Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion

The early-morning increase in insulin requirements of patients with insulin-dependent diabetes mellitus (IDDM) has been referred to as the "dawn phenomenon." To determine the roles of growth hormone levels and sympathoadrenal activity in this phenomenon, we studied six subjects with IDDM on four occasions during a constant overnight infusion of insulin. In control experiments (infusion of insulin alone), plasma glucose increased from 98 +/- 5 mg per deciliter at midnight to 225 +/- 36 at 8:00 a.m. (P less than 0.001), glucose production increased by 65 per cent (P less than 0.001), and glucose clearance decreased by 50 per cent (P less than 0.001). When nocturnal surges in growth hormone secretion were prevented by infusion of somatostatin plus replacement glucagon, neither plasma glucose levels nor glucose production increased significantly, and glucose clearance did not decrease. When nocturnal surges in growth hormone secretion were simulated by hourly intravenous injections of growth hormone (15 to 100 micrograms) during infusion of somatostatin and glucagon, plasma glucose levels and glucose production increased and glucose clearance decreased to values observed in control experiments. During combined alpha- and beta-adrenergic blockade (phentolamine and propranolol), values for plasma glucose, glucose production, and glucose utilization were not significantly different from those in control experiments. Increases in plasma glucose were significantly correlated with peak plasma growth hormone concentrations (r = 0.58, P less than 0.01). We conclude that nocturnal surges in growth hormone secretion are primarily responsible for the dawn phenomenon in patients with IDDM.     

The effect of somatostatin on coagulation and platelet function in man.

Preliminary evidence has suggested that somatostatin might interfere with platelet function in the baboon. Because this agent is currently being administered experimentally to human beings, we studied its effect on coagulation and platelet function in man. In five subjects, a four-hour infusion of somatostatin (500 micrograms per hour) had no definite effect on platelet count, leukocyte count, hematocrit, platelet adhesiveness and aggregation, bleeding time, partial thromboplastin time, prothrombin time, and fibrinogen levels. A similar infusion for 18 hours in three subjects was likewise without effect. These studies indicate that somatostatin does not affect coagulation and platelet function in man and that its prolonged administration lacks ostensible toxicity.     

Prospects for gene therapy in sports medicine

For the orthopedic sports medicine physician soft tissue injuries often present the greatest clinical problems. Not only do many of the most frequently injured tissues, such as the cruciate ligaments and articular cartilage, have very limited capabilities for spontaneous repair, but they also respond poorly to surgical or nonsurgical intervention. In this article we try to define the role of growth factors in these conditions and to outline concepts for future treatment based upon modulation of the native repair response. We suggest that gene transfer could improve the management of such injuries, particularly when used as vehicles for the targeted delivery of growth factors. The concept of gene therapy in orthopedic sports medicine can be extended to include disorders that present as laxity or mechanical weakness of ligaments. We speculate that subtle genetic differences between individuals may account for those who appear to be injury prone. In these cases it is likely that genes encoding the structural macromolecules of the matrix are defective. Local gene supplementation in such cases could be useful in the future.     

Metabolic and neurologic effects of an intravenous medium-chain triglyceride emulsion

These studies were undertaken to investigate the relationship between medium-chain fatty acid availability, medium-chain fatty acid oxidation, and central nervous system toxicity during infusion of medium-chain triglycerides in dogs. Six dogs received a sequential, stepwise infusion of trioctanoin at three different rates for 80 min each, providing calories below and equal to resting energy expenditure in the species. Ketone body production rates (using a 14C beta-hydroxybutyrate tracer) and plasma concentrations of lactate and octanoate were monitored. Three animals were infused with saline to serve as controls. Blood-brain barrier integrity was assessed with Evans blue dye, and brain samples were taken at the end of the study to quantify brain water. Three animals were studied under anesthesia to obtain good quality EEG and intracranial pressure measurements. Results were (1) plasma octanoate increased to 0.37 +/- 0.13, 0.78 +/- 0.2, and 1.44 +/- 0.41 mmol/liter during the three infusion intervals; (2) emesis, somnolence, and coma were observed at the two highest trioctanoin rates; (3) ketone body concentrations and production increased from 102 +/- 15 to 859 +/- 54 mumol/liter and 3.6 +/- 0.43 to 18.5 +/- 1.7 mumol/kg/min, respectively, at the highest trioctanoin infusion rate; and (4) plasma lactate also increased from 1.3 +/- 0.1 to 4.3 +/- 0.9 mmol/liter at the highest infusion rate. EEG changes were also observed, consisting of high amplitude slowing and reduction in amplitude of faster components. There was no extravasation of Evans blue dye, nor change in brain water or intracranial pressure. The conclusion--medium-chain triglycerides have significant dose-related central nervous system toxicity in dogs. Therefore, caution should be exercised in clinical studies with MCTs, including careful measurement of medium-chain fatty acid concentrations.     

Medium-term results of the operative treatment of recurrent patellar dislocation by Insall proximal realignment

Between 1984 and 1991, 36 patients with the diagnosis of recurrent patellar dislocation were treated operatively using the proximal realignment procedure. Thirty patients were available for follow-up. The average follow-up period was 6.3 years (range 2–9.6 years). The average age at injury was 21.3 years with a predominance of female patients. At follow-up all knees were physically examined. The results were evaluated using the score of Larsen and Lauridsen as well as the Tegner score and subjective assessment. Radiographs from 19 patients (63%) were available for review. At follow-up one patient suffered from a recurrence of patellar dislocation. All patients had stable knee joints and a full range of motion. There was no statistically significant difference between pre- and postoperative sports activity level. Seven patients (23.3%) had excellent results, 12 patients (39.9%) good results and 1 a poor result using the Larsen and Lauridsen score. Subjective assessment revealed the operative result as very good, good or satisfactory in 90%. Patellofemoral osteoarthritis was seen in 7 of 19 patients (36.8%). With a proximal realignment procedure good clinical results can be achieved for recurrent patellar dislocation. Subjective satisfaction with this procedure is rated as good. It is successful in preventing redislocation. Received: 18 January 1998 Accepted: 28 August 1998