Metabolic effects of IGF-I and insulin in spontaneously diabetic BB/w rats

1991 ◽  
Vol 260 (2) ◽  
pp. E262-E268 ◽  
Author(s):  
R. J. Jacob ◽  
R. S. Sherwin ◽  
L. Bowen ◽  
D. Fryburg ◽  
K. D. Fagin ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Metabolic Response ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Diabetic Rats ◽  
Metabolic Effects ◽  
Insulin Resistant ◽  
Igf I ◽  
Elevated Glucose ◽  
Beta Hydroxybutyrate

To examine the influence of insulin-dependent diabetes on the metabolic response to insulin-like growth factor I (IGF-I), awake chronically catheterized diabetic and nondiabetic BB/w rats received IGF-I (5 micrograms.kg-1.min-1) or insulin (2 mU.kg-1.min-1) for 2 h while maintaining euglycemia. In nondiabetic rats, IGF-I and insulin produced similar twofold increases in glucose uptake, but insulin was more effective in reducing hepatic glucose production (90 +/- 15 vs. 5 +/- 11%; P less than 0.001) and beta-hydroxybutyrate levels (94 +/- 1 vs. 19 +/- 6%; P less than 0.001). In diabetic rats, insulin-stimulated glucose uptake was impaired (8.5 +/- 0.9 vs. 11.5 +/- 0.9 mg.kg-1.min-1 in nondiabetics; P less than 0.05). In contrast, IGF-I-stimulated glucose uptake was identical in diabetic and nondiabetic rats. Furthermore, IGF-I suppressed glucose production by 73% (P less than 0.01) and caused a greater lowering of beta-hydroxybutyrate levels (from 2.9 +/- 0.8 to 0.8 +/- 0.3 mumol/l) in diabetic rats. We conclude that 1) the capacity of IGF-I infusion to stimulate glucose uptake is maintained in spontaneously diabetic BB rats that are insulin resistant, and 2) IGF-I infusion suppresses elevated glucose production rates and plasma ketone concentrations in diabetic rats but is relatively ineffective in nondiabetic rats. Thus the metabolic responses to infused IGF-I do not appear to be diminished in diabetic rats with impaired responses to insulin.

Insulin resistance but IGF-I sensitivity in chronic renal failure

1996 ◽  
Vol 271 (1) ◽  
pp. F114-F119
Author(s):  
R. H. Mak
Keyword(s):  
Insulin Resistance ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Insulin Resistant ◽  
Igf I ◽  
Total Body ◽  
And Control

The effects of insulin-like growth factor I (IGF-I) and insulin on glucose metabolism were compared in awake, chronically catheterized rats with chronic renal failure (CRF) and sham-operated, pair-fed controls. In control rats, IGF-I (5 micrograms.kg-1.min-1) and insulin (2 mU.kg-1.min-1) infusions produced similar twofold increases in total body glucose uptake from fasting values under euglycemic conditions (euglycemic clamps). Total body glucose uptake during euglycemic IGF-I clamps at 5 and 10 micrograms.kg-1.min-1 was not different between CRF and control rats. Total body glucose uptake during euglycemic insulin clamps at 2 and 4 mU.kg-1.min-1 was significantly lower in CRF rats compared with corresponding values in control rats. Hepatic glucose production was suppressed by insulin equally but not by IGF-I in both groups. Correction of metabolic acidosis by NaHCO3 partially improved insulin resistance in rats with CRF, whereas an equimolar amount of NaCl had no effect. Thus the capacity of IGF-I infusion to stimulate total body glucose uptake is maintained in CRF rats that are insulin resistant.

scholarly journals Acute activation of pyruvate dehydrogenase increases glucose oxidation in muscle without changing glucose uptake

2018 ◽  
Vol 315 (2) ◽  
pp. E258-E266 ◽  
Author(s):  
Lewin Small ◽  
Amanda E. Brandon ◽  
Lake-Ee Quek ◽  
James R. Krycer ◽  
David E. James ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Kinase Inhibitor ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Acetyl Coa ◽  
Insulin Resistant

