Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans

Denne viser hvordan selv de uten diabetes får økt cytokinverdi (betennelse) i blodet i 1-2 timer etter blodsukkerstigning. I denne studien var det snakk om blodsukker over 15 mmol/L. De sier at blodsukker økninger påvirker cytokinnivået mer enn et stabilt høyt blodsukker.

Control Subjects:

Plasma IL-6 levels rose from a basal value of 2.0±0.7 pg/mL to a peak of 3.1±0.9 pg/mL at 1 hour (P<0.01) and returned to basal level at 3 hours (Figure 2).

Fasting plasma TNF-α levels were 3.3±1.2 pg/mL; they peaked at 1 hour (4.9±1.4 pg/mL, P<0.01), and returned to baseline at 3 hours.

Plasma IL-18 levels rose from a basal value of 116±28 pg/mL to a peak of 140±31 pg/mL at 2 hours (P<0.01) and returned to basal levels at 3 hours (110±26 pg/mL).

The novel findings of the present study were that (1) acute hyperglycemia in control and in IGT subjects induces an increase in plasma IL-6, TNF-α, and IL-18 concentrations; (2) the effect of sustained hyperglycemia is reproduced by transient oscillations in plasma glucose and is amplified by the IGT status; and (3) the antioxidant glutathione completely prevents the rise in plasma cytokines induced by hyperglycemia. These results indicate that hyperglycemic spikes affect cytokine concentrations more than continuous hyperglycemia, at least in the short term, and suggest that an oxidative mechanism mediates the effect of hyperglycemia.

Another finding of the present study was that glutathione, a powerful antioxidant, completely prevented cytokine increase induced by oscillatory hyperglycemia in healthy humans. Hyperglycemia-induced oxidative stress, 32 along with soluble advanced glycation end products and products of lipid peroxidation, possibly serves as a key activator of upstream kinases, leading to induction of inflammatory gene expression.33

Inflammation-induced hyperalgesia: Effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia.

En studie til som bekrefter at lav-grads betennelse gir hyperalgesi, altså økt smerteopplevelse.



Inflammation-induced pain amplification and hypersensitivity play a role in the pathophysiology of numerous clinical conditions. Experimental endotoxemia has recently been implemented as model to analyze immune-mediated processes in human pain. In this study, we aimed to analyze dose- and time-dependent effects of lipopolysaccharide (LPS) on clinically-relevant pain models for musculoskeletal and neuropathic pain as well as the interaction among LPS-induced changes in inflammatory markers, pain sensitivity and negative affect.


In this randomized, double-blind, placebo-controlled study, healthy male subjects received an intravenous injection of either a moderate dose of LPS (0.8ng/kg Escherichiacoli), low-dose LPS (0.4ng/kg), or saline (placebo control group). Pressure pain thresholds (PPT), mechanical pain sensitivity (MPS), and cold pain sensitivity (CP) were assessed before and 1, 3, and 6h post injection to assess time-dependent LPS effects on pain sensitivity. Plasma cytokines (TNF-α, IL-6, IL-8, IL-10) and state anxiety were repeatedly measured before, and 1, 2, 3, 4, and 6h after injection of LPS or placebo.


LPS administration induced a systemic immune activation, reflected by significant increases in cytokine levels, body temperature, and negative mood with pronounced effects to the higher LPS dose. Significant decreases of PPTs were observed only 3h after injection of the moderate dose of LPS (0.8ng/kg). MPS and CP were not affected by LPS-induced immune activation. Correlation analyses revealed that decreased PPTs were associated with peak IL-6 increases and negative mood.


Our results revealed widespread increases in musculoskeletal pain sensitivity in response to a moderate dose of LPS (0.8ng/kg), which correlate both with changes in IL-6 and negative mood. These data extend and refine existing knowledge about immune mechanisms mediating hyperalgesia with implications for the pathophysiology of chronic pain and neuropsychiatric conditions.

Systemic Inflammation Decreases Pain Threshold in Humans In Vivo

Denne viser hvordan systemisk betennelse, til og med lav-grads systemisk betennelse (som kommer fra kosthold), bidrar til å øke smertesensitivitet.

In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

Inflammation leads to a broad constellation of adaptive changes, called the ‘sickness response’. Features of this response include fever, increased sleep, decreased locomotion, decreased food and water intake, and hormonal changes [1]. Furthermore, the pain threshold for painful stimuli is lowered, resulting in hyperalgesia, and normally non-painful stimuli can become painful (allodynia).

