Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs

1998 ◽  
Vol 274 (2) ◽  
pp. E346-E356 ◽  
Author(s):  
Richard H. McCall ◽  
Stephanie R. Wiesenthal ◽  
Z. Qing Shi ◽  
Kenneth Polonsky ◽  
Adria Giacca
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Insulin Infusion ◽  
Low Dose ◽  
Glucose Production ◽  
High Rate ◽  
High Dose ◽  
Insulin Levels ◽  
Predominant Effect

To determine whether the predominant effect of insulin in suppressing tracer-determined glucose production (Ra) is hepatic or peripheral, we infused insulin peripherally (PER) and portally (POR) at both low (0.75 pmol ⋅ kg−1 ⋅ min−1) and high physiological rates (2.7 pmol ⋅ kg−1 ⋅ min−1) during euglycemic clamps in normal dogs. We also infused insulin peripherally at one-half these rates (1/2 PER) to match the peripheral insulin levels in POR and thus obtain a selective POR vs. 1/2 PER difference in hepatic insulin levels. At the high-rate insulin infusion, peripheral insulin levels were greatest with PER (PER = 212 ± 10 pM, n = 5; POR = 119 ± 5 pM, n = 6; 1/2 PER = 122 ± 5 pM, n = 6). Calculated hepatic insulin levels were greatest with POR (POR = 227 ± 13 pM, PER = 206 ± 19 pM, 1/2 PER = 123 ± 8 pM). High-dose PER yielded a greater suppression of Ra than POR (79 ± 18 vs. 56 ± 6%, P < .001). Ra was only suppressed by 45 ± 6% with 1/2 PER ( P< 0.01 vs. POR on 6 paired experiments). Free fatty acid (FFA) was suppressed by 57 ± 8% with PER and only by 33 ± 5 and 37 ± 2% with POR and 1/2 PER, respectively. The low-dose PER and POR yielded an equal Ra suppression (PER = 46 ± 9%, POR = 43 ± 4%). Only 1/2 PER was associated with a lower suppression of Ra (36 ± 8, P < 0.05 vs. POR). FFA showed similar suppression in all three groups (∼25%). Using both insulin infusion rates, the percent Ra suppression per unit difference in peripheral insulin was approximately twofold greater than that per unit difference in hepatic insulin. These results suggest that, during euglycemic clamps without somatostatin in normal dogs, Ra suppression is mediated by both peripheral and hepatic effects of insulin and that peripheral insulin, at least at high physiological infusion rates, is more potent than hepatic insulin in suppressing Ra.

Mechanism of regulation of glucose production by lipolysis in humans

1992 ◽  
Vol 262 (3) ◽  
pp. E353-E358 ◽  
Author(s):  
F. Jahoor ◽  
S. Klein ◽  
R. Wolfe
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Nicotinic Acid ◽  
Plasma Insulin ◽  
Glucose Production ◽  
Plasma Free Fatty Acid ◽  
Insulin Levels ◽  
Plasma Insulin Levels ◽  
Normal Humans ◽  
The Relationship

The relationship between the rate of lipolysis and rate of glucose production (Ra) was investigated in 14- and 86-h fasted humans. [6,6-2H]glucose and [2H]5glycerol were infused to measure glucose and glycerol Ra in response to infusions of nicotinic acid in 14- and 86-h fasted subjects (protocol 1). The response of glucose Ra to nicotinic acid alone and nicotinic acid plus unlabeled glycerol was also measured in 86-h fasted subjects (protocol 2). After a 14-h fast, nicotinic acid caused a 30% decrease in plasma insulin levels and a marked (66%) decrease in plasma free fatty acid levels but did not have any significant effect on glucose Ra and concentration. After 86 h of fasting, nicotinic acid decreased glycerol Ra and hence lipolytic rate by approximately 60%. This caused a significant decrease (P less than 0.05) of 16-20% in glucose Ra and uptake. This decrease in glucose Ra was abolished when unlabeled glycerol was also infused with nicotinic acid to maintain glycerol Ra. These findings suggest that, in normal humans, a decrease in the rate of lipolysis regulates glucose Ra via its effect on the availability of glycerol for gluconeogenesis.

