Month: March 2020

Diabetes does not mean being immunocompromised

24 March, 2020

We with diabetes have since at least 35 years heard that we are, no matter type 1 or 2 diabetes, more susceptible for infections, viruses and influenza. I have personally read an enormous amount of papers that state that, but the majority are epidemiological looking at a huge group of people with diabetes. For me this is inconclusive, just a reminder that it might be so for some people. Should we really look at 425 million people in the world with diabetes as a homogenous group? (1) Of course not. But since there seems to be some association between diabetes and infections, viruses and influenza, what could be the reason? The last weeks I have spent a lot of time digging into this field of research. The evidence clearly point at a possible correlation: hyperglycemia over time, expressed as a higher HbA1c, and comorbidity. The questions that remains to be answered are if increased HbA1c itself can weaken the immune system? If so, at what level could that start to develop? Or is it rather comorbidity to blame, which often is a cause of elevated HbA1c over time? What impact has longer duration and higher age, since chances were different many years ago?

To write this article I did something I normally don´t do. I have a huge network of researchers around the globe, many belongs to the most competent in the world and among the highest ranked at Expertscape (2). I asked them for help: have I missed some papers? Some sent me to other researchers, some agreed on my thesis. I have had contact with many from Seattle in US to Beijing. It didn´t add data or evidence, but strengthen my thesis and was indeed many interesting discussions.

1. IMMUNE SYSTEM

The human immune system is a very complex process with many tasks, the main is to prevent infection, or limit the impact. There are numerous innate immune cell types in the entire body that have a specific function, and they mostly differentiate within the bone marrow. Continuously new cells are born from stem cells. The immune system is divided in two parts: the innate and the adaptive immune system. The innate is present from birth and is nonspecific, meaning anything that is identified as foreign or non-self is a target for an immune response. The innate immune system can´t distinguish between different bacteria and viruses. The innate immune cells are for example neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells and macrophages. Everything about the immune system is great described at the US National Institute of Allergy and Infectious Diseases website 3.

The adaptive immune cells are more specialized with lymphocytes, mainly B-cells and T-cells, that have receptors that identify specific antigens. Antigen (antibody generator) is any substance that causes your immune system to produce antibodies against it. This means your immune system does not recognize the substance, and trying to get rid of the intruder. There are several different types of T-cells, as helper T-cells (pictured at top in this article) and cytotoxic T-cells (killer cells, CD8+). T-cells are taught in the small organ thymus how to recognize foreign subjects and destroy them, and can only leave the thymus if not reacting to the body´s owns antigens. The lifespan of a T-cell is about seven weeks. Helper T-cells (CD4+) affect the B-cells and tells them to produce antibodies, and they are considered as the immune cells that produce most cytokines. Cytokines are small proteins responsible for signalling in the immune system, for example IL-1, TNF, IL-6, IL-4, IFN and IL-10. Some cytokines are considered as pro inflammatory and some anti-inflammatory (4). A subgroup of T-cells called regulatory T-cells or Treg´s inhibit other T and B-cells to attack the body´s healthy tissue, and destroy some if necessary. This fails sometimes and can lead to different autoimmune diseases. One example is in autoimmune diabetes/type 1 diabetes, when autoreactive T-cells manage to avoid the Tregs and suddenly sees the beta cells as foreign, and kills them (5). The biomarkers for autoimmune diabetes, five different form of autoantibodies (antibodies attack foreign subjects, autoantibodies own healthy tissues), are today believed to have less role in the destruction of the beta cells but the link to the autoimmune process is established. University of Southern California has some easy to understand material as well 6.

2. DIABETES AND RISK FOR INFECTIONS, INFLUENZA AND VIRUSES

There are many different forms of diabetes with different etiology, dominated by autoimmune diabetes and type 2 diabetes (5). The immune system might act different due to the fact of the autoimmune reaction occurring in autoimmune diabetes, unfortunately we are lack of separate papers in that sense. Some means that since autoimmune diabetes occur due to a mistake by the immune system who overreact, we have an immune system that is to efficient. It may be but the evidence for that is still weak. There are though some paper that have looked at the immune system in diabetes sine many years, I have read loads of papers but include those I find interesting or that actually add some knowledge. Particular focus at human studies.

Here follows some mixed papers, in fact almost none distinguish between autoimmune diabetes and type 2 diabetes. Please also note that all papers have sources that might be interesting as well, I have read many of them too. Let´s take a look at some systematic review, in general highest in the evidence hierarchy but in this case when we want to see details why an eventual association would occur, that type of study doesn´t answer that question since it just can find correlations. But still important.

A systematic review from 2013 showed a correlation between a severe or complicated influenza and diabetes. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. “Conclusion: The evidence supporting risk factors for severe outcomes of influenza ranges from being limited to absent. This was particularly relevant in the relative lack of data for studies on non-2009 H1N1 pandemics and for seasonal influenza. The level of evidence was low for any risk factor, obesity, cardiovascular diseases, and neuromuscular disease, and was very low for all other risk factors.” 7

A systematic review from 2017, The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies.” Our study supports the hypothesis that diabetes affects immunity leading to a higher chance of developing multiple types of infections. Indeed, our meta-analysis of adjusted results from both CS and CCS found statistically significant associations among all outcomes. These findings are supported by a large body of pathophysiological evidence across our outcomes of interest. In general, diabetes is known to affect healing, and hyperglycemia affects coagulation, fibrinolytic function, lipid metabolism and endothelial function. Moreover, hyperglycemia decreases function of neutrophils and monocytes by way of impaired chemotaxis, adherence, phagocytosis and other immune system impairment. In addition, people with diabetes are at higher risk of infections with certain microorganisms, mainly Streptococcus (Group A&B Streptococcus) and Staphylococcus.” 8

A mini-review from 2010, Diabetes and infection: Is there a link? “Collectively, the data show that there seems to be a tendency for hyperglycemia itself to impair the antibacterial function of neutrophils, while insulin was shown to restore and even enhance the inflammatory response in other trials.” 9

Let us look at some other papers I found interesting, mainly observational studies. I focus below mostly at studies that have tried to go deeper than just saying diabetes increase the risk for influenza and similar. I looked for a possible answer, there are studies that have found more intriguing information.

