Glucose and insulin metabolism in cirrhosis

Glucose intolerance, overt diabetes mellitus, and insulin resistance are characteristic features of patients with cirrhosis. Insulin secretion, although increased in absolute terms, is insufficient to offset the presence of insulin resistance. The defect in insulin-mediated glucose disposal involves peripheral tissues, primarily muscle, and most likely reflects a disturbance in glycogen synthesis. Hepatic glucose production is normally sensitive to insulin; at present, it is unknown whether hepatic glucose uptake is impaired in cirrhosis. One of the more likely candidates responsible for the insulin-resistant state is insulin itself. The hyperinsulinemia results from three abnormalities: diminished hepatic extraction, portosystemic/intrahepatic shunting, and enhanced insulin secretion.     

Effect of glucagon on amino acid and nitrogen metabolism in fasting man

The infusion of small amounts of glucagon into fasting subjects has been reported to paradoxically decrease urinary urea nitrogen excretion. The mechanism and tissues by which this apparent protein sparing was accomplished was examined in the current study by infusing glucagon ($\text{0.1 mg}\text{24 hr × 4}\text{days}$) into subjects who had fasted for 5–6 wk. It was found that circulating levels of alanine and glutamine declined while urinary urea nitrogen excretion decreased and ammonia nitrogen excretion increased. These findings suggested that hepatic gluconeogenesis had been diminished while renal ammoniagenesis and gluconeogenesis had increased. The further finding of a significant prolongation of the $\text{t}\text{,}\text{1}\text{2}$ of ¹⁴C-lalanine (U) 24 hr after the start of the infusion appeared to substantiate this diminution in hepatic gluconeogenesis. In addition, while serum insulin levels had declined significantly by the end of the infusion, circulating levels of the branched-chain amino acids had increased. It was concluded that the infusion of small amounts of glucagon may have resulted in a diminution of portal glucagon levels, which in turn resulted in a decrease in hepatic gluconeogenesis and, directly or indirectly, a compensatory increase in renal ammoniagenesis and gluconeogenesis. The coincidental decline in alamine and the increase in levels of the branched-chain amino acids suggest that the infused glucagon had affected peripheral amino acid metabolism as well.     

Glucose and related brain metabolism in normal aging

Normal brain function is strongly correlated with undisturbed cerebral circulation and the supply of the subrates oxygen and glucose. The mature, healthy, nonstarved mammalian brain uses glucose only to obtain biologically available energy as ATP. The glycolytic and oxidative cerebral glucose metabolism is controlled by means of various mechanisms. Glucose breakdown contributes to the formation of the neurotransmitters acetylcholine, glutamate, aspartate and GABA. ATP yields the basis for maintenance of cellular homeostasis via ion homeostasis, integrity of cellular components and intracellular transportation processes, and is necessary for the formation of several neurotransmitters and neurohormones. It is demonstrated that normal cerebral aging may be associated with an incipient perturbation of cerebral circulation and metabolism causing an imbalance of cell homeostasis beyond the age of 70 years pointing to a threshold phenomenon. If the disturbance in cell homeostasis cannot be counterbalanced, “normal” cerebral aging may be expected to develop into dementia in old age beyond a critical age-related threshold.     