Paradoxical insulin-induced increase in gluconeogenesis in response to prolonged hypoglycemia in conscious dogs

1995 ◽  
Vol 268 (3) ◽  
pp. E521-E530 ◽  
Author(s):  
S. N. Davis ◽  
R. Dobbins ◽  
C. Tarumi ◽  
J. Jacobs ◽  
D. Neal ◽  
...  
Keyword(s):  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
High Dose ◽  
Insulin Levels ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Dose Infusion ◽  
Arterial Insulin

The aim of this study was to determine the effects of differing insulin concentrations on the gluconeogenic response to equivalent prolonged hypoglycemia. Insulin was infused intraportally, for 3 h, into normal 18-h fasted conscious dogs at 2 (lower, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during high dose to maintain the hypoglycemic plateau (50 +/- 1 mg/dl) equivalent to lower. Epinephrine (806 +/- 180 vs. 2,589 +/- 260 pg/ml), norepinephrine (303 +/- 55 vs. 535 +/- 60 pg/ml), cortisol (5.8 +/- 1.2 vs. 12.1 +/- 1.5 micrograms/dl), and pancreatic polypeptide (598 +/- 250 vs. 1,198 +/- 150 pg/ml) were all increased (P < 0.05) in the presence of high-dose insulin. Net hepatic glucose production increased significantly from 2.2 +/- 0.3 to 3.8 +/- 0.5 mg.kg-1.min-1 (P < 0.05) during high-dose infusion but remained at basal levels (2.3 +/- 0.4 mg.kg-1.min-1) during lower-dose insulin. During the 3rd h of hypoglycemia, gluconeogenesis accounted for between 42 and 100% of glucose production during high-dose infusion but only 22-52% during lower-dose insulin. Intrahepatic gluconeogenic efficiency, however, increased similarly during both protocols. Lipolysis, as indicated by arterial blood glycerol levels, increased by a greater amount during high- compared with lower-dose insulin infusion. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. Gluconeogenesis remained similar to basal levels, but lipolysis was significantly suppressed during both series of hyperinsulinemic euglycemic studies. In summary, these data suggest that 1) the important counterregulatory processes of gluconeogenesis and lipolysis can be significantly increased during prolonged hypoglycemia despite an eightfold increase in circulating insulin levels and 2) the amplified gluconeogenic rate present during the hypoglycemic high-dose insulin infusions was caused by enhanced substrate delivery to the liver rather than an increase in intrahepatic gluconeogenic efficiency.

scholarly journals Free and esterified fatty acid and cholesterol synthesis in adult malesand its effect on the doubly-labelled water method

2000 ◽  
Vol 83 (3) ◽  
pp. 227-234 ◽  
Author(s):  
P. Haggarty ◽  
P. Shetty ◽  
S. Thangam ◽  
S. Kumar ◽  
A. Kurpad ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Energy Balance ◽  
Cholesterol Synthesis ◽  
Western Diet ◽  
Lipid Classes ◽  
High Rate ◽  
Whole Body ◽  
Doubly Labelled Water ◽  
Typical Western Diet

The purpose of the present study was to estimate whole-body fatty acid and cholesterol synthesis in weight-stable adults and to determine the likely effect on the doubly-labelled water (DLW) method for measuring energy expenditure. Synthesis was measured by 2H incorporation over 14 d in six adult males in approximate energy balance following noradrenaline infusion to maximize mobilization of free fatty acid from adipose tissue. The inter-individual variation in synthesis rates was large and in one subject the proportion of free fatty acid synthesized was ten times that of the mean of the rest of the group; the fasting concentration of esterified fatty acid in this subject was five times that of the rest of the group indicating likely violation of the assumptions underlying the calculation of whole-body synthesis. After 14 d of labelling in the other five subjects, 0·9 (SEM 0·3) % OF THE CIRCULATING FREE FATTY ACID, 9·3 (sem 3·0) % of the esterified fatty acid, 14·6 (sem 2·4) % of the free cholesterol and 28·3 (sem 3·7) % of esterified cholesterol had been synthesized de novo. A high rate of synthesis correlated with a low pre-dose 2H abundance both within and between lipid classes suggesting that natural 2H abundance variations in some lipid classes may be used to determine their metabolic origin. Whole-body synthetic rates were 8 g/d for fatty acid and 0·3–0·5 g/d for cholesterol. These values correspond to very small errors on DLW-derived estimates of CO2 production; -2·5 litres/d for fatty acid and -0·1 to -0·2 litres/d for cholesterol. These results, obtained in subjects typically consuming a diet with a lower fat and cholesterol content that the typical Western diet, suggest that the DLW method is unlikely to be affected by fatty acid and cholesterol synthesis in subjects in energy balance consuming a typical Western diet.