A few years ago a paper came with a new theory in type 2 diabetes, about dicarbonyls, performed in a dish in a lab. I have not seen anything after this, but a bit interesting. Modification of β-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. “What appears to happen, say researchers, is that the high glucose levels associated with type 1 and type 2 diabetes unleash destructive molecules that hamper the body’s natural immune defenses that fight infections.” 10

1999 and the paper Immune dysfunction in patients with diabetes. ”In conclusion, disturbances in cellular innate immunity play a role in the pathogenesis of the increased prevalence of infections in DM patients. In general, a better regulation of the DM leads to an improvement of cellular function. A second important mechanism is the increased adherence of the microorganism to diabetic cells. Furthermore, some microorganisms become more virulent in a high glucose environment.” 11

From 2012, Infections in patients with diabetes mellitus: A review of pathogenesis. “Regarding the mononuclear lymphocytes, some studies had demonstrated that when the glycated hemoglobin (HbA1c) is <8.0%, the proliferative function of CD4 T lymphocytes and their response to antigens is not impaired.” 8% in HbA1c in DCCT standard is similar as 64 mmol/mol, see my converter here 12. Further, “In general, infectious diseases are more frequent and/or serious in patients with diabetes mellitus, which potentially increases their morbimortality. The greater frequency of infections in diabetic patients is caused by the hyperglycemic environment that favors immune dysfunction (e.g., damage to the neutrophil function, depression of the antioxidant system, and humoral immunity), micro- and macro-angiopathies, neuropathy, decrease in the antibacterial activity of urine, gastrointestinal and urinary dysmotility, and greater number of medical interventions in these patients. The infections affect all organs and systems.” 13

There are some papers that speculate that even short-term hyperglycemia might have impact, even less evidence for this but a bit intriguing, I come back to this later. Here from 2016, The effect of short-term hyperglycemia on the innate immune system .”In summary, acute hyperglycemia can significantly alter innate immune responses to infection, and this potentially explains some of the poor outcomes in hospitalized patients who develop hyperglycemia.” 14

A population-based case-control study from 2008, Diabetes, Glycemic Control, and Risk of Hospitalization With Pneumonia, found that “in conclusion, our data, combined with previous results, provide strong evidence that diabetes is associated with a 25–75% increase in the RR of pneumonia-related hospitalization. Longer duration of diabetes and poor glycemic control increase the risk of pneumonia-related hospitalization. These results emphasize the value of influenza and pneumococcal immunization, particularly for patients with longer diabetes duration, and the importance of improved glycemic control to prevent pneumonia-related hospitalization among diabetic patients.” 15

A cohort study from UK in 2016, Association between glycaemic control and common infections in people with Type 2 diabetes: a cohort study. “Conditions most commonly caused by bacteria, fungi and yeasts were more common in people with worse glycaemic control (pneumonia, skin and soft tissue infections, urinary tract infections and genital and perineal infections). Conditions most commonly of viral origin showed no increased incidence in people with worsening glycaemic control (upper respiratory tract infections, influenza – like illness, intestinal infectious diseases [21,22 ] and herpes simplex).” 16

In 2008, a study evaluated eventual differences in type 2 diabetes between hyperglycemia and hyperinsulinemia, Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. ”In a more controlled setting, the same group applied clamp techniques in healthy volunteers and increased either glucose, insulin, both or none and administered a defined dose of LPS to induce a systemic inflammatory response [30]. After various time points, the inflammatory response and activation of coagulation/fibrinolysis was evaluated. The results demonstrate that hyperglycemia led to more pronounced activation of coagulation while at the same time neutrophil degranulation was diminished. Hyperinsulinemia in turn attenuated fibrinolysis, whereas inflammatory cytokines like TNF or IL-6 did not differ between the groups. The advantage of this latter study is the clear design and low interindividual variability, which possibly gives the best insight into the biological role of glucose and insulin levels during systemic inflammation in humans in vivo.” 17

In 2010, a group analysed two studies about pneumonia in diabetes, The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies. “We speculate that acceleration of pre-existing chronic disease may explain higher long-term mortality among those with diabetes. For instance, cardiovascular disease accounted for more than third of all deaths in individuals with diabetes. Pre-existing cardiovascular disease was more common among those with diabetes, which may be further accelerated by the acute infection. Early recognition or better management of atherosclerotic heart disease and concomitant risk factors, such as smoking and hyperlipidaemia, may improve outcomes. We showed that diabetes was associated with higher risk of acute kidney injury, which was associated with higher risk of 1-year mortality in our study and previous studies. Acute kidney injury itself or its sequela, CKD, may lead to death by several mechanisms, including increased risk of cardiovascular disease and infections.” 18

In 1999 a paper found that better regulated diabetes improved cellular functions associated with the immune system, Immune dysfunction in patients with diabetes mellitus (DM). “In conclusion, disturbances in cellular innate immunity play a role in the pathogenesis of the increased prevalence of infections in DM patients. In general, a better regulation of the DM leads to an improvement of cellular function. A second important mechanism is the increased adherence of the microorganism to diabetic cells. Furthermore, some microorganisms become more virulent in a high glucose environment.” 19

A study from 2019, Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes: “Compared with individuals with normal glucose tolerance or prediabetes, type 2 diabetes patients have a reduced NK cell activity, and it is significantly related to glucose control.” 20

