Carbohydrate J#{252}rgenFrohlich,

metabolism

Peter

Schollmeyer,

ABSTRACT in patients

insulin most

with

to glucose

insulin

during

insensitivity. likely.

increased

renal

failure.

hepatic

glucose

that

have

are

hormones,

an increase glucagon,

correlation

been

a preponderance Clin. Nutr. 31:

the

possible

Journal

of Clinical

pH,

antagonistic

to be of most

glucose

by and

has

antagonism

a disturbance

at the

glucose

in these “toxic”

among

been thus

proved, leading

indicating cellular

level

seems one

growth

the

interaction

to an

apparent

and other.

metabolism

in

or end-products. hormone,

individual

Of

catechohamines,

hormones

of all of them insulin

of

to be

hand the

of carbohydrate

them

ratio

a peripheral

on the

intermediates

for the

phenomena

elevated

gluconeogenesis-on

alterations

Although

known an

utilization

of

metabolic

well

subjects, observed

stimulation

hormones,

are

diabetic

is consistently

peripheral

significance.

intolerance

of insulin

Nutrition

reasons,

to be involved

electrolytes,

tolerance

to true

test

of reduced

resistance.

no equivocal may

result

in

Am.

.1.

1978.

Neubauer in 1910 (1) and Myers and Bailey in 1916 (2) reported fasting hyperglycemia in patients with renal failure and thus were the first to draw attention to alterations of carbohydrate metabolism in uremia. Since then, a lot of data have accumulated which allow us to characterize more precisely the kinds of alterations and possible sites of interference in carbohydrate metabolism by the uremic state. The abnormality of carbohydrate metabolism most commonly demonstrated in uremic subjects is a markedly delayed utilization of a glucose load, irrespective of oral or intravenous administration. Three characteristic alterations can be observed. First, there is a delayed fall in blood glucose resulting in a reduced glucose decay constant. Second, a slightly lowered peak of early insulin release is reported. Third, markedly elevated plasma insulin levels during the late phase of the glucose tolerance test are observed (3-6). While the inhibition of glucose assimilation is thus similar to that of true diabetics there is an essential difference with respect to plasma insulin. This becomes evident from the relation of insulin to glucose which is markedly elevated in patients with renal failure, in contrast to the reduced ratio of diabetic individuals (3). From this kind of behavior of glucose and insulin it was concluded that at least two disturbances of carbohydrate The American

glucose

In contrast tolerance

evidence

suggested

1541-1546,

impaired

glucose

failure1

Gerok

output-probably

in insulin seems

with

and

the

is some

uremia and

Wolfgang

Among

There

Agents these,

and

Hyperglycemia

occurring

in renal

31: SEPTEMBER

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metabolism exist in uremic patients: a reduced early insulin release and a peripheral antagonism toward insulin action which is associated with a net underutilization of glucose. Reduced

early

insulin

release

The reduced early pancreatic secretion of insulin is not universally observed. Some studies demonstrated normal or even increased insulin response to glucose (7-9). From theoretical considerations, however, at least a relative inhibition of insulin output must be postulated in order to explain glucose intolerance in these patients. A disturbance of peripheral glucose utilization alone would not fully explain this failure. Among the possible causes of diminished early pancreatic insulin release, a depletion of potassium, lack of calcium, and elevation of magnesium have been suggested (Table 1). It is well known that the normal rapid release of insulin is dependent on sufficient potassium and calcium (10, 11). A decrease in exchangeable body potassium in uremics has been demonstrated (12), and replacement of potassium could partially restore glucose tol-

‘From the Department sity of Freiburg, Freiburg public of Germany.

1978,

pp.

154 1-1546.

Printed

of Internal Medicine, Univeri.Br., Germany, Federal Re-

in U.S.A.