Renal amino acid,fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

Aims/hypothesis The aim of this study was to test the hypothesis that type 1 diabetes alters renal amino acid, glucose and fatty acid metabolism.Materials and methods We studied five C-peptide-negative, type 1 diabetic subjects during insulin replacement (glucose 5.6 mmol/l) and insulin deprivation (glucose 15.5 mmol/l) and compared them with six non-diabetic subjects. Leucine, phenylalanine, tyrosine, glucose and palmitate tracers were infused after an overnight fast and samples were obtained from the renal vein, femoral vein and femoral artery.Results Insulin deprivation significantly increased whole-body fluxes (20–25%) of phenylalanine, tyrosine and leucine, and leucine oxidation (50%). Kidney contributed 5–10% to the whole-body leucine and phenylalanine flux. A net uptake of phenylalanine, conversion of phenylalanine to tyrosine (5 μmol/min) and net release of tyrosine (∼5 μmol/min) occurred across the kidney. Whole-body (three-fold) and leg (two-fold) leucine transamination increased but amino acid metabolism in the kidney did not alter with diabetes or insulin deprivation. Insulin deprivation doubled endogenous glucose production, renal glucose production was unaltered by insulin deprivation and diabetes (ranging between 100 and 140 μmol/min). Renal palmitate exchange was unaltered by insulin deprivation.Conclusions/interpretation In conclusion, kidney postabsorptively accounts for 5–10% of whole-body protein turnover, 15–20% of leucine transamination and 10–15% of endogenous glucose production, and actively converts phenylalanine to tyrosine. During insulin deprivation, leg becomes a major site for leucine transamination but insulin deprivation does not affect renal phenylalanine, leucine, palmitate or glucose metabolism. Despite its key metabolic role, insulin deprivation in type 1 diabetic patients does not alter many of these metabolic functions.     

Effect of insulin and plasma amino acid concentration on leucine metabolism in cirrhosis

Clinically stable patients with cirrhosis demonstrate insulin resistance with regard to glucose metabolism. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in cirrhotic patients. To examine this question, we performed paired euglycemic insulin clamp studies in combination with 14C-leucine and indirect calorimetry. In the first study insulin alone was infused, and the plasma amino acid concentration was allowed to decline. During the second study a balanced amino acid solution was infused with insulin to increase the total plasma amino acid concentration approximately twofold. Insulin-mediated glucose disposal (4.68 vs. 6.45 mg/kg-min, p less than 0.01) was significantly impaired by 30% in cirrhotic patients during both insulin clamp studies. In the postabsorptive state, cirrhotic patients manifested low plasma leucine (76 vs. 102 mumol/L) and alpha-ketoisocaproate (19 vs. 30 mumol/L) concentrations, but all parameters of leucine turnover were normal. When insulin alone was infused, the endogenous leucine flux (an index of protein degradation) declined similarly in cirrhotic patients (30.8 mumol/m2-min) and control (26.9) subjects, and this was accompanied by a similar decrease in plasma leucine concentration (31% vs. 33%). The decline in circulating leucine concentration was accompanied by a parallel decline in leucine oxidation (5.1 vs. 4.6 mumol/m2-min) and nonoxidative (28.9 vs. 26.0 mumol/m2-min) leucine disposal, which were of similar magnitude in cirrhotic patients and control subjects, respectively. In both cirrhotic patients and control subjects, combined hyperinsulinemia/hyperaminoacidemia elicited a similar stimulation of nonoxidative leucine disposal (an index of protein synthesis) and leucine oxidation while causing a greater suppression of endogenous leucine flux than observed with insulin alone. Thus the suppressive effect of insulin on protein degradation and the stimulatory effect of insulin/amino acid infusion on protein synthesis are not impaired in cirrhotic patients, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism.     

Glucose metabolism in man: Responses to intravenous glucose infusion

We have determined the effect of unlabeled glucose infusions, with and without added insulin, on glucose metabolism in normal male volunteers by means of the simultaneous primed-constant infusion of 6-³H and U-¹³C-glucose. Glucose kinetics were measured after 90 min of infusion. When steady state had been reached, endogenous glucose production (2.53 ± .058 mg/kg·min, $\text{X}$ ± SEM) was suppressed at all rates of exogenous glucose tested (1, 2, and 4 mg/kg·min). The absolute degree of suppression was most marked (75%) at the highest rate of infusion, but the greatest degree of suppression, relative to infusion rate, was at the lowest infusion rate. The control of plasma glucose concentration during the glucose infusion was achieved primarily through regulation of endogenous Ra. The rate of uptake of glucose only increased during the 4 mg/kg·min infusion, even though there were significant elevations in the plasma glucose and insulin concentrations during the 2 mg/kg·min infusion as well. The glucose clearance rate increased only when sufficient insulin was infused with the 4 mg/kg·min glucose infusion to control the hyperglycemia that developed if no insulin was administered. Approximately 43% of the infused glucose was directly oxidized when the infusion rate was 1 or 2 mg/kg·min. That value fell to 32% when the infusion rate was increased to 4 mg/kg·min, regardless of whether insulin was infused or not.     

