Skip to content

diabetes

Gastroparesis: Diabetes and gastroparesis (Part 3)

Diabetes is one of the most common causes of gastroparesis. 40% of patients with long term diabetes mellitus type I and 20% with diabetes mellitus type II have delayed gastric emptying.   In 1995, 21% patient of gastroparesis patients had DM; in 2004, 26.7%.

Diabetes patients are more likely to have nausea and vomiting as the cardinal GP symptoms, rather than epigastric pain seen more frequently in idiopathic GP.  `Diabetic GP is known to cause more severe gastric retention than idiopathic GP.

Diabetic patients with gastroparesis are at risk for developing difficulty in managing sugar levels.  Poor control of blood sugar can contribute to delayed gastric emptying.  Hyperglycemia is associated with decreased movement of the stomach, an effect more pronounced above 250 mg/dL.  Additionally, some medications used for diabetes, like exenatide for type II diabetes, can delay gastric emptying.  Persistent hyperglycemia is often cited as contributing to vagus nerve damage, which can also result in GP.

In one series, 58% of DM patients had increased tone in the pyloric sphincter, through which food passes from the stomach into the small intestine.  Pyloric tone is often elevated in GP patients.  Botox injections into the pyloric sphincter has been associated with increased gastric emptying and relief of symptoms in diabetic GP patients.

Gastric electric stimulation is more likely to be successful in diabetic patients versus those whose GP is not associated with diabetes, showing 50% reduction in symptoms over those with idiopathic GP.  Patients also experience better glycemic control when GP is more controlled, as reflected by reduction in hemoglobin A1C.

Gastroparesis in diabetes patients is well studied.  Curiously, improving glycemic control is not associated with symptom improvement (or change at all) in patients with type II diabetes.  In type I diabetics, symptom change has only correlated well with depression.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

Gastroparesis: Part 1

Gastroparesis (GP) is a condition in which stomach contents are not emptied into the small intestine within an appropriate time period without an obvious anatomical explanation.  Gastroparesis patients are highly symptomatic, with approximately 90% reporting nausea, 84% vomiting, and abdominal pain, bloating, feeling unable to eat more after a small portion and feeling very “full” after even a small meal.  Some patients can manage their symptoms with dietary changes and medication, while others continue to be significantly symptomatic.

In some people, GP manifests episodically, with no symptoms for periods of time between flares.  In others, symptoms are chronic and perpetual.  Malnutrition, dehydration and weight loss can be severe in some cases.  Despite the primary functional feature of gastroparesis being the delayed emptying of the stomach, the degree to which gastric emptying is slowed correlates poorly with symptoms and severity of symptoms.

Gastroparesis affects at least 37.8 women/100000 persons and 9.6 men/100000 persons.  Once thought to be uncommon, it is now thought that gastroparesis may affect up to 2% of the population.  Hospital admissions for gastroparesis have increased dramatically in the last two decades, with a 158% increase between 1995 and 2004, with 138% of that increase occurring between 2000 and 2004.  There are several possible reasons for this phenomenon, including changes to criteria, better recognition and the withdrawal of cisapride from the market, a medication that alleviated some gastroparesis symptoms.

Gastroparesis is marked by generic gastrointestinal symptoms which can make it hard to identify unless the clinician is familiar with this condition.  Initially, it is often mistaken for functional dyspepsia.  For patients who have distinct episodes rather than continuous symptoms, patients are sometimes misdiagnosed with cyclic vomiting syndrome.

Gastroparesis can occur as a result of a number of diseases or circumstances.  Diabetes and surgery are the most commonly reported causes.  Idiopathic gastroparesis, in which no specific cause can be found, is often the most common in patient groups studied, with up to 1/3 of patients having this type.  Autonomic neuropathy, connective tissue diseases, autoimmune disease, thyroid disease can also cause gastroparesis, among many other conditions.

 

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Diabetes, steroids and hypoglycemia

Following alloxan induction of diabetes, rats overexpress glucocorticoids. This in turn depletes the mast cell populations in the skin, lungs and intestines. Glucocorticoids interfere with production and expression of tissue cytokines and stem cell factor, a growth factor for mast cells.

