Coffee and Lower Risk of Type 2 Diabetes: Arguments for a Causal Relationship

Abstract

Prospective epidemiological studies concur in an association between habitual coffee consumption and a lower risk of type 2 diabetes. Several aspects of these studies support a cause-effect relationship. There is a dependency on daily coffee dose. Study outcomes are similar in different regions of the world, show no differences between sexes, between obese versus lean, young versus old, smokers versus nonsmokers, regardless of the number of confounders adjusted for. Randomized controlled intervention trials did not find a consistent impact of drinking coffee on acute metabolic control, except for effects of caffeine. Therefore, lowering of diabetes risk by coffee consumption does not involve an acute effect on the post-meal course of blood glucose, insulin or insulin resistance. Several studies in animals and humans find that the ingestion of coffee phytochemicals induces an adaptive cellular response characterized by upregulation and de novo synthesis of enzymes involved in cell defense and repair. A key regulator is the nuclear factor erythroid 2-related factor 2 (Nrf2) in association with the aryl hydrocarbon receptor, AMP-activated kinase and sirtuins. One major site of coffee actions appears to be the liver, causing improved fat oxidation and lower risk of steatosis. Another major effect of coffee intake is preservation of functional beta cell mass via enhanced mitochondrial function, lower endoplasmic reticulum stress and prevention or clearance of aggregates of misfolded proinsulin or amylin. Long-term preservation of proper liver and beta cell function may account for the association of habitual coffee drinking with a lower risk of type 2 diabetes, rather than acute improvement of metabolic control.

Keywords: Nrf2; acids; beta cells; caffeine; chlorogenic; coffee; diabetes; hepatosteatosis; hormesis.

Figure 1

Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associating protein-1 (Nrf2/Keap1) system and of hydrophobic binding region (AHR) by phytochemicals in roasted (decaffeinated) coffee. Major coffee constituents exhibit binding properties to a number of cellular targets. Consistent physiological responses are elicited by direct (electrophilic) binding to cysteine residues of Keap1 and to AHR, causing the translocation of Nrf2 and AHR, respectively, to the nucleus and the increased expression of genes involved in cell protective activities. Furthermore, there is increased production of reactive oxygen species (ROS), either directly generated from reactive phenolics or indirectly via perturbation of mitochondrial function. Cysteine residues of Keap1 act as sensors of oxidative stress. The resulting modification of Keap1 allows Nrf2 to translocate to the nucleus. Cell stress may result in a lower energy level and increased concentrations of adenosine monophosphate (AMP) and (nicotinamide adenine dinucleotide) NAD⁺ which causes the activation of AMP-activated kinase and of sirtuins, respectively. AMPK lowers anabolic and increases catabolic activities for increasing (adenosine triphosphate) ATP levels. Sirtuins deacetylate histones and other targets leading to improved mitochondrial function, increased autophagy and the expression of genes mediating improved cell survival during periods of stress. ↑, upregulation; ↓ downregulation

Figure 2

Protective action of coffee on metabolic stress in islet beta cells and hepatocytes. Exposure to coffee or its major constituents leads to activation of nuclear factor erythroid 2-related factor 2 (Nrf2), in vitro as well as in vivo. Enhanced expression of Nrf2 regulated genes leads to improved mitochondrial function and oxidation of lipids, and to mitigating of endoplasmic reticulum (ER) stress in cells during periods of increased peptide synthesis. In beta cells, the insulin production capacity is further preserved by eliminating aggregates of misfolded proinsulin or amylin by increased autophagy, and by prevention of aggregation by binding of coffee phytochemicals to hydrophobic surface regions exposed by misfolded peptides. In hepatocytes, metabolic activity is preserved and steatosis prevented by improved mitochondrial beta-oxidation of fatty acids, increased autophagy for lipid disposal and less inflammatory stress from activated Kupffer cells because of less lipopolysaccharide (LPS) leakage from the colon. ↑, upregulation; ↓ downregulation