James J. Reilly

Role of Reduced Suppression of Glucose Production and Diminished Early Insulin Release in Impaired Glucose Tolerance

BACKGROUND Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.

Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM.

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g, P less than 0.01), but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.

Nutritional Support after Liver Transplantation: A Randomized Prospective Study

Nutritional support in patients with advanced cirrhosis is difficult due to protein, fluid and salt restrictions. Successful liver transplantation should improve nutrient tolerance. We randomly assigned 28 hypoalbuminemic cirrhotic patients to receive, immediately after liver transplantation, one of three regimens: group 1, no nutritional support (n = 10); group 2, total parenteral nutrition (TPN) (35 kcal/kg/day) with standard amino acids (1.5 g/kg/day) (n = 8); or group 3, isocaloric isonitrogenous TPN with added branched-chain amino acids (n = 10). Therapy was continued for 7 days posttransplant. Jaundice resolution was unaffected by nutritional support. Nitrogen balance favored both TPN groups. Branched-chain amino acid (BCAA) aromatic amino acid ratios were highest in group 3. Coma scores and serum ammonia levels were similar in all groups. Both TPN groups achieved respirator independence earlier; this difference was not statistically significant. Group 1 patients stayed longest in ICU; the difference was statistically significant. TPN with either standard or BCAA- enriched amino acids is tolerated well immediately after successful liver transplant. Positive nitrogen balance is achieved; large protein loads do not worsen encephalopathy. Nutritional support may improve respiratory muscle function, allowing earlier weaning from ventilatory support. A shortened length of ICU stay justifies the expense of TPN.

Indwelling venous access catheters in patients with acute leukemia

Reliable venous access is often a serious problem in the cancer chemotherapy patient. In one year, the authors of this report have inserted 26 chronic double‐lumen silastic Hickman catheters in 25 acute leukemia patients. Each patient received an average 12 courses of combination chemotherapy, 11.5 packed red blood cell units, 48.0 platelet units, 4.2 fresh frozen plasma units, and numerous antibiotic doses via the catheters, which remained in situ 101 ± 97.4 days. Complications included early hemorrhage in two cases, and catheter occlusion in six. Four catheters were removed for occlusion. Fourteen patients suffered bacteremia, predominantly due to gram‐negative organisms; six catheters were removed for persistent sepsis. The remaining catheters remained functional until death or elective removal. Eight patients are currently alive as outpatients with functional catheters. The Hickman catheter effectively achieves reliable venous access in the cancer patient. The risks of catheter sepsis must be considered carefully in the immunosuppressed, leukopenic patient.

Manganese levels in a jaundiced long-term total parenteral nutrition patient: potentiation of haloperidol toxicity?: Case report and literature review.

Manganese is vital in human nutrition. When oral intake is precluded, the recommended parenteral supplementation is 0.15 to 0.8 mg/day. Manganese is excreted primarily in the bile; during cholestasis, serum manganese levels may rise, and manganese toxicity ensue. Neuropsychiatric symptoms are prominent. Phenothiazine-derivative drugs may potentiate manganese toxicity. Serum or whole blood manganese levels should guide manganese therapy in jaundiced patients.

Blood glucose extraction as a mediator of perceived exertion during prolonged exercise

SummaryThe effect of blood glucose extraction on the perception of exertion was examined during prolonged arm exercise. Eight male subjects consumed in counterbalanced order a standard daily diet containing either (1) 75 g dihydroxyacetone and 25 g sodium pyruvate (DHAP) or (2) an isocaloric amount of placebo, to manipulate blood glucose extraction. Following each 7-day diet, subjects exercised to exhaustion at 60% of peak arm oxygen consumption. Ratings of perceived exertion (Borg, CR-10 scale) were obtained for the arms (RPE-A), legs (RPE-L), chest (RPE-C) and overall body (RPE-O) every 10 min of exercise. After 60 min of continuous exercise, blood samples were drawn from the radial artery and axillary vein. Ratings of perceived exertion did not differ between trials during the first 50 min of exercise. At the 60-min time point, perceived exertion was lower (P < 0.01) in the DHAP than placebo trials for the arms (RPE-A: 4.25 vs 5.50) and overall body (RPE-O: 3.25 vs 4.00). These differences persisted throughout exercise. RPE-L and RPE-C did not differ between trials. Whole-arm arterial-venous glucose difference was higher (P < 0.05) in the DHAP (1.00 mmol · 1−1) than placebo (0.36 mmol·1−1) trials, as was fractional extraction of glucose (22.5 vs 9.0%). Respiratory exchange ratio was the same between trials. Triceps muscle glycogen was (1) higher in the DHAP than placebo trial at pre-exercise (P < 0.05), (2) decreased during exercise and (3) did not differ between trials at exercise termination. Free fatty acids, glycerol, β-hydroxybutyrate, lactic acid, pH, norepinephrine and epinephrine did not differ between trials. These findings suggest that blood glucose extraction mediates the perceived intensity of exertion arising from active limbs during prolonged arm exercise.