Several experiments have definitively proven that these steroids are responsible for downregulating mast cell growth and activity. Treating diabetic rats with the steroid receptor blocker RU486 or removing adrenal glands on both sides of the animal causes an increase in intestinal mast cell numbers and IgE formation.

The mechanism by which steroids confer these effects is thought to involve insulin. Glucocorticoids inhibit secretion of insulin in the pancreas. In turn, insulin release decreases systemic glucocorticoids. Additionally, insulin also activates mast cell signaling pathways. In the presence of insulin, antigen induced mast cell degranulation and survival is upregulated. In diabetic rats, administration of insulin recruits mast cells and increases response to antigen. Insulin treatment can reverse the reductions in mast cell populations, histamine production and IgE release seen following alloxan administration.

Increased activity of the HPA axis is often seen in type I and II diabetics, resulting in elevated cortisol. One study showed that appropriate activity can be restored with insulin treatment. This is achieved by a complex mechanism in which expression of glucocorticoid receptor mRNA is elevated in the pituitary, facilitating glucocorticoids to suppress expression of ACTH release.

 

Can hypoglycemia cause mast cell degranulation?

Yes. Activation of histamine 1 and 2 receptors as a result of insulin or hypoglycemia causes release of ACTH. Hypoglycemia (low blood sugar, which can also be induced after administration of insulin) normally increases ACTH levels in the blood. However, higher than normal histamine levels in the blood can interfere with the action of ACTH, which would normally address hypoglycemia via production of glucocorticoids. One study found that this effect can be mostly ameliorated by pretreating with antihistamines, though I suspect in mast cell patients, this may not achieve the full response seen in non-mast cell patients.

 

Can anaphylaxis cause hypoglycemia?

Yes. In instances of severe stress (emotional or physical), corticotropin-releasing hormone (CRH), neurotensin and substance P are released. Among other things, CRH can induce mast cell degranulation (of note, CRH does not directly induce histamine release via degranulation). CRH also causes increased expression of the IgE receptor on mast cells, which increases the likelihood of being stimulated and thus degranulation (this may cause histamine release). In tandem, neurotensin and substance P increases the expression of the CRHR-1 receptor for CRH on mast cells so that they are more sensitive to CRH. Likewise, neurotensin and substance P act on mast cells via receptors to induce degranulation (this causes histamine release). As a result of this degranulation, histamine and other mediators are present to inhibit the action of ACTH, which would otherwise increase blood sugar (via the production of cortisol, epinephrine, and norepinephrine).

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

Diabetes, mast cells and allergic disease

Patients with either type I or II diabetes mellitus demonstrate unusual physiology pertaining to hypersensitivity and mast cell activation. This was first described in 1962, when a paper reported that diabetic animals do not experience anaphylactic shock.   Despite the amount of time that has passed, the reasons for this are still being unraveled.

The role of mast cells in type II diabetes mellitus is more straightforward. When mice are made obese through dietary manipulation, they normally develop glucose intolerance or insulin resistance. If the mice are mast cell deficient, they do not develop these conditions. Transfer of mast cells to mast cel deficient mice was shown to reverse this protection against these complications.

In mice without established type Ii diabetes that were given manipulated diets to induce obesity, treatment with mast cell stabilizers actually prevented the development of type II diabetes. In mice with pre-established type II diabetes, treatment with mast cell stabilizers cromolyn or ketotifen protected against glucose intolerance and insulin resistance. These findings have been replicated in at least one patient, a type II diabetic who had normalized plasma glucose and A1C after six months on cromolyn.

The relationship between mast cells and type I diabetes is far more intricate.   This is mostly understood through a diabetic rat model. It is possible to induce type I diabetes in rats by administering a chemical called alloxan. Triggering diabetes in this way causes a variety of mast cell changes in these animals. The same changes can be seen when causing diabetes via administration of another chemical, streptozotocin.

Diabetic rats have less vascular response to the action of histamine and reduced mast cell degranulation. These animals are resistant to both local and systemic allergic responses, including anaphylaxis.   Mast cell populations become depleted and less likely to activate. When exposed to antigen, diabetic rats have 50% less degranulated mast cells and histamine release compared to non-diabetic controls.

