Diabetes in adolescent patients: diagnostic dilemmas.

The classification of diabetes mellitus by types (1 or 2), or by age of onset (juvenile or adult), helps to clarify many aspects of pathophysiology, prognosis, and therapy. However, less-commonly encountered patients, presenting in childhood or adolescence, may not fit neatly into one or the other group. These include teenagers who present with new-onset diabetes with ketoacidosis, but who are later able to be managed permanently as type 2 patients. Other adolescent patients present with only minimal glucose intolerance, then proceed to develop type 1 diabetes, with evidence of autoimmune etiology, after a variable number of years. Four patients are presented to illustrate these diagnostic dilemmas.

Intractable diarrhea in hyperthyroidism: management with beta-adrenergic blockade.

OBJECTIVE: To describe a patient with intractable diarrhea and thyrotoxic Graves' disease, for whom b-adrenergic blockade ultimately proved to be effective therapy for the diarrhea, and to review the types of hyperthyroidism-associated diarrhea. METHODS: We present the clinical course of a young man with a prolonged siege of diarrhea that proved elusive to diagnostic inquiries and resistant to all means of management until its endocrine basis was discovered. Control of such cases with b-adrenergic blockade is discussed, as are the pathophysiologic bases of intestinal hypermotility in hyperthyroidism. RESULTS: A 26-year-old man with Down syndrome, and no prior gastrointestinal disorder, had insidious, chronic, constant diarrhea, which was associated with loss of 14 kg during a 5-month period. Numerous laboratory and imaging studies and endoscopic examinations failed to disclose the cause of the diarrhea. Furthermore, a broad range of antibiotics and other empiric remedies failed to control the problem. No other symptoms of hyperthyroidism were reported, but when the endocrinopathy was suspected and identified, the diarrhea was promptly controlled by treatment with propranolol. In patients with hyperthyroidism, two types of diarrheal disorders have been described-secretory diarrhea and steatorrhea; bile acid malabsorption may have a role in either of these settings. CONCLUSION: In addition to its capacity for blocking the peripheral effects of thyroid hormone on the heart and central nervous system, b-adrenergic blockade is effective in slowing intestinal transit time and ameliorating the uncommon diarrhea associated with hyperthyroidism. Thyroid hormone in excess, among its other possible effects on the gastrointestinal tract, may exert a stimulatory effect by means of intermediary sympathetic activation, as it does with the heart. Thus, sympathetic blockade can mimic the salutary effects on the gastrointestinal tract conventionally brought about by direct antithyroid therapy, and well before the hyperthyroid state per se is eliminated. The current patient illustrates the value of considering hyperthyroidism in the differential diagnosis of diarrhea of unknown cause.

Selective removal of plasma low density lipoprotein with the HELP system: biweekly versus weekly therapy.

PURPOSE: Biweekly (once every 2 weeks) heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels compared with weekly HELP therapy. PATIENTS AND METHODS: Biweekly treatments were given to high-risk, diet/drug resistant hypercholesterolemic patients (n = 23) after 6 months of weekly HELP therapy. Lipids, lipoprotein cholesterol, apolipoproteins A-I and B, and fibrinogen were measured on plasma samples before and after treatment. RESULTS: Mean plasma volume treated was 2.8 l and mean treatment duration 1.7 h. Therapy complications were minimal. In 98% of 268 biweekly HELP treatments, LDL cholesterol levels were reduced by > 30%. For patients completing 6 months of biweekly therapy following 6 months' weekly therapy (n = 23), mean LDL cholesterol levels were reduced 138.5 mg/dl (111.2 mg/dl weekly) with a time-averaged decrease from mean pre-apheresis levels of 33% for biweekly therapy (39% weekly). Mean total cholesterol (161.2 mg/dl biweekly versus 132.9 weekly) and apolipoprotein B (104.6 mg/dl versus 92.6) levels were also reduced with each treatment. Mean HDL cholesterol was reduced only 6.1 mg/dl (6.3 mg/dl weekly). CONCLUSIONS: Biweekly HELP treatments can safely reduce LDL cholesterol levels as consistently as weekly HELP treatments. However, the higher pre-treatment LDL cholesterol levels with biweekly treatments may produce less therapeutic benefit than with weekly therapy.

Weekly treatment of diet/drug-resistant hypercholesterolemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal.

Heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) weekly therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels. Weekly treatments (25) were given to high-risk hypercholesterolemic patients (n = 33) with screening LDL cholesterol levels > 160 mg/dl despite prior diet and drug therapy. Lipids, lipoprotein cholesterol, apolipoproteins A-l and B, and fibrinogen were measured on plasma samples before and after treatment. Mean plasma volume treated was 2.66 liters and mean treatment duration 1.7 hours. Therapy complications were infrequent and were primarily vascular access problems or hypotension. Treatment goals were > 30% LDL cholesterol reduction with each treatment. In 98% of 686 HELP treatments, LDL cholesterol levels were reduced > or = 30%. Mean LDL cholesterol levels were reduced 111.0 mg/dl (54%) with a time-averaged decrease of 39% over a 25-week course. Mean HDL cholesterol was reduced only 6.2 mg/dl (15%). Total cholesterol (134.4 mg/dl; 47% decrease) and apolipoprotein B (88.7 mg/dl; 53% decrease) levels were also reduced. Fibrinogen decreased 158.2 mg/dl (58%) without bleeding complications. HELP therapy can safely and selectively remove plasma LDL cholesterol, producing consistent reductions in LDL cholesterol, total cholesterol and apolipoprotein B levels.

Decreased serum cholesterol-binding reserve in diabetes mellitus.

Serum cholesterol-binding reserve (SCBR), the capacity of a serum sample to solubilize additional cholesterol in excess of its cholesterol content, was measured in 43 white male patients with maturity-onset diabetes in the age range of 35--59 years who were under treatment with insulin. The values were compared with those of 194 nondiabetic controls of the same race, sex, and age range. The mean +/- S.D. of SCBR of patients (71.9 +/- 29.3 mg./dl.) was lower than that of controls (88.9 +/- 30.9 mg./dl.) (p less than 0.001). Age in the range of 35 to 59 years had no correlation with SCBR in either patients or controls. SCBR was positively correlated with serum levels of cholesterol (SC) and triglycerides (TG) in both patients and controls. After adjustment for SC and TG, the difference in SCBR between patients and controls persisted (p less than 0.001). In 15 of 20 (75 per cent) patient-control pairs matched for SC and TG to within 5 per cent, the patient had lower SCBR (paired t-test, p less than 0.002). In 16 patients without elevation of serum lipid levels (SC below 250 and TG below 150 mg./dl.), the mean +/- S.D. of SCBR (59.1 +/- 17.7 mg./dl.) was lower than that of 49 controls having serum lipids in the same range (77.4 +/- 31.7 mg./dl.) (p less than 0.03). These results indicate an association of decreased SCBR with diabetes and are consistent with the hypothesis that low SCBR is associated with accelerated atherosclerosis and enhanced risk for coronary heart disease.

The cardiac sarcoplasmic reticulum-glycogenolytic complex. A possible effector site for cyclic AMP.

Cardiac sarcoplasmic reticulum-glycogenolytic complex, isolated as a single peak on sucrose density gradient, may function as a "compartmented" effector site for cyclic AMP resulting in modulation of both glycogenolysis and calcium transport. The conversion of phosphorylase b to a is stimulated by ATP and inhibited by protein kinase inhibitor. Cyclic AMP alone stimulated neither phosphorylase b to a conversion nor calcium uptake. An inhibitor of adenylate cyclase depressed both calcium uptake and phosphorylase activation and both functions were subsequently stimulated by micromolar concentrations of cyclic AMP. Endogenous phosphorylation of sarcoplasmic reticulum was also inhibited by adenylate cyclase inhibitor and the inhibition was reversed by cyclic AMP. These results suggest that the sarcoplasmic reticulum of cardiac muscle is an internal effector site for cyclic AMP which may regulate both calcium and metabolism. It appears that cyclic AMP formation in vitro is not the rate-controlling step in the activation sequence.

Adenosine 3',5'-monophosphate and the regulation of rat hepatic sterol synthesis: a reexamination based on Sutherland criteria.

Many investigators have reported that adenosine 3',5'-monophosphate (cyclic AMP) at supraphysiologic concentrations (10(-4) M) suppresses lipogenesis in rat livers in vitro. The data in this report demonstrate that the phosphodiesterase inhibitor theophylline does not suppress sterol synthesis by itself nor does it potentiate the cyclic AMP-mediated suppression. In addition the cyclic AMP-mediated effect was not specific as many structurally-related compounds including adenosine triphosphate, adenosine 5'-diphosphate, adenosine 5'-monophosphate, adenosine, coenzyme A, HMG coenzyme A, and guanosine 3',5'-monophosphate suppressed sterol synthesis. The phenomenon of cyclic AMP-suppression of sterol synthesis does not fulfill two of the four criteria defined by Sutherland to assess whether a given metabolic effect is mediated by cyclic AMP. Therefore, we conclude that the cyclic AMP mediated suppression of sterologenesis is not a physiologic effect of the nucleotide.

Isolation of a unique peptide inhibitor of hormone-responsive adenylate cyclase.

