The α2-Adrenoceptor Antagonist Yohimbine Normalizes Increased Islet Blood Flow in GK Rats: A Model of Type 2 Diabetes

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

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Are the metabolic benefits of resistance training in type 2 diabetes linked to improvements in adipose tissue microvascular blood flow?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00234.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. E1242-E1250 ◽

Cited By ~ 1

Author(s):

Donghua Hu ◽

Ryan D. Russell ◽

Devika Remash ◽

Timothy Greenaway ◽

Stephen Rattigan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Flow ◽

Adipose Tissue ◽

Resistance Training ◽

Blood Volume ◽

Fasting Blood Glucose ◽

Microvascular Blood Flow ◽

Oral Glucose ◽

Model Assessment

The microcirculation in adipose tissue is markedly impaired in type 2 diabetes (T2D). Resistance training (RT) often increases muscle mass and promotes a favorable metabolic profile in people with T2D, even in the absence of fat loss. Whether the metabolic benefits of RT in T2D are linked to improvements in adipose tissue microvascular blood flow is unknown. Eighteen sedentary people with T2D (7 women/11 men, 52 ± 7 yr) completed 6 wk of RT. Before and after RT, overnight-fasted participants had blood sampled for clinical chemistries (glucose, insulin, lipids, HbA1c, and proinflammatory markers) and underwent an oral glucose challenge (OGC; 50 g glucose × 2 h) and a DEXA scan to assess body composition. Adipose tissue microvascular blood volume and flow were assessed at rest and 1 h post-OGC using contrast-enhanced ultrasound. RT significantly reduced fasting blood glucose ( P = 0.006), HbA1c ( P = 0.007), 2-h glucose area under the time curve post-OGC ( P = 0.014), and homeostatic model assessment of insulin resistance ( P = 0.005). This was accompanied by a small reduction in total body fat ( P = 0.002), trunk fat ( P = 0.023), and fasting triglyceride levels ( P = 0.029). Lean mass ( P = 0.003), circulating TNF-α ( P = 0.006), and soluble VCAM-1 ( P < 0.001) increased post-RT. There were no significant changes in adipose tissue microvascular blood volume or flow following RT; however those who did have a higher baseline microvascular blood flow post-RT also had lower fasting triglyceride levels ( r = −0.476, P = 0.045). The anthropometric, glycemic, and insulin-sensitizing benefits of 6 wk of RT in people with T2D are not associated with an improvement in adipose tissue microvascular responses; however, there may be an adipose tissue microvascular-linked benefit to fasting triglyceride levels.

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MYH9 gene polymorphisms may be associated with cerebrovascular blood flow in patients with type 2 diabetes

Genetics and Molecular Research ◽

10.4238/2015.february.6.4 ◽

2015 ◽

Vol 14 (1) ◽

pp. 1008-1016 ◽

Cited By ~ 5

Author(s):

C. Ling ◽

C.Y. Cai ◽

B.C. Chang ◽

W.T. Shi ◽

F.J. Wei ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Flow ◽

Gene Polymorphisms ◽

Myh9 Gene

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Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue

Journal of Applied Physiology ◽

10.1152/japplphysiol.00751.2018 ◽

2019 ◽

Vol 126 (3) ◽

pp. 626-637 ◽

Cited By ~ 6

Author(s):

Jefferson C. Frisbee ◽

Matthew T. Lewis ◽

Jonathan D. Kasper ◽

Paul D. Chantler ◽

Robert W. Wiseman

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Structure Function ◽

Vascular Structure ◽

Gk Rats ◽

The Impact

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o2) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o2, and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A2 treatment.