1541

1542

FROHLICH

TABLE Inhibition

1 of early

release-possible

insulin reasons

1 . Depletion

of K of Ca Elevation of Mg

2. Lack 3.

TABLE Peripheral

2 antagonism

the I. 2. 3. 4.

towards by

insUlin-supported

following Insulin/glucose I Tolbutamide test Insulin tolerance test Insulin

responsiveness

of

the

human

forearm

erance in these patients (13). With respect to calcium, a similar marked reduction in insulin secretory response to acute hypocalcemia has been reported in patients with renal failure (14). However, whether a disturbance of these electrolytes plays any major role in reduced early insulin release is uncertain and needs further evaluation. The same applies to the role of magnesium. Peripheral action

antagonism

towards

insulin

In contrast to the conflicting results concerning early insulin release, a peripheral antagonism to insulin resulting in a net underutilization of glucose seems to be generally established in patients with renal failure. Insulin antagonism is supported by four lines of evidence (Table 2). First, there is an elevated ratio of plasma insulin to glucose during the glucose tolerance test. Second, with the tolbutamide test there is a delayed decay of blood glucose despite rather elevated endogenous insulin levels (6, 15). Third, further evidence comes from the insulin tolerance test. As with endogenous insulin, there is a diminished fall of blood glucose with exogenous insulin administration (3, 4, 6, 15, 16). Studying insulin resistance to acutely uremic dogs, Swenson et al. (17) demonstrated that while similar steady state levels of insulin were achieved by continuous infusion, the steady state plasma glucose concentrations were higher in uremic animals. Fourth, more direct evidence in support of peripheral insulin antagonism is supplied by the investigations of Westervelt (18). In his studies on metabolic rates across the

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ET

AL.

human forearm it was demonstrated that the insulin responsiveness of skeletal muscle in uremic subjects is distinctly blunted. Insulin stimulated net glucose uptake was considerably diminished, and there was a normal proportional reduction in lactate formation. In contrast to glucose, potassium uptake seemed to remain unimpaired. Which is the mechanism leading to insulin antagonism in uremia (Table 3)? The possibility has been considered that a biologically inactive insulin may be present. This could result from either structural alteration or neutralization by circulating insulin antagonists. Second, antagonism at the membrane level has been suggested. And finally, insensitivity of the peripheral tissues secondary to metabolic changes could account for this disturbance. There is very little information concerning the first two possibilities, and the data available do not support interference by uremia at these sites (15, 19). The question of a disturbance at the cellular level is somewhat better studied. A net reduction in glucose utilization may result from an inhibition of peripheral glycolysis, an increment in hepatic gluconeogenesis, or an inhibition of glycogen synthesis. As to the first point, an inhibition of basal glucose uptake by several tissues in the presence of uremic serum has been reported (20, 21). Dzurik et al. (22) were able to isolate a peptide of 1000 to 1500 molecular weight which could reproduce the inhibition. It was suggested that inhibition could occur proximal to the phosphofructokinase step since, in contrast to glucose, utilization of fructose seems to be unimpaired (23, 24). An increase in hepatic gluconeogenesis could lead to cellular insulin antagonism in uremia. Dzurik (20) observed an increase in TABLE 3 Peripheral antagonism insulin-suggested

towards

mechanisms

I. Biological inactive insulin 1.1. Structural alteration 1.2. Circulating antagonists 2. Antagonism

at the

membrane

level

3. Disturbances of cellular metabolism 3.1. Glycohysis 3.2. Gluconeogenesis I 3.3. Ghycogen synthesis

CARBOHYDRATE

METABOLISM

glucose formation from lactate in liver slices during incubation with uremic serum. Studies in our laboratory on the long-term effects of experimentally induced acute uremia on the metabolism of the isolated rat liver revealed a stimulation of gluconeogenesis from amino acids (25) (Fig. 1). It was shown that serine was the major contributor to the additional glucose formed by uremic liver, as stimulation of gluconeogenesis was essentially reproduced in the presence of serine alone (26). The underlying mechanism of this effect may be related to accelerated amino acid transport because the uptake of a-aminoisobutyric acid by the liver was considerably increased. Furthermore, an increase of serine dehydratase activity was established. This enzyme is re-

IN pMoI/g

.30

RENAL

1543

FAILURE

mm GLUCOSE

24

FORMED

10

J

20

4

10 16

12

8

II

4

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linE

4 SERINE

DEHYDRATASE

pmoi/g.min

4

4

0.4

0.3 sham

ur.mic

adx

ads +coi’tiso$

FIG. 2. The effect of adrenalectomy on gluconeogenesis of amino acids and on activity of serine dehydratase in livers of acutely uremic rats. Gluconeogenesis of a mixture of amino acids (twice the concentrations given in the legend to Fig. 1) was measured in livers of acutely uremic rats perfused in a recirculating system. Serine dehydratase activity was determined as previously described (26). Cortisol was administered as hydrocortisone sodium succinate, twice daily subcutaneously. Values are means ± SD. Numbers above bars indicate sample size. Hatched bars = livers of uremic rats; open bars = livers of sham operated controls; adx = adrenalectomized animals; adx + cortisol = adrenalectomized and cortisol substituted animals.

