Rick I. Meijer

Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension

Please cite this paper as: de Boer, Meijer, Wijnstok, Jonk, Houben, Stehouwer, Smulders, Eringa and Serné (2012). Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension. Microcirculation 19(1), 5–18.

Perivascular Adipose Tissue Control of Insulin-Induced Vasoreactivity in Muscle Is Impaired in db/db Mice

Microvascular recruitment in muscle is a determinant of insulin sensitivity. Whether perivascular adipose tissue (PVAT) is involved in disturbed insulin-induced vasoreactivity is unknown, as are the underlying mechanisms. This study investigates whether PVAT regulates insulin-induced vasodilation in muscle, the underlying mechanisms, and how obesity disturbs this vasodilation. Insulin-induced vasoreactivity of resistance arteries was studied with PVAT from C57BL/6 or db/db mice. PVAT weight in muscle was higher in db/db mice compared with C57BL/6 mice. PVAT from C57BL/6 mice uncovered insulin-induced vasodilation; this vasodilation was abrogated with PVAT from db/db mice. Blocking adiponectin abolished the vasodilator effect of insulin in the presence of C57BL/6 PVAT, and adiponectin secretion was lower in db/db PVAT. To investigate this interaction further, resistance arteries of AMPKα2+/+ and AMPKα2−/− were studied. In AMPKα2−/− resistance arteries, insulin caused vasoconstriction in the presence of PVAT, and AMPKα2+/+ resistance arteries showed a neutral response. On the other hand, inhibition of the inflammatory kinase Jun NH2-terminal kinase (JNK) in db/db PVAT restored insulin-induced vasodilation in an adiponectin-dependent manner. In conclusion, PVAT controls insulin-induced vasoreactivity in the muscle microcirculation through secretion of adiponectin and subsequent AMPKα2 signaling. PVAT from obese mice inhibits insulin-induced vasodilation, which can be restored by inhibition of JNK.

Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes

Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.

Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease.

Obesity is associated with insulin resistance, hypertension, and cardiovascular disease, but the mechanisms underlying these associations are incompletely understood. Microvascular dysfunction may play an important role in the pathogenesis of both insulin resistance and hypertension in obesity. Adipose tissue-derived substances (adipokines) and especially inflammatory products of adipose tissue control insulin sensitivity and vascular function. In the past years, adipose tissue associated with the vasculature, or perivascular adipose tissue (PAT), has been shown to produce a variety of adipokines that contribute to regulation of vascular tone and local inflammation. This review describes our current understanding of the mechanisms linking perivascular adipose tissue to vascular function, inflammation, and insulin resistance. Furthermore, we will discuss mechanisms controlling the quantity and adipokines secretion by PAT.

Bariatric Surgery as a Novel Treatment for Type 2 Diabetes Mellitus: A Systematic Review

OBJECTIVE To systematically review the literature pertaining to the reversal of type 2 diabetes mellitus (DM2) after Roux-en-Y gastric bypass and adjustable gastric banding. DATA SOURCES We conducted a review of the literature using PubMed and searched the reference lists of published studies to identify additional studies. STUDY SELECTION We selected all published articles that were relevant with respect to bariatric surgery and its metabolic effects. DATA EXTRACTION Only 9 original articles reporting on DM2 reversal rates after bariatric surgery were identified: 1 randomized controlled trial and 8 observational studies. Other referenced articles serve as background literature. DATA SYNTHESIS Roux-en-Y gastric bypass leads to a reversal rate of DM2 of 83%. Adjustable gastric banding confers a reversal rate of 62%, and this effect is achieved later after surgery. CONCLUSIONS Bariatric surgery leads to marked and long-lasting weight reduction. A large proportion of patients undergoing bariatric surgery have DM2. In fact, the presence of diabetes mellitus is a compelling argument to perform bariatric surgery in those who are eligible according to international criteria. Glycemic control improves in the months after laparoscopic adjustable gastric banding, but it improves more rapidly and completely after laparoscopic Roux-en-Y gastric bypass surgery. Thus, both types of surgery are capable of improving or even curing DM2, but the mechanisms may differ.

Insulin‐Induced Microvascular Recruitment in Skin and Muscle are Related and Both are Associated with Whole‐Body Glucose Uptake

Please cite this paper as: Meijer RI, de Boer MP, Groen MR, Eringa EC, Rattigan S, Barrett EJ, Smulders YM, Serne EH. Insulin‐induced microvascular recruitment in skin and muscle are related and both are associated with whole‐body glucose uptake. Microcirculation 19: 494–500, 2012.

Insulin-Induced Changes in Microvascular Vasomotion and Capillary Recruitment are Associated in Humans

Insulin‐induced capillary recruitment is considered a significant regulator of overall insulin‐stimulated glucose uptake. Insulins action to recruit capillaries has been hypothesized to involve insulin‐induced changes in vasomotion. Data directly linking vasomotion to capillary perfusion, however, are presently lacking. We, therefore, investigated whether insulins actions on capillary recruitment and vasomotion were interrelated in a group of healthy individuals. We further assessed the role of capillary recruitment in the association between vasomotion and insulin‐mediated glucose uptake.

Pathways for insulin access to the brain: the role of the microvascular endothelial cell

Insulin affects multiple important central nervous system (CNS) functions including memory and appetite, yet the pathway(s) by which insulin reaches brain interstitial fluid (bISF) has not been clarified. Recent studies demonstrate that to reach bISF, subarachnoid cerebrospinal fluid (CSF) courses through the Virchow-Robin space (VRS) which sheaths penetrating pial vessels down to the capillary level. Whether insulin predominantly enters the VRS and bISF by local transport through the blood-brain barrier, or by being secreted into the CSF by the choroid plexus, is unknown. We injected 125I-TyrA14-insulin or regular insulin intravenously and compared the rates of insulin reaching subarachnoid CSF with its plasma clearance by brain tissue samples (an index of microvascular endothelial cell binding/uptake/transport). The latter process was more than 40-fold more rapid. We then showed that selective insulin receptor blockade or 4 wk of high-fat feeding each inhibited microvascular brain 125I-TyrA14-insulin clearance. We further confirmed that 125I-TyrA14-insulin was internalized by brain microvascular endothelial cells, indicating that the in vivo tissue association reflected cellular transport, not simply microvascular tracer binding.

Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2

Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulins vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.

Body mass index is related to microvascular vasomotion, this is partly explained by adiponectin

obesity‐related microvascular dysfunction, including alterations in rhythmic changes in vascular diameter, so‐called ‘vasomotion’, may be important in the clustering of obesity with other cardiovascular risk factors. Adipokines have been suggested to play a role in obesity‐related vascular dysfunction. Alterations in vasomotion have been found using extreme body mass index (BMI) phenotypes. Whether these alterations can be translated to the general population is unknown. The aim was to retrospectively investigate relationships between BMI, vasomotion and adipokines in a population‐based cohort.