Mean Serum Insulin Concentrations Research Articles

Daily Walking Combined With Diet Therapy Is a Useful Means for Obese NIDDM Patients Not Only to Reduce Body Weight But Also to Improve Insulin Sensitivity

To evaluate the effects of walking combined with diet therapy (1,000-1,600 kcal/day) on insulin sensitivity in obese non-insulin-dependent diabetes mellitus (NIDDM) patients. Subjects were divided into two groups: 10 patients were managed by diet alone (group D), and 14 patients were placed in the diet and exercise group (group DE). Group DE was instructed to walk at least 10,000 steps/day on a flat field as monitored by pedometer (19,200 +/- 2,100 steps/day), and group D was told to maintain a normal daily routine (4,500 +/- 290 steps/day). A glucose clamp procedure at an insulin infusion rate of 40 microU.min-2.min-1 was performed before and after the 6- to 8-week training program. Mean serum insulin concentrations ranged from 720 to 790 pmol/l. While body weight (BW) in groups D and DE decreased significantly (P < 0.01) during the study, the amount of BW reduction in group DE was greater than that in group D (7.8 +/- 0.8 vs. 4.2 +/- 0.5 kg, P < 0.01). After training, glucose infusion rate (GIR) and metabolic clearance rate (MCR) in group D did not significantly increase; however, GIR and MCR increased significantly in group DE, from 17.21 +/- 1.11 to 26.09 +/- 1.11 mumol.kg-1.min-1 (P < 0.001) and from 3.0 +/- 0.3 to 5.3 +/- 0.4 ml.kg-1.min-1 (P < 0.001), respectively. The analysis of variance showed significant effects of exercise (time x exercise, P = 0.0005) for the improvement of MCR. Significant correlations were also observed between delta MCR and average steps per day (r = 0.7257, P < 0.005) in group DE. Walking, which can be safely performed and easily incorporated into daily life, can be recommended as an adjunct therapy to diet treatment in obese NIDDM patients, not only for BW reduction, but also for improvement of insulin sensitivity.

Can physical activity explain the differences in insulin levels and fibrinolytic activity between young indo-origin and European relatives of patients with coronary artery disease?

Summary In a comparison of young Indo-origin (IO) and young North European (NE) male relatives of patients with angiographically demonstrated coronary artery disease (CAD), we found a significant difference in daily leisure physical activity between the two groups, as measured both by a questionnaire and by pedometer readings. Mean daily walking distance by pedometer was 1.8 Km per day for the IO group and 2.4 Km per day for the NE group (P=0.007). Physical activity was an independent predictor of tissue plasminogen activator (t-PA) activity and of plasminogen activator inhibitor-1 (PAI-1) activity in both groups on multivariate analysis. On univariate analysis, physical activity (pedometer score) was negatively correlated with fasting serum insulin concentration (r=0.49 for IO and r=0.54 for NE subjects) and with PAI-1 activity (r=0.47 for IO, r=0.42 for NE), and positively correlated with t-PA activity (r=0.38 for IO, r=0.34 for NE). Mean serum insulin and lipoprotein (a) concentrations, and mean PAI-1 activity were significantly raised in IO as compared to NE subjects; however, when adjusted for pedometer scores the inter-ethnic differences for insulin concentration and PAI-1 activity, but not for Lp(a) concentration, were greatly reduced. Different levels of physical activity may contribute significantly to inter-ethnic differences in metabolic and fibrinolytic function.