Glucose metabolism in the newborn rat: The role of insulin

Summary The effect of the administration of anti-insulin serum to newborn rats, surgically delivered under ether anaesthesia at term, was examined with respect to liver glycogen concentration and plasma concentrations of glucose, lactate and free fatty acids. Newborn rats thus treated showed decreased liver glycogen concentrations and elevated plasma concentrations of glucose, lactate and free fatty acids compared to untreated control animals one hour later. These effects were dose-dependent with respect to the amount of anti-insulin serum administered. The simultaneous administration of glucagon with anti-insulin serum at birth was no more effective in mobilising glycogen stores than anti-insulin serum alone, although plasma glucose concentrations in these animals were higher and plasma lactate concentrations were lower. Either anti-insulin serum or glucagon abolished the postnatal hypoglycaemia observed in untreated neonatal rats. The rate of fall in plasma lactate concentrations after birth was stimulated in glucagon-treated rats but was retarded in rats treated with anti-insulin serum. Hormonal control over the initiation of glycogenolysis and gluconeogenesis in the newborn rat appears to be different, a fall in plasma insulin being the prime factor involved in triggering glycogen mobilization and a rise in plasma glucagon the prime event that initiates gluconeogenesis.     

Glucose metabolism and insulin activity during cardiac surgery

Disorders of glucose metabolism were investigated in 177 patients undergoing cardiac surgery. In group I patients, the cardiopulmonary bypass (CPB) priming fluid contained glucose. Patients in group II received neither glucose nor insulin during the operation. Group III received insulin-glucose therapy OGT) during the operation (insulin, 1 U/kg/h, glucose, 0.5 g/kg/h). At the onset of CPB in group I, hyperglycemia was produced by the glucose load and by a relative reduction in insulin secretion. In group 11, the start of the operation was accompanied by a rise in the titer of insulin antibodies. IGT resulted in normalization of the blood glucose level after CPB and stability of the insulin antibody titer during the investigation. The indices of myocardial contractility in group III were better than those of the “glucose free” group II before and after CPB. In group II, indices of β-cell function were moderately depressed 16 to 18 hours after the operation. Insulin and c-peptide level measurements demonstrated insulin production in group III on the first postoperative day. The results demonstrate that IGT has some potential benefit for glucose metabolism and myocardial function during cardiac surgery.     

Glucose and amino acid uptake by exercising muscles in vivo: effect of insulin, fiber population, and denervation

The first series of experiments was performed on control rats. The animals were injected iv with trace amounts of 2-deoxy-D-[1-14C]glucose [( 14C]DG) or alpha-[1-14C] aminoisobutyric acid with or without 0.1 U insulin/rat, and calf muscles of the right hindlimb were electrically stimulated to induce 1 contraction/sec. The exercise was discontinued 25 min after the injection, and cellular uptakes of DG or aminoisobutyric acid by soleus, plantaris, and gastrocnemius muscles in disintegrations per min/mg dry tissue weight were determined. The results of these experiments demonstrated that basal, insulin-induced, and exercise-induced uptakes of glucose and amino acids by muscles are dependent on muscle fiber population, and the stimulatory effects of exercise and insulin on soleus and plantaris muscles, but not gastrocnemius muscles, are synergistic rather than merely additive when both stimuli act together. The second series of experiments was performed in the same manner as the first series, except that the right hindlimb of each rat was denervated 3 days before the experiment. Cellular DG uptakes were determined in soleus, plantaris, and gastrocnemius muscles of the left (sham) hindlimb, which was always resting, and in corresponding muscles of the right (denervated) limb, which was either resting or exercising. In the resting state, the denervated soleus muscle had normal basal DG uptake, but, unlike sham soleus muscle, did not respond to insulin stimulation. Denervated plantaris and gastrocnemius muscles exhibited 264% and 150% elevations in basal glucose uptake, respectively, compared with corresponding sham muscles. The latter two denervated muscles did respond to insulin, but the hormone-induced increments in DG uptake were 68% and 45%, respectively, lower than in corresponding contralateral sham muscles. Under basal conditions, exercise had no effect on DG uptake by the denervated soleus muscle, but increased uptake by denervated plantaris and gastrocnemius muscles 207% and 778%, respectively. Stimulation of exercising denervated muscles with exogenous insulin did not increase DG uptake by any muscle above the level observed with exercise alone. The results show that manifestations of insulin resistance in denervated muscles depend on muscle fiber population; denervated muscles, which still retain some ability to respond to insulin, increase DG uptake during exercise, whereas such an increase is absent in denervated muscles completely unresponsive to insulin; and exercise does not improve or restore the ability of denervated muscles to respond to insulin.     

