Autonomic Nervous System Imbalance and Diabetes

Back in 2005, a group of Swedish researchers reported a link between autonomic nervous system imbalance and insulin resistance. Insulin resistance precedes type 2 diabetes (T2D). The study, led by Stina Lindmark, investigated associations between visceral adipose tissue (VAT), the cortisol axis, the autonomic nervous system, and insulin resistance in humans.¹ Thirty volunteers matched for age, sex, and body mass index (BMI) took part. Fifteen had first-degree relatives with type 2 diabetes, and 15 had no family history of diabetes.

Autonomic nervous system activity was assessed using heart rate variability. The researchers measured heart rate variability while the volunteers engaged in controlled breathing (12 breaths/min for 1 minute), rested in a tilted, 70-degree head-up position (4 minutes), and engaged in a cold pressor test (CPT) during which a lower arm was immersed in ice-cold water (2 minutes): “Controlled breathing stimulates parasympathetic nerve activity, whereas tilting and CPT stimulate sympathetic nerve activity.” Additional tests included oral glucose tolerance test, low-dose tetracosactin stimulation test, corticotropin releasing hormone stimulation test, oral dexamethasone suppression test, and diurnal salivary and urinary cortisol testing as well as anthropometric measures. In addition, the researchers used the euglycemic hyperinsulinemic clamp technique to measure insulin resistance. Volunteers with diabetes in their family histories exhibited less insulin sensitivity than the healthy controls, but the difference was not statistically significant (9.2 ± 1 vs. 10.3 ± 0.7 mg/kg per minute).

Lindmark et al reported a significant association between visceral fat, high sympathetic/parasympathetic ratio, and insulin resistance. The authors commented that “…the demonstrated association between the balance of sympathetic vs. parasympathetic nervous activity and VAT can suggest that a large amount of visceral fat may activate the sympathetic and/or inactivate the parasympathetic nervous system.” But they said it was also possible that autonomic dysregulation might instigate visceral fat accumulation and, thereby, promote insulin resistance. Adrenocortical function did not appear to be part of the visceral fat, autonomic nervous system, and insulin resistance association.

Ten years later, another Swedish study, led by Maria K. Svensson, provided more evidence that dominant sympathetic activity is linked to insulin resistance.² This time, the researchers used 24-hour ECG monitoring as well as short-term testing during controlled breathing, tilt, and cold pressor test. They estimated abdominal adipose tissue with computed tomography and insulin resistance with the euglycemic hyperinsulinemic clamp technique. The study involved 47 healthy, non-diabetic volunteers, 23 of whom had a family history of diabetes.

Svensson et al found significant positive associations between insulin resistance, BMI, abdominal fat, and sympathetic-parasympathetic ratios from both the short-term and the 24-hour heart rate variability assessments. The 24-hour assessment showed a greater difference in heart rate variability between the controls and those with diabetes in their histories. The researchers suggest that exercise and other personal lifestyle factors may be responsible for this difference. (I don’t know if they asked volunteers to record their activities during 24-hour monitoring.) ECG monitoring also showed significantly lower very low frequency power in those with a family history of diabetes, “indicating that reduced vagal activation potentially could be an early component in the development of T2D.” The vagus nerve is responsible for parasympathetic control over body organs, including the heart. The authors conclude: “…the present study shows that indices of heart rate variability during everyday life are associated with insulin sensitivity, and it suggests that a higher ratio of sympathetic to parasympathetic autonomic nerve activity promotes insulin resistance.”

Low heart rate variability, which indicates autonomic nervous system imbalance, was significantly associated with metabolic syndrome, according to a 2015 study that used data from the offspring cohort (n=1143) of the Framingham Heart Study.³ Metabolic syndrome consists of multiple risk factors, including insulin resistance, that precede the development of metabolic disorders such as diabetes and coronary heart disease. The researchers looked at multiple risk factors associated with metabolic syndrome and found that low heart rate variability, high resting heart rate, increased age, cigarette smoking, and being male were the significant risk factors for developing metabolic syndrome: “…in terms of the risk of developing metabolic syndrome within 12 years of baseline, one standard deviation decrease in HRV (SDNN) is equal to an additional 16 years in age or nearly one pack of cigarettes per day.”

