Åke Sjöholm

Endothelial inflammation in insulin resistance

CONTEXT Type 2 diabetes and attendant cardiovascular morbidity are becoming major health concerns globally. Obesity-related type 2 diabetes is rapidly rising in prevalence, probably largely because of increased longevity and sedentary lifestyles. Insulin resistance and type 2 diabetes are associated with increased coronary heart disease, but the severity of glycaemia during the diabetic phase can only to a minor extent explain the increased risk. Increased levels of the acute-phase inflammatory marker, C-reactive protein (CRP), are related to insulin resistance and the metabolic syndrome, suggesting a role for chronic low-grade inflammation. CRP levels might predict the development of type 2 diabetes. STARTING POINT Subodh Verma and associates (Circulation 2004; 109: 2058-67) recently showed that CRP attenuates the survival, differentiation, and function of endothelial progenitor cells, partly by CRP reducing expression of endothelial nitric-oxide synthase. Rosiglitazone, a peroxisome-proliferator-activator receptor gamma agonist, inhibits the negative effects of CRP on endothelial progenitor cells. The results are consistent with the suggestion that CRP directly promotes atherosclerotic processes and endothelial cell inflammation. CRP might thus directly trigger the development of a proinflammatory and proatherosclerotic state, leading to atherothrombosis. WHERE NEXT Cell-surface CRP receptors and signalling pathways need to be characterised. From such study might come novel drugs that will defer proinflammatory reactions leading to insulin resistance and atherothrombosis.

Inflammation and the etiology of type 2 diabetes

Type 2 diabetes is increasingly common worldwide and is beginning to strike younger age groups. Almost 90% of all patients with diabetes show insulin resistance, which also precedes the first symptoms of diabetes. The mechanisms underlying the development of insulin resistance are not well understood. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenetic factor in the development of insulin resistance and type 2 diabetes. This opens new perspectives for diagnosis and treatment of early insulin resistance and incipient glucose intolerance.

Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism

A lot of interest has engendered in glucagon-like peptide-1 (GLP-1) as an emerging new drug in the treatment of type 2 diabetes. GLP-1 exerts several effects that reduce glycemia in type 2 diabetes patients. We recently also demonstrated that GLP-1 ameliorates endothelial dysfunction in type 2 diabetes mellitus patients with established coronary heart disease, suggesting a new important cardioprotective role for GLP-1. Because hypertension is overrepresented in diabetes and is adversely influencing survival, we have now investigated direct GLP-1 effects on vascular beds in a rat organ bath model. It was found that GLP-1 relaxed femoral artery rings in a dose-response manner. The relaxant effect from GLP-1 was completely inhibited by the specific GLP-1 receptor antagonist, exendin(9-39). Neither the specific nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine, nor removing of endothelium, affected the GLP-1 relaxant effect. In conclusion, we now report a direct vascular action of GLP-1, relaxing conduit vessels independently of NO and the endothelium.

Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes

The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.

Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor

Endothelial cells have a robust capacity to proliferate and participate in angiogenesis, which underlies the maintenance of intimal layer integrity. We previously showed the presence of the GLP-1 receptor in human coronary artery endothelial cells (HCAECs) and the ameliorative actions of GLP-1 on endothelial dysfunction in type 2 diabetic patients. Here, we have studied the effect of exendin-4 on cell proliferation and its underlying mechanisms in HCAECs. Incubation of HCAECs with exendin-4 resulted in a dose-dependent increase in DNA synthesis and an increased cell number, associated with an enhanced eNOS and Akt activation, which were inhibited by PKA, PI3K, Akt or eNOS inhibitors and abolished by a GLP-1 receptor antagonist. Similar effects were obtained by applying GLP-1 (7-36) or GLP-1 (9-36). Co-incubation of exendin-4 and GLP-1 did not show additive effects. Our results suggest that exendin-4 stimulates proliferation of HCAECs through PKA-PI3K/Akt-eNOS activation pathways via a GLP-1 receptor-dependent mechanism.

Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice

BackgroundGreen tea was suggested as a therapeutic agent for the treatment of diabetes more than 70 years ago, but the mechanisms behind its antidiabetic effect remains elusive. In this work, we address this issue by feeding a green tea extract (TEAVIGO™) with a high content of epigallocatechin gallate (EGCG) or the thiazolidinedione PPAR-γ agonist rosiglitazone, as positive control, to db/db mice, an animal model for diabetes.MethodsYoung (7 week-old) db/db mice were randomized and assigned to receive diets supplemented with or without EGCG or rosiglitazone for 10 weeks. Fasting blood glucose, body weight and food intake was measured along the treatment. Glucose and insulin levels were determined during an oral glucose tolerance test after 10 weeks of treatment. Pancreata were sampled at the end of the study for blinded histomorphometric analysis. Islets were isolated and their mRNA expression analyzed by quantitative RT-PCR.ResultsThe results show that, in db/db mice, EGCG improves glucose tolerance and increases glucose-stimulated insulin secretion. EGCG supplementation reduces the number of pathologically changed islets of Langerhans, increases the number and the size of islets, and heightens pancreatic endocrine area. These effects occurred in parallel with a reduction in islet endoplasmic reticulum stress markers, possibly linked to the antioxidative capacity of EGCG.ConclusionsThis study shows that the green tea extract EGCG markedly preserves islet structure and enhances glucose tolerance in genetically diabetic mice. Dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes.

Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats

Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

The DPP-4 Inhibitor Linagliptin Counteracts Stroke in the Normal and Diabetic Mouse Brain: A Comparison With Glimepiride

Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.

Ceramide inhibits pancreatic β-cell insulin production and mitogenesis and mimics the actions of interleukin-1β

Ceramide, generated during sphingomyelinase‐induced sphingolipid cleavage, is considered an important mediator in cytokine signaling. The effects of endogenously generated and exogenously delivered ceramide on long‐term insulin secretion and replication by pancreatic β‐cells were investigated, and compared to the effects of interleukin 1β (ILI‐1β). Generation of β‐cell ceramide by exogenous sphingomyelinase, or addition of cell‐permeant ceramide analogs C2‐ceramide and C6‐ceramide, caused inhibitory effects on β‐cell insulin production and mitogenesis mimicing those evoked by IL‐1β. Hence, ceramide may be involved in transducing the cytostatic and cytotoxic actions of IL‐1β in the β‐cell.

Aspects of the involvement of interleukin-1 and nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus

The possible involvement of the cytokine interleukin-1 (IL-1) and nitric oxide (NO) in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is reviewed and current and potential therapies are discussed. IDDM is a common disorder in the Western world and it is rising in incidence. In IDDM, islet-infiltrating macrophages produce IL-1 which is cytotoxic specifically to β-cells in vitro. IL-1 increases β-cell formation of NO, ceramide, prostaglandins, heat-shock proteins, and activates a protease. Additionally, IL-1 depresses β-cell energy production, insulin gene expression and cyclic AMP synthesis, and impacts negatively on different parts of the insulin stimulus-secretion coupling, actions mimicked by NO. Conversely, blocking NO formation prevented many of these effects in most reports published. Also, changes in cyclic AMP and prostaglandins seem unlikely events in mediating the cytotoxicity of IL-1, while the role of ceramide remains less clear. Peptides capable of blocking β-cell IL-1 receptors, and agents blocking NO synthesis may prove valuable in preserving β-cell function in IDDM. Although IDDM causes immense morbidity and expense, uniformly effective preventive or β-cell protective therapy is not currently available. If IL-1 is causing β-cell dysfunction in human IDDM through NO production, several processes in the IL-1-NO connection are appropriate targets for agents protecting β-cells from destruction and functional inhibition in IDDM.