0

C 0

0.2 0 #{149}

a

0.1

u

2

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4 amino

6

acids

FIG. 1. The effect of acute uremia on gluconeogenesis in isolated perfused rat livers as a function of amino acid concentrations. Livers of fasted uremic (#{149}, n=7) and sham-operated control animals (R, n=7) were perfused without recirculation by a perfusate containing the indicated multiples of normal plasma concentrations of a mixture of serine (0.245 mmole/hiter), threonine (0.350 mmole/liter), lysine (0.409 mmole/hiter), glutamate (0.249 mmole/liter) ormthine (0.069 mmole/hiter, and citruhhine (0.063 mmole/hiter). Each point represents the rate obtained at the end of 15 min of perfusion at the indicated amino acid concentrations. Values are means ± SD.

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garded cose.

to limit In

contrast

conversion to

Dzurik

of serine (20),

no

to glustimula-

tion of gluconeogenesis from lactate was found. On the contrary, an inhibition was observed. Stimulation of gluconeogenesis from amino acids and activity of serine dehydratase are dependent on the presence of the adrenal cortex, as adrenalectomy abolished these effects (Fig. 2). The foregoing data suggest that an increase in hepatic gluconeogenesis may contribute to cellular insum antagonism in uremia, and second, that

1544

FROHLICH

this alteration of carbohydrate metabolism may be hormonally controlled. With oral administration of glucose, a considerable amount is immediately taken up by the liver and predominantly converted to glycogen. Thus, attention has been directed towards liver glycogen metabolism in uremia. Cohen et al. (5) obtained data suggesting a block in glycogen synthesis. Other investigators, however, could not confirm these results (6, 8, 15). In contrast, direct determination of glycogen in liver biopsy specimens revealed no difference between uremic patients and normal controls (20). It should be pertinent that repeated dialysis, which has been shown to improve glucose tolerance, will only be successful if continued for at least 2 weeks (6). This fmding seems to be incompatible with the possibility that peripheral insulin antagonism in uremia is caused by a dialyzable substance of low molecular weight that interferes with one distinct metabolic step. The metabolic interrelationships seem to be more complex. Agents which may be causally involved in peripheral insulin antagonism may be classified as follows (Table 4): hormones, electrolytes and pH, physiological end-products, and pathological intermediates. Hormones that are considered possible mediators of insulin antagonism in uremia indude growth hormone, parathyroid hormone, cortisol, catecholamines, and gluca-

gon. Elevated plasma growth hormone levels have been consistently reported in patients with renal failure (3, 27, 28). It was suggested that severe uremia induced hypersecretion of growth hormone which, by its antagonistic action toward insulin, induces glucose intolerance. However, no unequivocal correlation between growth hormone levels and glucose intolerance can be demonstrated in uremia (28). The same limitation applies to parathyroid hormone. Recent fmdings of insulin hyperresponsiveness in primary hyperparathyroidism have suggested a state of relative insulin resistance in this condition (11). A role for parathyroid hormone in insulin resistance of uremia has also been proposed (29). However, the data from clinical studies are conificting, and the role of parathyroid hormone in this disturbance is not clear (14). Cortisol has well known antagonistic ac-

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ET

AL.

TABLE 4 Peripheral antagonism towards insulin-possible causes 1. Hormones 1.1. Growth hormone 1.2. Parathyroid hormone 1.3. Cortisol 1.4. Catecholamines 1.5. Glucagon 2. Electrolytes, pH 2.1. K 2.2. Ca 2.3. Acidosis 3.

