Whole body protein turnover,studied with 15N-glycine,and muscle protein breakdown in mildly obese subjects during a protein-sparing diet and a brief total fast

A modification of the Picou and Taylor-Roberts Model was used to estimate rates of total body protein synthesis (S), breakdown (C), and amino nitrogen (N) flux (Q) in the metabolic N pool of five obese females. The subjects were fed egg white albumin at 1.5/kg ideal body weight (IBW) and total calories at 1.2 times the basal energy expenditure (fat:carbohydrate = 30%:50%) as a formula diet (period 1, 1 wk). This was followed by 3 wk during which the nonprotein calories were omitted (period 2, protein-sparing modified fast [PSMF]) and a 1-wk total fast (period 3). Estimates of body protein turnover and skeletal protein breakdown were made during the last 60 and 48 hr, respectively, of each period. Q, S, and C were 223 ± 22, 154 ± 22, and $\text{150 ± 22 g protein}\text{24 hr}$, respectively, for period 1. These values were unchanged at the end of period 2. Total fasting decreased Q and S by 36% and 27%, respectively (p < 0.001), but C remained unchanged. Skeletal protein breakdown, as estimated by urinary Nτ-methylhistidine excretion, was 108 ± 47 μmole in period 1, 79 ± 51 μmole in period 2 (p < 0.01), and 100 ± 49 μmole in period 3, representing 16 ± 5%, 12 ± 5% (p < 0.01), and 16 ± 4% of whole body breakdown. N balance was unchanged in period 1 (?0.4 ± 1.2 g N) and the final week of period 2 (?0.4 ± 1.5 g N), but was ?5.8 ± 0.6 g N in period 3. These data indicate that weight reduction with a PSMF is associated with a maintenance of total body protein turnover parameters and N balance but a reduction in skeletal protein breakdown, whereas a total fast causes a marked reduction in whole body protein synthesis and amino N flux with little change in the rate of total body and skeletal protein breakdown, resulting in a negative N balance. The minimization of N losses that develops after prolonged starvation is achieved at rates of whole body and skeletal protein breakdown similar to those found when the diet is adequate, suggesting that endogenous fat-derived fuels are as effective as exogenous energy in limiting protein catabolism. However, protein intake is necessary to maintain whole body protein synthesis under these conditions.     

Protein metabolism during total parenteral nutrition (TPN) in injured rats using medium-chain triglycerides

There are metabolic limitations to the infusion of large quantities of dextrose in critically ill patients receiving total parenteral nutrition. Of the alternative, nonprotein lipid sources, medium chain triglycerides (carbon chain length 8 and 10) are more rapidly oxidized and are deposited in the adipose tissue at rates much less than long chain triglycerides. In rats with burn injury receiving hypocaloric (dextrose and amino acids) parenteral feeding, we studied the changes in protein metabolism as a result of increasing the caloric intake by 33% by the addition of either dextrose, a soybean oil emulsion, a medium chain triglyceride emulsion, or a structured lipid emulsion of triglycerides synthesized from safflower oil (40%) and medium chain triglycerides (60%). Changes in body weight, blood glucose concentration, beta-hydroxybutyrate, lactate, amino acids, insulin, albumin, liver protein content, and nitrogen balance were measured during three days of feeding. Whole body leucine kinetics and muscle protein fractional synthetic rate were evaluated using a constant intravenous infusion of L-[1-14C]leucine. The addition of dextrose or soybean oil emulsion produced a significant increase in body weight and liver nitrogen but did not change albumin concentrations or leucine kinetics compared to those of the hypocaloric feeding group. Rats receiving medium chain triglycerides and structured lipid emulsions showed a reduction in branched chain amino acid concentrations and an improvement in serum albumin levels. However, the rats receiving the structured lipid emulsion also showed increased body weight, had a significant decrease in leucine oxidation, and showed a three day cumulative nitrogen balance significantly greater than zero.(ABSTRACT TRUNCATED AT 250 WORDS)     

The human metabolic response to chronic ketosis without caloric restriction: Preservation of submaximal exercise capability with reduced carbohydrate oxidation

