Dean Lockwood

Pituitary adrenal recovery following short-term suppression with corticosteroids

To provide clinical guidelines for the use of high-dose short-term glucocorticoid therapy, we studied recovery of the hypothalamic-pituitary-adrenal axis in 10 normal men following the administration of suppressive doses of prednisone (25 mg twice daily for five days). Cortisol responses to insulin-induced hypoglycemia and synthetic ACTH before treatment were compared with responses two and five days after concluding the prednisone course when adrenal function was not influenced by the presence of exogenous steroid. Two days after prednisone therapy, peak cortisol responses to both hypoglycemia (11.0 +/- 0.9 microgram/dl mean +/- SEM) and synthetic ACTH (13.3 +/- 1.4 microgram/dl) were significantly reduced compared to pretreatment (20.6 +/- 1.6 and 27.3 +/- 2.5 microgram/dl, respectively, p less than 0.001). Five days after concluding the prednisone therapy, peak cortisol response to hypoglycemia had returned to near pretreatment levels although peak cortisol response in the adrenal gland to synthetic ACTH (22.3 +/- 1.1 microgram/dl) remained reduced (p less than 0.05). These data suggest that brief courses of high-dose prednisone therapy may limit the adrenal component of the hypothalamic-pituitary-adrenal response to stress for up to five days.

Protein Nutrition and Liver Disease after Jejunoileal Bypass for Morbid Obesity

Abstract A role for protein malnutrition in the pathogenesis of liver dysfunction after jejunoileal bypass was sought in 18 patients undergoing bypass surgery for obesity. Four months after operation, when weight loss was rapid, serum glutamic oxalacetic transaminase was elevated in 12 patients, and most had marked hepatic steatosis. Of the essential amino acids plasma valine, isoleucine, leucine, phenylalanine, threonine and lysine declined, as did the nonessential amino acids, alanine, citrulline, cystine, tyrosine, ornithine and arginine. Glycine and serine were elevated. This profile is typical of protein-calorie malnutrition. Twelve to 36 months after operation weight stabilized, transaminase was normal, and hepatic fat diminished. Concentrations of many amino acids returned toward normal though moderate depression of valine, isoleucine, leucine, lysine, tyrosine, ornithine and arginine persisted. Glycine remained elevated. Oral amino acid tolerance tests suggested that improved absorption accounted ...

Impaired Glucose Tolerance is Normalized by Treatment With the Thiazolidinedione Troglitazone

OBJECTIVE The primary purpose of this study was to assess the effects of 12 weeks of treatment with either troglitazone, an investigational thiazolidinedione that acts as an insulin-action enhancer, or placebo in patients with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS A total of 51 subjects with IGT between 24 and 77 years of age were enrolled in this multicenter, double-blind, placebo-controlled, parallel group study (troglitazone, 25 patients; placebo, 26 patients). Patients were randomly assigned to receive either 400 mg troglitazone (every morning [QAM]) or placebo (QAM). The main outcome measure was the oral glucose tolerance test (OGTT) assessing glucose, insulin, and C-peptide levels in the fasting state and every 30 min up to 2 h after ingesting the glucose load. Fasting serum levels of HbA1c, fructosamine, lipids, and blood pressure were also measured. RESULTS A total of 46 patients completed the study. The glucose, insulin, and C-peptide responses after a glucose load were significantly reduced at 6 and 12 weeks in the troglitazone treatment group. After 6 weeks of treatment, 75% (n = 18) of those taking troglitazone had improved to normal glucose tolerance, whereas only 38% (n = 9) of those of placebo showed improvement (P = 0.008). After 12 weeks of treatment, 80% (n = 16) of the troglitazone treatment group had normalized their glucose tolerance, while only 48% (n = 10) of those on placebo had converted to normal (P = 0.016). Fasting triglyceride levels in the troglitazone treatment group had decreased by 40 mg/dl (0.45 mmol/l) (P = 0.0016). Other lipid measurements, blood pressure, glycosylated hemoglobin, and fructosamine were normal at baseline for both treatment groups and remained normal throughout the study. CONCLUSIONS The glycemic response after a glucose load is statistically and clinically significantly improved for patients with IGT treated with troglitazone.

Hormone-Dependent Differentiation of Mammary Gland: Sequence of Action of Hormones in Relation to Cell Cycle

Differentiation of mouse mammary gland in vitro requires insulin, hydrocortisone, and prolactin. The epithelial cells must first divide in order to synthesize casein in response to these hormones. Insulin is required for the initiation of DNA synthesis and is also necessary during G1 phase (after mitosis). Prolactin can elicit the overt differentiative responses after mitosis. Activity of hydrocortisone precedes that of prolactin, that is, after mitosis it is not capable of eliciting the differentiative response.

Hormone-dependent development of milk protein synthesis in mammary gland in vitro.

Abstract 1. 1. Insulin, hydrocortisone and prolactin acting synergistically selectively stimulate in vitro the synthesis of milk proteins by the pregnant mouse mammary gland. 2. 2. Synthesis of soluble cytoplasmic non-milk protein derived from epithelial cells is stimulated maximally by insulin alone and is believed to reflect proliferation. 3. 3. There is a coordinate increase in the synthesis of the casein components throughout mammary gland development. 4. 4. The increase of α-lactalbumin and β-lactoglobulin synthesis is not coordinate throughout mammary gland development. Thus as the lactational state is approached the ratio β-lactoglobulin to α-lactalbumin increases. 5. 5. Culture of mid-pregnancy mammary gland demonstrates that the 3 hormone combination effects stimulation of casein and whey protein synthesis of the same magnitude, with the same time course, and that the ratio of whey proteins to casein synthesized corresponds well with the ratio found in mouse milk.