Plasma free fatty acid turnover during insulin-induced hypoglycemia

1961 ◽  
Vol 201 (3) ◽  
pp. 535-539 ◽  
Author(s):  
D. T. Armstrong ◽  
R. Steele ◽  
N. Altszuler ◽  
A. Dunn ◽  
J. S. Bishop ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Uptake ◽  
Plasma Glucose ◽  
Glucose Concentration ◽  
Insulin Infusion ◽  
Plasma Free Fatty Acid ◽  
Plasma Glucose Concentration ◽  
Free Insulin ◽  
Adrenal Response

Plasma free fatty acid (FFA) concentration falls when an infusion of glucagon-free insulin is initiated in the normal unanesthetized dog in the postabsorptive state. Using C14 palmitate it was shown that the lowered FFA concentration is caused by decreased FFA production. This decreased FFA production accompanies increased glucose uptake by the tissues as demonstrated using C14 glucose. During slow insulin infusion, when plasma glucose concentration remains above 75 mg%, FFA production and concentration remain low. However, during more rapid insulin infusion, when plasma glucose concentration falls below 50 mg%, the initially lowered FFA production rebounds and FFA production and concentration exceed the preinsulin level. Glucose uptake always remains elevated during insulin infusion. Dibenzyline or guanethidine pretreatment blocks the rebound in FFA production. Thus decreased FFA production, due presumably to decreased FFA release by adipose tissue because of insulin-stimulated glucose uptake, can be overpowered by a sympatho-adrenal response to hypoglycemia during a continued infusion of insulin and a resulting continued increased glucose uptake.

PLASMA GLUCOSE, INSULIN AND FREE FATTY ACIDS DURING LONG-TERM CORTICOSTEROID TREATMENT IN CHILDREN

1974 ◽  
Vol 77 (4) ◽  
pp. 699-704 ◽  
Author(s):  
Gábor Gács ◽  
Katalin Berend
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Tolerance ◽  
Fasting Blood Glucose ◽  
Corticosteroid Treatment ◽  
Oral Glucose ◽  
Plasma Insulin Concentration ◽  
Glucose Administration ◽  
Insulin Levels

ABSTRACT The effect of long-term corticosteroid treatment on glucose-insulin-free fatty acid interrelationships was studied in 25 children. The fasting blood glucose level and glucose tolerance after oral glucose administration were normal in all cases. The mean plasma insulin concentration on the other hand was significantly higher during the glucose tolerance tests. Free fatty acid levels were moderately lower in the fasting plasma and significantly lower 30 min after glucose administration. This shift in the balance between the changes studied may contribute to the fat deposition often seen during corticosteroid treatment. There was no correlation between the actual dose of the drug and the insulin levels. Children – even if treated with corticosteroids for years – are able to maintain a normal glucose tolerance as a result of a continuous elevated insulin level. Arginine stimulation also resulted in a trend to higher insulin levels in the corticosteroid treated group but the difference from the normal was much smaller than after glucose administration.

Effects of differing insulin levels on response to equivalent hypoglycemia in conscious dogs

1992 ◽  
Vol 263 (4) ◽  
pp. E688-E695 ◽  
Author(s):  
S. N. Davis ◽  
R. Dobbins ◽  
C. Tarumi ◽  
C. Colburn ◽  
D. Neal ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
High Dose ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Hepatic Glucose ◽  
High Insulin ◽  
Arterial Insulin