Perhaps the most interesting study in this field is the newest as well, published in Nature 2019. High Glucose Environments Interfere with Bone Marrow-Derived Macrophage Inflammatory Mediator Release, the TLR4 Pathway and Glucose Metabolism. “Hyperglycaemia appears to impair the immune response and the clearance of pathogens by macrophages in diabetic subjects. A lack of glucose homeostasis can be an important key to macrophage deregulation in a hyperglycaemic environment under a variety of stimuli. Due to the high susceptibility to infections and elevated risk of developing complications after surgery in diabetic patients, failures in inflammation resolution contribute to the high rates of morbidity and mortality in diabetic subjects.” From the conclusion: “The effects of high glucose on macrophages have been shown to be primarily due to high glucose itself. Hyperglycaemia disrupts many cellular functions, and the “legacy effect” triggered by uncontrolled glycaemia may be associated with a short or long period of high glucose exposure. It is possible that diabetic BMDMs cannot overcome high glucose to maintain regular inflammatory functions, promoting the establishment of “glycaemic memory”. In addition, it appears that non-diabetic BMDMs are more resistant to changes triggered by persistent high glucose than diabetic BMDMs, and a long exposure time is necessary to promote substantial changes in the levels of cytokine release.” 21

3. WHAT ELSE CAN WEAKEN THE IMMUNE SYSTEM?

It´s well established that aging can weaken the immune system, of course heterogeneous as well. It´s called immunosenesescence and refers to changes in the immune system that might increase the susceptibility for diseases. There are many papers in this area, Science Direct has a category here for those who might be interested to read more 22.

A number of factors are well-known that they can negatively affect your immune system. Please note that there are no magic shortcuts, even though many claims so. A popular scientific article from Harvard 2014 summarize it in a simple manner, which should be interpreted what is rather normal, general advices for public health (23):

Don’t smoke.
Eat a diet high in fruits and vegetables.
Exercise regularly.
Maintain a healthy weight.
If you drink alcohol, drink only in moderation.
Get adequate sleep.
Take steps to avoid infection, such as washing your hands frequently and cooking meats thoroughly.
Try to minimize stress.

Easier said than done of course. A paper from 2006 in Diabetes Care touched this topic and comorbidity, The impact of comorbid chronic conditions on diabetes care. It might lead to a sort of catch 22 scenario, if getting more chronic diseases the burden and the physiological impact can be huge, which in turn can worsen some diseases or the health in general: 24

There are some studies that have looked into the impact of comorbidity having diabetes and MERS, another coronavirus discovered in 2012. In mice though, but “These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response, which results in more severe and prolonged lung pathology.” 25

Another paper from 2019 about comorbidity and type 2 diabetes, particular tuberculosis, summarized “Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM.” 26

If having autoimmune diabetes there seems to be increased risk for at least some other autoimmune conditions. About 80 autoimmune diseases are known today 27. In Sweden and the international TEDDY study, about 10% of all children diagnosed with autoimmune diabetes within five years develop celiac disease as well (28). The researchers don´t know why and it doesn´t imply there is a link between the diseases, it can be due to the similar environmental factors. We also knows some autoimmune diseases share some risk genes as well. A study in USA from T1D Exchange in 2016 showed that 27% of those diagnosed with autoimmune diabetes was affected with at least one additional autoimmune disease as well. Most common was autoimmune thyroiditis with 24% (29). How that might impact the immune response to viruses, influenza and infections is not studied.

4. NOT TO FORGET – OTHER POSSIBLE CONTRIBUTIONS

On top of all this is another very important topic. All of us that has diabetes are more than aware of that having an infection, virus or influenza affect our stress hormones and cause a higher insulin need, more swings and often higher values. Some ends up at a hospital with a ketoacidosis (30) and it can be fatal. It´s natural defence from the body to fight off the unwelcome intruder, releasing stress hormones that are the number 1 diabetes antagonists. In humans, the natural endocrine and immunological responses to stress ensure adequate availability of glucose by activating gluconeogenesis and by reducing the sensitivity to insulin for those organs and tissues that predominantly rely upon glucose as metabolic substrate, such as the brain and blood cells. Gluconeogenesis is a process in the liver where glucose is made from protein (particular alanin) and the glycerol part in fat. Both epinephrine (adrenaline) and norepinephrine (noradrenaline) stimulate gluconeogenesis and glycogenolysis (release of stored glycogen in the liver), norepinephrine has the added effect of increasing the supply of glycerol to the liver via lipolysis. Interestingly, inflammatory mediators, specifically the cytokines TNF-α, IL-1, IL-6, and C-reactive protein, also induce peripheral insulin resistance. Cortisol affect the glucose level through the activation of key enzymes involved in gluconeogenesis and inhibition of glucose uptake in tissues such as the skeletal muscles. Growth hormone can reduce the insulin sensitivity as well and adrenaline stimulates glucagon release which affect the glycogenolysis. This means that adrenaline affect the liver to release glucose in two ways.

In diabetes this is naturally challenging of course, and a major issue often when having a flu, virus or infection. To manage the disease if being more ill is indeed very tough, and if not being able to do it due to critical illness that can worsen the outcome through hyperglycemia and ketones, leading to an ketoacidosis. This can naturally be a challenge ending up at a hospital of another reason than diabetes, important to ensure people close to us are at least aware of that we do have the disease (31, 32, 33, 34, 35)

5. VACCINES

Everything so far is the reason that people with diabetes are recommended to take vaccines for influenza and anything that is possible. Diabetes is considered a risk group in that case, personally I would say the reason in the past was rather that researchers saw a correlation with risk for, and severity, of, influenza, viruses and infections. Today, it´s more about the part in chapter 4. Anecdotal I never get sick and it has been the reality whole my life, but I take the flu vaccine just to increase my chances to avoid the influenza since it might give a roller coaster glucose for some days, and worsen my condition.

