Insulin-insensitive variety of combined types A and B diabetes mellitus progressing to systemic lupus erythematosus.

We have described a patient whose clinical course suggests that Kahn's types A and B insulin-resistant diabetes mellitus can exist as insulin-insensitive variants, type A can progress to type B, and type B insulin-insensitive diabetes can be associated with classical SLE long after the diabetes (and acanthosis nigricans) have resolved.

Insulin receptor proliferation: a mechanism for tumor-associated hypoglycemia.

A 30-yr-old man was found to have intractable hypoglycemia associated with colon carcinoma metastatic to the liver. Analysis of glucose requirements before death revealed a level of glucose turnover in excess of 12.9 mg/kg X min, consistent with maximally stimulated whole body glucose utilization. This high level of glucose turnover was present at a time when plasma immunoreactive insulin was very low. Insulin binding was measured in freshly isolated circulating mononuclear cells before death and in plasma membranes prepared from several tissues obtained at autopsy. A 3- to 5-fold increase in insulin receptor number was found in the mononuclear cells and liver and muscle plasma membranes. In contrast, skin fibroblasts maintained in tissue culture demonstrated no increase in insulin binding, thus suggesting that the increase in insulin receptors in freshly isolated tissues was acquired rather than intrinsic. Antibodies directed against the insulin receptor were not present. The patient's serum concentration of insulin-like growth factor I was low, but the serum level of nonsuppressible insulin-like protein was elevated. Serum bioassayable insulin-like activity was decreased. Based on tumor bulk at autopsy and in vitro analysis of glucose transport by his tumor cells maintained in monolayer tissue culture, it was estimated that his tumor could directly account for less than one third of the whole body glucose requirement. These data suggest that the increased tissue utilization of glucose in this hypoglycemic patient was caused by proliferation of insulin receptors in liver and muscle induced by his nonislet cell tumor through an unknown humoral mechanism(s).

Continuous subcutaneous infusion of glucagon by portable pump in non beta cell tumor hypoglycemia.

Subcutaneous infusion of glucagon by portable pump appears to give very effective symptomatic relief from non beta cell tumor hypoglycemia when surgery, radiotherapy and chemotherapy are impossible or ineffective. This mode of glucagon administration was proposed in a patient who had severe nocturnal hypoglycemic attacks. The aim of the study was to specify the modes of utilization and to test the efficiency and the tolerance of this treatment. Glucagon was infused at 400 micrograms/h during every 12 hour night. Because of the hepatic action of glucagon it is very important to use this treatment with an adequate diet and to stop the infusion during the day to reconstitute the glycogen overload. This mode of glucagon administration was very effective in over 6 months of use and well tolerated.

The storage stability of 3-hydroxybutyrate in serum, plasma, and whole blood.

The storage stability of 3-hydroxybutyrate in whole blood, serum, and plasma was evaluated. The levels of 3-hydroxybutyrate were measured using an enzymatic rate reaction of the specific 3-hydroxybutyrate dehydrogenase with the NAD-NADH coupled reaction. 3-Hydroxybutyrate was found to be a stable analyte in whole blood, plasma, and serum. The long-term stability of beta-hydroxybutyrate allows ample time for separation of blood components and offers storage of samples to meet quality control needs as well as the possibility of mailing specimens. Further studies indicate that NaF plasma, heparin plasma, and serum are the preferred specimens, because both EDTA and oxalate showed the most significant interference with the determination of 3-hydroxybutyrate.

Surgical cure of hypoglycemia associated with cystosarcoma phyllodes and elevated nonsuppressible insulin-like protein.

A woman with a large, benign cystosarcoma phyllodes of the breast was found to have recurrent, profound hypoglycemia. Plasma levels of nonsuppressible insulin-like protein were increased (15.18 micrograms/ml; normal = 1 to 4 micrograms/ml), whereas levels of insulin and nonsuppressible insulin activity soluble in acid ethanol were normal. Surgical excision of the tumor resulted in immediate and lasting correction of the metabolic abnormalities, although nonsuppressible insulin-like protein levels did not completely return to normal. Surprisingly, preoperative nonsuppressible insulin-like protein levels were highest in blood distant from the tumor site.