To study the effect of chronic ketosis on exercise performance in endurance-trained humans, five well-trained cyclists were fed a eucaloric balanced diet (EBD) for one week providing 35–50 kcal/kg/d, 1.75 g protein/kg/d and the remainder of kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD), isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented to meet the recommended daily allowances for vitamins and minerals. Pedal ergometer testing of maximal oxygen uptake (V?O₂max) was unchanged between the control week (EBD-1) and week 3 of the ketogenic diet (EKD-3). The mean ergometer endurance time for continuous exercise to exhaustion (ENDUR) at 62%–64% of V?O₂max was 147 minutes at EBD-1 and 151 minutes at EKD-4. The ENDUR steady-state RQ dropped from 0.83 to 0.72 (P < 0.01) from EBD-1 to EKD-4. In agreement with this were a three-fold drop in glucose oxidation (from 15.1 to 5.1 mg/kg/min, P < 0.05) and a four-fold reduction in muscle glycogen use (0.61 to 0.13 mmol/kg/min, P < 0.01). Neither clinical nor biochemical evidence of hypoglycemia was observed during ENDUR at EKD-4. These results indicate that aerobic endurance exercise by well-trained cyclists was not compromised by four weeks of ketosis. This was accomplished by a dramatic physiologic adaptation that conserved limited carbohydrate stores (both glucose and muscle glycogen) and made fat the predominant muscle substrate at this submaximal power level.     

The human metabolic response to chronic ketosis without caloric restriction: Physical and biochemical adaptation

To study the metabolic effects of ketosis without weight loss, nine lean men were fed a eucaloric balanced diet (EBD) for one week providing 35–50 kcal/kg/d, 1.75 g of protein per kilogram per day and the remaining kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD)—isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented with minerals and vitamins. Weight and whole-body potassium estimated by potassium-40 counting (⁴⁰K) did not vary significantly during the five-week study. Nitrogen balance (N-Bal) was regained after one week of the EKD. The fasting blood glucose remained lower during the EKD than during the control diet (4.4 mmol/L at EBD, 4.1 mmol/L at EKD-4, P < 0.01). The fasting whole-body glucose oxidation rate determined by a ¹³C-glucose primed constant infusion technique fell from 0.71 mg/kg/min during the control diet to 0.50 mg/kg/min (P < 0.01) during the fourth week of the EKD. The mean serum cholesterol level rose (from 159 to 208 mg/dL) during the EKD, while triglycerides fell from 107 to 79 mg/dL. No disturbance of hepatic or renal function was noted at EKD-4. These findings indicate that the ketotic state induced by the EKD was well tolerated in lean subjects; nitrogen balance was regained after brief adaptation, serum lipids were not pathologically elevated, and blood glucose oxidation at rest was measurably reduced while the subjects remained euglycemic.     

Structured medium-chain and long-chain triglyceride emulsions are superior to physical mixtures in sparing body protein in the burned rat

The present study was undertaken to compare the effectiveness of a physical mixture of long-chain and medium-chain triglycerides with an emulsion consisting of chemically synthesized triglycerides composed of medium-chain and long-chain fatty acids in similar proportions. Sprague-Dawley rats received a 25% body surface area full-thickness scald burn on the dorsum. For the next three days, all rats received 300 kcal/kg/day as 160 kcal/kg/day glucose, 50 kcal/kg/day amino acid, and an additional 90 kcal/kg/day lipid emulsion as either long-chain triglyceride, medium-chain triglyceride, a 1:1 physcial mix of medium-chain and long-chain triglycerides or a chemically structured triglyceride made up of 60% medium-chain fatty acid and a 40% safflower oil. Rats receiving the chemically structured lipid emulsion showed the greatest gain in body weight, the greatest positive nitrogen balance, and the highest serum albumin concentration, outstripping rats receiving the long-chain triglyceride, medium-chain triglyceride, and even the physical mixture long-chain and medium-chain trigylcerides (P < 0.01). A 30% increase in oxygen consumption and 35% increase in energy expenditure in rats given the medium-chain triglyceride emulsion alone (P < 0.01) was observed. This study confirms that the metabolism of chemically structured triglycerides composed of medium-chain and long-chain fatty acids markedly differs from similar physical mixtures. For these reasons, the new structured lipid emulsions may prove advantageous in feeding the severely injured patient.     

