Diabetes mellitus-Progress and opportunities in the evolving epidemic

Abstract

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

Figure 1.. Schematic representation of the potential ways in which pancreatic beta cells are damaged through environmental and genetic factors.

Thin arrows represent genetic or environmental determinants. Bold arrows represent mechanisms leading to beta cell dysfunction. Diabetes can arise due to abnormal beta cell development, loss of functional beta cell mass, or through defects in beta cell function. Figure was prepared in BioRender.

Figure 2.. Schematic representation of the interactions between the brain and periphery that may regulate systemic glucose homeostasis.

Outputs of glucose sensing neurons a transmitted via the brain stem and the autonomic nervous to modulate hepatic glucose production and insulin and glucagon release by the liver.

Figure 3.. Lipid mediated disruption of insulin signaling.

In type 2 diabetes (T2D) and the Metabolic Syndrome, basal lipolysis is increased, leading to elevated circulating free fatty acids. These free fatty acids directly inhibit insulin signaling in several tissues including hepatocytes and skeletal muscle. Once taken up into these cells, these free fatty acids are processed into ceramides and DAGs (diacylglycerides) which activate PP2A (protein phosphatase 2A) and PKC (protein kinase C) to inhibit AKT (protein kinase B) and mTOR. Decreased insulin signaling in hepatocytes increases glucose production through inhibition of FOXO1 (forkhead box protein O1) contributing to elevated blood glucose levels. The insulin induced mTOR mediated lipogenesis through SREBP1 (sterol regulatory element binding protein 1) remains intact despite impaired insulin signaling via AKT, leading to fatty liver. In skeletal muscle cells (not shown) similar signaling defects contribute to impaired translocation of glucose transporters.

Figure 4.. Mechanisms by which environmental and social determinants increase the likelihood of developing type 2 diabetes in susceptible individuals.

Social determinants of health including air pollution and nutrition insecurity activate several pathways including hypothalamic pituitary adrenal (HPA) axis, which contributes to insulin resistance and exacerbates beta cell dysfunction. These environmental stressors have also been associated with activation of inflammatory pathways, promotion of oxidative stress, gut microbial dysbiosis and epigenetic modifications, all of which have been implicated in accelerating metabolic disturbances that are characteristic of T2D and the metabolic syndrome.

Figure 5.. Systemic changes and mechanisms leading to increased risk of cardiovascular disease in diabetes.

Systemic changes characterized by altered release of adipokines and increased release of inflammatory cytokines by adipose tissues, bone marrow activation by hyperglycemia and increased hepatic generation of pro-atherogenic lipoproteins and procoagulant factors perturbs the systemic metabolic milieu leading to accelerated atherosclerosis and diabetic cardiomyopathy. Diabetes accelerates atherosclerotic plaque progression and retards plaque regression as a result of endothelial dysfunction, monocyte activation, increased inflammation and vascular smooth muscle cell proliferation. The prothrombotic milieu and platelet activation increases the likelihood of thrombotic events. In the heart, glucotoxicity and lipotoxicity induces mitochondrial bioenergetic disturbances (decreased oxidative phosphorylation and increased mitochondrial uncoupling), oxidative stress and altered excitation-contraction (E-C) coupling. Coupled with pro-hypertrophic insulin and cytokine signaling, disturbances in cellular metabolic homeostasis induces epigenetic and transcriptional regulation changes leading to altered gene expression that induce pathological ventricular remodeling, matrix remodeling and increased fibrosis. Coupled with microvascular dysfunction and increased coronary ischemia these changes synergistically increase the likelihood of heart failure in patients with diabetes. AGE – Advanced glycation end products, APOC3 – Apolipoprotein C3, DAG – Diacyl glycerol, DNL – De novo lipogenesis, EC – Endothelial Cell, EC coupling – Excitation-contraction coupling, ECAM – Endothelial cell adhesion molecule, FAO – Fatty Acid oxidation, FFA – Free fatty acids, GFR – glomerular filtration rate, ICAM – Intercellular adhesion molecule, IL – Interleukin, JNK – c-Jun N-terminal Kinase, NFkB – Nuclear factor kappa-light-chain-enhancer of activated B cells, NO – Nitric oxide, NOS3 – Nitric oxide synthase 3 (endothelial NOS-eNOS), OGlcNAc – O-linked-N-acetylglucosamine, OXPHOS – oxidative phosphorylation, PAI 1 – plasminogen activator inhibitor 1, PKC – Protein Kinase C, RAAS – Renin angiotensin aldosterone system, ROS – Reactive oxygen species, TAG – triacylglycerol, TG – triglyceride, SM – Smooth muscle, TNF-a – Tumor necrosis factor-alpha, VCAM – Vascular cell adhesion molecule, VLDL – Very low-density lipoprotein, VO₂ – rate of oxygen consumption, VSMC – Vascular smooth muscle cells.

Figure 6.. Evolution of GLP-1-based therapeutics for the treatment of cardiometabolic and neurodegenerative disorders.

GLP-1RAs targeting the GLP-1 receptor (GLP1R) alone or in combination with one or more additional metabolic peptides, are being studied beyond classical indications such as T2D or obesity. The figure summarizes existing combination molecules that are being tested in a variety of syndromes including heart failure, diabetes, obesity, CKD, MAFLD and neurodegenerative syndromes. GIPRA=GIP receptor agonist; GIPRAnt=GIP receptor antagonist, GCGRA=glucagon receptor agonist; AMLNRA=amylin receptor agonist, GLP-1R=GLP-1 receptor, GIPR=GIP receptor, GCGR=glucagon receptor, AMLNR=Amylin receptor, HFpEF=heart failure with preserved ejection fraction