Tolbutamide pharmacogenetics and the UGDP controversy.

We analyzed the relationship between the pharmacogenetics of tolbutamide metabolism and the controversial University Group Diabetes Program (UGDP) study. Before the institution of that study, the extent of genetic control over the variation in the rate of tolbutamide metabolism was unknown, and all subjects included in the tolbutamide treatment group were given 1,500 mg/day of tolbutamide in a fixed dosage. We addressed the hypothesis that high accrued blood levels of tolbutamide in genetically predisposed slow inactivators might have contributed to the toxic effects reported by the UGDP study. This proposal is based on recent findings from population, twin, and family studies that tolbutamide metabolism is under monogenic control, with nearly one fourth of the population classified as slow inactivators.

Pharmacogenetics of tolbutamide metabolism in humans.

This study was designed to focus on the genetic control of tolbutamide dispositon in humans and to provide insight into the potential for high accrued blood levels in individuals receiving fixed dosage regimens. Tolbutamide was administered intravenously to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins. A ninefold variation in the rate of tolbutamide disappearance from plasms (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate. Interindividual differences in the binding of 35S-tolbutamide to serum proteins were also assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control. In conclusion, this study provides evidence for monogenic control of tolbutamide metabolism in man. The results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.

Mixed acid-base abnormalities in diabetes.

This study is a description of a patient who exhibited diabetic ketosis associated with an alkalosis rather than acidosis and a review of eight previously reported cases. Precipitating factors for this syndrome are severe vomiting with loss of hydrogen, potassium, and chloride ions, and dehydration. The ingestion of alkali may also result in this mixed acid-base disturbance. Treatment consists primarily of replacement of potassium and chloride. All reported patients had received large doses of insulin for initial therapy; however, limited insulin (20 U) therapy in this patient almost completely reversed the metabolic abnormality with 12 hours.

Effect of nonsupressible insulin-like protein on glomerular protein synthesis.

Partially purified preparations of NSILP were evaluated for effect on incorporation of labeled precursors into protein, collagen, and basement membrane by isolated rat renal glomeruli. Dowex-adsorbed NSILP (0.5 mU/mg) inhibited the secretion of protein and collagen and resulted in a significant diminution of incorporation of labeled lysine into glomerular basement membrane. Glomerular protein and collagen secretion were also inhibited in the presence of Sephadex G-200 NSILP (4.5 mU/mg), but an effect on incorporation of radiolabeled proline, hydroxyproline, lysine, and hydroxylysine into glomerular basement membrane was not observed. The in vitro response of renal glomeruli to NSILP constitutes another "insulin-like" effect of this substance.

Role of serum nonsuppressible insulin-like activity (NSILA) in wound healing. I. Influence of thyroparathyroidectomy on serum NSILA and wound healing in the rat.

Serum contains a 90,000 molecular weight glycoprotein that exhibits insulin-like activity on adipocytes, skeletal muscle, and fibroblasts in tissue culture; however, this protein is physicochemically and immunochemically distinct from insulin and presently is termed "nonsuppressible insulin-like activity ("nsilA)." This study was designed to assess the response of serum NSILA to thyroparathyroidectomy (TPTHX) and to associate this response with tissue repair processes in the injured rat. It was postulated that NSILA modulates the fibroblastic response in wound healing. TPTHX decreased NSILA to 40 percent of control levels (p less than 0.001); 90 male animals subsequently were wounded by either a 10 percent third-degree burn or skin excision. Following injury, NSILA significantly increased in both control and TPTHX groups, but this acute-phase response was attenuated in TPTHX animals. Light microscopy of granulation tissue demonstrated a diminution in the fibroblastic response in TPTHX animals. Hydroxyproline analysis of granulation tissue revealed a significant decrease (p less than 0.025) in collagen content in TPTHX animals with low NSILA levels. The results suggest that serum NSILA levels are controlled, in part, by thyroid hormone and that NSILA may modulate the fibroblastic response of connective tissue repair processes.

