Abstract
This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the ...microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.
Graphical Abstract
Graphical Abstract
In each of the 6 tissues reviewed, we highlight the reciprocal relationship(s) between the tissue’s somatic cells and the microvasculature serving them. Together these components function as a microvascular unit. Early in their course, diabetes mellitus and cardiometabolic disease disrupt these microvascular units and produce tissue dysfunction. Over time, this disruption leads to common (eg, increased endothelial barrier permeability, pericyte loss, capillary rarefaction, disordered angiogenesis, etc.) as well as tissue-specific (eg, microglia activation in the central nervous system and retina, sympathetic overactivity, and perivascular adipose inflammation in peripheral tissues) microvascular injury responses that are orchestrated by a host of both systemic and local signaling processes.
Abstract
Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or ...reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.
This scientific statement reviews and discusses the microvascular complications of diabetes on an organ-by-organ basis.
We have learned over the last several decades that the brain is an important target for insulin action. Insulin in the central nervous system (CNS) affects feeding behavior and body energy stores, ...the metabolism of glucose and fats in the liver and adipose, and various aspects of memory and cognition. Insulin may even influence the development or progression of Alzheimer disease. Yet, a number of seemingly simple questions (e.g., What is the pathway for delivery of insulin to the brain? Is insulin's delivery to the brain mediated by the insulin receptor and is it a regulated process? Is brain insulin delivery affected by insulin resistance?) are unanswered. Here we briefly review accumulated findings affirming the importance of insulin as a CNS regulatory peptide, examine the current understanding of how peripheral insulin is delivered to the brain, and identify key gaps in the current understanding of this process.
Aims/hypothesis
For circulating insulin to act on the brain it must cross the blood–brain barrier (BBB). Remarkably little is known about how circulating insulin crosses the BBB’s highly restrictive ...brain endothelial cells (BECs). Therefore, we examined potential mechanisms regulating BEC insulin uptake, signalling and degradation during BEC transcytosis, and how transport is affected by a high-fat diet (HFD) and by astrocyte activity.
Methods
125
I–TyrA14-insulin uptake and transcytosis, and the effects of insulin receptor (IR) blockade, inhibition of insulin signalling, astrocyte stimulation and an HFD were tested using purified isolated BECs (iBECs) in monoculture and co-cultured with astrocytes.
Results
At physiological insulin concentrations, the IR, not the IGF-1 receptor, facilitated BEC insulin uptake, which required lipid raft-mediated endocytosis, but did not require insulin action on phosphoinositide-3-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK). Feeding rats an HFD for 4 weeks decreased iBEC insulin uptake and increased NF-κB binding activity without affecting insulin PI3K signalling, IR expression or content, or insulin degrading enzyme expression. Using an in vitro BBB (co-culture of iBECs and astrocytes), we found insulin was not degraded during transcytosis, and that stimulating astrocytes with
l
-glutamate increased transcytosis, while inhibiting nitric oxide synthase decreased insulin transcytosis.
Conclusions/interpretation
Insulin crosses the BBB intact via an IR-specific, vesicle-mediated transport process in the BECs. HFD feeding, nitric oxide inhibition and astrocyte stimulation can regulate BEC insulin uptake and transcytosis.
Insulin, at physiological concentrations, regulates the volume of microvasculature perfused within skeletal and cardiac muscle. It can also, by relaxing the larger resistance vessels, increase total ...muscle blood flow. Both of these effects require endothelial cell nitric oxide generation and smooth muscle cell relaxation, and each could increase delivery of insulin and nutrients to muscle. The capillary microvasculature possesses the greatest endothelial surface area of the body. Yet, whether insulin acts on the capillary endothelial cell is not known. Here, we review insulin's actions at each of three levels of the arterial vasculature as well as recent data suggesting that insulin can regulate a vesicular transport system within the endothelial cell. This latter action, if it occurs at the capillary level, could enhance insulin delivery to muscle interstitium and thereby complement insulin's actions on arteriolar endothelium to increase insulin delivery. We also review work that suggests that this action of insulin on vesicle transport depends on endothelial cell nitric oxide generation and that insulin's ability to regulate this vesicular transport system is impaired by inflammatory cytokines that provoke insulin resistance.