Vaccines are safe, the association with autoimmune diabetes has been researched extensively since people saw a correlation with the increase of evidence of autoimmune diabetes in the beginning of the eighties and the MMR vaccine. There are also some reviews and meta-analysis, here a quite new review from Sweden in 2019, Environmental risk factors for type 1 diabetes, said “There has been speculation that vaccines might trigger autoimmunity, but no association has been detected with islet autoimmunity or type 1 diabetes. A recent meta-analysis of 23 studies investigating 16 vaccinations concluded that childhood vaccines do not increase the risk of type 1 diabetes”. 36. The meta-analysis they refer to is Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies: “Meta-analyses found no significant association between any of the 11 vaccinations and the risk of type 1 diabetes. Conclusion: This study found no evidence that any of the reported vaccinations were associated with the risk of childhood type 1 diabetes. These findings were little altered after adjustment for potentially confounding factors. Results were also largely unchanged after two sensitivity analyses investigating the effect of study design and quality assessment score were conducted.” 37

Huge and international ongoing TEDDY-study, who as a different to almost all studies are looking on everything that happens before eventual autoantibodies appears, in fact life. Most other studies try to find a causal link after diagnose, this is a very important difference. They looked at Pandemrix, not MMR, but interesting was that the Finnish children (Finland has absolute highest incidence of autoimmune diabetes since many years) showed a protection to develop autoantibodies if they have had Pandemrix, not conclusive yet though 38

As long as we don’t know all we must be humble, but as for vaccine no causal link to the development of autoimmune diabetes. In fact vaccines are now tested as prevention, the most interesting is a vaccine targeting the Coxsackievirus, slightly delayed and expected to start later in 2020 one of the project leaders, Professor Mikael Knip from Finland, told me 39. Virus is not the sole cause of autoimmune diabetes but the evidence is getting stronger continuously that it has some role. TEDDY showed this recently as well 40.

6. SUMMARY

Taking all together, diabetes can of course not be lumped together as one individual. All evidence point in the direction that if it is an increased risk for viruses, infections and influenza in diabetes it´s because of hyperglycemia over time, expressed as a higher HbA1c, and that comorbidity have a role too. The questions are rather: when do the risk eventually increase if HbA1c alone really is enough? What impact has duration of diabetes in this, particular in people who were diagnosed long ago when the chances were very different?

We already knew enough to do what we can do reduce the HbA1c and other parameters we measures. Particular since more or less all complications associated to diabetes, both autoimmune diabetes and type 2, are due to higher glucose over time, even though genetics might play a minor role too. The risk for viruses, influenza and infections are yet another reason. But if you want to state that “people with diabetes are at risk” as if 425 million people with diabetes globally (1) were one individual it´s not science, and the evidence we do have shows that if any risk at all, it´s rather linked to higher HbA1c over time and more probably, comorbidity.

7. WHAT IS THE TAKE HOME MESSAGE?

People with diabetes are not per se immunocompromised, nor have a dysregulated or weakened immune system. Ask for evidence. Important is to avoid being to black and white – as well as many people with diabetes don´t are at higher risk for viruses, influenza and infections we know some are, and we might know some of these people too. People with diabetes are often questioning the blaming of being a “bad diabetic” and prejudices from those who don´t understand. If anyone should ensure we stop the stigmatization we must start within the world of diabetes. Diabetes is tough, people are different and possibilities too – it´s life.

References:

Hans Jönsson
Scientific diabetes writer and lecturer
https://www.facebook.com/diabethics
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Har personer med diabetes ett nedsatt immunförsvar eller är det en myt?

Vi med diabetes har i minst 35 år fått höra att vi oavsett form av diabetes är mer mottagliga för infektioner, virus och influensa. Jag har personligen läst enormt många studier som statuerar detta, i princip uteslutande epidemiologiska studier dock som tittat på en stor grupp människor. För mig är detta inget slutgiltigt svar, bara en påminnelse att kanske det är så för en del. Frågan är dock, skall vi verkligen titta på 425 miljoner personer med diabetes i världen som en homogen grupp? (1) Naturligtvis inte. Men då det ändå uppenbarligen finns någon korrelation mellan diabetes och virus, infektioner och influensa, vad kan möjligen vara orsaken? Senaste tre veckorna har jag ägnat väldigt mycket tid att finna ett svar på denna fråga. Evidensen som finns pekar tydligt på ett möjligt samband: hyperglykemi över tid, uttryckt som högt HbA1c, och samsjuklighet. Frågorna som återstår att bli besvarade är dock om ett förhöjt HbA1c är tillräckligt för att försämra immunförsvaret? Om så, när kan detta möjligen tänkas ske? Eller, är det snarare samsjuklighet som är problemet, som i sig ofta kan bero på just förhöjt HbA1c över tid? Vad har lång diabetesduration för eventuell betydelse, diskonterat hur förutsättningarna var förr i tiden kontra idag?

För att skriva denna artikel så gjorde jag något jag inte normalt gör. Jag har kontinuerlig kontakt med väldigt många forskare inom diabetes runt jordklotet, flera av dem tillhör de högst rankade i världen på Expertscape (2). Jag frågade dem om hjälp, har jag verkligen missat något? Några gav mig tips på andra att rådfråga, de flesta bekräftade min tes. Jag har haft kontakt med forskare från Seattle till Peking, det adderade inte något i form av evidens men bekräftade min tes och det var likt alltid väldigt givande diskussioner.

1. IMMUNFÖRSVAR

Immunförsvaret hos människor är ett väldigt komplext system med många uppgifter, den huvudsakliga uppgiften är att förhindra infektion eller minimera effekten. Det finns flera medfödda immunceller i människokroppen, som alla har en specifik uppgift, och samtliga har sitt ursprung i benmärgen. Nya celler uppstår kontinuerligt, från stamceller. Immunförsvaret är uppdelat i främst två delar: det medfödda och det adaptiva. Det medfödda immunförsvaret föds vi således med och detta är ospecifikt, vilket betyder att allting som identifieras som en inkräktare eller icke kroppseget ger upphov till ett immunsvar. Det medfödda immunförsvaret kan inte heller skilja mellan olika bakterier eller virus. De medfödda immuncellerna är exempelvis neutrofila leukocyter, eosinofila leukocyter, basofiler, mastceller, monocyter, dendritiska celler och makrofager. Allt om immunförsvaret är väldigt fint beskrivet på amerikanska myndigheten National Institute of Allery and Infectious Diseases hemsida 3.

