (-32%), ornithine (-30%), tyrosine (-23%), glycine (-20%), threonine (-21%), and alanine (18%) concentrations. Urinary urea nitrogen and total nitrogen excretions were lower during glucagon deficiency than during glucagon excess (3.1 +/- 0.2 vs. 6.3 +/- 2.3 g/8 h, P less than 0.05 and 4.8 +/- 1.0 vs 7.0 +/- 2.6 g/8 h, respectively, P less than 0.05). Biostator-controlled euglycemic glucagon deficiency was produced in four normal subjects for 4 h to eliminate possible effects of changes in glucose concentration on amino acids. Amino acid concentration (sum of 18 amino acids) increases occurred in arginine (+42%), alanine (+28%), glutamine (+25%), and glycine (+16%) concentrations. The data show that small changes (-66 pg/ml and +50 pg/ml) in basal glucagon concentrations cause plasma amino acid concentrations to change in opposite directions. The finding that urinary excretion of nitrogen and urea nitrogen was greater during glucagon excess than during glucagon deficiency suggested alterations in the rate of gluconeogenesis from amino acids as one mechanism by which glucagon controls blood amino acid levels.

Altered arachidonic acid synthesis and lipid peroxidation in diabetes mellitus: Possible roles in leukocyte dysfunction and other cellular defects

Hyperglycemic diabetics are prone to unusual or especially severe infections; at the cellular level, diabetic polymorphonuclear leukocytes (PMNs) show defects in several antimicrobial functions. However, the basis for these defects is unknown, and they may not be fully ascribable to hyperglycemia, hypoinsulinemia or acidosis alone. Recently, it has been shown that several important PMN functions may be mediated (at least in part) by metabolites of arachidonic acid synthesized via the lipoxygenase pathway, especially arachidonate hydroperoxides and leukotriene (LT) B 4. We speculate that synthesis of these mediators may be deficient in severely hyperglycemic diabetics (fasting plasma glucose > 250–300 mg/dl) due to deficiencies of substrate (arachidonic acid) synthesis and release. Such defects might be expected since, in animal studies, severe insulin lack and glucagon excess inhibit the desaturation of precursor fatty acids to arachidonic acid. On the other hand, whereas low levels of lipid peroxides or their derivatives may be required in certain cells for normal function, excessive levels of such compounds also are detrimental to cellular function and could play a role as well in the complications of milder or partially treated diabetics who manifest high basal insulin levels. For example, cells which may be particularly sensitive to an excess of peroxides include islet beta cells, PMNs and possibly vascular endothelial cells (all of which appear to be deficient in glutathione peroxidase). These observations suggest a role for accumulation of lipid peroxides in the impaired insulin secretion, defective PMN function and possibly endothelial death and increased vascular (retinal, endothelial, and renal) permeability of some milder diabetics. The available data are compatible with the speculation that in partially treated or lesser degrees of hyperglycemia, increased arachidonate synthesis and excessive lipid peroxidation may be present. Although it remains to be established that all of the results from experimentally-induced diabetics can be extrapolated to humans, these findings suggest that the cell damage attendant upon peroxide generation might be susceptible to prophylactic treatment with anti-oxidants such as α-tocopherol or ascorbic acid. In the more severe or later stages of hyperglycemia, a deficiency of lipoxygenase-derived products may supervene; dietary modifications designed to increase essential fatty acid availability might present a unique ancillary therapeutic approach at this stage of diabetes.

Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man.

