The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

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Whole body and hepatic insulin action in normal, starved, and diabetic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.6.e825 ◽

1991 ◽

Vol 260 (6) ◽

pp. E825-E832 ◽

Cited By ~ 6

Author(s):

S. J. Koopmans ◽

S. F. de Boer ◽

H. C. Sips ◽

J. K. Radder ◽

M. Frolich ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Whole Body ◽

Plasma Norepinephrine ◽

Complete Suppression ◽

Catabolic State ◽

Insulin Responsiveness

In normal (N), 3-days starved (S), and streptozotocin-treated (65 mg/kg) 3-days diabetic (D) rats we examined the in vivo dose-response relationship between plasma insulin levels vs. whole body glucose uptake (BGU) and inhibition of hepatic glucose production (HGP) in conscious rats, as determined with the four-step sequential hyperinsulinemic euglycemic clamp technique, combined with [3-3H]glucose infusion. Twelve-hour fasting (basal) HGP was 3.0 +/- 0.2, 2.1 +/- 0.2, and 5.4 +/- 0.5 mg/min in N, S, and D rats, respectively. Next, all rats were clamped at matched glycemia (6 mM). Lowering plasma glucose in D rats from +/- 20 to 6.0 mM did not increase plasma norepinephrine, epinephrine, glucagon, and corticosterone levels. For BGU, insulin sensitivity was increased (70 +/- 11 microU/ml) in S and unchanged (113 +/- 21 microU/ml) in D compared with N rats (105 +/- 10 microU/ml). Insulin responsiveness was unchanged (12.4 +/- 0.8 mg/min) in S and decreased (8.5 +/- 0.8 mg/min) in D compared with N rats (12.3 +/- 0.7 mg/min). For HGP, insulin sensitivity was unchanged (68 +/- 10 microU/ml) in S and decreased (157 +/- 21 microU/ml) in D compared with N rats (71 +/- 5 microU/ml). Insulin responsiveness was identical among N, S, and D rats (complete suppression of HGP). In summary, 1) insulin resistance in D rats is caused by hepatic insensitivity and by a reduction in BGU responsiveness. 2) S rats show normal hepatic insulin action, but insulin sensitivity for BGU is increased. Therefore, S and D rats both suffering from a comparable catabolic state (10-15% body wt loss in 3 days) show opposite effects on in vivo insulin action. This indicates that in vivo insulin resistance in D rats is not caused by the catabolic state per se.

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Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.259.2.e210 ◽

1990 ◽

Vol 259 (2) ◽

pp. E210-E215 ◽

Cited By ~ 5

Author(s):

J. R. Lupien ◽

M. F. Hirshman ◽

E. S. Horton

Keyword(s):

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Disposal ◽

Glucose Turnover ◽

Adrenergic Blockade ◽

Sprague Dawley ◽

Euglycemic Hyperinsulinemic Clamp ◽

Peripheral Tissues

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

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In vivo insulin sensitivity in the rat determined by euglycemic clamp

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.1.e1 ◽

1983 ◽

Vol 245 (1) ◽

pp. E1-E7 ◽

Cited By ~ 21

Author(s):

E. W. Kraegen ◽

D. E. James ◽

S. P. Bennett ◽

D. J. Chisholm

Keyword(s):

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Porcine Insulin ◽

Metabolic Clearance ◽

Conscious Rat ◽

Insulin Levels ◽

In Vivo Measurement ◽

Plasma Insulin Levels

Our aim was to develop the glucose clamp (GC) technique in the conscious rat for assessment of in vivo insulin sensitivity. A 2-h euglycemic GC could be performed in chronically cannulated rats using 625 microliter blood. Overnight-fasted rats were infused with porcine insulin (1.67 mU . kg-1 . h-1). Insulin levels of 41 +/- 2 (SE) mU/liter were produced in rats aged 91 +/- 4 days with a 60- to 120-min glucose infusion rate (GIR60-120) of 10.6 +/- 0.6 mg . kg-1 . min-1 (n = 9) during euglycemia. GIR60-120 was significantly (P less than 0.025) reduced in rats aged greater than 130 days (mean, 169 +/- 16 days) to 7.7 +/- 1.2 mg . kg-1 . min-1 (n = 7). Metabolic clearance rate of porcine insulin (46 +/- 3 ml . kg-1 . min-1) and GIR60-120 compared with plateau plasma insulin levels are higher than values reported in humans. The latter may be due to suppression of a higher basal hepatic glucose production or increased potency of porcine compared with native insulin. We conclude that the GC can be accomplished in the rat. When combined with tracer administration and subsequent killing, it should provide a quantitative in vivo measurement of insulin sensitivity in individual tissues.