Physiological end-products 3.1. Urea 3.2. Creatinine

4.

Pathological intermediates 4.1. “Middle molecules” 4.2. Guanidines 4.3. Ahiphatic amines 4.4. Acetone 4.5. Others

tions towards insulin and has been implicated in the glucose intolerance of uremia. However, cortisol levels are normal or at best slightly elevated in renal failure (30). No data are available concerning catecholamine metabolism and glucose intolerance. Glucagon is also elevated in renal failure (31, 32). Glucagon acts antagonistically to insulin in liver, but probably not in muscle and other peripheral tissues. Thus, an increase in plasma. glucagon could hardly explain the inhibited insulin responsiveness of the human forearm, as shown by Westervelt (16). Furthermore, the fact that elevated glucagon levels remain essentially unchanged by dialysis, in contrast to the improvement of glucose tolerance, appears to argue against a major role of this hormone (31). However, recent data by Sherwin et al. (33) may contribute a new aspect. Their data suggest an augmented tissue sensitivity to glucagon in uremia which is normalized by dialysis treatment. It is possible that increased tissue responsiveness to glucagon may be the primary cause of insulin resistance. However, the opposite could also prove true. Insulin insensitivity may be the primary event and in turn cause glucagon hyperresponsiveness. The effects of glucagon and possibly other antagonistic hormones to insulin might be further supported by the observation that plasma

CARBOHYDRATE

cyclic AMP levels are In addition, a rise in been demonstrated in (35, 36). Finally, fatty acids action (37); however,

METABOLISM

elevated in uremia tissue cyclic AMP chronically uremic

(34). has rats

can antagonize insulin their levels are within

the normal range in uremic patients (6). Besides hormonal factors, an imbalance in electrolyes and/or pH may be involved in disturbed carbohydrate metabolism in uremia. A possible role of potassium and calcium in early insulin release has already been mentioned. Hypercalcemia may lead to inhibition of glucose utilization (14). However, an increase in serum calcium is an unusual finding in chronic renal failure. Acidosis may also result in glucose intolerance (38). However, this occurs only in severe rather than the mild acidosis which is commonly observed in patients with renal failure. Urea and creatinine are metabolic endproducts which, in increased concentrations, may interfere with peripheral glucose utilization (39). Urea at very high concentrations may lead to an irreversible inhibition of enzyme activity in vitro (40). However, such concentrations do not occur in man (41). The role of urea in glucose intolerance is further limited by the fact that abnormal glucose tolerance may also be corrected in patients dialyzed against high concentrations of urea (6). Finally, urea is without effect on insulin stimulated glucose oxidation by rat epididymal fat pads and hemidiaphragm (3, 4). Pathological intermediates may accumulate in chronic renal failure (42). These include substances of a peptide nature which are isolated

from

uremic

glycolysis,

serum

and which

as formerly

(22).

They

antagonistic

1. NEUBAUER,

2.

3.

4.

4ctoxins). 6.

cyclic AMPf

I gIycoIysis -

gluconeogenesis glycog.nesls 4 blood

t 7.

glucosef 8.

--

FIG. ment

secondary

3. Hypothetical of glucose intolerance

hyperinsulinism

mechanism in renal

for failure.

the

develop-

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1545

Hyperglykhmie bei Hochdie Beziehungen zwischen Glyk#{228}mie und Glukosurie beim Diabetes melhitus. Biochem. Z. 25: 284, 1910. MYERS, V. C., AND C. V. BAILEY. The Lewis and Benedict method for the estimation of blood sugar, with some observations obtained in disease. J. Biol. Chem. 24: 147, 1916. HORTON, E. S., C. JOHNSON AND H. E. LEBOvITZ. Carbohydrate metabolism in uremia. Ann. Internal Med. 68: 63, 1968. PERKOFF, 0. T., C. L. THOMAS, J. D. NEWTON, J. C. SELLMAN AND F. H. TYLER. Mechanism of impaired glucose tolerance in uremia and experimental hyperazotemia. Diabetes 7: 375, 1958. COHEN, B. D. Abnormal carbohydrate metabolism in renal disease. Blood glucose unresponsiveness to hypoglycemia, epinephrine, and glucagon. Ann. Internal Med. 57: 204, 1962. HAMPERS, C. L., J. S. SOELDNER, P. B. DOAK AND J. P. MERRILL. Effect of chronic renal failure and hemodialysis on carbohydrate metabolism. J. Chin. Invest. 45: 1719, 1966. Lowiui, E. G., J. S. SOELDNER, C. L. HAMPERS AND J. P. MERRILL. Glucose metabolism and insulin secretion in uremic, prediabetic, and normal subjects. J. Lab. Chin. Med. 76: 603, 1970. HUTCHINGS, R. H., R. M. HEGSTROM AND B. H. SCRIBNER. Glucose intolerance in patients on longterm intermittent dialysis. Ann. Internal Med. 65: 275, 1966. BRIGGS, J. D., K. D. BUCHANAN, R. G. LUKE AND drucknephritis