Det adaptiva immunförsvaret är mer specialiserat med lymfocyter, huvudsakligen B- och T-celler, som har receptorer som identifierar specifika antigen. Antigen (av antibody generator) är vilket ämne som helst som gör att immunförsvaret producerar antikroppar mot det. Det innebär att immunförsvaret inte känner igen substansen eller ämnet och försöker bli av med det. Det finns flera olika typer av T-celler, som T-hjälparceller (på toppbilden i denna artikel) och cytotoxiska T-celler (mördarceller, CD8+). T-celler lärs upp i det lilla organet brässen (thymus), hur de ska känna igen okända ämnen och förstöra dem, och får endast lämna brässen under förutsättning att de inte reagerar med kroppens egna antigen. Livslängden på en T-cell är ungefär sju veckor. T-hjälparceller (CD4+) påverkar B-cellerna och förmår dem att producera antikroppar, de anses också vara de som producerar mest cytokiner. Cytokiner är små proteiner som fungerar som signalmolekyler i immunförsvaret, exempelvis IL-1, TNF, IL-6, IL-4, IFN och IL-10. Vissa ses som proinflammatoriska och vissa anti-inflammatoriska (4). En subgrupp av T-celler kallas regulatoriska T-celler eller Tregs och dessa förhindrar andra T- och B-celler att angripa frisk kroppsvävnad, och förstör dem om nödvändigt. Ibland felar detta och det kan leda till att en autoimmun sjukdom uppstår. Ett exempel är autoimmun diabetes/typ 1 diabetes, där autoreaktiva T-celler lyckas undkomma Tregs och plötsligt ser betacellerna som inkräktare, och förstör dem (5). Biomarkörer för autoimmun diabetes, fem olika typer av autoantikroppar (observera, antikroppar angriper främmande ämnen, autoantikroppar frisk kroppsvävnad), tros idag ha mindre betydande roll i själva destruktionen av betaceller men kopplingen till förloppet för autoimmun diabetes är väletablerat. University of Southern California hare n del lättförståeligt material likväl 6.

2. DIABETES OCH RISK FÖR INFEKTIONER, INFLUENSA OCH VIRUS

Det finns flera olika former av diabetes med olika etiologi, som domineras av formerna autoimmun diabetes och typ 2 diabetes (5). Immunförsvaret kan agera något annorlunda diskonterat den autoimmuna reaktion som sker vid autoimmun diabetes, tyvärr saknas det onekligen publicera studier som tydligt separerar detta. Vissa menar emellanåt att då autoimmun diabetes uppstår efter ett misstag av immunförsvaret som överreagerar, så skulle vi ha ett immunförsvar som egentligen är överaktivt. Möjligt, evidensen för detta är svag dock. Däremot finns väldigt många studier som tittat på immunförsvaret vid diabetes, sedan många år. Jag har läst väldigt många men nedan inkluderar jag ett urval av de jag ser som mer intressanta. Särskilt fokus på humanstudier.

Här kommer lite mixat med studier, i själva verket så skiljer i princip ingen mellan autoimmun diabetes och typ 2 diabetes, synd. Om ni har lust att läsa referenserna så rekommenderar jag även att från dessa klicka er vidare, där finns mycket intressant likväl. Låt mig först visa ett par systematiska översiktsstudier, i praktiken överst i evidenshierarkin men här vill jag alltså gå djupare, förbi detta och inte endast se ett samband utan i sådana fall varför ett samband, en korrelation, finns. Den typen av studier kan inte besvara den frågan, dock fortsatt intressant.

En systematisk översiktsstudie från 2013 visar en korrelation mellan allvarlig eller komplicerad influensa och diabetes. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. Conclusion: “The evidence supporting risk factors for severe outcomes of influenza ranges from being limited to absent. This was particularly relevant in the relative lack of data for studies on non-2009 H1N1 pandemics and for seasonal influenza. The level of evidence was low for any risk factor, obesity, cardiovascular diseases, and neuromuscular disease, and was very low for all other risk factors.” 7

En annan systematisk översiktsstudie från 2017, The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies.” Our study supports the hypothesis that diabetes affects immunity leading to a higher chance of developing multiple types of infections. Indeed, our meta-analysis of adjusted results from both CS and CCS found statistically significant associations among all outcomes. These findings are supported by a large body of pathophysiological evidence across our outcomes of interest. In general, diabetes is known to affect healing, and hyperglycemia affects coagulation, fibrinolytic function, lipid metabolism and endothelial function. Moreover, hyperglycemia decreases function of neutrophils and monocytes by way of impaired chemotaxis, adherence, phagocytosis and other immune system impairment. In addition, people with diabetes are at higher risk of infections with certain microorganisms, mainly Streptococcus (Group A&B Streptococcus) and Staphylococcus.” 8

2010 kom en mini-review, Diabetes and infection: Is there a link? “Collectively, the data show that there seems to be a tendency for hyperglycemia itself to impair the antibacterial function of neutrophils, while insulin was shown to restore and even enhance the inflammatory response in other trials.” 9

Låt mig istället gå vidare och visa studier som är mer intressanta, mestadels observationsstudier. Jag fokuserar nedan på de som faktiskt försökt svara på frågan istället för att bara statuera ett eventuellt samband mellan diabetes och risk för influensa och liknande. Jag sökte efter en möjlig förklaring, det finns studier som har funnit mer spännande svar.

