By Max Bingham, PhD
The 2015 Banting Lecture: The Many Faces of Adipose Tissue
The 2015 Banting Medal for Scientific Achievement was awarded to Philipp E. Scherer at the 75th Scientific Sessions of the American Diabetes Association. He gave the Banting Lecture on “The Multifaceted Roles of Adipose Tissue –Therapeutic Targets for Diabetes and Beyond.” The associated publication appears this month in Diabetes (p. ) and charts the emerging role of adipocytes in diabetes and well beyond. As Scherer writes: “I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility.” Initially focusing on fat and energy balance, Scherer introduces a phenomenon known as “metabolic flexibility” and the ability of the adipocyte to expand and shrink according to dietary calorie load. The expansion that happens results in metabolically fit or dysfunctional cells. This, in turn, translates to being metabolically healthy–or not–and goes some way toward explaining what might be happening in obesity and diabetes. Scherer then guides us through the pathways and studies that have revealed a critical role for inflammation and its relationship to insulin resistance in determining the function, the metabolic flexibility, and the health of adipose tissue. The much broader role of adipocytes and their contribution to systemic health is highlighted with a focus on adiponectin, sphingolipids, and uridine–key mediators in a number of biochemical pathways. Commenting more widely on his research, Scherer told Diabetes: “The adipocyte remains a somewhat mysterious cell. We still do not fully understand what leads to the emergence of fat pads at their respective locations and how the biochemical properties of individual adipocytes are programmed to give rise to the fat distribution we see under normal and pathological conditions. Our abilities to modify adipocytes genetically and biochemically are rapidly evolving and will hopefully give us an opportunity to ultimately better direct excess calories to specific locations.”
The 2015 Edwin Bierman Award Lecture: Selective Insulin Resistance May Explain Atherosclerosis in Diabetes
The role of insulin in preventing cardiovascular pathology was the subject of the 2015 Edwin Bierman Award Lecture given by George L. King at the 75th Scientific Sessions of the American Diabetes Association. The lecture, presented in this issue of Diabetes (p. ), highlights the importance of insulin receptors on the endothelium and how they mediate the action of insulin in muscle, heart, fat, and the brain. Central to the review is the notion that insulin’s actions on vascular cells are mediated by two pathways: IRS1/2/PI3K/Akt and Grb/Shc/MAPK and that the balance between the two may be important in determining whether atherosclerosis develops. According to King and his colleagues, the IRS1/2/PI3K/Akt pathway is likely antiatherogenic while the Grb/Shc/MAPK kinase pathway is likely proatherogenic. As such, this dichotomy of the action of insulin led the authors to propose the idea of selective insulin resistance in diabetes and possibly explains why it raises risk in terms of various cardiovascular outcomes with atherosclerosis being of primary concern in people with diabetes and insulin resistance. Their further research subsequently showed that elevated levels of glucose, free fatty acid, and inflammatory cytokines due to diabetes and insulin resistance may all be involved in inhibiting the IRS1/2/PI3K/Akt pathway and thus insulin’s antiatherogenic action. The researchers said: “We believe that there are multiple therapeutic sites of intervention possible on the endothelium which can specifically enhance insulin’s actions without affecting systemic metabolism in order to decrease atherosclerosis in people with diabetes and insulin resistance.” Commenting more widely on the research, George L. King told Diabetes: “The idea of selective resistance being partly responsible for the acceleration of cardiovascular disease in people with diabetes has therapeutic importance since this suggests that insulin analogues or agents that can enhance specifically the IRS/Akt pathway may improve glycemic control and decrease the risks of cardiovascular diseases.”