In vivo demonstration of nitrogen-sparing mechanisms for glucose and amino acids in the injured rat

Changes in protein metabolism 8 hr after anesthesia and femur fracture were studied in healthy rats fasted or receiving either intravenous glucose or crystalline amino acids. Whole body rates of amino acid turnover (flux) and release from protein (breakdown) as well as fractional synthetic rates of mixed muscle, liver, and plasma protein were measured using the constant infusion of L-(I-¹⁴C)-leucine. Injury resulted in a 24% and 63% increase in the synthesis of liver (p < 0.05) and plasma proteins (p < 0.01), respectively. Amino acid infusions in the injured animals further increased the synthesis of liver protein (from 36.6% to 44.3%/day, p < 0.05) and increased muscle protein synthesis (from 7.0% to 9.3%/day, p < 0.05) without altering rates of protein breakdown. Glucose infusions, in contrast, reduced whole body protein breakdown 36% (p < 0.05) when compared to fasting, and depleted the plasma essential amino acid pool (p < 0.05). The usual increases in liver protein synthesis observed in fasted rats following injury were not seen when the animals were receiving intravenous glucose. The nitrogen-sparing mechanism of these two infusions are different. Protein-free glucose infusions impair the normal response to injury aimed at increasing visceral protein synthesis and maintaining plasma essential amino acid concentrations.     

The influence of intravenous nutrition on protein dynamics following surgery

Rates of whole body protein turnover were measured in 13 adult patients one day following abdominal surgery. A constant intravenous infusion of L-(1-¹⁴C)-leucine was used to estimate rates of whole body protein flux, synthesis, breakdown and fractional synthesis rates of albumin and mixed globulins. After a baseline measurement when saline was infused, patients were assigned to one of three groups in order to assess the relative effects of three hypocaloric intravenous nutrition regimens upon these rates. Group A (n = 5) was given 108 g/day of crystalline L-amino acids. Group D (n = 4) received 216 g/day of glucose and 22 units of insulin/day. Group AD (n = 4) received a combination of the two regimens (108 g/day amino acids, 216 g/day glucose and 22 units insulin/day). The two isotope infusion studies lasted 20 hr after which the specific intravenous diet was continued for a total of three days. The amino acid infusion increased whole body protein flux from 3.07 g/kg ideal body weight · day to 4.56 g/kg ideal body weight · day (p < 0.05), amino acid oxidation from 0.59 g/kg ideal body weight · day to 1.82 g/kg ideal body weight · day (p < 0.05) and improved protein balance from −0.59 g/kg ideal body weight · day to −0.12 g/kg ideal body weight · day (p < 0.05). Plasma globulin synthesis was also increased from 19.2%/day to 36.0%/day (p < 0.05). In contrast, glucose and insulin infusions reduced amino acid oxidation from 0.54 g/kg ideal body weight · day to 0.35 g/kg ideal body weight · day (p < 0.05) by decreasing the rate of protein breakdown (from 3.09 g/kg ideal body weight · day to 2.55 g/kg ideal body weight · day). Both globulin and albumin synthesis were also reduced from 26.1%/day to 18.8%/day (p < 0.05) and 7.5%/day to 4.2%/day (p < 0.05), respectively. The combined regimen of amino acids, glucose and insulin produced the greatest improvement in protein balance from −0.42 g/kg ideal body weight · day to +0.83 g/kg ideal body weight · day (p < 0.05) through a reduction in protein breakdown and an increase in protein synthesis. However, plasma protein synthesis was not significantly affected. Amino acid oxidation rates were positively correlated to the rate of nitrogen excretion in the urine when dietary intake was constant (r = 0.84, p < 0.01). Further significant correlations were observed between whole body protein flux and body weight (r = 0.70), amino acid intake and whole body protein synthesis (r = 0.82), flux and amino acid oxidation (r = 0.60), flux and globulin (r = 0.65) and albumin synthesis (r = 0.54) and finally, oxidation and globulin synthesis (r = 0.69). The positive correlations observed between protein flux and whole body and plasma protein synthesis suggest that increased amino acid availability promotes whole body and plasma protein synthesis. Protein synthesis is supported in postoperative patients by amino acid containing infusions and suppressed by solutions containing only glucose and insulin.     

Metabolism of apolipoproteins CII,CIII1, CIII2 and VLDL-B in human subjects consuming high carbohydrate diets

Simultaneous kinetics of apoproteins CII, CIII₁ and CIII₂ and VLDL-B were determined in six normal subjects initially while consuming a control diet and subsequently while consuming a high carbohydrate diet. Mean triglyceride levels in plasma and VLDL were significantly increased, from 110 to 173 mg/dl and 40 to 114 mg/dl respectively, by the high carbohydrate diet. Specific radioactivity of each C peptide was determined, following injection of ¹²⁵I-VLDL, in both VLDL and HDL from plasma samples taken over 48 hr using a technique involving analytical isoelectric focusing. Specific activity vs time curves for VLDL and HDL were almost superimposable on either diet, suggesting that CII, CIII₁ and CIII₂ were catabolized as a group. The high carbohydrate diet resulted in a significant increase in the mass of each C peptide which was brought about by an increase in production since no change in fractional removal rate (FRR) was observed. The pool size of VLDL apo B was also significantly increased and was a function of both increased production as well as decreased FRR. The proportion of CIII₂ mass relative to those of CII and CIII₁ was lower in both VLDL and HDL with the high carbohydrate diet. These observations indicate that the metabolism of the B and C apoproteins are independent of each other and do not respond in the same manner to changes in VLDL triglyceride and that increased triglyceride synthesis and secretion stimulates C apoprotein production.     

Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridemia

In this report, kinetic studies of plasma very low-density lipoprotein-triglyceride (VLDL-TG) were examined in five brothers (three affected and two unaffected) from a family with primary hypertriglyceridemia. Synthesis and catabolism of VLDL-TG were studied by in vivo labelling of plasma TG with 3H-glycerol, and multicompartmental analysis of the plasma die-away curves. Results of the kinetic studies revealed the following information: (1) one brother, who had the highest plasma TG level and was obese, had both overproduction and a reduced fractional catabolic rate (FCR) of VLDL-TG; (2) second brother, who had moderate hypertriglyceridemia, had a low FCR and high-normal synthesis of VLDL-TG; (3) a third, who had only mildly elevated TG, had a low FCR and normal synthesis of VLDL-TG; and (4) the two normolipidemic brothers had neither overproduction nor decreased FCR of VLDL-TG. The composition of the soluble apoproteins of VLDL was normal. The apoprotein E phenotypes were E4/3 in four brothers, and E3/2 in the fifth. We have reached the following conclusions regarding this family: (1) the common kinetic abnormality of VLDL-TG metabolism in the hypertriglyceridemic brothers was a low clearance of VLDL-TG; (2) impaired catabolism of VLDL could not be explained by the apoprotein C or E patterns; and (3) the most severe hypertriglyceridemia occurred when the decreased FCR was present in conjunction with VLDL-TG overproduction due to obesity. Thus, a moderate defect in catabolism of plasma TG appears to be responsible for one familial form of primary hypertriglyceridemia.     

The effect of diabetic control on very low-density lipoprotein--triglyceride metabolism in patients with type II diabetes mellitus and marked hypertriglyceridemia

We examined the effect of diabetic control on very low-density lipoprotein-triglyceride (VLDL-TG) metabolism in six patients with type II (noninsulin-dependent) diabetes mellitus and marked hypertriglyceridemia. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were evaluated by multicompartmental analysis. Studies were performed in the hypertriglyceridemic diabetic subjects during poor diabetic control and again after 3 months of diabetic treatment, and the results were compared to studies in nondiabetic normolipidemic subjects and nondiabetic subjects with familial forms of hypertriglyceridemia. In the poorly controlled diabetics, mean VLDL-TG synthesis was threefold higher than in the normolipidemic subjects, and the mean fractional catabolic rate (FCR) of VLDL-TG was only one-third of the normals. With diabetic treatment, plasma triglyceride levels fell by more than 50%, but remained fourfold higher than the normals. This was associated with a decrease in mean VLDL-TG synthesis to a level similar to that observed in the genetic hyperlipidemic subjects, but still 2.6-fold higher than the normals. In addition, the mean FCR rose after diabetic control to a level slightly above that of the genetic hyperlipidemic subjects, but remained less than one-half of the normal value. However, the response of VLDL-TG kinetics to diabetic treatment was not uniform. In four subjects, control of hyperglycemia ameliorated the hypertriglyceridemia primarily by decreasing VLDL-TG overproduction. In the other two subjects, diabetic treatment had a greater effect on the FCR than an overproduction of VLDL-TG. Thus, in this select group of diabetic, hypertriglyceridemic subjects, poor diabetic control contributed to both VLDL-TG overproduction and low FCRs. Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for coordinate genetic control of Na,K pump density in erythrocytes and lymphocytes

The erythrocyte is widely used as a model cell for studies of the Na,K pump in health and disease. However, little is known about the factors that control the number of Na,K pumps expressed on the erythrocytes of a given individual, nor about the extent to which erythrocytes can be used to validly assess the pump density on other cell types. In this report, we have compared the interindividual variance of Na,K pump density in erythrocytes of unrelated individuals to that seen with identical twins. Unlike unrelated individuals, in whom pump parameters, ie, ouabain binding sites. 86Rb uptake, cell Na concentration vary widely, identical twin pairs showed no significant intrapair variation for these values. Thus, a role for genetic factors is suggested. In addition, we established and validated a method for determining Na,K pump density and pump-mediated 86Rb uptake in human peripheral lymphocytes. Using this method, we show that whereas Na,K pump density differs markedly between erythrocytes (mean of 285 sites per cell) and lymphocytes (mean 40,600 sites per cell), there is a strong and highly significant correlation (r = 0.79, P less than 0.001) between the pump density in these cell types in any given individual. Taken together, these studies suggest that genetic factors are important determinants of Na,K pump expression, and that pump density appears to be coordinately regulated in two cell types in healthy individuals.     