För ett par år sedan kom en ny förklaringsmodell gällande typ 2 diabetes, om dikarbonyler, utfört i en skål i ett labb. Jag har tyvärr inte sett något om detta senare, men ändå lite småintressant. Modification of β-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. “What appears to happen, say researchers, is that the high glucose levels associated with type 1 and type 2 diabetes unleash destructive molecules that hamper the body’s natural immune defenses that fight infections.” 10

1999 kom studien Immune dysfunction in patients with diabetes. ”In conclusion, disturbances in cellular innate immunity play a role in the pathogenesis of the increased prevalence of infections in DM patients. In general, a better regulation of the DM leads to an improvement of cellular function. A second important mechanism is the increased adherence of the microorganism to diabetic cells. Furthermore, some microorganisms become more virulent in a high glucose environment.” 11

Från 2012, Infections in patients with diabetes mellitus: A review of pathogenesis. “Regarding the mononuclear lymphocytes, some studies had demonstrated that when the glycated hemoglobin (HbA1c) is <8.0%, the proliferative function of CD4 T lymphocytes and their response to antigens is not impaired.” 8% i HbA1c i amerikansk DCCT-standard motsvarar 64 mmol/mol, se min konverterare här 12. Vidare, “In general, infectious diseases are more frequent and/or serious in patients with diabetes mellitus, which potentially increases their morbimortality. The greater frequency of infections in diabetic patients is caused by the hyperglycemic environment that favors immune dysfunction (e.g., damage to the neutrophil function, depression of the antioxidant system, and humoral immunity), micro- and macro-angiopathies, neuropathy, decrease in the antibacterial activity of urine, gastrointestinal and urinary dysmotility, and greater number of medical interventions in these patients. The infections affect all organs and systems.” 13

Det finns ett fåtal studier som spekulerar i om även kortvarig hyperglykemi skulle kunna spela in, evidensen är svag men intressant, återkommer till det senare. Här från 2016, The effect of short-term hyperglycemia on the innate immune system .”In summary, acute hyperglycemia can significantly alter innate immune responses to infection, and this potentially explains some of the poor outcomes in hospitalized patients who develop hyperglycemia.” 14

En fallkontrollstudie på en större population från 2008, Diabetes, Glycemic Control, and Risk of Hospitalization With Pneumonia, fann att “in conclusion, our data, combined with previous results, provide strong evidence that diabetes is associated with a 25–75% increase in the RR of pneumonia-related hospitalization. Longer duration of diabetes and poor glycemic control increase the risk of pneumonia-related hospitalization. These results emphasize the value of influenza and pneumococcal immunization, particularly for patients with longer diabetes duration, and the importance of improved glycemic control to prevent pneumonia-related hospitalization among diabetic patients.” 15

En kohortstudie från UK 2016, Association between glycaemic control and common infections in people with Type 2 diabetes: a cohort study. “Conditions most commonly caused by bacteria, fungi and yeasts were more common in people with worse glycaemic control (pneumonia, skin and soft tissue infections, urinary tract infections and genital and perineal infections). Conditions most commonly of viral origin showed no increased incidence in people with worsening glycaemic control (upper respiratory tract infections, influenza – like illness, intestinal infectious diseases [21,22 ] and herpes simplex).” 16

2008 tittade en grupp forskare på eventuella skillnader på hyperglykemi och hyperinsulinemi vid typ 2 diabetes, Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. ”In a more controlled setting, the same group applied clamp techniques in healthy volunteers and increased either glucose, insulin, both or none and administered a defined dose of LPS to induce a systemic inflammatory response [30]. After various time points, the inflammatory response and activation of coagulation/fibrinolysis was evaluated. The results demonstrate that hyperglycemia led to more pronounced activation of coagulation while at the same time neutrophil degranulation was diminished. Hyperinsulinemia in turn attenuated fibrinolysis, whereas inflammatory cytokines like TNF or IL-6 did not differ between the groups. The advantage of this latter study is the clear design and low interindividual variability, which possibly gives the best insight into the biological role of glucose and insulin levels during systemic inflammation in humans in vivo.” 17

2010 analyserade en grupp forskare två studier som tittat på lunginflammation vid diabetes, The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies. “We speculate that acceleration of pre-existing chronic disease may explain higher long-term mortality among those with diabetes. For instance, cardiovascular disease accounted for more than third of all deaths in individuals with diabetes. Pre-existing cardiovascular disease was more common among those with diabetes, which may be further accelerated by the acute infection. Early recognition or better management of atherosclerotic heart disease and concomitant risk factors, such as smoking and hyperlipidaemia, may improve outcomes. We showed that diabetes was associated with higher risk of acute kidney injury, which was associated with higher risk of 1-year mortality in our study and previous studies. Acute kidney injury itself or its sequela, CKD, may lead to death by several mechanisms, including increased risk of cardiovascular disease and infections.” 18

1999 fann en forskargrupp att bättre reglerad diabetes förbättrade funktionerna hos celler förknippade med immunförsvaret, Immune dysfunction in patients with diabetes mellitus (DM). “In conclusion, disturbances in cellular innate immunity play a role in the pathogenesis of the increased prevalence of infections in DM patients. In general, a better regulation of the DM leads to an improvement of cellular function. A second important mechanism is the increased adherence of the microorganism to diabetic cells. Furthermore, some microorganisms become more virulent in a high glucose environment.” 19

En studie från 2019, Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes. “Compared with individuals with normal glucose tolerance or prediabetes, type 2 diabetes patients have a reduced NK cell activity, and it is significantly related to glucose control.” 20

Av den stora manga studier jag plöjt sista tre veckorna är kanske den mest intressanta en av de färskaste, publicerad i Nature 2019. High Glucose Environments Interfere with Bone Marrow-Derived Macrophage Inflammatory Mediator Release, the TLR4 Pathway and Glucose Metabolism. “Hyperglycaemia appears to impair the immune response and the clearance of pathogens by macrophages in diabetic subjects. A lack of glucose homeostasis can be an important key to macrophage deregulation in a hyperglycaemic environment under a variety of stimuli. Due to the high susceptibility to infections and elevated risk of developing complications after surgery in diabetic patients, failures in inflammation resolution contribute to the high rates of morbidity and mortality in diabetic subjects.” Här från studiens sammanfattning: “The effects of high glucose on macrophages have been shown to be primarily due to high glucose itself. Hyperglycaemia disrupts many cellular functions, and the “legacy effect” triggered by uncontrolled glycaemia may be associated with a short or long period of high glucose exposure. It is possible that diabetic BMDMs cannot overcome high glucose to maintain regular inflammatory functions, promoting the establishment of “glycaemic memory”. In addition, it appears that non-diabetic BMDMs are more resistant to changes triggered by persistent high glucose than diabetic BMDMs, and a long exposure time is necessary to promote substantial changes in the levels of cytokine release.” 21

3. VAD MER KAN FÖRSVAGA IMMUNFÖRSVARET?

Det är väletablerat att immunförsvaret kan försvagas med åldern, naturligtvis olika även det. Finns faktiskt ett uttryck för detta på engelska, immunosenesescence, och det avses alltså förändringar I immunförsvaret som kan öka risken för mottagligheten att drabbas av sjukdomar. Finns många artiklar i ämnet, Science Direct har en hel kategori där de samlat allt, för de intresserade att läsa mer 22.