FAILURE

hormones

FAILURE

References

5.

insulin

RENAL

may be identical to the so-called middle molecules described by Furst et al. (43). Other substances of low molecular weight such as phenols, guanidines, amines, acetoin and others which may accumulate in uremia, have not been proven to impair glucose tolerance. In conclusion, no uniform concept exists with respect to the possible reasons for glucose intolerance in uremic subjects. Thus, the scheme presented in Figure 3 (which limits itself to the liver) represents rather a hypothetical concept than a summary of our present knowledge. Accordingly, an increased concentration of insulin antagonistic hormones, such as glucagon, probably caused by a reduced metabolic clearance (33), may occur. By an antagonistic action at the level of adenyl cyclase or more distally in cellular metabolism, this could lead to insulin resistance. Blood glucose would therefore increase which in turn would stimulate secretion of pancreatic insulin. In addition, basal or insulin stimulated utilization of glucose via glycolysis or glycogen synthesis would be inhibited by toxic substances accumulating in uremia.

can inhibit

mentioned

RENAL

IN

9.

E.

Uber

und

FROHLICH

1546 M.

MCKIDDIE. Role of insulin in glucose intolin uraemia. Lancet 1: 462, 1967. SAGILD, U., V. ANDERSEN AND P. B. ANDREASEN. Glucose tolerance and insulin responsiveness in cxperimental potassium depletion. Acta Med. Scand. 169: 243, 1961. KIM, H., R. K. KALKHOFF, N. V. COSTRINI, J. M. CERLE1-FI AND M. JACOBSON. Plasma insulin disturbances in primary hyperparathyroidism. J. Chin. Invest. 50: 2596, 1971. BODDY, K., R. C. KING, R. M. LINDSAY, J. WIN. CHESTER AND A. C. KENNEDY. Exchangeable and total body potassium in patients with chronic renal failure. Brit. Med. J. 1: 140, 1972. SPERGEL, G., S. J. BLEICHER, M. GOLDBERG, J. ADESMAN AND M. 0. GOLDNER. The effect of potassium on the impaired glucose tolerance in chronic uremia. Metabolism 16: 581, 1967. AMEND, W. J. C., JR., S. M. STEINBERG, E. 0. L0wRIE, J. M. LAZARUS, J. S. SOELDNER, C. L. HAMPERS AND J. P. MERRILL. The influence of serum calcium and parathyroid hormone upon glucose metabolism in uremia. J. Lab. Chin. Med. 86: 435, 1975. CERLETTY, J. M., AND ENGBRING, H. H. Azotemia and glucose intolerance. Ann. Internal Med. 66: 1097, 1967. WESTERVELT, F. B., JR., AND 0. E. SCHREINER. The carbohydrate intolerance of uremic patients. Ann. Internal Med. 57: 266, 1962. SWENSON, R. S., D. T. PETERSON, M. ESHLEMAN AND 0. M. REAVEN. Effect of acute uremia on various aspects of carbohydrate metabolism in dogs. Kidney Internat. 4: 267, 1973. WESTERVELT, F. B., JR. Insulin effect in uremia. J. Lab. Clin. Med. 74: 79, 1969. DAVIDSON, M. B., E. 0. LOWRIE AND C. L. HAMPERS. Lack of dialyzable insulin antagonist in uremia. Metabolism 18: 387, 1969. DZURIK, R. Uraemia. The pathophysiology of carbohydrate metabolism. Bratislava: Publishing House of the Slovac Academy of Sciences. 1973. HEINTZ, R., AND D. RENNER. Uber Hemmwirkungen des Serums von Kranken mit hepatorenalem Syndrom und mit chronischer Ur#{228}mie auf Sauerstoffverbrauch und Kohlenhydratstoffwechseh von Nierenund Hirngewebe der Ratte. KIn. Wochenschr. 43: 1167, 1965. DZURIK, R., V. HUPKOVA, P. CERNACEK, E. VALOV1KOVA AND T. R. NIEDERLAND. The isolation of an inhibitor of glucose utilization from the serum of uraemic subjects. Chin. Chim. Acta 46: 77, 1973. DZURIK, R., M. GAJDOS, V. SPUSTOVA AND P. CERNACEK. Glucose utilization in uremia. Proc. 6th Int. Congr. N#{231}phroh., Florence 1975. Basel: Karger, 1976, p. 590. LUKE, R. 0., A. J. DINWOODIE, A. L. LINTON AND A. C. KENNEDY. Fructose and glucose tolerance in uremia. J. Lab. Chin. Med. 64: 731, 1964. FROHLICH, J., J. SCHOLMERICH, G. HOPPE.SEYLER, K. P. MAIER, H. TALKE, P. SCHOLLMEYER AND W. GEROK. The effect of acute uraemia on gluconeogenesis in isolated perfused rat livers. Europ. J. Chin. Invest. 4: 453, 1974. FROHLICH, J., G. HOPPE-SEYLER, P. SCHOLLMEYER, K. P. MAIER AND W. GEROK. Possible sites of interaction of acute renal failure with amino acid utihi-