A method for the rapid determination of protein turnover

In order to shorten the time necessary to measure rates of protein synthesi and catabolism, we primed the urea pool with [¹⁵N₂] urea prior to a primed constant infusion of L[α-¹⁵N]lysine. After determining the correct [¹⁵N₂] urea prime in dogs, we duplicated this method in humans. Our data indicate an isotopic equilibrium in nitrogen derived from urinary urea can be achieved within 2 hr. Our technique therefore enables the measurement of acute changes in rates of whole body protein synthesis and catabolism.     

Pathways of insulin degradation in isolated adipocytes: evaluation by gel filtration and differential precipitation

Insulin degradation by isolated rat adipocytes was evaluated using gel filtration and a new technique of differential precipitation to fractionate the sample by molecular size using polyethylene glycol and trichloracetic acid. At 37 degrees C, 125I-insulin bound to adipocytes was rapidly degraded into small fragments or iodotyrosine. 125I-insulin in the medium was also degraded into iodotyrosine, as well as fragments intermediate in molecular weight between insulin and iodotyrosine. Lowering the temperature to 15 degrees C or adding bacitracin to the medium inhibited degradation in the medium but had little effect on cell-associated degradation. Methylamine, on the other hand, inhibited cell-associated degradation, but had little effect on the insulin degradation in the medium. Addition of methylamine or bacitracin or lowering of the temperature increased the amount of 125I-insulin bound to the cell and prolonged the steady-state of binding. Bacitracin also produced a slight shift to the left in the dose response curve for insulin-stimulated glucose oxidation. Methylamine increased basal glucose oxidation, but had no effect on insulin sensitivity as measured in the glucose oxidation bioassay. These data suggest that isolated adipocytes in vitro exhibit at least two distinct pathways of insulin degradation, a cell-associated pathway which can be inhibited by methylamine and a medium pathway which can be inhibited by bacitracin. Neither pathway, however, appears to be closely linked to insulin's ability to stimulate glucose metabolism in these cells.     

Metabolic effects of high-protein diets in Zucker rats

The effects of dietary protein on the metabolism of proteins, carbohydrates, and especially, lipids were investigated in genetically obese Zucker rats and their lean siblings. For 40 days the rats received diets containing 15%, 64%, or 82% protein, included at the expense of cornstarch. In the obese animals, the high-protein diets led to decreased food intake and weight gain. While these diets decreased the activities of lipogenic enzymes along with the lipid gain, they did not decrease the final body-fat content. The increase protein intake stimulated hepatic ureogenesis and gluconeogenesis. Lipolysis was stimulated, as demonstrated by an accumulation of ketone bodies in the liver. Blood levels of triacylglycerols, free glycerol, and nonesterified fatty acids were concomitantly decreased, which suggests an accelerated turnover of lipids. Whatever the composition of the diet, total energy retention of the lean rats was always less than that of the obese rats. The changes observed on high-protein diets were essentially the same for the two groups, except that the final body-content of lipids in the lean rats was significantly lower. In the absence of exogenous carbohydrate, the lean rats were barely able to retain nitrogen and to maintain hepatic lipogenesis. Unlike the rats from other strains, the lean Zucker rats could not adapt to a low-carbohydrate diet; this failure may be due to a metabolic disorder.     

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.     

Insulin, growth hormone, and glucagon in prediabetes mellitus — A review

Insulin, growth hormone, and glucagon responses have been extensively studied in “prediabetic” man by a variety of perturbations. Insulin responses have been reported to be high, normal, or low. Growth hormone levels appear generally to be high. Glucagon levels have received only scant attention, but the available information suggests an enhanced response. It appears that a better definition of the prediabetic state is required in addition to techniques that can adequately quantify both secretion and clearance rates of these hormones.     

