Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse

Shen, Hua-Qiong; Zhu, Jin-Su; Baron, Alain

doi:10.1016/s0026-0495(99)90191-9

Cited by 14 publications

(18 citation statements)

References 17 publications

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“…At matched glycemia during the last 40-min period of the hypoglycemic clamp, however, the lower rate of glucose infusion in NIRKO does reflect whole-body insulin resistance (in the setting of a diminished counterregulation). In separate experiments under hyperinsulinemic-euglycemic clamp conditions, we (30) and others (31,32) have shown that insulin infusion rates of 20 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 require glucose infusion rates of 580 -900 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 to maintain euglycemia in control mice. In this current study, the same insulin doses (20 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) resulted in markedly reduced glucose infusion rates (ϳ100 -150 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) indicating profound insulin resistance induced by hypoglycemic counterregulation.…”

Section: Discussionmentioning

confidence: 82%

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

et al. 2005

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Hypoglycemia, hypoglycemia unawareness, and impaired counterregulation are major challenges to the intensive management of type 1 diabetes. While the counterregulatory response to hypoglycemia is predominantly determined by the degree and duration of hypoglycemia, there is now evidence that insulin per se may influence the counterregulatory response to hypoglycemia. To define the role of insulin action in the central nervous system in regulating the counterregulatory response to hypoglycemia, mice with a brain/neuron-specific insulin receptor knockout (NIRKO) and littermate controls were subjected to 90-min hyperinsulinemic (20 mU ⅐ kg ؊1 ⅐ min ؊1 ) -hypoglycemic (ϳ1.5 mmol/l) clamps. In response to hypoglycemia, epinephrine levels rose 5.7-fold in controls but only 3.5-fold in NIRKO mice. Similarly, in response to hypoglycemia, norepinephrine levels rose threefold in controls, but this response was almost completely absent in NIRKO mice. In contrast, glucagon and corticosterone responses to hypoglycemia were similar in both groups. Thus, insulin action in the brain is critical for full activation of the sympathoadrenal response to hypoglycemia, and altered neural insulin signaling could contribute to defective glucose counterregulation in diabetes.

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Section: Discussionmentioning

confidence: 82%

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

et al. 2005

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“…Although the steady-state insulin levels in the eNOS KO mice were somewhat lower, this is likely to be due to the overall variability (in specimen collection and assay) rather than as evidence for accelerated insulin clearance in the eNOS KO mice (33). Previously, our laboratory has demonstrated that the dose of insulin to achieve maximal rates of insulin-stimulated glucose uptake in normal mice during euglycemic clamps is 10 mU · k g -1 · m i n -1 (33), thus the insulin infusion rate of 20 mU · k g -1 · min -1 used in this study ensures that maximal insulin stimulation was achieved. Most insulin-resistant animals maintain fasting normoglycemia by secreting more insulin to overcome the resistance.…”

Section: Discussionmentioning

confidence: 92%

“…The animals were studied after a 24-h fast while the animals were awake, unrestrained, and unstressed in their regular cages. All of the mice were studied at an insulin infusion rate of 20 mU · k g -1 · min -1 as described by our group (33). Glucose turnover.…”

Section: Rapid Publicationmentioning

confidence: 99%

Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.

et al. 2000

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Studies from our laboratory using acute pharmacologic blockade of nitric oxide synthase (NOS) activity have suggested that nitric oxide (NO) has an important role in regulating carbohydrate metabolism. We now report on insulin sensitivity in mice with targeted disruptions in endothelial NOS (eNOS) and neuronal NOS (nNOS) genes compared with their wild-type (WT) counterparts. Mice underwent hyperinsulinemic-euglycemic clamp studies after a 24-h fast, during an insulin infusion of 20 mU · k g -1 · min -1 . Glucose levels were measured at baseline and every 10 min during the clamp. Insulin levels were measured at baseline and at the end of the clamp study. Glucose infusion rates (GIRs) during the last 30 min of the clamp study were in a steady state. Tritiated glucose infusion was used to measure rates of endogenous glucose output (EGO) both at baseline and during steady-state euglycemia. Glucose disposal rates (GDRs) were computed from the GIR and EGO. Fasting and steady-state glucose and insulin levels were comparable in the 3 groups of mice. No differences in fasting EGO were noted between the groups. GIR was significantly reduced (37%, P = 0.001) in the eNOS knockout (KO) mice compared with the WT mice, with values for the nNOS mice being intermediate. EGO was completely suppressed in the nNOS and WT mice during insulin infusion, but not in the eNOS mice. Even so, the eNOS mice displayed significantly reduced whole-body GDRs compared with those of the WT mice ( 8 2 . 6 7 ± 10.77 vs. 103.67 ± 3.47 m g · k g -1 · min -1 , P = 0.03). eNOS KO mice are insulin resistant at the level of the liver and peripheral tissues, whereas the nNOS KO mice are insulin resistant only in the latter. These data indicate that NO plays a role in modulating insulin sensitivity and carbohydrate metabolism and that the eNOS isoform may play a dominant role relative to nNOS. Diabetes 49:XXX-XXX, 2000 N itric oxide (NO) has emerged as an important molecule with diverse biological functions. In the blood vessels, NO mediates endotheliumdependent vasodilation (1-3) in response to diverse stimuli such as shear stress (4-6), insulin (7), acetylcholine (8,9), and bradykinin (3,10). In the central nervous system (CNS) and peripheral nervous tissue, NO is an unusual neurotransmitter (11-13). NO is generated when the amino acid L-arginine is converted to citrulline by the enzyme NO synthase (NOS) (14,15). Three separate genes encode the known isoforms of NOS (16): endothelial NOS (eNOS or NOS III) and neuronal NOS (nNOS or NOS II) catalyze the constitutive production of NO in a calcium-dependent manner predominantly in the blood vessels and neural tissues, respect i v e l y. The third isoform, inducible NOS (iNOS or NOS I) is located in macrophages and catalyzes NO formation in i n flammatory cells.Intravenous administration of N G -m o n o m e t h y l -L-a r g i n i n e (L-NMMA), a competitive inhibitor of all NOS isoforms, acutely induces hypertension and insulin resistance in rats ( 1 7 ) . M o r e r e c e n t l y, we reported that acute pharm...

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“…Hyperinsulinemic-euglycemic clamp studies were used to assess insulin sensitivity at 2 weeks after ASC infusion, as described previously [12]. Blood glucose concentrations were monitored at 10-min intervals throughout the clamp studies.…”

Section: Observation and Assessmentmentioning

confidence: 99%

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

Chen

et al. 2015

Endocr J

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Type 2 diabeTes melliTus (T2DM) accounts for more than 90% of all diabetic patients and is characterized by insulin resistance, hyperglycemia, systemic low-grade inflammation, and relative lack of insulin. Most T2DM patients experience β-cell exhaustion several years after diagnosis, and thus have to accept insulin therapy. However, insulin therapy is inconvenient for patients and does not completely prevent the development of diabetic complications. Stem cells are an attractive option to ameliorate diabetes for its abundant source and potential to acquire glucose-dependent insulin secretory function. Adult stem cells are an especially good candidate for its safety in terms of tumorigenicity and ethical concerns.Adipose-derived stem cells (ASC) have been stud- The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet β cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1β in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet β cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

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Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse

Cited by 14 publications

References 17 publications

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

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