Treatment of diabetes by targeting macrophages

Abstract

Scientific: Metabolic homeostasis is represented by euglycemia, eulipidemia and heathy obesity. Metabolic dysregulation is clinically diagnosed as metabolic syndrome and represented by hyperglycemia, hyperlipidemia and/or lipotoxicity resulting in metabolic diseases. T2DM and its complications are caused by hyperglycemia and glucotoxicity. T2DM complications include (a) microvascular complications of diabetic retinopathy, diabetic nephropathy and diabetic neuropathy and (b) macrovascular complications of myocardial infarction, stroke and foot ulcer and amputation. Hyperglycemia is due to impairment of insulin signaling leading to insulin resistance (constituting pre-diabetes). Hyperglycemia and insulin resistance will result in compensatory hyperinsulinemia. Hyperinsulinemia will eventually lead to insulin exhaustion and beta cell loss and dysfunction (resulting in full blown diabetes). Insulin signaling and insulin resistance are caused by many factors, two of which are lipotoxicity (unhealthy obesity) and meta-inflammation which are related and intertwined. Based on prior research as herein referenced, this paper proposes, based on immunometabolism, that lipotoxicity leads to meta-inflammation, that meta-inflammation impairs insulin signaling resulting in insulin resistance, and that insulin resistance leads to hyperglycemia and T2DM. This paper further proposes that meta-inflammation is caused by necrosis and senescence of adipocytes thereby (a) forming crown like structures (b) releasing pro-inflammatory cytokines and adipokines and (c) resulting in M1 macrophage infiltration and adipose tissue remodeling towards pro-inflammatory. Given that macrophages are plastic and may be re-polarized from M1 to M2 macrophages, macrophages may be the therapeutic target in the treatment of diabetes. In this paper, M1/M2 macrophage repolarization is proposed by and through (a) lifestyle changes (b) pharmacological agents (c) genes and transcriptional regulation (d) epigenetics (e) microRNAs and lncRNAs (f) antisense oligonucleotides and nanoparticles (g) gut microbiome and (h) trained innate immunity. This paper concludes with caveats and future directions.

Plain Language: Diabetes (sweet urine disease) is a pandemic affecting many people around the world. Uncontrolled diabetes may lead to heart attack, stroke, kidney failure, foot ulcer and eye diseases. There is no cure for diabetes but only medication to manage it. Diabetes is caused by high glucose in blood due to insulin resistance. Insulin resistance is due to increase in body weight called obesity in particular around the waist region as a result of eating too much and sedentary lifestyle. In this paper, it is proposed that obesity will lead to the death of fat cells causing inflammation in fat tissue. This inflammation is related to metabolism and is called metabolic inflammation (meta-inflammation). Meta-inflammation will lead to the infiltration of white blood cells (called the macrophages) and their polarization from anti-inflammatory (called M2 macrophages) to pro-inflammatory (called M1 macrophages). Based on this hypothesis, it is possible to manage or even cure diabetes by changing the macrophages from M1 to M2 by a process called macrophage repolarization. Macrophage repolarization may be done (a) by lifestyle changes through diet and exercise, (b) by drugs or supplements, (c) by targeting gene transcription (through transcription factors) and gene expression (through epigenetics), (d) by targeting noncoding genes which are regulatory (called microRNA and/or lncRNA), (e) by targeting antisense oligonucleotides and nanoparticles (f) by tampering with the prebiotics and probiotics in the microbiome and (g) by exploring the trained innate immunity. The paper ends by drawing the concerns of (a) animal model v human model (b) in vitro (under laboratory setting) v in vivo (under human) (c) observational studies v clinical trials (d) correlation v causation and (e) multiple pathways and their cross-talks. The paper concludes that treatment of diabetes is a long and hard journey but is promising.