We have perfused isolated rat livers with hypocalcemic (4.4 mg 100 ml) Krebs-Ringer bicarbonate albumin buffer. After 15 min of perfusion, a substance appeared in the perfusate which decreased rat renal adenylate cyclase activation by parathyroid hormone (PTH). The material in the perfusate was purified greater than 50,000-fold by Bio-Gel P-10 chromatography. The purified antagonist decreased the activation of rat renal cortical adenylate cyclase by PTH, glucagon, and epinephrine 75 to 100%. Concentration response curves for each of the hormones indicated a noncompetitive interaction of the inhibitor with the hormone. The inhibition was not species-specific, as the activation of the parathyroid hormone-responsive adenylate cyclase in cat renal cortex was also abolished by the inhibitor from the perfused rat liver. The inhibitor is a peptide, Mr equal to similar to 1000, which is heat-stable, acid-stable, alkai-labile, and is destroyed by trypsin, leucine aminopeptidase, and elastase. It is not destroyed by phosphodiesterase, 5'-nucleotidase, alkaline phosphatase, neuraminidase, RNase, or phospholipase A. The inhibitor is not produced by isolated rat livers perfused with normocalcemic perfusion media. It is unclear whether the peptide is synthesized by the liver or whether it is a breakdown product of a larger peptide or protein in the liver. This is the first reported peptide inhibitor of adenylate cyclase.

A phylogenetic study of the role of cyclic AMP in lipid synthesis in vertebrates.

The effect of cyclic AMP on the incorporation of acetate-2-14C into sterols and fatty acid in vitro in slices of liver and intestine was examined in various representatives of the vertebrate group. In no instance was an effect on lipid synthesis noted in intestine. Cyclic AMP exerted no significant effects on hepatic lipogenesis in lower vertebrates, including the nurse shark, catfish, toad, or iguana. However, the nucleotide strongly inhibited the incorporation of acetate-2-14C into fatty acid by the chicken liver. Similar inhibition of fatty acid synthesis was also noted in rat liver, but in this mammalian species hepatic sterol synthesis was also strikingly suppressed by cyclic AMP. Interruption of the enterohepatic circuit in the rat, while enhancing rates of sterol synthesis in both liver and intestine, neither enhanced nor diminished hepatic susceptibility to suppressed sterologenesis by cyclic AMP, nor did it confer on the intestine any newfound capacity for cyclic AMP-regulated lipid synthesis.

Metabolism of bovine parathyroid hormone. Immunological and biological characteristics of fragments generated by liver perfusion.

The metabolism of bovine parathyroid hormone (PTH) by the perfused rat liver was studied. Labeled hormone, with or without cold hormone, was infused into the circulating perfusion medium containing various calcium concentrations. Pefusate samples at various time periods after the introduction of PTH into the system were chromatographed on Bio-gel P-10; radioactivity and/or immunoreactivity were measured in eluted fractions. Before the perfusion, all immuno- and radioactivity eluted in a single peak, with an apparent mol wt of 9,500 (peak I). After perfusion for 15 min, two other peaks with approximate mol wt of 7,000 (peak II) and 3,500 (peak III) were discernible. Peak I contained both NH2-terminal and COOH-terminal immunoreactivity and was biologically active at all time periods tested. The relative contribution of NH2-terminal and COOH-terminal immunoreactivity to the total immunoreactivity remained constant in this peak throughout the perfusion. In every respect, peak I had the characteristics of intact hormone. At all times, peak II consisted of only COOH-terminal immunoreactivity and was biologically inactive. At early time periods, peak III contained predominantly NH2-terminal immunoreactivity and was biologically active. With time, the relative contribution of NH2-terminal immunoreactivity decreased strikingly while that of COOH-terminal immunoreactivity increased. The three peaks identified in these experiments were analogous in size, biological activity, and immunological characteristics to those we have previously described for fractionated human hyperparathyroid serum. The rate of metabolism of PTH appeared to be regulated by the calcium concentration in the medium. At a high concentration of calcium (greater than 11 mg/100 ml), PTH metabolism was greatly retarded. At a low concentration of calcium (smaller than 5 mg/100 ml), the rate of metabolism was greatly increased. The physiological significance of our observations on the metabolism of PTH by isolated perfused rat liver is not known. However, since such metabolism results in a biologically active fragment, it is suggested that metabolism of intact hormone may be required before full biological expression is possible.

Studies of the in vivo metabolism of mevalonic acid in the normal rat.

Studies were performed to examine synthesis, tissue localization, and metabolism of mevalonic acid in normal rats. Circulating mevalonate was found to have a rapid turnover phase of 5 min and a slower phase of 40-50 min. Under in vitro conditions the synthesis of mevalonate is carried out most actively by the liver and only to a minor extent by the other tissues studied. The most unexpected finding of this study was that both in vivo and in vitro the kidneys rather than the liver are the primary site of the metabolism of circulating mevalonate. Whereas mevalonate in the liver is rapidly transformed to cholesterol, the major products of mevalonate metabolism in the renal tissues during the same time period are squalene and lanosterol. Exogenous in contrast to circulating mevalonate is metabolized primarily in the intestine.