Differential Effects Of Insulin Research Articles

Glucose and amino acid metabolism in aging man: Differential effects of insulin

Insulin is a major regulator of glucose and body protein homeostasis, both of which demonstrate age-related changes. To clarify insulin's role in these age-related changes and to compare age-related glucose and protein homeostatic responses, insulin-mediated aspects of glucose and amino acid metabolism were simultaneously examined in healthy postabsorptive young (n = 5, mean age, 25 years) and elderly (n = 5, mean age, 76 years) men. Primed constant infusions of L-[1- 13C]leucine and L-[ 15N]alanine were administered during a basal period (0 to 180 minutes) and during four separate single rate euglycemic insulin infusions (180 to 360 minutes). Steady state insulin concentrations were 16 ± 1, 29 ± 3, 75 ± 5, and 2407 ± 56 μU/mL in the young and 23 ± 4, 37 ± 8, 96 ± 11 and 3,357 ± 249 μU/mL in the elderly at the different insulin infusion rates of 6, 10, 30, and 400 mU mU · m −2 · min −1, respectively. For the 6 and 10 mU insulin infusion rates, a primed, constant infusion of [6.6 − 2H 2]glucose permitted quantitation of hepatic glucose production. Glucose disposal rates adjusted for lean body mass (LBM) were lower in the elderly than in the young at the 6, 10, and 30 mU insulin infusion rates and similar in the two age groups in the 400 mU studies. Insulin dose-dependent reductions occurred in eight of ten plasma amino acids and were not influenced by age. There was an insulin dose-dependent reduction in plasma leucine flux which was similar in both age groups. Alanine flux and de novo alanine synthesis increased to a similar extent at the 30 and 400 mU insulin infusion rates in both age groups. These data indicate differential changes during aging in the sensitivities of glucose v amino acid metabolism to insulin action with preservation of insulin-mediated suppression of body protein breakdown at physiologic levels of insulin.

Control of the adipogenic differentiation of 3T3‐F442A cells by retinoic acid, dexamethasone, and insulin: A topographic analysis

Differentiation of 3T3-F442A adipocytes, monitored by accumulation of neutral lipid and by using the sensitive marker glycerophosphate dehydrogenase, is inhibited by incubation of confluent 3T3-F442A fibroblasts in medium containing retinoic acid or dexamethasone. When added together, dexamethasone (0.25 microM) potentiates about 50-fold the inhibitory effect of retinoic acid (10 microM). Insulin cannot counteract the retinoic acid blockade; however, it can overcome the inhibition of differentiation elicited by dexamethasone. These differential effects of insulin are used for characterizing the adipose conversion cycle. We describe cell culture conditions where terminal differentiation of 3T3-F442A preadipocytes is achieved by low, physiological levels of insulin. They include the switch from a high-serum medium containing isobutyl methyl xanthine and dexamethasone to a serum-free, hormone-supplemented medium. The data reported establish the existence of two successive states for commitment to adipogenic differentiation: a first commitment point (CA) to differentiation which requires serum adipogenic factors, and a second commitment point (CH) controlled by lipogenic hormones, namely insulin, after which terminal maturation can resume. We demonstrate that retinoic acid can prevent and interrupt differentiation by blocking the cells within the early differentiation phase.

Differential effects of insulin, antibodies against rat adipocyte plasma membranes, and other agents that mimic insulin action in rat adipocytes

The effects of insulin and several insulin-mimetic agents on rat adipocyte D-glucose metabolism were studied in an effort to determine if any of the insulin-mimetic agents could be used to define the mechanism of insulin action. Antibodies against rat adipocyte plasma membranes have been characterized as having insulin-mimetic effects on glucose transport and these effects may be caused by divalent clustering of cell surface antigens. In contrast to insulin, antimembrane antibodies had little stimulatory effect on D-glucose conversion to lipids in isolated rat adipocytes, under conditions where both reagents stimulated D-glucose oxidation. Among other insulin-mimetic agents tested, the reagents hydrogen peroxide and concanavalin A most closely resembled insulin in their ability to increase both [ 14C]-CO 2 and [ 14C]-lipid formation from [ 14C]D-glucose in rat adipocytes. Vitamin K5 and diamide had the unusual effect of inhibiting [1- 14C]D-glucose conversion to [ 14C]-lipids at a concentration that gave maximal stimulation of glucose oxidation by rat adipocytes. Analysis of the lipid components into which glucose derivatives were incorporated revealed that insulin increased D-glucose incorporation into both nonesterified fatty acids and triglycerides and H 2O 2 and concanavalin A had similar effects. These findings argue against the possibility that insulin and the antimembrane antibodies or the insulin-mimetic agents other than H 2O 2 and concanavalin A share the same mechanism of action.

Differential effects of insulin on brain monoamine metabolism in rats.

The effect of a subconvulsive dose of insulin, which caused a 70% reduction of plasma glucose levels, on catecholamine and 5-hydroxytryptamine turnover in different brain regions of rats was investigated. The turnover of norepinephrine was found to be increased in the hemispheres and that of 5-hydroxytryptamine was increased in the limbic forebrain and hemispheres, whereas the dopamine turnover was decreased in the striatum and limbic forebrain.

Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man.

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg(-1) min(-1)) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg(-1) min(-1); (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg(-1) min(-1)); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg(-1) min(-1)). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls ( approximately 170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 muU/ml at 90 min. NSGB switched from a net output of 1.71+/-0.13 to a net uptake of 1.5-1.6 mg kg(-1) min(-1) due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78+/-0.13 to 1.6-1.8 mg kg(-1) min(-1); P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 muU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 muU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 muU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg(-1) min(-1)). Peripheral glucose uptake rose to the same extent as in controls. IT IS CONCLUDED THAT: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

Differential effects of insulin in ischaemic working rat hearts with and without reperfusion: A.J. Higgins, Pfizer Central Research, Sandwich, Kent, U.K.

Differential effects of insulin in ischaemic working rat hearts with and without reperfusion: A.J. Higgins, Pfizer Central Research, Sandwich, Kent, U.K.