Inflammation is a biological response launched by the immune system against dangerous assaults which threaten the integrity and normal physiology of an organism. Chronic nutrient overload causes an increase in adipose irregularities in that, if adipose tissue expandability is low, there will be an increased presence of thickened tissue. This condition would lead to a proinflammatory state that can trigger insulin resistance, release of macrophage chemoattractant proteins, and in chronic inflammation, even the death of the thickened adipose tissue itself. This creates cyclic a action that extends the insulin resistance to all adipose tissue.

An important characteristic of overnutrition-induced diseases is chronic low-grade inflammation caused by nutritional excess. Overnutrition-induced inflammation is thought to occur in the brain and thus plays an extensive and steering role in overnutrition-induced diseases.

ROS action is generally beneficial. However, under diabetic conditions, chronic hyperglycemia and consequent augmentation of reactive oxygen species (ROS) deteriorate beta-cell function and escalate insulin resistance. This leads to an aggravation of type 2 diabetes. Additionally, chronic hyperglycemia and ROS are also involved in the development of atherosclerosis which is often observed under diabetic conditions.

Such disturbances contribute to the pathogenesis of various diseases, including diabetes. To counteract these insults, most cells, including β-cells, have intricate mechanisms of defense against ROS toxicity. Among these, the transcription factor NF-E2–related factor 2 (Nrf2) is a pivotal component for protecting cells from oxidative damage.

In response to oxidative stress, activation of Nrf2 dramatically increases intracellular antioxidant potential by directly increasing the transcription of many so-called antioxidant enzymes. Thus, the Nrf2-mediated induction of antioxidant enzymes is critically important for proper oxidation/reduction (redox) homeostasis to protect cells from irreversible oxidative damage.

Hyperinsulinemia (HI) serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome.

The obesity-associated metabolic phenotype elevated pro-inflammatory cells (M1 macrophages and NK-cells) suppressed anti-inflammatory cells (M2 macrophages, eosinophils, and regulatory T-cells).

Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity.

Mol Cell Endocrinol. 2018 Dec 5;477:15-28. doi: 10.1016/j.mce.2018.05.010. Epub 2018 May 10.

For Type 2 Diabetes to occur, both insulin resistance and comparative inadequate insulin secretion must co-exist. For example, overweight individuals may have insulin resistance, but diabetes only develops in those who cannot increase insulin secretion sufficiently to compensate for their insulin resistance.

Unfortunately, this period of hyperinsulinemia prior to the collapse of insulin production permits is the cause of significant tissue damage.

The problem is that the disease of hyperinsulinemia is highly inflammatory and leads to almost all of the metabolic diseases of Western Society. Treating hyperinsulinemia with more insulin only accelerates the disease.

The correct treatment should be geared to reducing the insulin requirement, by reducing carbohydrate consumption.

The more insulin you have, the more fat you accumulate.

Insulin activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell, (and inhibits the activity of glucose-6-phosphatase, preventing phosphorylated glucose from being returned to glucose). Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect of insulin in the presence of an abundant supply of glucose, the liver quickly uptakes glucose and stores it as glycogen, which reduces serum glucose levels. The serum carrying capacity of glucose is approximately 5gm.

As glycogen storage capacity exceeds approximately 500gm (approximately 2,000 calories), the overflow is shunted to lipid. Failing to deplete the glycogen reserve prior to refeeding results in shunting of glucose to lipid. When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to the synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins provide free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglycerides. Insulin inhibits the breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Insulin facilitates the entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, is used to synthesize triglyceride within the adipocyte.

Your pain physician should be addressing obesity and insulin resistance if they hope to ever reverse your pain. Metabolic inflammation (metainflammation) of obesity and hyperinsulinemia is an under-recognized cause of pain in the United States.

Musculoskeletal pain has been estimated to affect 13.5%–47% of the general population, and 75 percent of those affected have two or more areas of pain. Multi-joint pain and progression, including non-weight bearing joints, are linked independently to the inflammatory cascade triggered by obesity, not just simply the biomechanical forces.

Arthritis Care Res (Hoboken). 2017 Apr;69(4):509-516. DOI: 10.1002/acr.22963. Epub 2017 Feb 28.

Fibromyalgia pain is closely associated with insulin resistance, and elevated HgBA1C and fibromyalgia symptoms are improved with metformin therapy to reverse insulin resistance.

Pappolla MA, Manchikanti L, Andersen CR, Greig NH, Ahmed F, Fang X, et al. (2019) Is insulin resistance the cause of fibromyalgia? A preliminary report. PLoS ONE 14(5): e0216079.