The effect of dietary salt on insulin sensitivity

Acute reduction of salt intake causes an increase in serum lipid and insulin levels in healthy volunteers and patients with essential hypertension, suggesting induction of insulin resistance by salt restriction. Direct measurements of insulin sensitivity using the euglycaemic clamp showed no significant change after 7 days of salt restriction. Our previous study showed a time dependent course of dyslipidaemia after institution of a low salt diet. We therefore assessed insulin sensitivity (M-value) under euglycaemic conditions (clamp technique) at discrete time points using a parallel group design. Two groups of healthy males were examined on high (200 mmol d-1) and low (20 mmol d-1) salt intake. One group (n = 7, 25 +/- 3 years, BMI 22.4 +/- 2.1 kg m-2) received high and low salt diet in random order each for 7 days. The other group (n = 7, 26 +/- 3 years, 22.1 +/- 1.9 kg m-2) received the respective diet in random order for 3 days. A significantly (P < 0.01) different mean M-value was noted in the group receiving the diets for 3 days, i.e. after low salt intake it was 7.4 +/- 1.2 mg kg-1 min-1 and after high salt intake 8.6 +/- 1.1 mg kg-1 min-1. In contrast, the mean M-value was similar after low and high salt periods in the group of individuals who had been studied after 7 days on either salt take (7.8 +/- 1.8 on low salt vs. 7.6 +/- 1.3 mg kg-1 min-1 on high salt).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two ultralente insulin preparations with protamine zinc insulin in clinically normal cats

Summary The absorption kinetics and glycemic effects of 3 long-acting insulin preparations (protamine zinc beefpork insulin, ultralente beef-pork insulin, and ultralente human insulin) were evaluated in 9 healthy, adult, domestic shorthair cats (6 males, 3 females). A triple crossover study was performed, in which the serial serum concentrations of insulin and glucose were determined over a 24-hour period after SC administration of the 3 insulin preparations (dosage, 1.0 U/kg of body weight) at 3-week intervals. A control study was also performed in 4 of the cats by serially collecting samples for insulin and glucose determinations after administration of insulin diluent. After administration of protamine zinc insulin (pzi), mean (± sem) serum insulin concentration increased significantly (P &lt; 0.05) above baseline, reached a peak value (484 ± 287 pmol/L) at 1 hour, and remained significantly (P &lt; 0.05) higher than baseline at 24 hours. After administration of ultralente human insulin, the serum insulin curve was similar to that obtained after pzi administration, but mean serum insulin concentration took longer to peak (538 ± 177 pmol/L at 4 hours). After administration of ultralente beef-pork insulin, mean peak serum insulin concentration was lower (220 ± 54 pmol/L, not statistically significant) than that obtained after administration of pzi and ultralente human insulins; it then decreased to values statistically indistinguishable from baseline by 16 hours. The area under the serum insulin concentration curve for pzi (5,063 ±681 pmol • h/L) and ultralente human insulin (4,138 ± 439 pmol • h/L) was significantly (P &lt; 0.05) larger than that for ultralente beef-pork insulin (2,378 ± 561 pmol • h/L). Serum glucose concentration decreased after administration of all 3 insulins, but the decrease was not different from that observed after diluent (control) administration. Results of this study indicate that differences may exist between absorption of pzi, ultralente human, and ultralente beef-pork insulins. Of the 2 ultralente insulin preparations, human insulin appears better absorbed than beef-pork insulin, but these findings need to be confirmed in cats with naturally acquired diabetes mellitus.

Effect of glipizide on serum insulin and glucose concentrations in healthy cats

With the recent identification of non-insulin-dependent diabetes mellitus (NIDDM) in cats, new possibilities arise for the use of oral hypoglycaemic agents in the treatment of feline NIDDM, similar to their use in humans. To identify the future applicability of the oral hypoglycaemic agent, glipizide, in the treatment of feline NIDDM, its effects on serum insulin and glucose concentrations in healthy cats was examined. In addition, adverse effects seen clinically or on bloodwork following shortterm use of the drug were looked for. Serum insulin and glucose concentrations were evaluated after the oral administration of 2·5 5·0 and 10·0 mg glipizide and placebo in 10 healthy cats. For each drug trial, blood was obtained five minutes before, immediately before, and 7·5 15, 30, 45, 60, 90 and 120 minutes after glipizide or placebo administration. Mean serum insulin concentration increased after glipizide administration, with peak mean serum insulin concentration occurring 15 minutes after administration and declining to baseline by 60 minutes. There was no significant difference in peak mean serum insulin concentration, mean serum insulin concentration at 60 minutes after glipizide administration, or mean total insulin secretion between the three glipizide dosages. Mean serum glucose concentration decreased within 15 minutes of glipizide administration, with the glucose nadir occurring 60 minutes after glipizide administration. Placebo trials showed no significant change in mean serum insulin or glucose concentrations from baseline concentrations.

