Ageing impairs insulin‐mediated vasodilatation but not forearm glucose uptake
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It is unclear if insulin-mediated vasodilatation is altered by ageing and if this affects insulin-mediated glucose uptake.A 2-h euglycaemic hyperinsulinaemic clamp (56 mU m(-2) min(-1)) was performed in 10 healthy, nonobese elderly men (70-75 years) and 13 young men (23-28 years). Forearm blood flow (FBF) was measured by venous occlusion plethysmography and forearm glucose uptake was calculated by arterial and venous serum glucose determinations in the forearm.Insulin induced an increase in FBF in the younger men (from 3.9 +/- 1.1 SD to 5.9 +/- 2.2 mL min(-1) 100(-1)mL tissue, P < 0.001), but this insulin-mediated vasodilatation was completely blunted in the elderly subjects. Glucose extraction during the clamp was significantly higher in the elderly subjects (1.2 +/- 0.76 vs. 0.82 +/- 0.37 mmol L(-1) at 120 min, P < 0.01), resulting in a similar forearm glucose uptake in the two groups. On the other hand, whole-body glucose uptake was significantly decreased in the elderly subjects (5.3 +/- 1.8 vs. 8.0 +/- 1.1 mg kg(-1) min(-1), P < 0.001).The present study showed that the ability of insulin to induce vasodilatation is blunted in the forearm in healthy, nonobese elderly subjects. However, the elderly compensate for this impairment with an increased glucose extraction from arterial blood to maintain an unaltered forearm glucose uptake.Keywords:
Glucose clamp technique
Plethysmograph
Hyperinsulinemia
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We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.
Prediabetes
Hyperinsulinemia
Glucose clamp technique
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High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats ( n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3- 3 H]glucose was used to determine glucose clearance, whereas 2-[ 14 C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR ( P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR ( P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR ( P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.
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Forearm plethysmography affords a simple noninvasive method of studying dynamic changes in the microcirculation. This technic was used to study the peripheral circulation of normotensive nongravid women and normotensive and untreated hypertensive pregnant women during the third trimester. The variables of forearm blood flow, vascular resistance, venous capacitance, and capillary filtration coefficient were measured in the resting state and during and after exercise. The pregnant women demonstrated an increase in forearm blood flow over the nonpregnant women. As expected, vascular resistance was higher in the hypertensive pregnant patients than in normotensive pregnant women. The possible predictive value of these findings is discussed.
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Peripheral resistance
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ABSTRACT—The purpose of the present study was to determine whether insulin-like growth factor (IGF)-I would increase whole body and muscle glucose uptake in septic rats that are known to be insulin resistant. Animals were infused with either saline, low-dose IGF-I, high-dose IGF-I, or a maximally stimulating dose of insulin for 2 h, and the glucose metabolic response was assessed using a euglycemic clamp in combination with [3-3H]glucose. Under basal conditions, sepsis increased the rates of whole body glucose uptake, glycolysis, and hepatic glucose production. Under euglycemic hyperinsulinemic conditions, septic rats demonstrated a marked insulin resistance as evidenced by the impaired rate of insulin-stimulated glucose uptake and muscle glycogen synthesis. In contrast, the infusion of either dose of IGF-I increased total glucose uptake, glycolysis, and glycogen synthesis in both control and septic rats to the same extent. Furthermore, there was no difference in the IGF-I stimulation of glucose uptake (as determined by [14C]-2-deoxyglucose) in the gastrocnemius, soleus, and heart between control and septic rats. These results indicate that the glucose metabolic response to IGF-I is intact in insulin-resistant septic rats.