Flera faktorer är väl kända att kunna negativt påverka immunförsvaret. Vänligen observera att det inte finns några genvägar, även om många hävdar detta. En populärvetenskaplig artikel från Harvard från 2014 summerar det på ett enkelt sätt, och den skall snarare utläsas som att detta är de normala råden för befolkningen i stort gällande folkhälsa och vad man bör göra för att förbättra chanserna till ett bra immunförsvar (23):

Rök inte
Ät en diet med mycket grönsaker och frukt.
Motionera regelbundet.
Eftersträva en normal vikt.
Om du dricker alkohol, gör det med måtta.
Se till att sova ordentligt.
Försök med små åtgärder undvika infektioner, såsom att tvätta händerna ofta och genomstek maten.
Minimera stress.

Allt lättare sagt än gjort, förstås. En studie från 2006 och Diabetes Care handlade om utmaningarna med detta och samsjuklighet, The impact of comorbid chronic conditions on diabetes care. Det kan bli lite av ett moment-22 scenario, drabbas man av fler kroniska sjukdomar så blir bördan större och den psykologiska påverkan kan bli mycket stor, vilket i sin tur kan förvärra de etablerade fysiska sjukdomarna, 24.

Det finns även studier som tittat på detta med samsjuklighet vid diabetes och MERS, ett annat coronavirus som upptäcktes 2012. Dock utförd på möss, men “These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response, which results in more severe and prolonged lung pathology.” 25

En annan studie från 2019 som handlar om typ 2 diabetes och samsjuklighet, särskilt tuberkulos, summerade “Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM.” 26

Har man autoimmune diabetes verkar risken för att drabbas av åtminstone vissa andra autoimmuna sjukdomar. Ungefär 80 andra autoimmuna sjukdomar är kända idag 27. I Sverige och den internationella TEDDY-studien så har ca 10% av alla barn som drabbats av autoimmun diabetes inom fem år även fått celiaki (28). Man vet inte varför och det måste inte betyda i ett samband mellan sjukdomarna, utan de kan bottna i samma miljöfaktorer. Vi vet dessutom att sjukdomarna delar viss genetisk risk. En studie från T1D Exchange i USA 2016 visade att 27% av de som diagnostiseras med autoimmun diabetes har minst en till autoimmun sjukdom. Vanligast var autoimmun tyreoidit, eller Hashimotos, med 24% (29). Hur det eventuellt kan påverka immunförsvarets respons mot virus, infektioner och influensa är inte studerat.

4. ICKE ATT FÖRGLÖMMA- ANDRA FAKTORER

På toppen av allt hittills finns ytterligare en viktig faktor. Alla vi som själva har diabetes är väl medveten om att får vi ett virus, infektion eller influensa så gör våra stresshormoner att vårt insulinbehov stiger, vi får lätt mer fluktuationer och lite högre värden. En del drabbas av höga ketoner och en del hamnar tyvärr på sjukhus med en ketoacidos som kan vara dödlig, (30). Idag är detta något lättare att hantera för oss som i Sverige har autoimmun diabetes, eftersom nästan alla har sensorbaserad glukosmätning och inte kan preventivt undvika detta men hänga med någorlunda (31). Vad som sker i kroppen vid en infektion, virus eller influensa är välstuderat sedan länge. Stressreaktionen är kroppens naturliga försvar för att mota den ovälkomna gästen, och stresshormoner frisätts som är absoluta nr 1 av diabetesantagonister. Hos människor säkerställer denna endokrina och immunologiska reaktion adekvat tillgång på glukos genom att stimulera glukoneogenes i levern och sänka insulinkänsligheten för de organ och vävnader som är mer beroende av glukos som energi, som exempelvis hjärnan och de röda blodkropparna. Glukoneogenes är en process i levern där glukos tillverkas från protein (främst alanin) och i viss mån även glyceroldelen i fett. Både adrenalin och noradrenalin stimulerar glukoneogenes och glykogenolys (nedbrytning och frisättning av lagrat leverglykogen som blir till glukos i kroppen), noradrenalin har även tilläggseffekten att öka tillgången på glycerol till levern genom lipolys (nedbrytning av fett). Intressant nog, vissa inflammationsmarkörer och speciellt cytokinerna TNF, IL-1, IL-6, och C-reaktivt protein, bidrar även till att sänka insulinkänsligheten i främst muskler. Kortisol, ett annat stresshormon, påverkar glukosnivån genom att aktivera viktiga enzymer som är involverad i glukoneogenesen och hämmande av glukosupptag i exempelvis skelettmuskulatur. Tillväxthormon kan även det sänka insulinkänsligheten, och adrenalin stimulerar glucakonfrisättning vilket påverkar glykogenolys. Det här innebär alltså att adrenalin på två sätt påverkar levern att frisätta lagrat glykogen, som alltså blir glukos.

Vid diabetes är allt ovan en stor utmaning, och kan bli problematiskt om man drabbas av ett virus, infektion eller influensa. Att hantera sjukdomen diabetes om man är sjuk är onekligen tufft, och är man kritiskt sjuk och inte alls kan ta hand om den själv kan situationen försämras ytterligare genom hyperglykemi, höga ketoner och en ketoacidos. Det här är naturligtvis även ytterligare problematiskt om man hamnar på sjukhus av andra skäl än sin diabetes, en anledning ytterligare att informera sin omgivning och nära och kära lite om sin sjukdom (32, 33, 34, 35, 36).