Effects of rapid depletion of phenylalanine and tyrosine on sleep and behavior.

The effects of fluctuations of free amino acid concentrations in plasma on sleep patterns and operant behavior in the squirrel monkey were studied. Plasma phenylalanine (PHE) and tyrosine (TYR) were rapidly lowered to trace levels within 4 hr by intraperitoneal administration of phenylalanine ammonia-lyase (PAL), an enzyme which specifically deaminates both PHE and TYR to inactivate products. Significant alterations in sleep patterns and in performance on a chained operant task involving hold and reaction time components were found, but no significant effect on the performance of a simple operant task was observed. Adminstration of saline or trans-p-cinnamic acid and trans-p-coumaric acid, the products of PHE and TYR deamination, produced no changes in behavior or sleep patterns. The reduction of plasma PHE and TYR resulted in a significant decrease in PHE and TYR levels in whole rat brain. Brain serotonin levels were increased within 4 hr after PAL administration, whereas, dopamine and norepinephrine levels were decreased subsequently (within 8 hr). These studies suggest that circulating levels of PHE and TYR are involved directly or indirectly in the modulation of certain parameters of brain function.

Inhibition of insulin degradation by nonsuppressible insulin-like activity.

Nonsuppressible insulin-like activity, provided by three sources, was evaluated for its effect on the proteolytic degradation of insulin utilizing insulin protease obtained from rat liver homogenate as well as liver cell membranes. All three preparations of nonsuppressible insulin-like activity were found to be competitive inhibitors of insulin degradation. In addition human plasma was fractionated yielding an acetone precipitate which was found to have nonsuppressible insulin-like activity and to be a competitive inhibitor of insulin protease.

The direct relationship of proinsulin-insulin hypersecretion to basal serum levels of cholesterol and triglyceride in myotonic dystrophy.

Excessive pancreatic insulin secretory responses to a variety of beta-cytotropic agents have been observed in 40 to 60 per cent of subjects with myotonic dystrophy; in addition, 25 to 30 per cent of affected persons manifest mild glucose intolerance, suggesting that circulating insulin may be biologically ineffective. To test this hypothesis, 8 men with myotonic dystrophy were challenged with a 100 gm. oral glucose load; responses were compared to an age, sex, weight-matched control group. Fasting serum immunoreactive insulin (IRI), cholesterol, and triglyceride levels in the myotonic group did not differ significantly from the controls. In contrast, fasting blood glucose and serum free fatty acid (FFA) levels in the myotonic group were significantly elevated above control, although still within the accepted normal range. Following oral glucose challenge, myotonic subjects exhibited mild glucose intolerance and excessive IRI response, but the FFA and serum alpha-amino nitrogen responses were comparable to control responses. Serum proinsulin was separated from insulin by gel filtration and quantitated by immunoassay. Overall, the proinsulin level in myotonic serum was not greater than the accepted normal level. The mean proinsulin level at the peak serum IRI response during the test was 18.6 +/- 4.1 per cent of the total IRI; 3 myotonic subjects responded with greater than 20 per cent proinsulin. The proinsulin secretory response correlated significantly with basal triglyceride (r = 0.972) and cholesterol (r = 0.794) levels but not with fasting glucose or FFA levels. Peak insulin response was also significantly correlated with triglyceride but not with cholesterol levels. Serum insulin-like activity (ILA) from myotonic dystrophic patients was assessed in vitro employing rat adipose tissue and skeletal muscle in the presence and absence of excess guinea pig anti-insulin serum. Comparison of suppressible insulin-like activity to immunoreactive insulin revealed that the mean biological recovery of serum insulin in these assay systems was 85 to 90 per cent, indicating that endogenous insulin was biologically active on both adipose tissue and skeletal muscle in vitro. We conclude that a biologically ineffective form of circulating insulin does not exist in myotonic dystrophy and that the pancreatic insulin response mechanism may be excessively sensitive, resulting in balanced hypersecretion of proinsulin and insulin. The highly significant correlation between proinsulin and serum triglyceride or cholesterol levels suggests that, in addition to insulin, proinsulin may also exert an important influence on lipid metabolism.