ET

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erance

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AL. zation

for

liver.

Europ.

J. Chin. H.,

ORSKOV, mone

in

and

glucagon

uremic

in isolated perfused 7: 261, 1977.

gluconeogenesis

N. J.

AND

uremia. subjects.

Invest.

CHRISTENSEN.

Growth

rat hor-

I. Plasma growth hormone, insulin after oral and intravenous glucose in Scand. J. Clin. Lab. Invest. 27: 51,

1971. 28.

hormone 19: 102, 29.

N.

SAMAAN,

levels 1970. A.,

A.,

AND

in severe

M. renal

FREEMAN.

failure.

uremic

Insulin

COHEN

hypersecretion

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SCHMIDT,

man.

CARMENA,

S.

Growth

Metabolism

AND C. in patients on chronic hemodialysis. Role of parathyroids. J. Chin. Endocrinol. Metabol. 32: 653, 1971. 30. ENGLERT, E., JR., H. BROWN, D. 0. WILLARDSON, S. WALLACH AND E. L. SIM0NS. Metabolism of free and conjugated l7-hydroxycorticosteroids in subjects with uremia. J. Chin. Endocrinol. Metabol. 18: 36, 1958. 31. BILBREY, 0. L., 0. R. FALOONA, M. G. WHITE AND J. P. KNOCHEL. Hyperglucagonemia of renal failure. J. Chin. Invest. 53: 841, 1974. 32. BILBREY, 0. L., G. R. FALOONA, M. G. WHITE, C. ATKINS, A. R. HULL AND J. P. KNOCHEL. Hyperglucagonemia in uremia: reversal by renal transplantation. Ann. Internal Med. 82: 525, 1975. 33. SHERWIN, R. S., C. BASTL, F. 0. F1NKELSTEIN, M. FISHER, H. BLACK, R. HENDLER AND P. FELIG. Influence of uremia and hemodialysis on the turnover and metabolic effects of ghucagon. J. Chin. Invest. 57: 722, 1976. 34. HAMET, P., D. A. STOUDER, H. E. GINN, J. 0. HARDMAN AND G. W. LIDDLE. Studies of the elevated extracellular concentration of cyclic AMP in LINDALL,

COMTY.

R.

R.

G.,

Carbohydrate metabolism in renal failure.

Carbohydrate J#{252}rgenFrohlich, metabolism Peter Schollmeyer, ABSTRACT in patients insulin most with to glucose insulin during insensitivi...
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