CME INDIA Presentation by Dr. Shaibal Guha M.D., Medicine, Director Positive Health Centre, Patna.

Diabetes and Immunity

Linking Diabetes and Immunity Leads to Unique Therapeutic Targets
  • Immune and metabolic systems are interrelated and most fundamental requirement for survival.
  • Complications in diabetes are mainly caused by chronically elevated inflammatory immunity -> major cause of morbidity and mortality.
  • There may not be any direct alteration in the adaptive immunity, whereas in innate immunity, there is an alteration in its functions like cytokine response, chemotaxis, phagocytosis.

Are these protecting you?

  • The three components of T2 diabetes:
    1. Insulin resistance,
    2. Decreased insulin secretion, and
    3. Glycosuria
  • These are basically protective mechanisms against overnutrition.
  • When these fail/ are overwhelmed -> activation of the innate immune system -> stimulation of proinflammatory cytokine network -> damage of pancreatic beta cells/ other complications of DM.
Linking Diabetes and Immunity Leads to Unique Therapeutic Targets

B Cells in T2DM

  • Play a central role in the development of insulin resistance by producing IgG Abs and the activation of T cells & macrophages.
  • DNA methylation, probably an important mechanism contributing to the inter-individual variation in function of immune cells, was shown to stimulate B cell proliferation in patients with obesity or T2DM.
  • They promote insulin resistance and glucose intolerance by activating T-helper (Th1 & Th17) cells and releasing pathogenic antibodies.

T Cells in T2DM

  • DM associated with overactivated T cells the activation of the inflammatory pathways
    • CD4+ T cells -> imp role in the pathology of obesity and insulin resistance -> an imbalance in the differentiation in CD4+ T cells seen in obese T2DM.
    • CD8+ T cells can also synthesize the proinflammatory cytokine IL-17, which is present in inflammatory tissues in various human inflammatory diseases
    • inhibition of the normal proliferative response to different stimuli in the lymphocytes of poorly controlled diabetics.
    • An abnormal delayed type hypersensitivity reaction (cell-mediated immunity) has also been described in DM type 1 and type 2 patients.
    • Nevertheless, they don’t have Pneumocystis carinii pneumonia or mycobacterial infections more frequently (as in patients with cellular immunity dysfunctions e.g. AIDS) in vitro disturbances ≠ in vivo?

Historical Evidence

  • Insulin resistance in obese mice is associated with raised levels of inflammation mediators (TNF-α, interleukin (IL)-6, C-reactive protein, plasminogen activator inhibitor, etc.)
  • In humans, experimental endotoxemia produced hyperinsulinemia and consequent hypoglycemia. (alters beta cell function)
  • Immune mediators like IL-1 lead to increased beta cell proliferation –> insulin production and secretion (a role in increasing insulin secretion in times of stress and consequent increased demand.)  (pathways involved in controlling the pathological responses to IL1 in infection or inflammation are different from the physiological ones)

Clinical factors suggesting association of Diabetes with immune function

A – Association of InflammatoryMarkers with Beta Cell Pathology

  • Type 1 Diabetes: there is a disproportionately more impairment of the insulin secretory response rather than reduced beta cell mass. (role of various additional factors -glucose toxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress, alteration of gut microbiota, or of the intestinal mucosal barrier)
  • The cytotoxic T cells cause the immune destruction through the inflammatory cytokines. However, few cells like theca granulosa cells of the ovary, neuronal cells, and pancreatic beta cells are affected by direct action of these effector T cells (selective destruction of beta cells in Type 1 diabetes may be due to higher    expression of IL-1 receptors by the beta cells)

B – Prediction of T2DM by Presence of Inflammatory markers

  • Circulating levels of some inflammatory markers, like fibrinogen, serum albumin, CRP, IL-6, and sialic acid, etc., can be used to predict the development of insulin resistance and type 2 diabetes in adults. (higher levels -> decreased insulin sensitivity, rather than insulin secretion)
  • Decreased levels of adiponectin were found to predict type 2 diabetes in Pima Indians.

C – Atherosclerosis-Inflammation is a Key Component in Its Pathogenesis

  • Elevation of circulating levels of inflammatory markers like CRP, sialic acid, and proinflammatory cytokines.
  • Postprandial hyperglycemia starts an inflammasome activation in the omental fat macrophages -> production of IL-1 beta along with the usual postprandial insulin spike activation of the innate immune system is possibly one of the common preceding steps of both atherosclerosis and type 2 diabetes. (“common soil hypothesis”) this partially explains why atherosclerosis is accelerated in type 2 diabetes.

D – GDM Is Also Associated with an Elevated Inflammatory Response

  • Pregnant women who subsequently develop GDM have a higher CRP in their first trimester than in women who remain euglycemic.
  • Sialic acid (another acute phase reactant) is also higher in women with previous history of GDM.
Linking Diabetes and Immunity Leads to Unique Therapeutic Targets

Negative impacts of T2D on immunological control of viral infection.