5. VACCIN

Mycket av det ni läst hittills är skälet till att personer med diabetes rekommenderas att vaccinera för influensa och allt i övrigt möjligt. Diabetes ses som en riskgrupp, personligen menar jag att skälet till att personer med diabetes sågs som en riskgrupp för var annan och mer då att man såg en korrelation mellan diabetes och risk för influensa, virus och infektioner, kom ihåg att förutsättningarna var sämre och HbA1c över en population högre. Därför var många fler i riskgruppen. Idag handlar det mer om delen ovan i kapitel 4. Helt anekdotiskt så blir jag sällan sjuk och det har alltid varit så, men jag tar influensavaccin för att minska risken att bli sjuk då det blir lite jobbigt att hantera sin diabetes ett par dagar med svängande blodsocker, då man kanske dessutom inte är så mentalt skärpt.

Vaccin är säkra och välstuderade, sambandet med utvecklandet av autoimmun diabetes har studerats väldigt mycket efter att man såg en korrelation mellan ökning av incidensen av autoimmun diabetes och MPR-vaccin för ca 35 år sedan. Det finns flera översiktsartiklar och meta-analyser, här en lite nyare från Sverige från 2019, Environmental risk factors for type 1 diabetes, ”There has been speculation that vaccines might trigger autoimmunity, but no association has been detected with islet autoimmunity or type 1 diabetes. A recent meta-analysis of 23 studies investigating 16 vaccinations concluded that childhood vaccines do not increase the risk of type 1 diabetes”. 37. Meta-analysen som hänvisas till är Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies, “Meta-analyses found no significant association between any of the 11 vaccinations and the risk of type 1 diabetes. Conclusion: This study found no evidence that any of the reported vaccinations were associated with the risk of childhood type 1 diabetes. These findings were little altered after adjustment for potentially confounding factors. Results were also largely unchanged after two sensitivity analyses investigating the effect of study design and quality assessment score were conducted.” 38

Intressant från den stora TEDDY-studien, som till skillnad från närmast alla studier tittar vad som sker innan autoantikroppar uppstår, det vill säga långt innan diagnos, i själva verket tittar på allt som sker i livet. De flesta studier i ämnet försöker se ett mönster och hitta korrelationer efter diagnos, det är omöjligt att veta vad som skett ibland i många år innan diagnos, en väsentlig skillnad mot TEDDY. De tittade på effekten av Pandemrix, inte MPR med andra ord, men väldigt intressant var att de finska barnen (Finland har överlägset högst incidens i världen av autoimmun diabetes hos barn, sedan många år) visade sig ha ett skydd mot att utveckla autoantikroppar om de fått Pandemrix, dock inget slutgiltigt svar ännu, 39.

Så länge vi inte vet allt om utvecklingen av autoimmun diabetes och vad som orsakar sjukdomen måste vi förhålla oss ödmjuka, men gällande vaccin anser jag att vi kan avskriva det som eventuellt bidragande. I själva verket testas nu vaccin som prevention, det mest intressanta riktar sig mot coxsackievirus, det virus med starkast evidens att kunna bidra till utvecklandet av autoimmun diabetes. Det projektet berättade professor Mikael Knip, en av de bakom detta försök, nyligen för mig var något försenat men beräknas startas under senare delen av 2020. 40. Virus är inte den enskilda orsaken till utvecklingen av autoimmun diabetes men evidensen stärks löpande för att det har någon roll, TEDDY visade detta nyligen också 41.

6. SUMMERING

Allt sammantaget, diabetes kan naturligtvis inte klumpas ihop till en enskild individ. All samlad evidens pekar dock mot att om någon ökad risk för influensa, infektioner och virus vid diabetes så bottnar det i hyperglykemi över tid, uttryckt som förhöjt HbA1c, och att samsjuklighet har en roll likväl. Frågorna är snarare: om HbA1c räcker för att på något sätt försvaga immunförsvaret, vid ungefär vilken nivå sker det? Sedan det viktiga, vad har diabetesduration för betydelse här, det vill säga hur länge man haft sjukdomen, i synnerhet för de med lång duration som haft sjukdomen då förutsättningarna var mycket sämre?

Vi visste redan tillräckligt för att arbeta hårt för att nå bra målvärden på det vi följs upp på. I synnerhet eftersom i princip alla komplikationer som vi kan drabbas av har ett samband med främst höga glukosvärden över tid, både för autoimmun diabetes och typ 2 diabetes, även om genetiken möjligen kan ha en mindre betydelse. Risken för virus, influensa och infektioner är ytterligare ett skäl till att arbeta hårt. Men om man vill statuera att ”personer med diabetes har ökad risk” som att vi 425 miljoner människor med diabetes globalt (1) vore en individ så är det inte vetenskap, och evidensen som vi de facto har visar att om någon risk alls, så korrelerar det med högt HbA1c över tid och troligen, säger jag, samsjuklighet.

7. VAD ÄR DET VIKTIGASTE ATT TA MED SIG FRÅN ALLT DETTA?

Personer med diabetes har inte per se ett nedsatt immunförsvar. Fråga efter evidens. Viktigt här är naturligtvis att inte vara svartvitt – likväl som många med diabetes inte löper högre risk att drabbas av virus, influensa och infektioner så vet vi att vissa tyvärr kanske gör det, och vi kanske även känner någon i den kategorin. Många personer med diabetes vänder sig ofta mot uttrycket från de utan insyn i diabetes som talar om ”en dålig diabetiker” och andra fördomar. Om någon ska bidra till att motverka stigmatiseringen så är det vi själva inom diabetesvärlden. Diabetes är en tuff sjukdom, människor är olika och förutsättningarna likaså – livet.

Jag tackar en följare som heter Martin som skickade en QR-kod han tagit fram för mig, helt på eget bevåg som support. Om du vill stödja mitt arbete så tar du en bild på den i din swish-app. Tack.

Referenser:

Hans Jönsson
Vetenskaplig diabetesskribent och föreläsare
https://www.facebook.com/diabethics
https://www.instagram.com/diabethics