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Pilot Study for the Evaluation of Morphological and Functional Changes in Retinal Blood Flow in Patients with Insulin Resistance and/or Type 2 Diabetes Mellitus

Journal of Diabetes Science and Technology ◽

10.1177/193229681200600120 ◽

2012 ◽

Vol 6 (1) ◽

pp. 163-168 ◽

Cited By ~ 5

Author(s):

Thomas Forst ◽

Matthias M. Weber ◽

Michael Mitry ◽

Thomas Schöndorf ◽

Senait Forst ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Blood Flow ◽

Type 2 Diabetes Mellitus ◽

Pilot Study ◽

Retinal Blood Flow ◽

Functional Changes

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Impairment of microvascular blood flow in patients with type 2 diabetes and cardiovascular autonomic neuropathy

Diabetes Mellitus ◽

10.14341/dm12372 ◽

2021 ◽

Vol 24 (1) ◽

pp. 32-44

Author(s):

T. A. Zelenina ◽

V. V. Salukhov ◽

A. B. Zemlianoi ◽

S. G. Zheleznjak ◽

O. A. Klitsenko

Keyword(s):

Type 2 Diabetes ◽

Blood Flow ◽

Autonomic Neuropathy ◽

Diabetic Foot ◽

Microvascular Complications ◽

Cold Test ◽

Microvascular Blood Flow ◽

Diabetic Patients ◽

History Of

BACKGROUND: Diabetic autonomic neuropathy is the reason for early morbidity and mortality on diabetic patients. The pathology not only cardiac innervation but microvascular is presented.AIMS: We estimated the parameters of skin microvascular blood flow in accordance with cardiovascular autonomic neuropathy (CAN) staging in diabetic patients. We also assessed other risk factors of CAN in patients with diabetes.MATERIALS AND METHODS: We included 76 patients with type 2 diabetes in the study (24 patients with resent-onset diabetes and/or diabetes without microvascular complications, 26 with diabetic sensorimotor neuropathy (SMN) and 26 with SMN and previous history of diabetic foot amputation). The SMN was diagnosed on the basis of patients complaints, anamnesis and data of clinical neurological examinations. CAN was detected using several cardiovascular autonomic reflex tests (CART) as a gold standard of diagnosis: the tilt-table test, a deepbreathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction. According to the Toronto Diabetic Neuropathy Expert Group Recommendation all patients was separated on the groups: CAN 0 (all CARTs were normal), CAN 1 (possible/early CAN — one abnormal CART was presented), CAN 2 (definite/confirmed CAN –at least two abnormal CARTs were found), CAN 3 (severe/advanced CAN — in the cases of orthostatic hypotension in addition to CARTs abnormalities). Microvascular blood flow of skin at the nail roller of fingers skin was valuated at rest as well as in functional cold test by the method of High-frequency Ultrasonic Dopplerography using the “Minimax Doppler K” device (LLC JV “Minimax”, St. Petersburg, Russia).RESULTS: CAN 1 was found in 8% diabetic patients without microvascular complications, 42 and 21% patients with SMN and diabetic foot amputations respectively. CAN 2 was diagnosed in 27% patients with SMN and 58% patients history of diabetic foot amputations. CAN 3 in 8% and 19% cases in patients with SMN and history of diabetic foot amputations respectively. The parameters of microvascular blood flow at rest were significantly decreased in patients with confirmed/severe CAN in comparison with early staging of CAN and patients without CAN (Vm=2.5±0.66 sm/sec vs. 4.4±0.54 sm/sec and 5.1±1.01 sm/sec respectively; p=0.0033). The abnormal result of cold test was detected in 94% patients with confirmed/ severe CAN and 26% patients with CAN 1.CONCLUSIONS: This investigation has demonstrated in a cohort with type 2 diabetes patients with/without SMN and with/ without history of previously foot amputations that decrease the Vm (the variable of microvascular blood flow assessed by High-frequency Ultrasonic Dopplerography) lower than 2.4 sm/sec is associated with 6.4 times increased likelihood of confirmed/severe CAN as well as positive cold test result. That the patients with positive cold test results were 28.6 times more likely have confirmed/severe CAN.

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