Specific types of colonic fermentation may raise low-density-lipoprotein-cholesterol concentrations

To assess the effects of increased colonic fermentation on serum lipids, eight healthy volunteers were placed on two identical 2-wk metabolic diets, one of which was supplemented with lactulose (18-25 g/d). Lactulose raised day-long concentrations of breath hydrogen and serum glutamine as indicators of increased colonic fermentation by 78 +/- 13% (P less than 0.001) and 24.7 +/- 9.5% (P less than 0.05), respectively). Unexpectedly, however, fasting serum total and low-density-lipoprotein cholesterol and apolipoprotein B concentrations were higher at 2 wk by 8.9 +/- 1.5% (P less than 0.001), 10.9 +/- 2.2% (P less than 0.005), and 18.9 +/- 5.9% (P less than 0.02), respectively, compared with the control diet. With lactulose, mean free fatty acid concentrations were reduced over the day by 19.5 +/- 5.9% (P less than 0.02), with no change in mean day-long blood glucose, serum insulin, or C-peptide concentrations. We conclude that certain rapidly fermented substrates may raise rather than lower serum lipids, possibly through increasing the amount of acetate absorbed from the colon.

Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats

Absorption kinetics of regular, isophane (NPH), and protamine zinc (PZI) insulin were evaluated in seven clinically normal domestic shorthair cats by measurement of serial serum concentrations of insulin after subcutaneous administration of each insulin preparation. These results were compared to measurements of serial serum insulin concentrations after similar dosages of regular insulin were administered intravenously. Regular insulin administered subcutaneously was better absorbed than NPH and PZI insulins (mean bioavailability index 45.4% vs. 33.0% for NPH and 27.3% for PZI), and resulted in a significantly greater maximal increase in mean circulating insulin concentrations above baseline values (3529 pM vs. 1044 pM for NPH and 344 pM for PZI, P<0.05). The mean time interval between insulin administration and time to reach peak concentrations was significantly shorter for regular insulin than for NPH or PZI insulin (0.5 hr vs. 1.6 hr for NPH and 4.1 hr for PZI, P<0.05). There was also a significant difference (P<0.05) in the mean time interval between insulin injection and return of serum insulin concentrations to baseline values between regular insulin (5.6 hr) and NPH (7.7 hr) or PZI (13.1 hr) insulins. When compared with PZI, NPH insulin showed a significantly (P<0.05) greater maximal increase in mean serum insulin concentrations over baseline values. In addition, the interval between insulin administration and time to reach peak concentrations, as well as the time between insulin injection and return of serum insulin concentrations to baseline values, were also significantly shorter with NPH insulin than with PZI. These results suggest that NPH and PZI insulins administered subcutaneously to cats may require a short time to reach peak serum insulin concentrations as well as a relatively short time for circulating insulin concentrations to return to baseline values. If the absorption kinetics are similar to that in this study, most cats with diabetes mellitus would need twice daily injection of NPH or PZI insulin to adequately control the diabetic state.

Tumor necrosis factor enhances glucose uptake by peripheral tissues.

Anesthetized dogs received a constant intravenous infusion of tumor necrosis factor (TNF) or saline over 6 h. Glucose kinetics were studied by determining the rate of glucose turnover and hindlimb substrate flux. Cardiovascular responses were monitored and concentrations of counterregulatory hormones were also measured. TNF infusion caused a fall in blood glucose concentration from 4.6 +/- 0.1 to 3.9 +/- 0.2 mmol/l by 6 h (P less than 0.05). This mild hypoglycemia was associated with increased circulating levels of cortisol, glucagon, and epinephrine. The rate of glucose production increased from 26.5 +/- 2.1 to 32.5 +/- 0.7 mumol.min-1.kg body wt-1 (P less than 0.05) over the 6-h infusion period; this response was associated with increased glucose disappearance (26.4 +/- 2.2 to 32.7 +/- 0.9 mumol.min-1.kg body wt-1, P less than 0.05) and enhanced clearance (5.7 +/- 0.5 to 9.0 +/- 0.6 ml.min-1.kg body wt-1, P less than 0.05). As blood glucose levels fell, hindlimb glucose uptake and glucose clearance increased markedly in TNF-infused animals as compared with controls despite a 50% fall in mean serum insulin concentration. The exchange of lactate, pyruvate, and total amino acid nitrogen across the hindlimbs was similar in both groups of animals. However, arterial concentrations of lactate and pyruvate rose to two to three times their initial values. The hypoglycemia associated with the infusion of TNF results from a disparity between the rate of glucose appearance and disappearance. There is an increased uptake of glucose across the hindlimb; this response appears to be independent of insulin concentrations and may be related to direct effects of TNF.(ABSTRACT TRUNCATED AT 250 WORDS)