Image Credit: Tamara Turk Wensveen et al.Diabetes research and clinical practice. VOLUME 172, 108637, FEBRUARY 01, 2021

Conversely: Anti-inflammatory Agents may Be Useful in Reducing DM

  • Aspirin: Glycosuria in diabetics may be reduced by high doses (not through the classic cyclooxygenase pathway of NSAIDs, but by inhibition of the NF-kB).
  • Also, reverse the insulin resistance found in genetically obese fa/ fa rats.
  • Two weeks’ treatment of T2DM with high-dose aspirin causes a 25% decrease in FPG, a 50% decrease in   TG, and a 15% decrease in CRP concentration, independently of changes in plasma insulin concentration.
  • Statins: Pravastatin therapy resulted in a 30% risk reduction in developing T2DM in the Scotland Coronary Prevention Study.
  • HMG-CoA reductase inhibitors lower the cholesterol, and also reduce CRP levels in post MI patients and in type 2 diabetics.
  • Glitazones: are insulin sensitizers through altered transcription of insulin sensitive genes control lipogenesis, adipocyte differentiation and fatty acid uptake, and GLUT4 expression are anti-inflammatory, inhibit cytokine production and macrophage activation decrease inflammatory markers such as CRP, and WBC count in T2DM.

Probable Pathways of Innate Immunity Activation in Diabetes

A) Genetics

  • Polymorphisms of the TNF-gene promoter, TNF receptor gene, and IL-6 gene are often associated with insulin resistance.
  • Even non-diabetic persons with a F/H of T2DM have CRP levels higher in than in matched controls.
  • Asian type 2 diabetics of Indian origin living in London have a higher incidence of type 2 diabetes than the Caucasian population, & have a higher serum level of sialic acid than the matched cohort.

B) Diet

  • Fat rich diet -> increased IL-6 production in the adipose tissue (hypercytokinemia).
  • Vitamin E in diet, conversely, inhibits production of proinflammatory cytokines, over and above its antioxidant action.

C) Insulin Resistance

  • Activated innate immunity may lead to cytokine-induced insulin resistance and impaired insulin secretion (also, increased capillary permeability and microalbuminuria, dyslipidemia, hypercortisolemia, hypertension, central obesity, and a hypercoagulant state).
  • Insulin itself inhibits the production of acute phase reactants.
  • This insulin resistant state, coupled with insulin deficiency in type 2 diabetes, leads to a vicious cycle of a stronger acute phase response.

D) In-utero Programming

  • Innate immunity is protective by nature, and helps to achieve equilibrium after stress.
  • However, prolonged stimulus may lead to maladaptation, causing disease instead of repair after phase of stress.
  • Thus, after birth stress (LBW, or large for date babies), acute phase agents like cortisol or fibrinogen are often elevated in later life.

E) Stress

  • Psychological stress could possibly increase the risk of diabetes by:
    • Central activation of the HPA axis with counterregulatory hormone release.
    • cytokine-induced insulin resistance.
    • reduced intestinal blood flow, along with increasing intestinal permeability, and increased absorption of lipopolysaccharides (LPS) from the gut, leading to activation of Kupffer cells and increased cytokines. Also, repeated stress causes repeated stimulation of corticosteroid release, causing defective feedback inhibition of steroid secretion.

World has witnessed Diabetes and COVID connection

Linking Diabetes and Immunity Leads to Unique Therapeutic Targets

Image Credit: Tamara Turk Wensveen et al.Diabetes reserch and clinical practice. 2020

  • Viral infection activates a Type-I immune response.
  • It results in the production of cytokines such as TNF, IFNγ and IL-6.
  • These induce transient insulin resistance in muscle and liver.
  • The pancreas compensates IR through increased secretion of insulin, which directly promotes the antiviral immune system. In obesity, cytokine-induced IR can contribute to the formation of IR.
  • Several viruses infect the pancreas, which negatively impacts its ability to produce insulin.
  • This may also contribute to loss of pancreatic β-cell function.

Final Points

Diabetes is a complex disorder which is very closely linked with the immune system

  • Type 1 Diabetes: auto immune beta cell destruction and immune mediated reduction in insulin sensitivity is the core defect (by the inflammatory cytokines, or directly by the cytotoxic T cells.)
  • Type 2 Diabetes: defective function of neutrophils, macrophages and natural killer cells, along with immunosuppression by hyperglycemia.

Future Areas of Research

  • The timeline of appearance of acute-phase markers with insulin resistance during the development of IGT and type 2 diabetes – a causal relationship?
  • Children, esp. with other risk factors and/ or obesity, need to be followed up.
  • Ethnic groups with a high incidence of type 2 diabetes to be researched for the presence, and levels of, inflammatory markers.
  • Conversely, it has to be seen whether these markers can be used to screen the population
  • Whether anti-inflammatory drugs have any role in the management of diabetes
  • To isolate other features of type 2 diabetes which are cytokine induced (like depression, sleep disturbances, fatigue), and see their association with other disease entities of metabolic syndrome, as well as with cytokine levels and insulin resistance.

References:

  1. Immune Dysfunction in Diabetes Mellitus (DM) Vinod Kumar Rajana Junior Research Fellow, Department of Biotechnology, IIT Guwahati, www.ijhsr.org, ISSN: 2249-9571
  2. Hindawi Journal of Diabetes Research, Volume 2018, Article ID 7457269, 9 pages, https://doi.org/10.1155/2018/7457269
  3. Frontiers in Endocrinology , December 2014 | The role of the immune system in the pathogenesis of diabetic complications
  4. Front. Immunol., 24 March 2022 | https://doi.org/10.3389/fimmu.2022.833355
  5. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol Mech Dis 2011; 6(1): 275-97
  6. Type 2 Diabetes and its Impact on the Immune System. Current Diabetes Reviews, 2020, 16, 442 -449
  7. Type 2 diabetes and viral infection; cause and effect of disease.Tamara Turk Wensveen et al.Diabetes reserch and clinical practice. 2020DOI:https://doi.org/10.1016/j.diabres.2020.108637



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