Contribution of Impaired Muscle Glucose Clearance to Reduced Postabsorptive Systemic Glucose Clearance in NIDDM

The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified, it is generally assumed to be primarily muscle, the major site of insulin-mediated glucose disposal. To test this hypothesis, we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weightmatched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 ± 0.5 vs. 11.2 ± 0.2 μmol · kg−1 · min−1, P < 0.001), systemic glucose clearance was reduced 1.40 ± 0.06 vs. 2.13 ± 0.05 ml · kg−1 · min−1, P < 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 ± 0.058 vs. 0.411 ± 0.019 μmol · dl−1 · min−1, P < 0.001), forearm glucose dl−1 clearance was reduced (0.628 ± 0.044 vs. 0.774 ± 0.037 ml · L−1 · min−1, P < 0.01). However, extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 ± 21 μmol<min, whereas impaired systemic clearance reduced systemic glucose disposal by 662 ± 82 μmol<min. Thus, impaired muscle glucose clearance accounted for <10% of the reduced systemic glucose clearance in NIDDM subjects. Therefore, we conclude that muscle insulin resistance plays only a minor role in the reduced systemic glucose clearance found in NIDDM in the postabsorptive state and propose that reduced brain glucose clearance is largely responsible.

Jejeunal Variceal Hemorrhage: An Unusual Complication of Needle Catheter Jejeunostomy

Needle catheter jejeunostomy is a useful method for providing fluid and nutritional support in selected patients after laparotomy. The technique is widely used, and complications are infrequent. We report herein a new complication of this procedure. A cirrhotic patient with portal hypertension underwent needle catheter jejeunostomy subsequent to esophageal transection for esophageal hemorrhage. The catheter functioned satisfactorily in the postoperative period and was removed before discharge. Approximately 1 yr later, gastrointestinal hemorrhage recurred which was localized to the site of the previous needle catheter jejeunostomy. Portasystemic collaterals between the small bowel and the abdominal wall at the jejeunostomy were the source of bleeding. Take-down of the jejeunostomy site and resection of the involved bowel successfully controlled hemorrhage. Needle catheter jejeunostomy may be contraindicated in patients with portal hypertension.

Amino acid arterial concentration and muscle exchange during submaximal arm and leg exercise: The effect of dihydroxyacetone and pyruvate

The mixture of dihydroxyacetone and pyruvate (DHAP) is an ergogenic aid that enhances muscle glucose extraction during prolonged aerobic exercise. In order to evaluate the effect of DHAP on muscle amino acid extraction during exercise, we measured arterial concentration and muscle exchange of amino acids in 18 untrained healthy male subjects (aged 20-30 years) performing dynamic arm (60% VO2 max, n = 9) or leg (70% VO2 max, n = 9) exercise to exhaustion with and without dietary supplementation of DHAP. The subjects consumed diets (146 kJ kg body weight-1 day-1) containing either 100 g polyglucose, Polycose (placebo, P) or DHAP (3:1, treatment) substituted for a portion of carbohydrate. The two diets were administered in a double-blind, random, crossover order for a 7-day period. At least 7 days separated the dietary protocols. Blood samples were drawn through radial artery and axillary or femoral vein catheters at rest, during exercise and at exhaustion. Arterial alanine concentration increased by 30% during arm exercise and by 50-60% during leg exercise. No other arterial amino acid concentration changed during exercise. At exhaustion, arterial alanine concentration decreased to pre-exercise levels with arm exercise but remained elevated after leg exercise. Despite changes in arterial concentrations of alanine with exercise, muscle exchange of alanine was not altered with exercise. Exercise did not alter muscle exchange of any amino acid. Arterial amino acid concentrations and muscle exchange of amino acids with exercise were similar with or without DHAP feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin K therapy in severe liver disease.

A middle-aged man with parenchymatous liver disease and a decrease in vitamin K-dependent factors was given large doses of intravenous phylloquinone (10 mg/d for 20 days) without improvement in the synthesis of vitamin K-dependent factors. During subsequent liver transplantation, he exsanguinated. Although the exact role of over treatment with phylloquinone in this case is unclear, plasma levels of phylloquinone 300 times normal were attained after 5 days of treatment without effect on factors II, VII, IX, and X. Further therapy with vitamin K was unnecessary.