The present studies were undertaken to assess the relative effects of free fatty acid (FFA) availability, glucagon excess, and insulin deficiency on ketone body (KB) production in man. To determine whether an increase in FFA availability would augment KB production in the absence of insulin deficiency and glucagon excess, plasma insulin and glucagon were maintained at basal concentrations by infusion of somatostatin and exogenous insulin and glucagon, and plasma FFA were increased from 0.32 +/- 0.06 to 1.4 +/- 0.1 mM by a 2.5-h-infusion of a triglyceride emulsion plus heparin. KB production increased fivefold from 2.2 +/- 0.4 to 11.4 +/- 1.2 mumol . kg-1 . min-1, P less than 0.001. To determine whether insulin deficiency would further augment KB production, analogous experiments were performed but the replacement infusion of insulin was stopped. Despite a greater increase in plasma FFA (from 0.26 +/- 0.04 to 1.95 +/- 0.3 mM), KB production increased (from 1.5 +/- 0.3 to 11.1 +/- 1.8 mumol . kg-1 . min-1) to the same extent as in the absence of insulin deficiency. To determine whether hyperglucagonemia would augment KB production beyond that accompanying an increase in plasma FFA and, if so, whether this required insulin deficiency, similar experiments were performed in which the glucagon infusion rate was increased to produce plasma glucagon concentrations of 450-550 pg/ml with and without maintenance of the basal insulin infusion. When basal plasma insulin concentrations were maintained, hyperglucagonemia did not further increase KB production; however, when the basal insulin infusion was discontinued, hyperglucagonemia increased KB production significantly, whereas no change was observed in saline control experiments. These studies indicate that, in man, FFA availability is a major determinant of rates of KB production; insulin does not appear to influence ketogenesis rates by a direct hepatic effect, and glucagon can further augment KB production when FFA concentrations are increased but only in the setting of insulin deficiency.

Current concepts in the pathophysiology and management of diabetic ketoacidosis.

Recent studies indicate that for the development of diabetic ketoacidosis glucagon excess is essential in addition to a deficiency of insulin. Glucagon activates the carnitine acyl transferase I leading to ketonemia. Low dose continuous infusion of insulin appears to be the ideal mode of therapy for the correction of hyperglycemia. The use of sodium bicarbonate and phosphate as adjuvants in management is discussed in the light of recent observations.

Glucagon binding to purified liver plasma membranes from growing rats undergoing energy restriction

The purpose of this work was to investigate liver glucagon receptors in growing rats fed a control diet (11.8% crude protein) or a high-protein diet (19.8% crude protein) given in restricted amounts. The animals were fed every 4 hours. 125I-glucagon binding to purified liver plasma membranes was studied. Membrane purity was analysed with marker enzymes. The alteration of glucagon during incubation was measured. The results show that specific 125I-glucagon binding increased with time at 30 degrees C, reaching a maximal value within 120 min. The increasing level of unlabelled glucagon inhibited 125I-glucagon binding at steady state. Apparent specific 125I-glucagon binding at steady state was lower in experimental animals than in controls. This correlated with the increase in glucagon breakdown and decrease in membrane purity. Alternatively, glucagon binding to its receptors could drop. Unlabelled glucagon excess produced a time-dependent dissociation of glucagon-receptor complexes (half-life: up to 1 h). Feeding the experimental diet increased the dissociation of labelled glucagon-receptor complexes.

Insulin and glucagon release in the diabetic Chinese hamster: differences among inbred sublines.

Release of insulin and glucagon from perfused pancreases in vitro of 40 normal male and female Chinese hamsters (from one inbred subline) and 110 male and female diabetic hamsters (from three inbred sublines) was measured in response to glucose plus arginine, theophylline alone, or potassium alone, in order to determine if differences in hormone secretion exist among different diabetic sublines. Glucose plus arginine and potassium produced subnormal insulin responses in all three diabetic sublines, whereas theophylline induced 'normal' or above normal insulin responses. Excessive glucagon release was consistently seen in only one diabetic subline. The female normal animals showed greater insulin release than the male normal hamsters in response to glucose plus arginine. This sex difference was not seen in the diabetic animals.