The induction of milk protein synthesis in post-mitotic mammary epithelial cells exposed to prolactin

Abstract Prolactin causes the emergence of casein synthesis by mammary epithelial cells formed in vitro in the presence of insulin and hydrocortisone. Prolactin similarly exerts a stimulatory effect on the synthesis of α-lactalbumin and β-lactoglobulin.

Insulin resistance: Receptor and post-binding defects in human obesity and non-insulin-dependent diabetes mellitus

Insulin resistance is a prominent feature of three clinical conditions: obesity, impaired glucose tolerance, and non-insulin-dependent (type II) diabetes mellitus. Numerous studies over the past 15 years have provided a better understanding, from both a clinical and cellular standpoint, of the pathophysiology of these insulin-resistant states as well as of insulin action. In addition, it has recently been recognized that correction of glucose intolerance leads to an improvement in insulin secretion and a reduction in insulin resistance. Examination of the most recent data suggests that the basis for insulin resistance in these common clinical disorders is often multifactorial. In uncomplicated obesity, the cellular alterations responsible for insulin resistance appear to be at the level of the hepatic insulin receptor and in post-binding processes in peripheral target tissues. In type II diabetes, a post-binding defect(s) in peripheral tissues appears to be the primary lesion. In humans, many of the factors that mediate the changes leading to insulin resistance are still unknown and are the object of current investigations.

Effects of metformin on insulin receptor tyrosine kinase activity in rat adipocytes

SummaryThe cellular mechanism(s) by which the biguanide, metformin, exerts its antihyperglycaemic effect was investigated. Rat adipocytes were either treated acutely (2 h) or maintained in a biochemically defined medium (20 h) in the presence or absence of metformin (1 x 10−4 mol/1). Exposure to the drug resulted in a significant enhancement (p < 0.01) of hexose transport in both the absence (basal) and presence of insulin. Stimulation of transport was not explained by the increase in the basal state alone, since the incremental response to maximally effective concentrations of insulin was significantly enhancedp<0.025. Insulin-receptor tyrosine kinase activity was examined under the same experimental conditions. Activity of the kinase was unaltered as evaluated by phosphorylation of an artificial substrate and by phosphorylation of the receptor in situ. Furthermore, in this investigation neither insulin receptor number nor affinity was changed in adipose tissue treated with metformin. These studies indicate that metformin potentiates the effect of insulin on glucose transport at a site(s) beyond insulin receptor binding and phosphorylation.

Vigorous supplementation of a hypocaloric diet prevents cardiac arrhythmias and mineral depletion

We have previously demonstrated that a hypocaloric, nutritionally deficient, liquid protein diet is associated with potentially life-threatening cardiac arrhythmias, which increased in frequency and complexity over the duration of the study. The present investigation was designed to evaluate the metabolic and cardiac changes associated with a hypocaloric, but otherwise nutritionally complete, diet. Six healthy, obese females from 154 to 182 percent of ideal body weight were evaluated in a metabolic ward for 48 days. The subjects ingested a weight maintenance diet during an eight-day period, which was followed by 40 days of an experimental diet containing 472 kcal of a mixture of protein (60 percent of calories), carbohydrate (25 percent), and fat (15 percent). This diet equaled or exceeded the recommended daily allowances for minerals, trace elements, vitamins, and essential fatty acids. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Nitrogen balance was positive, and the previously demonstrated negative balances for potassium, sodium, calcium, magnesium, and phosphorus were either reversed or markedly decreased. In contrast to our previous study, no arrhythmias were observed in subjects ingesting the present experimental diet, and no significant change in cardiac rhythm was found in 13 obese, but otherwise healthy, outpatients. The data, based on a limited number of subjects, suggest that a hypocaloric diet vigorously supplemented with essential elements, micronutrients, and vitamins appears to be safer than the once popular, incomplete liquid protein preparation.

Insulin induced changes in insulin binding and insulin-sensitivity of adipocytes

The ability of insulin to regulate the insulin sensitivity of adipose tissue was directly studied by maintaining fat in Medium 199 for 17 hr in the presence or absence of the hormone (10.5 X 10 −9 M ). Following this “chronic” treatment with insulin, the tissue was washed and the adipocytes isolated by collagenase treatment that removes essentially all of the insulin from the cells. The insulin responsiveness of the cells was then tested in “acute” 1–2 hr experiments and the results correlated with their ability to specifically bind 125 I-labeled insulin. “Chronic” insulin treatment did not change the basal glucose transport rate as measured by 2-deoxyglucose uptake. Also, the maximum insulin-stimulated rate of 2-deoxyglucose uptake in the “acute” experiments was similar for both chronically insulin-treated and untreated cells. In these experiments, the only difference noted between the two groups of adipocytes was in their response to submaximally stimulating concentrations of insulin. Insulin-treated cells required approximately three times the amount of insulin to produce half-maximal stimulation of 2-deoxyglucose uptake than the amount needed by the untreated cells. “Chronic” insulin treatment also produced an alteration in the high affinity interaction between the fat cells and 151-labeled insulin. This alteration was characterized by a decrease in insulin binding at low concentrations of the labeled hormone, while at higher concentrations the binding was similar to that of untreated cells. These results show that a high concentration of insulin can produce insulin resistance in fat cells by causing a rightward shift in the insulin dose-response curve. Furthermore, this change in hormonal sensitivity may be a consequence of the insulin-induced decrease in the insulin binding ability of the fat cells.