The effects of hyperinsulinemia on arterial wall and peripheral muscle metabolism in dogs

Peripheral hyperinsulinemia may be associated with metabolic consequences that could contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. Arterial wall and striated muscle cells were studied in dogs to examine the effect of hyperinsulinemia on the lipid content and on lipogenic and glycolytic enzyme activity. Eight pancreatectomized dogs received segmental pancreatic autografts with venous drainage into the iliac vein. Glucose disappearance rates (K values) were normal four years after transplantation, but both fasting serum insulin levels (48.9 +/- 4.8 v 11.8 +/- 1.9 microU/mL) and the total area under the glucose-insulin response curve (1797 +/- 196 v 1110 +/- 158 microU X min/mL) were significantly greater than in control animals (P less than 0.05). The hyperinsulinemic dogs had a marked triglyceride elevation in arterial smooth muscle (20.6 +/- 8.0 v 0.5 +/- 0.4 mumol/g) and striated muscle (171.4 +/- 46.6 v 41.2 +/- 7.7 mumol/g) (P less than 0.001). Moreover, key enzymes in lipid synthesis (glucose-6-phosphate dehydrogenase, malic enzyme, and 3-hydroxyacyl-CoA DH) were significantly increased (P less than 0.01) in the hyperinsulinemic animals, while the glycolytic enzymes, (phosphofructokinase, hexokinase, pyruvate kinase, and alpha-glycerophosphate DH) were not significantly different. These data demonstrate substantial enhancement of lipid synthesis in arterial wall and striated muscle in hyperinsulinemic dogs. Altered substrate metabolism in arterial walls, in association with hyperinsulinemia, may have important implications with regard to macrovascular disease in diabetes, particularly in insulin-treated patients. In addition, these studies may serve to stimulate longer term assessments of macroangiopathy in the increasing number of patients with functioning pancreatic allografts draining into the systemic circulation.     

Improved carbohydrate tolerance and stimulation of carbohydrate oxidation and lipogenesis during short-term carbohydrate overfeeding

The carbohydrate intake of seven healthy men was increased from 220-265 g/d to 620-770 g/d for 17 days, while protein and fat intake remained constant. Carbohydrate loading did not affect the preprandial plasma glucose levels after an overnight fast, but reduced the postprandial increment in plasma glucose levels after 5, 11, and 17 days of overfeeding. Preprandial plasma insulin levels were slightly increased during carbohydrate overfeeding, but no increase in the postprandial rise in insulin levels was found until 11 days after the start of carbohydrate loading. Whole-body rates of carbohydrate oxidation and of glucose conversion to fat were estimated by indirect calorimetry. Basal carbohydrate oxidation rate was increased by 95% at the end of 17 days of overfeeding, but there was no potentiation in the stimulation of the carbohydrate oxidation rate induced by a meal. There was no net fat synthesis from glucose before carbohydrate loading; carbohydrate overfeeding produced nonprotein respiratory exchange ratios greater than 1.00, suggesting net fat synthesis from glucose. Meals did not stimulate net lipogenesis from glucose, either before or after overfeeding. These results indicate that the improvement in carbohydrate tolerance associated with short-term carbohydrate loading does not appear to depend on elevated insulin levels. Increased carbohydrate oxidation and lipogenesis elevated carbohydrate disposal is more than necessary to account for the improvement in carbohydrate tolerance.     

Glucose metabolism in glucose-intolerant older people during chromium supplementation

The effects of chromic chloride (CrCl3) administered orally for 12 weeks to five elderly subjects with glucose intolerance were assessed. Pretreatment and posttreatment, the hyperglycemic clamp technique was employed to determine glucose utilization, beta-cell sensitivity to glucose, and tissue sensitivity to insulin. In addition, erythrocyte insulin binding was studied. Urinary chromium excretion increased approximately 5 fold indicating good compliance with supplementation. The oral glucose tolerance curves following supplementation were lowered from 60 to 120 minutes but only the 60-minute values were significantly lowered. In agreement with this was significantly increased glucose utilization during the hyperglycemic clamp studies. Tissue sensitivity to insulin, receptor affinity, and total insulin binding were unchanged by supplementation while beta-cell sensitivity to glucose increased following supplementation (P less than 0.04), and explained the increased glucose utilization. HDL and LDL and total cholesterol levels were slightly lower after chromium supplementation, but no change reached statistical significance. The LDL/HDL cholesterol ratio was unchanged. This study shows small but statistically significant effects of CrCl3 on carbohydrate metabolism. The clinical relevance of these effects, that is, their prophylactic or therapeutic significance, remains to be determined.