Insulin transport into the brain Gray, Sarah M; Barrett, Eugene J
American Journal of Physiology: Cell Physiology,
08/2018, Volume:
315, Issue:
2
Journal Article
Peer reviewed
Open access
While there is a growing consensus that insulin has diverse and important regulatory actions on the brain, seemingly important aspects of brain insulin physiology are poorly understood. Examples ...include: what is the insulin concentration within brain interstitial fluid under normal physiologic conditions; whether insulin is made in the brain and acts locally; does insulin from the circulation cross the blood-brain barrier or the blood-CSF barrier in a fashion that facilitates its signaling in brain; is insulin degraded within the brain; do privileged areas with a "leaky" blood-brain barrier serve as signaling nodes for transmitting peripheral insulin signaling; does insulin action in the brain include regulation of amyloid peptides; whether insulin resistance is a cause or consequence of processes involved in cognitive decline. Heretofore, nearly all of the studies examining brain insulin physiology have employed techniques and methodologies that do not appreciate the complex fluid compartmentation and flow throughout the brain. This review attempts to provide a status report on historical and recent work that begins to address some of these issues. It is undertaken in an effort to suggest a framework for studies going forward. Such studies are inevitably influenced by recent physiologic and genetic studies of insulin accessing and acting in brain, discoveries relating to brain fluid dynamics and the interplay of cerebrospinal fluid, brain interstitial fluid, and brain lymphatics, and advances in clinical neuroimaging that underscore the dynamic role of neurovascular coupling.
Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin ...improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD) as well as muscle microvascular perfusion contrast-enhanced ultrasound (CEU) before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (
< 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate,
< 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin
< 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (
< 0.02 for each) but not after metformin. Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles.
Metformin, a first-line treatment for type 2 diabetes, is often used in patients with insulin resistance and metabolic syndrome. Here, we provide the first evidence for metformin improving muscle microvascular insulin sensitivity in insulin-resistant humans. Simultaneously, metformin improved muscle glucose disposal, supporting a close relationship between insulin's microvascular and its metabolic actions in muscle. Whether enhanced microvascular insulin sensitivity contributes to metformin's ability to decrease microvascular complications in diabetes remains to be resolved.
Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To ...examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet HFD) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin's metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy.
Insulin increases muscle microvascular perfusion, which contributes to its metabolic action in muscle, but this action is impaired in obesity. Metformin improves endothelial function beyond its ...glucose lowering effects. We aim to examine whether metformin could prevent microvascular insulin resistance and endothelial dysfunction during the development of obesity. Adult male rats were fed a high-fat diet (HFD) with or without simultaneous metformin administration for either 2 or 4 wk. Insulin's metabolic and microvascular actions were determined using a combined euglycemic-hyperinsulinemic clamp and contrast-enhanced ultrasound approach. Compared with chow-fed controls, HFD feeding increased body adiposity without excess body weight gain, and this was associated with a marked decrease in insulin-mediated whole body glucose disposal and abolishment of insulin-induced muscle microvascular recruitment. Simultaneous administration of metformin fully rescued insulin-induced muscle microvascular recruitment as early as 2 wk and normalized insulin-mediated whole body glucose disposal at
. The divergent responses between insulin's microvascular and metabolic actions seen at
were accompanied with reduced endothelial oxidative stress and vascular inflammation, and improved endothelial function and vascular insulin signaling in metformin-treated rats. In conclusions, metformin could prevent the development of microvascular insulin resistance and endothelial dysfunction by alleviating endothelial oxidative stress and vascular inflammation during obesity development.
Muscle microvascular insulin action contributes to insulin-mediated glucose use. Microvascular insulin resistance is an early event in diet-induced obesity and is associated with vascular inflammation. Metformin effectively reduces endothelial oxidative stress, improves endothelial function, and prevents microvascular insulin resistance during obesity development. These may contribute to metformin's salutary diabetes prevention and cardiovascular protective actions.
Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular ...insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS endothelial nitric oxide (NO) synthase phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications.
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