Rat Insulin-Receptor Kinase Activity Correlates With In Vivo Insulin Action

Tyrosine kinase activity of skeletal muscle-derived insulin receptors isolated from rats that had undergone euglycemic clamps at various insulin infusion rates was examined. Receptors were isolated under conditions designed to preserve their in vivo phosphorylation state, and their kinase activity toward histone was measured in the absence of in vitro exposure to insulin. Results showed that significant activation of the insulin-receptor kinase occurred after exposure in vivo to mean serum insulin concentrations as low as 34 +/- 3.5 microU/ml and that maximal activation was achieved by insulin levels less than or equal to 2000 microU/ml. There was a highly significant correlation between receptor kinase activity and serum insulin concentration in the physiologic range (r = .92, P less than .0001) and between kinase activity and glucose utilization rate (r = .74, P less than .0001). These findings further support a role for the insulin-receptor kinase in insulin action in vivo, and this model provides a novel method for the study of the effect of factors known to influence insulin action on the insulin-receptor kinase under physiologic conditions.

Carbohydrate metabolism during fasting in chronic hemodialysis patients

Carbohydrate metabolism was studied during a 72-hr fast in 11 nondiabetic endstage renal disease (ESRD) patients on chronic hemodialysis and six normal subjects. Blood was obtained every 12 hr for metabolic substrate, insulin, and potassium concentrations. Serum potassium concentrations were significantly higher in the ESRD patients at the end of each fasting day, and two patients were removed before completion of the fast when severe hyperkalemia developed. Mean blood glucose, alanine, pyruvate, beta-hydroxybutyrate, and serum insulin concentrations were similar in the two groups. Mean blood lactate concentration tended to be higher in the ESRD group. Mean blood acetoacetate and plasma free fatty acid (FFA) concentrations were lower in the ESRD group. When compared to serum insulin levels, the FFA concentration was lower in the ESRD group.

Hormonal and metabolic changes in hepatic cirrhosis.

The hormonal and metabolic response to 50 g oral glucose has been studied in fifteen patients with hepatic cirrhosis and seven control subjects. Fasting blood glucose concentration was similar in both groups but cirrhotics showed higher glucose levels throughout the glucose tolerance test. Fasting serum insulin concentration was raised in the patient group (0.12 +/- 0.02 vs 0.07 +/- 0.01 nmol/l, p less than 0.05 and hyperinsulinaemia persisted after oral glucose. Blood lactate and pyruvate concentrations were elevated in cirrhotic patients, both fasting and post-glucose, while mean blood lactate correlated with mean serum insulin concentrations (rs 0.55, p less than). Plasma glucagon concentrations although highly variable, did not differ significantly in control and cirrhotic subjects before or after oral glucose. Fasting blood glycerol was increased in the patient group (O.11 +/- 0.01 vs 0.06 +/- 0.01 mmol/l, p less than 0.05) but fasting blood ketone body levels were normal and both glycerol and ketone body concentrations fell normally after glucose. Basal serum cortisol levels were similar in patient and control groups but the expected fall in cortisol concentration found in the control group over the test period was absent in cirrhotics. The hormonal and metabolic abnormalities did not correlate with severity of disease assessed by liver function test and abnormalities were not related to the presence or absence of portal-systemic shunting.

Insulin release and carbohydrate tolerance in hyperthyroid patients during non-selective or selective beta-1-adrenoceptor blockade.