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia. Insulin was infused intraportally into normal 18-h-fasted conscious dogs at 2 (low, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during the high dose to maintain plasma glucose similar to low (50 +/- 1 mg/dl). Despite similar plasma glucose levels, epinephrine (2,589 +/- 260, 806 +/- 180 pg/ml), norepinephrine (535 +/- 60, 303 +/- 55 pg/ml), cortisol (12.1 +/- 1.5, 5.8 +/- 1.2 micrograms/dl), and pancreatic polypeptide (1,198 +/- 150, 598 +/- 250 pg/ml) were all increased in the presence of high-dose insulin (P < 0.05). Glucagon levels were similar during both insulin infusions. Hepatic glucose production, measured with [3-3H]-glucose, rose from 2.6 +/- 0.2 to 4.7 +/- 0.3 mg.kg-1.min-1 in response to high insulin (P < 0.01) but remained unchanged, 3.0 +/- 0.5 mg.kg-1.min-1, during low-dose infusions. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. By the final hour of the high-dose euglycemic clamps, cortisol (2.4 +/- 0.4 to 4.8 +/- 0.8 micrograms/dl) and norepinephrine (125 +/- 34 to 278 +/- 60 pg/ml) had increased (P < 0.05) compared with baseline. Plasma epinephrine levels remained unchanged during both series of euglycemic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Bedtime insulin for suppression of overnight free-fatty acid, blood glucose, and glucose production in NIDDM

Diabetes ◽  
1989 ◽  
Vol 38 (5) ◽  
pp. 580-588 ◽  
Author(s):  
M. R. Taskinen ◽  
T. Sane ◽  
E. Helve ◽  
S. L. Karonen ◽  
E. A. Nikkila ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Free Fatty Acid ◽  
Glucose Production

Combination Therapy of Bortezomib with Low-Dose Bendamustine in Elderly Patients with Advanced Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5122-5122 ◽  
Author(s):  
Irena Hrusovsky ◽  
Hans-Heinrich Heidtmann
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Elderly Patients ◽  
Low Dose ◽  
Alkylating Agents ◽  
High Rate ◽  
Treatment Modalities ◽  
Cross Resistance ◽  
High Dose ◽  
Indolent Lymphoma

Abstract Bortezomib has been approved for recurrent or therapy-resistent multiple myeloma in 2003. There is growing evidence that combination therapy of bortezomib with other agents considerably improves results (Richardson P, ASH 2004). Bendamustine is an alkylating agent widely used in Germany for treatment of multiple myeloma and indolent lymphoma. There is no cross-resistance to other alkylating agents. Weekly low dose application is well tolerated and highly effective in elderly patients with pretreated indolent lymphoma (Bremer K, ASCO 2003, Abstract 2410). Treatment modalities: We treated 17 pts (8 female, 9 male, median age 70 yrs (range 51–82) with relapsed multiple myeloma. Previous therapies ranged from 2 to 7 (median 4), and included 15 x thalidomide, 2 x tandem high dose melphalan, 2 x bortezomib/dexamethasone. Therapy regimen: bortezomib 1 – 1.3 mg/m2 d 1,4,8,11; bendamustine 60 mg/m2 d 1+8, dexamethasone 3x8 mg orally d 1–3 and d 8–10: ondansetrone 8 mg intravenously d 1,4,8,11. Cycles were repeated q3w until best response. The median number of cycles applied was 4 (range 3 – 6). Results: Outcome was evaluated according to SWOG criteria. ORR: 88%; CR (neg. immunofixation): 12% (n=2); PR 58% (n=10); MR 18% (n= 3); NC 12% (n=2). Median remission duration was 6+ months (range 3–12+ months). Until today, we observed 4 recurrences after 3 – 8 months. Toxicity comprised mild fatigue and thrombopenia. Lowest platelet count was 55/pL without bleeding, spontaneously reversible within 1 week. Three cases of neuropathia occurred, with controllable symptoms, in patients pretreated with thalidomide or bortezomib mono. Conclusion: Combination therapy of bortezomib with low dose bendamustine is well tolerated, induces a high rate of responses in spite of unfavourable patient characteristics, leads to early responses and can be limited to 3 months (i.e., 4 cycles), and can be done in an outpatient setting. Thus, bendamustine is a very promising agent to enhance bortezomib action, which warrants further study.

Bedtime Insulin for Suppression of Overnight Free-Fatty Acid, Blood Glucose, and Glucose Production in NIDDM

Diabetes ◽  
1989 ◽  
Vol 38 (5) ◽  
pp. 580-588 ◽  
Author(s):  
M.-R. Taskinen ◽  
T. Sane ◽  
E. Helve ◽  
S.-L. Karonen ◽  
E. A. Nikkila ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Free Fatty Acid ◽  
Glucose Production
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