Pyruvate dehydrogenase (PDH) activity is a key component of the glucose/fatty acid cycle hypothesis for the regulation of glucose uptake and metabolism. We have investigated whether acute activation of PDH in muscle can alleviate the insulin resistance caused by feeding animals a high-fat diet (HFD). The importance of PDH activity in muscle glucose disposal under insulin-stimulated conditions was determined by infusing the PDH kinase inhibitor dichloroacetate (DCA) into HFD-fed Wistar rats during a hyperinsulinemic-euglycemic clamp. Acute DCA infusion did not alter glucose infusion rate, glucose disappearance, or hepatic glucose production but did decrease plasma lactate levels. DCA substantially increased muscle PDH activity; however, this did not improve insulin-stimulated glucose uptake in insulin-resistant muscle of HFD rats. DCA infusion increased the flux of pyruvate to acetyl-CoA and reduced glucose incorporation into glycogen and alanine in muscle. Similarly, in isolated muscle, DCA treatment increased glucose oxidation and decreased glycogen synthesis without changing glucose uptake. These results suggest that, although PDH activity controls the conversion of pyruvate to acetyl-CoA for oxidation, this has little effect on glucose uptake into muscle under insulin-stimulated conditions.

AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B

2006 ◽  
Vol 291 (1) ◽  
pp. H239-H250 ◽  
Author(s):  
Luc Bertrand ◽  
Audrey Ginion ◽  
Christophe Beauloye ◽  
Alexandre D. Hebert ◽  
Bruno Guigas ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Protein Kinase B ◽  
Hepatic Glucose Production ◽  
Active Form ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
Ampk Activation ◽  
Insulin Resistant ◽  
Stimulation Of

Diabetic hearts are known to be more susceptible to ischemic disease. Biguanides, like metformin, are known antidiabetic drugs that lower blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in muscle. Part of these metabolic effects is thought to be mediated by the activation of AMP-activated protein kinase (AMPK). In this work, we studied the relationship between AMPK activation and glucose uptake stimulation by biguanides and oligomycin, another AMPK activator, in both insulin-sensitive and insulin-resistant cardiomyocytes. In insulin-sensitive cardiomyocytes, insulin, biguanides and oligomycin were able to stimulate glucose uptake with the same efficiency. Stimulation of glucose uptake by insulin or biguanides was correlated to protein kinase B (PKB) or AMPK activation, respectively, and were additive. In insulin-resistant cardiomyocytes, where insulin stimulation of glucose uptake was greatly reduced, biguanides or oligomycin, in the absence of insulin, induced a higher stimulation of glucose uptake than that obtained in insulin-sensitive cells. This stimulation was correlated with the activation of both AMPK and PKB and was sensitive to the phosphatidylinositol-3-kinase/PKB pathway inhibitors. Finally, an adenoviral-mediated expression of a constitutively active form of AMPK increased both PKB phosphorylation and glucose uptake in insulin-resistant cardiomyocytes. We concluded that AMPK activators, like biguanides and oligomycin, are able to restore glucose uptake stimulation, in the absence of insulin, in insulin-resistant cardiomyocytes via the additive activation of AMPK and PKB. Our results suggest that AMPK activation could restore normal glucose metabolism in diabetic hearts and could be a potential therapeutic approach to treat insulin resistance.

64-LB: Aerobic Exercise Decreases Hepatic Glucose Production via Asprosin Pathway in Diabetic Rats

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 64-LB
Author(s):  
JEONGRIM KO ◽  
TAE NYUN KIM ◽  
DAE YUN SEO ◽  
JIN HAN
Keyword(s):  
Aerobic Exercise ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Diabetic Rats ◽  
Hepatic Glucose

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A

1994 ◽  
Vol 131 (3) ◽  
pp. 251-257 ◽  
Author(s):  
Peter D Zenobi ◽  
Yvonne Glatz ◽  
Annamarie Keller ◽  
Susanne Graf ◽  
Silvia E Jaeggi-Groisman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Type A ◽  
Metabolic Effects ◽  
Insulin Like Growth Factor ◽  
Severe Insulin Resistance ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Zenobi PD, Glatz Y, Keller A, Graf S, Jaeggi-Groisman SE, Riesen WF, Schoenle EJ, Froesch ER. Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A. Eur J Endocrinol 1994;131:251–7. ISSN 0804–4643 Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an iv bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 × 150 μg rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1–5) in the two patients were 9.6±1.3 and 9.2 ± 1.2 mmol/l, respectively, and fell to 4.4±0.4 and 5.1±0.5 mmol/l on treatment days 8–10. Fasting insulin (2950±450 and 690±125 pmol/l), C-peptide (2217±183 and 1317±235 pmol/l) and proinsulin control levels (125±35 and 66±0 pmol/l) also decreased by ~65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent. E Rudolf Froesch, Department of Internal Medicine, University Hospital, Rämistrasse 100, 8091 Zurich, Switzerland