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Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.2.534 ◽

1994 ◽

Vol 77 (2) ◽

pp. 534-541 ◽

Cited By ~ 14

Author(s):

J. Gao ◽

W. M. Sherman ◽

S. A. McCune ◽

K. Osei

Keyword(s):

Heart Failure ◽

Insulin Sensitivity ◽

Acute Exercise ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Whole Body ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Insulin Responsiveness ◽

Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

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Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00126.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. E536-E543 ◽

Cited By ~ 21

Author(s):

Chaodong Wu ◽

Salmaan A. Khan ◽

Li-Jen Peng ◽

Honggui Li ◽

Steven G. Carmella ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Flux ◽

Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

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Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00116.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. E551-E561 ◽

Cited By ~ 145

Author(s):

Eugenia Carvalho ◽

Ko Kotani ◽

Odile D. Peroni ◽

Barbara B. Kahn

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Transport ◽

Fat Mass ◽

Glucose Transporter ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Whole Body ◽

Hepatic Glucose ◽

Clamp Study

Adipose tissue plays an important role in glucose homeostasis and affects insulin sensitivity in other tissues. In obesity and type 2 diabetes, glucose transporter 4 (GLUT4) is downregulated in adipose tissue, and glucose transport is also impaired in muscle. To determine whether overexpression of GLUT4 selectively in adipose tissue could prevent insulin resistance when glucose transport is impaired in muscle, we bred muscle GLUT4 knockout (MG4KO) mice to mice overexpressing GLUT4 in adipose tissue (AG4Tg). Overexpression of GLUT4 in fat not only normalized the fasting hyperglycemia and glucose intolerance in MG4KO mice, but it reduced these parameters to below normal levels. Glucose infusion rate during a euglycemic clamp study was reduced 46% in MG4KO compared with controls and was restored to control levels in AG4Tg-MG4KO. Similarly, insulin action to suppress hepatic glucose production was impaired in MG4KO mice and was restored to control levels in AG4Tg-MG4KO. 2-Deoxyglucose uptake during the clamp was increased approximately twofold in white adipose tissue but remained reduced in skeletal muscle of AG4Tg-MG4KO mice. AG4Tg and AG4Tg-MG4KO mice have a slight increase in fat mass, a twofold elevation in serum free fatty acids, an ∼50% increase in serum leptin, and a 50% decrease in serum adiponectin. In MG4KO mice, serum resistin is increased 34% and GLUT4 overexpression in fat reverses this. Overexpression of GLUT4 in fat also reverses the enhanced clearance of an oral lipid load in MG4KO mice. Thus overexpression of GLUT4 in fat reverses whole body insulin resistance in MG4KO mice without restoring glucose transport in muscle. This effect occurs even though AG4Tg-MG4KO mice have increased fat mass and low adiponectin and is associated with normalization of elevated resistin levels.

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Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.5.e807 ◽

1993 ◽

Vol 265 (5) ◽

pp. E807-E813 ◽

Cited By ~ 14

Author(s):

S. Bisbis ◽

D. Bailbe ◽

M. A. Tormo ◽

F. Picarel-Blanchot ◽

M. Derouet ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Gk Rat ◽

Peripheral Tissues ◽

Relative Index ◽

Gk Rats ◽

Euglycemic Clamp

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of 125I-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

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Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar

Endocrinology ◽

10.1210/en.2004-0260 ◽

2004 ◽

Vol 145 (7) ◽

pp. 3158-3164 ◽

Cited By ~ 54

Author(s):

Bronwyn D. Hegarty ◽

Stuart M. Furler ◽

Nicholas D. Oakes ◽

Edward W. Kraegen ◽

Gregory J. Cooney

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Insulin Action ◽

Whole Body ◽

Peroxisome Proliferator ◽

The Novel ◽

High Fat

Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

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Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e859 ◽

1997 ◽

Vol 273 (5) ◽

pp. E859-E867 ◽

Cited By ~ 4

Author(s):

M. Hettiarachchi ◽

S. Chalkley ◽

S. M. Furler ◽

Y.-S. Choong ◽

M. Heller ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Insulin Action ◽

Glycogen Synthesis ◽

Human Growth ◽

Whole Body ◽

Nonesterified Fatty Acids ◽

Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00332.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. E281-E290 ◽

Cited By ~ 95

Author(s):

Tony K. T. Lam ◽

Gérald Van de Werve ◽

Adria Giacca

Keyword(s):

Insulin Resistance ◽

Phosphatase Activity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Fatty Acyl ◽

Hepatic Insulin Resistance ◽

P Content ◽

Hepatic Glucose ◽

Fasted Rats

To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO − EGP), hepatic glucose 6-phosphate (G-6- P) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6- P), and EGP ( P < 0.001). During the clamp compared with the basal experiments, 2-h insulin infusion increased GC and in vivo glucokinase activity (GC/TGO; P < 0.05) and suppressed EGP ( P< 0.05) but failed to significantly affect TGO and in vivo glucose-6-phosphatase activity. IH decreased the ability of insulin to increase GC and in vivo glucokinase activity ( P < 0.01), and at 7 h, it also decreased the ability of insulin to suppress EGP ( P < 0.001). G-6- P content was comparable in all groups. In vivo glucose-6-phosphatase and glucokinase activities did not correspond to their in vitro activities as determined in liver tissue, suggesting that stable changes in enzyme activity were not responsible for the FFA effects. The data suggest that, in overnight-fasted rats, FFA increased basal EGP and induced hepatic insulin resistance at different sites. 1) FFA increased basal EGP through an increase in TGO and in vivo glucose-6-phosphatase activity, presumably due to a stimulatory allosteric effect of fatty acyl-CoA on glucose-6-phosphatase. 2) FFA induced hepatic insulin resistance (decreased the ability of insulin to suppress EGP) through an impairment of insulin's ability to increase GC and in vivo glucokinase activity, presumably due to an inhibitory allosteric effect of fatty acyl-CoA on glucokinase and/or an impairment in glucokinase translocation.

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