The insulin release and the glucose disappearance rate (K-value) during an iv glucose tolerance test were evaluated in 20 hyperthyroid patients before and during treatment with either a non-selective (propranolol, n = 10) or a selective (metoprolol, n = 10) beta-1-adrenoceptor blocking agent. Mean daily doses were 240 mg of propranolol and 280 mg of metoprolol, administered four times daily for 10 to 14 days. The insulin increase after glucose injection remained unchanged during treatment with each drug. Fasting blood glucose concentrations and the K-values were not altered during treatment. Sixteen patients were re-investigated 10 to 36 weeks later when euthyroid due to treatment by surgery, thyrostatic drugs or radioiodine. In the euthyroid state mean serum insulin concentrations after the glucose load were not significantly different from the values found when the patients were hyperthyroid. However, mean fasting blood glucose concentrations decreased from 5.5 mmol/l to 5.0 (P less than 0.01) and the mean K-value increased from 1.5 to 2.0 (P less than 0.05) when the patients were euthyroid. It is concluded that short-term treatment of hyperthyroid patients with non-selective or selective beta-1-adrenoceptor blocking agents does not impair the glucose stimulated insulin secretion or the carbohydrate tolerance.

Consequences of modified fasting in obese pediatric and adolescent patients. I. Protein-sparing modified fast

Sixteen obese patients 9 to 16 years of age were treated with a protein-sparing modified fast for four weeks in a metabolic unit, using lean meat as the sole calorie-containing nutrient. Total weight loss was 7.11 +/- 0.33 kg (mean +/- SEM). One-half of the patients achieved positive daily nitrogen balance by the fourth week. Cumulative N balance was -28.8 +/- 10.0 gm. Serum albumin concentration remained normal. Hemoglobin and hematocrit values were stable, but decreases in total lymphocyte (P less than 0.005) and neutrophil counts (P less than 0.01) were noted. Cell-mediated immunity (four patients) remained normal. Protein synthetic and catabolic rates (two patients) revealed only minimal changes. Cumulative N balance correlated (P less than 0.01) with mean fasting serum insulin concentration, which was related (P less than 0.005) to body fat mass. The PSMF has therapeutic potential for achieving safe, rapid weight loss in severely obese older children and adolescents.

Bioactivity of Instant Glucose

The efficacy of instant glucose as a potential treatment for hypoglycemia was studied in normal volunteers, with therapeutic doses administered in the buccal cavity. 2-Tritiated glucose (50 mu Ci) was homogenized into each dose before use. Mean blood glucose and serum insulin concentrations were unaltered by instant glucose. Glucose absorption was less than 0.05 mg at any time, and total glucose absorbed was less than 0.1 mg. For comparison purposes, volunteers swallowed a dose of instant glucose. Approximately 88% of the dose was absorbed during a 30-minute interval. Blood glucose and insulin levels increased. Instant glucose appears to be of therapeutic value only if swallowed by fully conscious, hypoglycemic patients. It should not benefit unconscious patients because of its poor absorption through the buccal mucosa.

Bioactivity of instant glucose. Failure of absorption through oral mucosa

The efficacy of instant glucose as a potential treatment for hypoglycemia was studied in normal volunteers, with therapeutic doses administered in the buccal cavity. 2-Tritiated glucose (50 μCi) was homogenized into each dose before use. Mean blood glucose and serum insulin concentrations were unaltered by instant glucose. Glucose absorption was less than 0.05 mg at any time, and total glucose absorbed was less than 0.1 mg. For comparison purposes, volunteers swallowed a dose of instant glucose. Approximately 88% of the dose was absorbed during a 30-minute interval. Blood glucose and insulin levels increased. Instant glucose appears to be of therapeutic value only if swallowed by fully conscious, hypoglycemic patients. It should not benefit unconscious patients because of its poor absorption through the buccal mucosa. (<i>JAMA</i>240:1611-1612, 1978)

Diabetes among men in a general population. Prevalence and associated physiological findings

A random sample of 281 men, aged 30 through 69, resident in the community of Tecumseh, Mich, was studied with the use of standard glucose tolerance tests, including serum insulin assays and fasting serum lipid concentrations. Diagnoses of diabetes and probable diabetes were made according to a modification of the criteria of Fajans and Conn. Prevalence of diabetes and probable diabetes was considerably higher among men aged 40 through 49 than among those aged 30 through 39, but it increased little in the 50-through-59 and 60-through-69 age groups. Lean nondiabetics and probable diabetics had similar mean systolic blood pressures and similar mean levels of serum cholesterol, serum triglycerides, and serum insulin, but fat probable diabetics had much higher mean serum lipid and serum insulin concentrations that fat nondiabetics. Adiposity grouping discriminated by variable levels less well between diabetics and nondiabetics.