Effect of sulphonylurea administration on insulin secretion and amino acid metabolism in non-insulin-dependent diabetic patients

Sulphonylureas lower blood glucose but other metabolic effects have been little studied. In an assessment of carbohydrate and amino acid metabolism in 9 patients with non-insulin-dependent diabetes mellitus (NIDDM) before and after 3 months' therapy with gliclazide, glycaemic control was improved (mean +/- S.D. glycosylated haemoglobin 13.8 +/- 1.9% before therapy, 10.2 +/- 2.1% after therapy (p less than 0.01], but fasting amino acid levels were not altered. In contrast, postprandial levels of branched chain amino acids (BCAA) were significantly reduced: total BCAA (valine, leucine, and isoleucine) 120 mins following a standard test meal fell from 717 +/- 71 mumol/l before therapy to 600 +/- 90 mumol/l after 3 months' therapy (p less than 0.01). This finding implies an increased action of endogenous insulin on skeletal muscle to promote uptake of BCAA postprandially and, in accord with this, peripheral insulin levels were significantly increased following drug treatment (peak insulin level 55.6 +/- 20.2 mU/l before therapy, 91.3 +/- 17.9 mU/l after therapy (p less than 0.01]. Sulphonylurea drugs therefore do not simply have a hypoglycaemic action but also affect amino acid metabolism in NIDDM patients.     

Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid.

The leucine analog beta-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) activates glutamate dehydrogenase [L-glutamate:NAD+ oxidoreductase (deaminating), EC 1.4.1.2] in pancreatic islet homogenates. In intact islets, BCH increased the islet content or output of NH4+, 2-ketoglutarate, malate, pyruvate, and alanine. BCH caused a dose-related increase in 14CO2 output from islets prelabeled with L-[U-14C]glutamine. BCH increased the islet content of ATP and stimulated both 45Ca net uptake and insulin release. The capacity of seven distinct amino acids to activate glutamate dehydrogenase tightly correlated with their ability to augment 14CO2 output from islets prelabeled with [U-14C]-glutamine and to stimulate insulin release in the presence of L-glutamine. The activation of glutamate dehydrogenase by BCH may thus account for the insulin-releasing capacity of the leucine analog.     

Glucose metabolism and insulin sensitivity in patients on chronic hemodialysis

In order to evaluate the potential role of parathyroid hormone on glucose metabolism in patients on chronic hemodialysis hyperglycemic clamp studies were performed in 7 parathyroidectomized and 11 nonparathyroidectomized patients on chronic hemodialysis and in healthy controls. There were no significant differences in the peripheral glucose uptake of the 3 groups. The beta cell response to hyperglycemia during the early phase as well as during the steady state was almost identical in controls and in nonparathyroidectomized uremics, whereas in the parathyroidectomized group a markedly enhanced insulin secretion was found. Calculated tissue sensitivity to insulin therefore was equal in controls and in nonparathyroidectomized uremics, whereas patients after parathyroidectomy had peripheral insulin resistance. Our results demonstrate that patients on chronic hemodialysis apparently have normal peripheral glucose uptake. The subgroup of patients who have undergone parathyroidectomy, however, show an enhanced insulin response to hyperglycemia suggesting peripheral insulin resistance. We conclude that longstanding and severe secondary hyperparathyroidism--the usual cause for parathyroidectomy in these patients--results in irreversible insulin resistance with a compensatory increase of insulin secretion.