I would suggest that most chronic pain pathologies are maintained by metainflammation, derived primarily from lifestyle choices leading to insulin resistance. In our chronic interventional pain clinic, we spend more than half of our time reversing the course of diabetes.

The prevalence of vending machines that stock soda in schools, particularly elementary schools, is concerning for the overall health and well-being of the country. Sodas are made largely with high fructose corn syrup. Fructose activates the dopaminergic reward system more than glucose, and high fructose corn syrup is spiked with extra fructose, far beyond what the labels suggest. Additionally, reinforced behavior, accentuated by the casino-like feel of vending machines, increases consumption in vulnerable populations, such as young children.

The ability of children, not adults, to make these choices, combined with the hedonic reward of dopamine, only increases consumption. Fructose preferentially is stored as fat through first-pass hepatic effects, leading to insulin resistance and potentially diabetes.

Background:

The per capita consumption of high fructose corn syrup — the mainstay of soft drinks and other sweetened beverages — has increased from 38.2 pounds in 1980 to 868 pounds in 1998 (Chou et al., 2004). In 1942, the annual U.S. production of soft drinks was 90 8 oz. servings per person; in 2000, it was 600 servings (Jacobson, 2005). Sodas and other sweetened beverages are readily available in our nation’s schools. Vending machines are placed in almost all of the nation’s middle and high schools (Weicha, Finkelstein, Troped, Fragala, & Peterson, 2006) and are in approximately 40 percent of our elementary schools (Fernandes, 2008). Both school vending machines and fast food restaurant use have been associated with increased intake of sugar-sweetened beverages by youth (Weicha et al, 2006). When vending machines are placed in elementary schools, black children are more likely to purchase a soft drink from these machines (39 percent) compared to white children (23 percent) (Fernandes, 2008). Could it be that these machines are becoming vendors of death?

Pain is the leading reason why people come to my practice, and it is the common link between untreated metabolic syndrome and untreated diabetes. I personally evaluate and treat several thousand patients per year for chronic pain, in an urban setting where access to high-intensity healthcare is readily available through several large academic centers as well as government-sponsored outreach clinics. Unfortunately, despite the availability of cutting-edge medical treatment, the overall health of individuals and populations continues to decline each year. Over 90% of the patients have untreated metabolic syndrome and over 60% have undiagnosed pre-diabetes or type 2 diabetes. Pain is the final common symptom for the human body to signal impending tissue damage, and most patients avoid contact with the health delivery system until they develop a symptom that they can no longer ignore. Unfortunately, my clinical practice is not unique; pain is the leading reason for patients seeking medical care and is one of the most disabling, burdensome, and costly conditions in the United States. Overall, pain care/treatment and lost productivity costs the U.S. $635 billion per year. Hyper-inflammation is the common link between metabolic syndrome and chronic pain.

Sugar addiction, especially glucose, leads to obesity because of how it is metabolized. Sucrose (table sugar) is a disaccharide made of 50% fructose and 50% glucose. Sucrose is metabolized primarily in the small intestine, releasing equal parts glucose and fructose. Glucose causes insulin release and is rapidly cleared from the bloodstream by insulin-dependent channels. Fructose is independent of insulin and is rapidly taken up by the liver by a first-pass effect and is preferentially stored as fat.

Further increasing obesity risks, glucose and fructose have different effects on the addiction centers in the brain. Although glucose does not directly activate the brain’s reward center, fructose does produce activation in the brain’s “reward circuit,” and increases the desire for food.

American College of Neuropsychopharmacology. “Fructose and glucose: Brain reward circuits respond differently to two kinds of sugar.” ScienceDaily. ScienceDaily, 10 December 2014. www.sciencedaily.com/releases/2014/12/141210080734.htm

Our eating patterns can influence insulin production and weight gain, and it’s important to give our bodies time to burn energy from food. Most people eat from the time they wake up until the time they go to bed — typically three main meals, multiple snacks, and often soda in between. This pattern leads to chronic high insulin production, which fatigues the insulin receptors. In addition, insulin is a fat storage hormone, and elevated insulin levels lead to fat accumulation in the liver, creating metabolic inflammation.

Your metabolism exists in two states – the “fed” (insulin high) state and the “fasted” (insulin low) state. Either we are storing food energy (increasing storage), or we are burning stored energy (decreasing storage or fat lysis). If we start eating the minute we roll out of bed and do not stop until we go to sleep, we spend almost all our time in the fed state. Over time, we gain weight, because we have not allowed our body time to burn stored food energy.