Systemic inflammation has previously been shown to alter pain perception in animals and humans. Recently, Benson and colleagues reported altered pain perception after the administration of a very low dose of endotoxin (0.4 ng/kg) to healthy volunteers, mimicking low grade systemic inflammation [26].


Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats.

Denne beskriver hvordan hyperglycemi (regnes som blodsukker over 7 mmol/L i lengre perioder, eller fastende blodsukker over 7) gir økt cytokin-aktivitet i flere timer etter en stressende episode. Om man spiser en snickers går blodsukkeret opp til over 10, og om man kontinuerlig spiser mat som øker blodsukkeret er det en stor sjangse for at man har en kronisk betennelsesreaskjon med økt cytokin aktivitet.

Kobler vi det med denne, som nevner at cytokiner tilført fra utenfor muskelen kan gi hyperalgesi, så begynner bildet å bli klarere: «One mechanism of action, the immune-to-brain communication through activation of brain and spinal cord glial cells was reviewed by Wieseler-Frank et al. (2005). Activation of CNS glia and subsequent production of inflammatory cytokines can lead to hyperalgesia.»



The aim of this study was to investigate whether hyperglycemia enhances the systemic inflammatory response and oxidative stress induced by endotoxin.


Laboratory investigation.


University medical school.


Forty-one male Sprague-Dawley rats.


A hyperglycemic condition was produced in rats by glucose clamp for 3 hrs. Immediately on stopping the glucose infusion, animals received different doses of endotoxin injection (0, 0.2, or 1 mg/kg), and then blood glucose concentration was monitored over the ensuing 2 hrs. At the end of 2 hrs, levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, corticosterone, and alpha-1 acid glycoprotein were determined in serum, and malondialdehyde and total glutathione content were determined in the liver.


Over the 2-hr period, blood glucose concentrations returned to normal in initially hyperglycemic rats. However, the levels of cytokines, corticosterone, and alpha-1 acid glycoprotein were significantly higher in these animals compared with nonhyperglycemic controls, demonstrating an extended effect of prior hyperglycemia on markers of systemic inflammation. With low-dose (0.2 mg/kg) but not high-dose (1 mg/kg) endotoxin administration, hyperglycemic animals had significantly higher levels of cytokines compared with controls, indicating that prior hyperglycemia can enhance the systemic inflammatory response to a moderate endotoxin dose, but that the maximum effects of endotoxin on production of inflammatory cytokines are not altered by transient high glucose exposure.


Systemic inflammation persists for a period following hyperglycemia, and this can enhance the systemic inflammatory response to a subsequent moderate stress.

Noen studier om hvordan Substans P forholder seg til mat

Denne nevner at en 10% reduksjon av anbefalt daglig magnesium inntakt øker sjangsen for osteoporose og Substans P

Bone Loss Induced by Dietary Magnesium Reduction to 10% of the Nutrient Requirement in Rats Is Associated with Increased Release of Substance P and Tumor Necrosis Factor-α1

These data demonstrated that a Mg intake of 10% of NR in rats causes bone loss that may be secondary to the increased release of substance P and TNF-α.

Denne nevner hvordan tiltak som reduserer SP bidrar til å redusere de negative virkningene av magnesiummangel.

Neurogenic Inflammation and Cardiac Dysfunction due to Hypomagnesemia.

Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.

Denne nevner hvordan SP er involvert i insulin regulering og diabetes.

Role of Substance P in the Regulation of Glucose Metabolism via Insulin Signaling-Associated Pathways

Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.

ACE ID genotype affects blood creatine kinase response to eccentric exercise

Hvordan genetiske forskjeller gir økt disponering from CK respons fra trening.

Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals’ CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and postexercise CK activity was determined. ACE genotype was significantly associated with postexercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean ± SE U/L: II, 8,882 ± 2,362; ID, 4,454 ± 1,105; DD, 2,937 ± 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, body mass index, and genotype subtypes, revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95% confidence interval 1.03–1.64, P = 0.02). In conclusion, we indicate a positive association of the ACE ID genotype with CK response to strenuous exercise. We suggest that the IIgenotype imposes increased risk for developing muscle damage, whereas the DD genotype may have protective effects. These findings support the role of local RAS in the regulation of exertional muscle injury.