Astaxanthin (ASTX): a natural, safe, powerful and multi-faceted anti-inflammatory with potential in the treatment of Type 2 Diabetes Mellitus (T2DM) and Insulin Resistance (IR)

By Timothy J. King, Ph.D., Vice President, Research, and A. David Hieber, Ph.D., Associate Director, Biology

Type 2 Diabetes Mellitus (T2DM)

T2DM is one of the most common age related diseases both in the U.S. and internationally. In 2012, approximately 29.1 million people in the U.S. were currently diagnosed with Type 2 Diabetes Mellitus (T2DM) in addition to as many as 8.1 million (28%) estimated remaining undiagnosed [1]. In addition, approximately 86 million are pre-diabetic in the U.S. T2DM is the 7^th leading cause of death and is also the leading cause of kidney failure in the U.S. As of 2012, the total cost of diagnosed diabetes in the U.S. was $245 billion dollars. Using appropriately adjusted estimates, average medical expenditures were calculated to be 2.3 times higher among people diagnosed with T2DM compared to those diabetes-free. T2DM accounts for up to 95% of diabetes cases and is often comorbid with obesity, hypertension and dyslipidemia [2].

In support of a global epidemic, 387 million people globally have diabetes and will rise to 592 million by 2035 according to the International Diabetes Federation [3]. Undiagnosed diabetes estimates are 179 million globally. In 2014, diabetes caused 4.9 million deaths, one death every seven seconds. Globally, health expenditures towards addressing diabetes were approximately $612 billion U.S. dollars in 2014 (11% of total adult expenditures).

Oral anti-diabetes drugs and insulin are in part effective but do not always correct the associated metabolic and insulin regulatory dysfunction and are associated with common adverse effects including hypoglycemia and weight gain. A clear need exists for aggressive therapeutic options to halt the progression of T2DM. A safe, economical, and efficacious treatment option for T2DM represents one of the largest potential market opportunities in the pharmaceutical industry. Assuming a drug with a Generally-Recognized As Safe (GRAS) designation from the FDA, a clinically meaningful impact on HbA1c or insulin resistance (IR) biomarkers, and a cost of just $0.50 a day, the potential global market for such a treatment exceeds $90 billion annually.

T2DM Disease Pathology

Generally, T2DM is categorized by insufficient insulin production in the context of insulin resistance (IR) in contrast to Type 1 Diabetes Mellitus that is caused by autoimmune destruction of insulin-producing beta cells in the pancreas. Basically, IR is an inability of cells to respond normally to insulin with particular importance in liver, muscle and fat tissue function. IR can lead to persistent hyperglycemia and is diagnosed with measures of increased fasting plasma glucose levels and/or elevated glycated hemoglobin (HbA1c) and a substandard response to oral glucose tolerance test. IR is found in a high percentage of people categorized with metabolic syndrome and is strongly associated with other metabolic-related disease risk factors.

Long-term complications of T2DM include: 1) heart disease and stroke, with heart disease death rates and stroke frequency 2 to 4 times higher: 2) retinopathy and blindness, more than 28% of all diabetics have diabetic retinopathy which is the leading cause of blindness among adults; 3) renal complications, in 2008 alone 48,374 people with diabetes began treatment for end-stage kidney disease and is the leading cause of kidney failure; 4) neuropathy, about 60% to 70% of people with diabetes have mild to severe forms of nervous system damage; and 5) 20-fold increase in amputations [4].

Mechanistically, under normal physiological conditions insulin is released from pancreatic beta cells in response to elevated levels of glucose in the blood stream. Insulin then binds to the insulin receptor (IR) inducing autophosphorylation of the receptor, phosphorylation of IRS-1/2 adaptor proteins, activation of PI3K and subsequent downstream pathway effectors including the AKT signaling pathway. The PI3K-AKT pathway axis directs several responses to glucose including; 1) intracellular GLUT4-containing storage vesicle migration to the cell surface mediating transport of glucose into cells and regulating blood glucose levels, 2) upregulation of endothelial nitric oxide synthase (eNOS) production of nitric oxide (NO) and subsequent NO-dependent vasodilation, 3) inhibition of gluconeogenesis and lipogenesis, and 4) reduction of inflammation and oxidative stress. Normally, 65-90% of insulin-induced glucose uptake is mediated via skeletal musculature. Increased blood supply (NO-induced vasodilation) and upregulated GLUT4 activation (vesicle translocation) mediate a majority of glucose uptake in response to increased insulin stimulation.

Chronic inflammation and increased oxidative stress play critical roles in the pathophysiology leading to initiation and propagation of IR and T2DM [5]. IR is associated with increased visceral adipose tissue that becomes refractory to normal insulin signaling due to elevated inflammatory cytokine secretion from infiltrating inflammatory cell types. Increased cytokines, including TNF-α, IL-1β, IL-6, and downstream inflammatory pathways, including NF-κB and JNK, lead to dysfunction of insulin signaling pathways. Indeed, JNK and IKK kinases inactivate the insulin signaling adaptor proteins IRS-1/2 and the downstream kinase AKT is directly nitrosylated and inactivated as a direct result of increased oxidative stress [5,6].

T2DM can often be delayed or prevented through proper nutrition and regular exercise. Standard of care begins with diet and lifestyle changes followed by pharmaceutical intervention initially with metformin and if needed escalating to two or even three drug-combinations including exogenous insulin supplementation. Current pharmaceuticals approved for T2DM treatment include insulin, metformin, thiazolidinediones, alpha-glucosidase inhibitors, renal sodium-dependent glucose cotransporter inhibitors, sulfonylureas and incretin modulators (GLP-1 agonists, DPP-4 inhibitors). While in part effective under chronic use, there remains an unmet need for safe and effective mediation of T2DM-related chronic inflammation and oxidative stress. Due to a multitude of properties possessed by astaxanthin (ASTX), we believe it will be effective in the treatment of T2DM and amelioration of IR.