Regulation of glucose turnover and hormonal responses during electrical cycling in tetraplegic humans

1996 ◽  
Vol 271 (1) ◽  
pp. R191-R199 ◽  
Author(s):  
M. Kjaer ◽  
S. F. Pollack ◽  
T. Mohr ◽  
H. Weiss ◽  
G. W. Gleim ◽  
...  
Keyword(s):  
Heart Rate ◽  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Turnover ◽  
Hormonal Responses ◽  
Hepatic Glucose ◽  
Exercise Period ◽  
Exercise Activity ◽  
Beta Hydroxybutyrate

To examine the importance of blood-borne vs. neural mechanisms for hormonal responses and substrate mobilization during exercise, six spinal cord-injured tetraplegic (C5-T1) males (mean age: 35 yr, range: 24-55 yr) were recruited to perform involuntary, electrically induced cycling [functional electrical stimulation (FES)] to fatigue for 24.6 +/- 2.3 min (mean and SE), and heart rate rose from 67 +/- 7 (rest) to 107 +/- 5 (exercise) beats/min. Voluntary arm cranking in tetraplegics (ARM) and voluntary leg cycling in six matched, long-term immobilized (2-12 mo) males (Vol) served as control experiments. In FES, peripheral glucose uptake increased [12.4 +/- 1.1 (rest) to 19.5 +/- 4.3 (exercise) mumol.min-1.kg-1; P < 0.05], whereas hepatic glucose production did not change from basal values [12.4 +/- 1.4 (rest) vs. 13.0 +/- 3.4 (exercise) mumol.min-1.kg-1]. Accordingly, plasma glucose decreased [from 5.4 +/- 0.3 (rest) to 4.7 +/- 0.3 (exercise) mmol/l; P < 0.05]. Plasma glucose did not change in response to ARM or Vol. Plasma free fatty acids and beta-hydroxybutyrate decreased only in FES experiments (P < 0.05). During FES, increases in growth hormone (GH) and epinephrine and decreases in insulin concentrations were abolished. Although subnormal throughout the exercise period, norepinephrine concentrations increased during FES, and responses of heart rate, adrenocorticotropic hormone, beta-endorphin, renin, lactate, and potassium were marked. In conclusion, during exercise, activity in motor centers and afferent muscle nerves is important for normal responses of GH, catecholamines, insulin, glucose production, and lipolysis. Humoral feedback and spinal or simple autonomic nervous reflex mechanisms are not sufficient. However, such mechanisms are involved in redundant control of heart rate and neuroendocrine activity in exercise.

scholarly journals Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

2016 ◽  
Vol 311 (3) ◽  
pp. E620-E627 ◽  
Author(s):  
Tianru Jin ◽  
Jianping Weng
Keyword(s):  
Insulin Resistance ◽  
Degradation Products ◽  
Hepatic Glucose Production ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Beneficial Effects ◽  
Metabolic Functions ◽  
Pathway Activation ◽  
Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

2002 ◽  
Vol 282 (6) ◽  
pp. E1360-E1368 ◽  
Author(s):  
Thongchai Pratipanawatr ◽  
Wilailak Pratipanawatr ◽  
Clifford Rosen ◽  
Rachele Berria ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Control Subjects ◽  
Igf I ◽  
Plasma Ffa ◽  
Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

scholarly journals mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Aleksandra Kezic ◽  
Ljiljana Popovic ◽  
Katarina Lalic
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
Calorie Restriction ◽  
Mtor Inhibitor ◽  
Hepatic Glucose Production ◽  
Mtor Inhibitors ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Solid Organ ◽  
Amp Activated Protein Kinase

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

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