Basal (medicine)
Glucose clamp technique
Carbohydrate Metabolism
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Glucose clamp technique
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To determine the tissue localization of insulin resistance in type 1 diabetic patients, whole body and regional glucose uptake rates were determined under euglycemic hyperinsulinemic conditions. Leg, arm, and heart glucose uptake rates were measured using positron emission tomography-derived 2-deoxy-2-[18F]-fluoro-D-glucose kinetics and the three-compartment model described by Sokoloff et al. (L. Sokoloff, M. Reivich, C. Kennedy, M.C. DesRosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897–916, 1977) in eight type 1 diabetic patients and eight matched normal subjects. Whole body glucose uptake was quantitated by the euglycemic insulin clamp technique. Whole body glucose uptake was approximately 31% lower in the diabetic patients (P < 0.01) than in the normal subjects, thus confirming the presence of whole body insulin resistance. The rate of glucose uptake was approximately 45% lower in leg muscle when measured in the femoral region (55 +/- 7 vs. 102 +/- 13 mumol.kg muscle-1.min-1, diabetic patients vs. normal subjects, P < 0.05) and approximately 27% lower in the arm muscles (66 +/- 4 vs. 90 +/- 13 mumol.kg muscle-1.min-1, respectively, P < 0.05), whereas no difference was observed in heart glucose uptake [789 +/- 80 vs. 763 +/- 58 mumol.kg muscle-1.min-1 not significant (NS)]. Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.93, P < 0.005) and arm muscles (r = 0.66, P < 0.05) but not with glucose uptake in the heart (r = 0.04, NS). We conclude that insulin resistance in type 1 diabetic patients is localized to skeletal muscle, whereas heart glucose uptake is unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
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Local vasodilatation with metacholine, but not with nitroprusside, increases forearm glucose uptake.
Insulin is known to increase blood flow in parallel to glucose uptake in skeletal muscle. However, it is not known if an increase in blood flow by itself is associated with an increase in glucose uptake in the absence of hyperinsulinemia. To investigate further this matter, the effect of increased blood flow on forearm glucose uptake was studied in the fasting state during intra-arterial infusions of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min) increased resting forearm blood flow, measured by venous occlusion plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for both). However, metacholine infusion increased the forearm glucose uptake from 2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001), while no significant change in glucose uptake was seen during nitroprusside infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation induced by metacholine, but not by nitroprusside, increased glucose uptake in the forearm of hypertensive patients. Thus, an increase in forearm blood flow does not necessarily improve glucose uptake in the forearm during the fasting state.
Plethysmograph
Hyperinsulinemia
Sodium nitroprusside
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Basal (medicine)
Hyperinsulinemia
Glucose clamp technique
Carbohydrate Metabolism
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To test whether early, insulin-mediated microvascular recruitment in skeletal muscle predicts steady-state glucose metabolism in the setting of physiological elevation of free fatty acid concentrations.We measured insulin's microvascular and metabolic effects in 14 healthy young adults during a 2-h euglycemic insulin clamp. Plasma free fatty acid concentrations were raised (Intralipid and heparin infusion) for 3 h before the clamp and maintained at postprandial concentrations during the clamp. Microvascular blood volume (MBV) was measured by contrast-enhanced ultrasound (CEU) continuously from baseline through the first 30 min of the insulin clamp. Muscle glucose and insulin uptake were measured by the forearm balance method.The glucose infusion rate (GIR) necessary to maintain euglycemia during the clamp varied by fivefold across subjects (2.5-12.5 mg/min/kg). The early MBV responses to insulin, as indicated by CEU video intensity, ranged widely, from a 39% decline to a 69% increase. During the clamp, steady state forearm muscle glucose uptake and GIR each correlated significantly with the change in forearm MBV (P < 0.01). To explore the basis for the wide range of vascular and metabolic insulin sensitivity observed, we also measured V(O(2max)) in a subset of eight subjects. Fitness (V(O(2max))) correlated significantly with the GIR, the forearm glucose uptake, and the percentage change in MBV during the insulin clamp (P < 0.05 for each).Early microvascular responses to insulin strongly associate with steady state skeletal muscle insulin-mediated glucose uptake. Physical fitness predicts both metabolic and vascular insulin responsiveness.
Glucose clamp technique
Carbohydrate Metabolism
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