Diabetes Among Men in a General Population

A random sample of 281 men, aged 30 through 69, resident in the community of Tecumseh, Mich, was studied with the use of standard glucose tolerance tests, including serum insulin assays and fasting serum lipid concentrations. Diagnoses of diabetes and probable diabetes were made according to a modification of the criteria of Fajans and Conn. Prevalence of diabetes and probable diabetes was considerably higher among men aged 40 through 49 than among those aged 30 through 39, but it increased little in the 50-through-59 and 60-through-69 age groups. Lean nondiabetics and probable diabetics had similar mean systolic blood pressures and similar mean levels of serum cholesterol, serum triglycerides, and serum insulin, but fat probable diabetics had much higher mean serum lipid and serum insulin concentrations that fat nondiabetics. Adiposity grouping discriminated by variable levels less well between diabetics and nondiabetics.

Rapid intravenous sodium acetoacetate infusion in man. Metabolic and kinetic responses.

The metabolic and kinetic responses to rapidly intravenously administered sodium acetoacetate (1.0 mmol/kg body wt) was studied after an overnight fast in 12 male and female adults weighing between 88 and 215% of average body weight. Blood was obtained before, during, and after the infusion for determination of circulating concentrations of immunoreactive insulin, glucose, acetoacetate, beta-hydroxybutyrate and free fatty acids. In three obese subjects the studies were repeated after 3 and 24 days of total starvation. After the overnight fast acetoacetate rose rapidly reaching a peak concentration at the end of the infusion; beta-hydroxybutyrate concentrations also increased rapidly and exceeded those of acetoacetate 10 min postinfusion. Total ketone body concentration at the end of the infusion period was comparable to that found after prolonged starvation. After the initial mixing period, acetoacetate, beta-hydroxybutyrate and total ketone bodies rapidly declined in a parallel manner. There were no obvious differences between the subjects with regard to their blood concentrations of ketone bodies. The mean plasma free fatty acid concentration decreased significantly during the 20th to 90th min postinfusion period; for example the control concentration of 0.61 mmol/liter fell to 0.43 mmol/liter at 60 min. In the three obese subjects studied repeatedly, fasting plasma free fatty acids decreased with acetoacetate infusion from 0.92 to 0.46 mmol/liter after the 3 day fast and from 1.49 to 0.71 mmol/liter after the 24 day fast. Acetoacetate infusion caused no changes in blood glucose concentration after an overnight fast. However, in the three obese subjects restudied after 3- and 24-day fasts blood glucose decreased, respectively, from 3.49 to 3.22 mmol/liter and from 4.07 to 3.49 mmol/liter. The mean serum insulin concentration in all subjects significantly increased from 21 to 46 muU/ml at the completion of the infusion and rapidly declined. In the three obese subjects restudied after 3- and 24-day fasts an approximate two-fold increase of serum insulin was observed after each acetoacetate infusion. The mean fractional utilization rate of exogenously derived ketone bodies for all 12 subjects after an overnight fast was 2.9% min(-1). In the three obese subjects studied after an overnight, 3 and 24 day fast the mean fractional utilization rates were 2.1%, 1.5%, and 0.6% min(-1), respectively. Ketone body volumes of distribution in the overnight fasted subjected varied from about 18% to 31% of body wt, suggesting that ketone bodies are not homogenously distributed in the body water. In the three obese subjects restudied after 3- and 24-day fasts volumes of distribution remained approximately constant. When total ketone body concentrations in the blood were below 2.0 mmol/liter, there was a linear relationship between ketone body utilization rates and ketone body concentrations; no correlation was found when blood concentrations were higher.