We do not yet know whether autonomic imbalance causes insulin resistance and metabolic syndrome or is simply the result. The Framingham study researchers point out that exercise, biofeedback, relaxation training, β-blockers, and SSRIs are known to moderate heart rate variability and resting heart rate. (Controlled breathing practices may also help.) They suggest investigating the effect of these interventions on autonomic imbalance in clinical studies with patients at risk for developing diabetes, heart disease, and other conditions associated with metabolic syndrome.

Artificial Sweeteners, Gut Microbiota, and Glucose Intolerance

Non-caloric artificial sweeteners (NAS) promote glucose intolerance by changing the composition of gut bacteria, according to a 2014 Nature article by Jotham Suez and colleagues.⁴ Commensal gut bacteria are known to produce biochemicals that regulate all aspects of physiology, including metabolic processes and weight. These sweeteners are widely used in sugar-free processed foods and drinks—the same foods recommended to people with diabetes and obesity.

In the first of a series of animal and human experiments, Israeli researchers added commercial formulations of saccharin, sucralose, or aspartame to the drinking water of lean 10-week-old mice. After one week, the three NAS mouse groups exhibited glucose intolerance while the control groups that consumed plain water, water with glucose, or water with sucrose displayed similar glucose tolerance curves (P<0.001). Saccharin showed the greatest effect, so the researchers decided to use it in further studies.

Since artificial sweeteners are largely undigested and come into direct contact with gut microbes, the researchers decided to test whether a change in the microbiota accounted for the development of glucose intolerance. They fed two groups of mice normal chow and gave them water with commercial saccharin or water with glucose to drink. They then transplanted fecal microbiota from the two groups to germ-free mice:

“Notably, recipients of microbiota from mice consuming commercial saccharin exhibited impaired glucose tolerance as compared to control (glucose) microbiota recipients, determined 6 days following transfer (p<0.03).” Microbiota from saccharin-consuming mice showed dysbiosis with significant increases in the Bacteroides genus and decrease in Lactobacillus reuteri.

Suez and colleagues also looked at non-caloric artificial sweetener consumption in humans. In one study, they used data from an ongoing clinical nutritional study involving 381 non-diabetic volunteers (44% males and 56% females; age 43.3 ± 13.2). The researchers found correlations between NAS consumption and obesity, higher fasting blood glucose, and elevated serum alanine aminotransferase (ALT, a measure of liver damage). “Moreover, the levels of glycosylated haemoglobin indicative of glucose concentration over the previous 3 months, were significantly increased when comparing a subgroup of high NAS consumers (40 individuals) to non-NAS consumers (236 individuals),” write the authors.

Suez et al also asked seven healthy volunteers who did not normally use NAS or NAS-containing foods to consume commercial saccharin for one week, using the FDA’s guideline for maximal acceptable daily intake (5 mg/kg body weight). Four out of seven developed poorer glycemic response after five to seven days of saccharin consumption. Interestingly, the microbiota composition in the NAS-responders noticeably differed from the non-responders before and after saccharin consumption. The artificial sweetener had little observable effect on the microbiome of the three non-responders.

Suez and colleagues took stool samples from two NAS responders and two non-responders, before and after NAS consumption, and transplanted the samples into groups of germ-free mice. Post-NAS stool from the responders “induced significant glucose intolerance” in the mice compared to stool from the same responders taken at baseline.          The authors conclude, “Our findings suggest that NAS may have directly contributed to enhancing the exact epidemic that they themselves were intended to fight. Moreover, our results point towards the need to develop new nutritional strategies tailored to the individual while integrating personalized differences in the composition and function of the gut microbiota.”

Plasma Manganese Levels and Type 2 Diabetes

Low and high blood levels of manganese are associated with type 2 diabetes (T2D), according to a 2016 study.⁵ Manganese (Mn) at excessive levels is toxic, but micro levels are a necessity. Manganese is required for normal immune function, blood glucose regulation, bone growth, cellular energy, and for production of the antioxidant manganese superoxide dismutase (MnSOD), which protects the mitochondria from reactive oxygen species (ROS).

The 2016 study, led by Zhilei Shan, involved 1614 newly diagnosed, drug-naïve Chinese Han patients with type 2 diabetes (T2D) and 1614 controls with normal glucose tolerance. The researchers looked for associations between plasma manganese (categorized in tertiles), polymorphisms in the MnSOD gene, and glucose tolerance. The median plasma manganese concentration for the people with diabetes was 4.37 µg/L (2.73-7.62), compared to 5.26 µg/L (3.67-8.33) for the control group.