Astaxanthin (ASTX)

ASTX is a safe, orally bioavailable, naturally occurring molecule with strong antioxidant and anti-inflammatory activity [7-9]. Normally found in yeast, algae, krill, crustaceans and salmon, ASTX is routinely added to animal feed to improve health and reproductive capacity. Following oral administration and intestinal uptake, ASTX is shuttled to the liver via chylomicrons with subsequent distribution to a variety of tissues throughout the body (heart, liver, intestine, adipose, lung, kidney) via plasma lipoprotein particles including VLDL, HDL and LDL. Once in the cell, ASTX accumulates within the lipid structures of various organelles including plasma, nuclear, endoplasmic reticular and, importantly, mitochondria membranes. Localization within mitochondria is highly restricted by the cell and allows ASTX to regulate oxidative and nitrosative stress in a privileged location critical to normal cellular functions controlling cell death, metabolic function and aging. ASTX’s unique chemical structure allows complete spanning of the lipid bilayer component of cell membranes facilitating biphasic (aqueous and lipid) antioxidant functions. In addition to mitochondrial influence, ASTX’s remarkable antioxidant functions have the capacity to influence intracellular inflammation and metabolic pathway signaling as many of these pathways are directly modulated by inflammatory and oxidative stress mediators.

In humans, ASTX has been shown to significantly lower important inflammatory and metabolic disease measures including tumor necrosis factor-alpha (TNF-α), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides while significantly increasing adiponectin and high density lipoprotein cholesterol (HDL-C) levels [10-12]. ASTX has also positively affected markers of oxidative stress in humans including; significantly lowering isoprostanes and malondialdehyde (MDA) levels and significantly increasing total antioxidant capacity (TAC) and superoxide dismutase (SOD)[12,13]. Germane to this discussion, in humans ASTX administration was associated with a statistically significant decrease in HbA1c in two separate studies [10,14] however it should be noted that the HbA1c reductions were not clinically relevant. ASTX, and ASTX delivered via Cardax proprietary ASTX-conjugates, have demonstrated efficacy in animal models of inflammatory-mediated disease including reduction of TNF-α levels equivalent to a steroid, reduction of cholesterol levels, reduction of elevated triglycerides, decrease in atheroma formation, and reduction in blood clot formation [15-19]. Additionally, many studies support the strong influence of ASTX on mitochondrial functionality as well as inflammatory and metabolic intracellular signaling in animal and cell-based models [7,20-24]. Specifically, ASTX has been shown to; 1) decrease mitochondrial oxidative stress, 2) stabilize mitochondrial membranes leading to decreased pro-apoptotic mediators (Bax, cytochrome C release) and increased anti-apoptotic mediators (Bcl-2), 3) decrease subsequent activation of JNK pathways that induce cell death and 4) upregulate PGC-1α, a master regulator of mitochondrial biogenesis, as well as critical metabolic regulators such as CPT-1 [20-26].

ASTX: Potential T2DM Treatment

More specifically related to T2DM pathophysiology, administration of ASTX in several animal models of diabetes and metabolic dysfunction has been shown to positively influence blood glucose levels, insulin levels, homeostatic index of IR (measured as HOMA-IR), and adiponectin levels [17,23,27-29]. One study demonstrated ASTX efficacy nearly equivalent to pioglitazone’s influence on insulin resistance reduction (HOMA-IR)[30]. ASTX treatment also improved insulin pathway activation and increased critical translocation of the insulin-regulated glucose transporter GLUT4 both in vivo (skeletal muscle) and in cell culture [23,31]. Significant improvement in the profiles of hepatic glucose catabolic and regulatory enzymes was also seen in addition to increased activation of hepatic insulin signaling proteins including, IRS-1/2, PI3K and AKT [23,31]. Additionally, a high-fat high-fructose diet activated the stress response as well as pro-inflammatory signaling pathways JNK-1 and ERK-1 with significant reduction in the ASTX treated groups [29].

All these studies clearly demonstrate a robust capacity of ASTX to support many important aspects of insulin functionality in an insulin resistant environment by improving insulin signaling (IRS, AKT, PI3K) and glucose metabolism (enzymes and GLUT4) while protecting these pathways from increased oxidative stress insults as evidenced by improved insulin resistance (HOMA, QUICK 1) and improved antioxidant status (antioxidant levels, decreased ERK and JNK activation). ASTX has also been shown to act through AKT and the Keap1/Nrf2 pathways to protect cells from oxidative stress insult [32,33].

As mentioned earlier, comorbidity is a significant health challenge in T2DM including diabetic nephropathy. In related disease models of nephropathy, ASTX treatment decreased blood glucose, reduced oxidative stress markers (MDA, protein carbonyl, urinary albumin and 8-hydroxydeoxyguanosine) and increased antioxidant markers resulting in an amelioration of kidney histopathological changes [34,35].

Summary

Current T2DM treatments including oral anti-diabetes drugs and insulin are in part effective but are associated with many adverse events. A clear need exists for aggressive therapeutic options to attenuate and manage T2DM. A safe, economical, and efficacious treatment option for T2DM represents one of the largest potential market opportunities in the pharmaceutical industry. All the above described scientific evidence in both humans and animal models, highlight the capacity of ASTX to positively affect important mechanisms critical to T2DM and IR pathology in humans (oxidative stress, inflammation) and underscores the enormous potential of ASTX to ameliorate disease progression and symptoms in T2DM patients.