Brown adipose tissue metabolism in vivo and serum insulin concentrations in rabbits soon after birth.

1. In rabbits kept unfed for 4 or 24 or 48 hr after delivery by Caesarean section at term, noradrenaline infusion (I.V. for 30 min) caused a similar increase in oxygen consumption but the increase in serum free fatty acid concentration was greatest in rabbits kept unfed for 48 hr.2. The brown adipose tissue of anaesthetized rabbits under 3 hr old took glucose from the circulation but did not release fatty acids. In similar rabbits noradrenaline infusion stimulated the tissue to generate heat, but there was no release of fatty acids even though the rate of triglyceride hydrolysis was high (as judged by the rate of glycerol release).3. In rabbits kept unfed for 48 hr from birth in a warm environment, brown adipose tissue released small amounts of fatty acids but continued to take glucose from the circulation. Heat production in response to noradrenaline infusion was accompanied by an increased release of fatty acids. The fat content of the brown adipose tissue did not fall with starvation.4. The mean serum insulin concentration of rabbits at birth was 54 muu./ml. compared to 23 muu./ml. in the mother. In new-born rabbits kept unfed for 48 hr the insulin concentration had fallen to 14 muu./ml.5. It is concluded (i) that at birth brown adipose tissue has the capacity to generate heat but the tissue is slow to release its stores of fat in response to starvation, (ii) that brown adipose tissue has a high rate of glucose uptake even during starvation and (iii) that the high circulating concentration of insulin may be responsible for the tissue's slow adaptation to the demands of starvation.

Growth hormone-induced diabetes and high levels of serum insulin in dogs.

Single injection of growth hormone (3 mg. per kilogram of body) in fasting dogs did not appreciably alter serum insulin and glucose concentrations within five hours. However, serum free fatty acids (FFA) decreased initially, then rose to two- and fourfold the initial at five and twenty-four hours. Following intravenous injection of glucose (1 gm. per kilogram of body) in the control period, serum insulin rose fourfold in 15 min. then regressed exponentially to the initial. Glucose/insulin remained unchanged during the two-hour test period, despite great alterations in the concentrations of glucose and insulin. Serum FFA decreased, then returned to or above the initial at one to two hours. Single injection of growth hormone did not alter these responses to the infusion of glucose. During the daily administration of 2 mg. of growth hormone per kilogram of body per day: (1) Mean serum insulin concentrations, in the postabsorptive periods, increased to two-, six- and eightfold the control value after one, two and four days, respectively, in six dogs, and thereafter the values remained high during seven to eleven days of observation in four dogs, while two developed resistance. (2) Serum insulin increased before an appreciable rise in serum glucose occurred. (3) Due to a greater rise in insulin than in glucose, the glucose/insulin ratio decreased. (4) After two days of injection the increase in serum insulin was most pronounced in those dogs that exhibited hyperglycemia and glycosuria. (5) Serum FFA increased greatly after one day of injection and remained high. During this growth hormone treatment, in one hour after injection of growth hormone with the ingestion of a meal, serum insulin rose, with lesser rise in glucose (further decrease in glucose/insulin), and fall in FFA. In the control period, however, no appreciable changes in serum insulin or glucose occurred following a meal. During daily growth hormone treatment, following glucose infusion: (1) Mean peak concentrations of serum insulin increased sevenfold in four days. (2) The rate of regression of serum insulin decreased. (3) Areas under the serum insulin curves increased up to tenfold the control value. (4) The mean rate of regression of serum glucose decreased, from the control value k — 4.28 per cent to —1.14 per cent after seven days. (5) The serum glucose/insulin ratio was unaltered, although the initial (fasting) values decreased. (6) The decline in serum FFA in 15 to 30 min. was more marked, but the levels remained above control. The changes in glucose/insulin indicate that growth hormone administration altered homeostatic control of pancreatic beta cells, such that at any given concentration of glucose in blood a greater rate of insulin secretion occurred. It is concluded that the “hyperinsulinemia” induced by the daily administration of growth hormone was associated with sustained increase in insulin secretion, and with augmentation of insulin secretion in response to a meal and to the infusion of glucose.