Tetraspanin-7: The Fifth Target of Autoantibodies in Type 1 Diabetes
The identity of a fifth autoantibody involved in the development of type 1 diabetes has been uncovered, completing the story of how the immune system is involved in the destruction of β-cells. Previously known as Glima and only by a few (physical) characteristics, McLaughlin et al. (p. ) reveal its true identity: tetraspanin-7, a multipass transmembrane glycoprotein. Four major autoantigens had been identified previously with specificity towards insulin, glutamate decarboxylase, IA2, and zinc transporter-8. However, the fifth one, a 38-kDa membrane protein termed Glima, which was first reported in 1996, has remained elusive despite being detectable in 19–38% of adult patients and up to 50% in children with type 1 diabetes. To uncover its identity, the authors first showed that the mouse brain and lung can express Glima. Then, they gradually managed to purify gel extracts corresponding to the known size of the molecule using a series of molecular approaches. Using chromatography and mass spectrometry designed for protein identification, the authors then managed to identify three candidate molecules. Only tetraspanin-7 corresponded to the known physical characteristics of Glima. They then confirmed it as an autoantigen by demonstrating binding to autoantibodies in type 1 diabetes. According to the authors, the immediate significance of the discovery is that it will improve the screening strategies used to identify specific autoantibodies to multiple islet autoanitgens and therefore risk of type 1 diabetes. Commenting more widely on the study, author Michael R. Christie told Diabetes: “Our discovery will now allow the development of antigen-specific immunotherapies to block immune responses to all the major targets of the immune response in type 1 diabetes in order to prevent disease in those at risk. Very little is known about the function of tetraspanin-7. Its identification as an autoantigen in type 1 diabetes will stimulate research to discover its role in the pancreatic β-cell and to investigate reasons as to why it is targeted by the immune system in the disease.”
More Evidence for AMPK Regulation in Atherosclerosis: Animal Study Data
The enzyme AMPK is thought to act as an energy sensor linking nutrient metabolism to the regulation of various inflammatory processes. Specifically, many are interested in its anti-inflammatory potential. Cao et al. (p. ) report this month on the role of AMPK as a regulator of macrophage inflammation and that a specific subunit of the enzyme may play a crucial role in atherogenesis.The investigation focused on LDL cholesterol receptor knockout (LDLRKO) mice that have a significant tendency to develop atherosclerotic plaques when given an atherogenic diet. On the basis of this genetic background, the authors then generated myeloid α1AMPK knockout mice where the α1 subunit of the enzyme had been knocked out specifically only in AMPK originating from bone marrow (myeloid). When fed the atherogenic diet, the α1AMPK knockout mice had considerably reduced levels of the subunit in bone marrow–derived macrophages but also increased levels of atherosclerotic lesions and plaques in various anatomical regions. While investigating the underlying pathophysiological pathways, the authors reported increased macrophage inflammation and infiltration into atherosclerotic plaques and that the deletion of α1AMPK likely results in hypercholesterolemia. The deletion also reportedly did not affect insulin sensitivity in the knockout mice when on the atherogenic diet, but did result in insulin resistance when on a high-fat diet (in comparison to controls). The conclusion of the authors is straightforward: “that macrophage α1AMPK is atheroprotective in LDLRKO mice and may serve as a therapeutic target for prevention and treatment of atherosclerosis.”
Representative cross-sectional images of aortic sinus with fluorescent bead-labeled macrophages (arrows).
Representative cross-sectional images of aortic sinus with fluorescent bead-labeled macrophages (arrows).
Brain Insulin to Stimulate Secretion of Fat From Liver: Potential Role in Steatosis?
Insulin signaling in the brain may be important for the regulation of VLDL secretion from the liver according to Scherer et al. (p. ) and that may prove important for the treatment of hepatic steatosis—fatty liver disease—which is commonly associated with obesity and insulin resistance.The conclusions are the result of a combination of rat and mouse studies designed to test the hypothesis that brain insulin signaling augments triglyceride mobilization from the liver and that brain insulin resistance results in impaired secretion and hence the build-up of fat in the liver (steatosis). According to the study researchers, infusion of insulin into the third ventricle of the brain of rats increased hepatic triglyceride secretion and reduced liver fat content in a manner that was independent of changes in lipogenesis in the liver or food intake. Follow-up genetic studies with mice confirmed the observations. The researchers concluded that “restoration of brain insulin signaling should ameliorate the susceptibility to hepatic steatosis in conditions such as obesity and diabetes.” Commenting more widely on the implications of their findings, authors Thomas Scherer and Christoph Buettner stated: “These studies provide a mechanism for the recent observation from human studies demonstrating that intranasal insulin, an application mode that delivers insulin chiefly to the brain, rapidly reduces fat content in the liver. Namely, that brain insulin does so by increasing mobilization of triglycerides in the liver by stimulating VLDL secretion. An important conclusion of this study is that it may not be a good idea to develop an insulin analogue that preferentially works in the liver as this increases the risk for fatty liver disease. Vice versa, insulin analogues that actively cross the blood-brain barrier might have beneficial effects to ameliorate nonalcoholic fatty liver disease, which is a common problem in people with type 2 diabetes and the metabolic syndrome.”