The researchers report, “Compared with the middle tertile, the multivariate-adjusted [odds ratios] of T2D associated with the lowest tertile and the highest tertile of plasma manganese were 1.89…and 1.56 respectively.” The Mn-diabetes association was stronger in people age 55 or older than in those under 55. The odds ratio of Mn-diabetes association was also affected by physical activity. People in the lowest Mn tertile who reported “no or rare” physical activity had greater odds of having diabetes than those who were physically active (1.97 vs. 1.56). Yet, in the highest Mn tertile, the opposite was true; those who reported little physical activity had an OR of 1.37 compared to 2.11 for those who were active. The researchers found the U-shaped Mn-diabetes association in all tested genotypes.

The authors point out that this case control study design cannot show whether insulin resistance and T2D affect manganese levels or manganese levels affect insulin resistance. They also say that plasma manganese may not be the best way to assess manganese status.

Corn and wheat and other cereal grains are among the food sources for manganese; yet, these foods are also the ones most likely to be exposed to glyphosate, the active ingredient in Roundup® herbicide. Glyphosate depletes Mn levels in plants, which means less manganese for animals and humans who rely on the plants for food, according to Samsel and Seneff.⁶

Persistent Organic Pollutants and Liver Fibrosis

Environmental persistent organic pollutants (POPs), which have a long half-life and accumulate in adipose tissue and the liver, contribute to inflammation that leads to liver fibrosis in animals. In their 2017 study, French researchers exposed mice to TCDD, a POP that strongly activates the aryl hydrocarbon receptor (AhR).⁷ AhR activates enzymes that take part in the elimination of xenobiotics. It also affects lipid metabolism and has a role in the development of hepatic steatosis. Other sources of environmental AhR ligands include polychlorinated biphenyls, cigarette smoke, and diesel particles.

For their TCDD study, Caroline Duval and colleagues used two weight-matched groups of mice (n=30). One group was fed a high-fat diet (45% energy from fat) and the other ate a low-fat diet (10% energy from fat) for 14 weeks. During the last six weeks, mice from each group were injected with 5 µg/kg TCDD in corn oil (n=16) or the corn oil vehicle (n=14) once a week. The TCDD dosage was calculated to create a final blood concentration below 70 ppt, higher than that found in the general population but lower than the amounts measured in people near the Seveso industrial accident and in US Vietnam veterans (Ranch Hand cohort) exposed to Agent Orange.

TCDD exposure produced inflammation in all exposed mice. In the low-fat group, the controls injected with corn oil had normal liver histology with no sign of inflammation; but those injected with TCDD developed steatosis “with infiltration of inflammatory cells grouped in islets.” Although the high-fat diet, as expected, produced steatosis, the vehicle-control mice in this group had no sign of inflammation. Exposure to TCDD, however, produced evidence of inflammation and “dramatically worsened the steatosis.”

Although this study looks at the effect of just one POP on the liver of just one species, it opens the possibility that these pollutants may be contributing to the increased incidence of liver disease in humans.

This article was originally published in Townsend Letter, June 2017.

References

1. Lindmark S, et al. Dysregulation of the Autonomic Nervous System Can Be a Link between Visceral Adiposity and Insulin Resistance. Obesity Research. April 2005;13(4): 717-728.
2. Svensson MK, et al. Alterations in heart rate variability during everyday life are linked to insulin resistance. A role of dominating sympathetic over parasympathetic nerve activity? Cardiovasc Diabetol. 2016; 15:91.
3. Wulsin LR, et al. The Contribution of Autonomic Imbalance to the Development of Metabolic Syndrome. Psychosomatic Medicine. 2015
4. Suez J, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014.
5. Shan Z, et al. U-Shaped Association between Plasma Manganese Levels and Type 2 diabetes. Environ Health Perspect. December 2016;124(12):1876-1881.
6. Samsel A, Seneff S. glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies. Surg Neurol Int. 2015;6:45.
7. Duval C, et al. Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BlL/6J Diet-Induced Obesity Mouse Model. Environ Health Perspect. March 2017;125(3):428-436.