Bihormonal theory of diabetes gets solid backing

Researchers at the University of Arizona, Tucson, have discovered evidence to support the "bihormonal" theory of diabetes—that the disease is caused by an excess of glucagon as well as a deficiency of insulin. Professor of chemistry Victor J. Hruby, PhD, working with Marvin D. Bregman, PhD, and Dev Trivedi, MS, produced an analog of glucagon ([1-Nα-trinitrophenylhistidine, 12-homoarginine] glucagon, or THG) by altering the side groups of two amino acids on the hormone. The resulting THG is a potent antagonist of the glucagon-stimulated adenylate cyclase system in rat liver. It presumably works by reversibly binding to glucagon receptors on liver cells, competing successfully with glucagon and thereby preventing glycogenolysis (and release of glucose) in the liver. The substance was tested for its ability to lower blood glucose concentrations in diabetic rats by David G. Johnson, MD, associate professor of pharmacology, and Camy Ulichny Goebel, of the Department of Internal Medicine at

Acute hormonal effects on carnitine metabolism in thin and obese subjects: Responses to somatostatin, glucagon, and insulin

Plasma free carnitine and acylcarnitines were determined in man during acutely induced insulin deficiency. A 5-hr infusion of somatostatin at 6 μg/min in 10 thin subjects produced profound, sustained hypoinsulinemia and led to rapid increases in plasma free fatty acids and ketoacids (peak increments of 0.67 m M each). Simultaneously, plasma free carnitine decreased, while plasma long-chain and short-chain acylcarnitines increased significantly. When hyperglucagonemia was created by inclusion of glucagon with the somatostatin, the hyperketonemia was reversed after 2 hr and the increase in acylcarnitine abolished. However, the decrease in free carnitine was accentuated. The antiketogenic effect of adding glucagon was due to an eventual breakthrough of the somatostatin blockade on insulin secretion, the latter gradually returning toward preinfusion levels. Inclusion of exogenous insulin with the somatostatin-glucagon infusion immediately lowered free fatty acids and ketoacids. Acylcarnitines also declined promptly, while the accelerated fall in free carnitine produced by glucagon was blunted by the addition of insulin. Qualitatively and quantitatively comparable results were seen in seven obese subjects. This study suggests: (1) the increase in plasma acylcarnitines previously described in fasting and diabetic ketosis is largely due to insulin deficiency; (2) the corresponding decrease in plasma free carnitine is attributable both to insulin deficiency and glucagon excess; and (3) the resistance of obese subjects to ketosis is unlikely to be due to deficits in carnitine or carnitine acyltransferases.

Hyperkalemia and Hyperglycemic Increments in Plasma Potassium in Diabetes Mellitus

The frequency of persistent or intermittent hyperkalemia in patients with diabetes is unknown. In 405 predominantly insulin-treated patients, major hyperkalemia was not common (< 5.0 mEq/L in 2.5%). In ten insulin-treated patients sampled hourly from 8 AM through 8 PM, major intermittent hyperkalemia was not detected (< 4.8 mEq/L in all samples). However, mean plasma potassium values paralleled mean glucose values; these variables were significantly correlated in seven of ten patients. In contrast, there were no relationships between plasma potassium and plasma free insulin, glucagon, epinephrine, or norepinephrine values. We conclude that (1) hyperkalemia--fasting or intermittent--does not occur commonly in patients with diabetes, and (2) hyperglycemia, but not insulin or epinephrine lack or glucagon excess, appears to be a direct determinant of plasma potassium but is not a sufficiently potent determinant to commonly produce clinically important hyperkalemia in insulin-treated diabetic patients.

Glucagonoma and Diabetic Ketoacidosis?

To the Editor. —Domen et al, in theArchives(140:262-263, 1980), describe an interesting report of a mildly diabetic patient who was discovered to have a metastatic glucagonoma and in whom an episode of diabetic ketoacidosis supervened during the course of an apparent infection. The authors state that glucagon appears to have played an important role in the development of diabetic ketoacidosis in their patient. On the contrary, the data presented in their report indicate that insulin deficiency, rather than glucagon excess, was the major factor in the genesis of ketoacidosis in this patient. This is clearly supported by the subnormal insulin levels in the fasting state, as well as by the markedly attenuated response to oral glucose. Patients with glucagonsecreting islet cell tumors have generally been found to have appropriately elevated insulin levels (60 to 70 μU/ mL, basal), 1.2 unlike the patient of Domen et al, thus explaining