IgE production is also suppressed in diabetic rats, both antigen specific IgE and total IgE. If you transfer mast cells from the spleen and lymph nodes of non-diabetic rats to diabetic rats, IgE production is diminished. Likewise, if mast cells from diabetic rats are transferred into non-diabetic animals, IgE production is restored.

This protection from allergic processes is well established in animals, but also translates to humans. Children with type I diabetes, and their siblings, are less likely to develop asthma. The incidence of bronchial asthma, rhinitis, and atopic dermatitis is lower than predicted in patients with diabetes mellitus.   Risk of death due to anaphylactic shock is significantly reduced in diabetes. This has been attributed to both the depletion of mast cell populations in diabetics, but also to the overproduction of corticosteroids in the body.

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

 

Mast cells and metabolic syndrome: Hypertension, obesity and atherosclerosis

Metabolic syndrome is defined as impaired glucose tolerance (IGT) or type 2 diabetes and/or insulin resistance with two or more of the following findings:

1.       Abdominal obesity, defined as a BMI ≥30; and/or waist to hip ratio >0.90 in men and >0.85 in women
2.       Baseline blood pressure >160/90 mm Hg
3.       Increased plasma triglycerides >1.7 mmol/L; and/or low levels of HDL cholesterol (<0.9 mmol/L in men; <1.0 mmol/L in women
4.       Microalbuminuria (overnight urinary albumin excretion rate > equal to 20 ug/min.)
Inflammation is a known effector of obesity.  Microscopic examination of obese adipose tissue reveals chronic inflammation and excessive amounts of white blood cells, leukocytes.  Macrophages, white cells that are very important in the inflammatory response, are found in adipose tissue in numbers that are directly proportional to the degree of obesity.  T cells, other white cells, also accumulate in adipose tissue. 
Until recently, most of the research on inflammatory cells in adipose tissue focused on macrophages and T cells.  However, we now know that mast cells congregate in larger than normal numbers in white adipose tissue in obese patients.  These patients also demonstrate a higher serum tryptase concentration than in lean individuals.  Mast cells are usually found near microvessels, very small blood vessels, in white adipose tissue.  The number of microvessels correlate with mast cell count in the tissue, implying that a relation between the microvessels and mast cells.
Mast cells release many chemicals, including TNF (tumor necrosis factor.)  TNF is known to mediate insulin resistance, and is overexpressed in white adipose tissue in obese patients.  Treatment with TNF blockers in patients with inflammatory diseases has demonstrated a significant reduction of blood insulin levels as well as the insulin/glucose index.  Several other mast cell mediators contribute to insulin resistance in fat cells, including IL-6, iNOS, MCP-1 and IL-1. 
Research has shown that mast cell stabilizers, cromolyn and ketotifen, can prevent diet induced obesity and diabetes.  In mice, these medications have been able to reverse obesity and diabetes, as well as reducing body weight and glucose intolerance.  These findings have been very exciting for mast cell patients with diabetes.
It is important to know that while metabolic syndrome is usually associated with obesity, patients of normal weight may also be insulin resistant and have metabolic syndrome.
Hypertension (high blood pressure( in mast cell disease is a topic of a lot of recent debate.  In spontaneously hypertensive rats (SHR), the density of cardiac mast cells is significantly higher than normal immediately after birth.  Throughout life, cardiac mast cell density is much higher in these rats than in controls of the same age.  Mast cell chemicals TNF, NF-kB and IL-6 were overexpressed in these rats even before they became hypertensive.  In later stages of hypertension, hearts of these rats showed increased areas of fibrosis in the heart.  These areas of fibrosis were full of activated mast cells.  Expression of two mast cell chemicals, TGF-B1 and bFGF (basic fibroblast growth factor) is much higher than normal in aging and failing hearts in spontaneously hypertensive rats. 
Importantly, mast cell stabilizer nedocromil was able to prevent fibrosis in SHR rats.  Tryptase levels were elevated in SHRs that were not receiving treatment, but returned to normal after treatment with nedocromil.  In untreated SHRs, levels of interferon gamma and IL-4 were elevated, while IL-6 and IL-10 were lower than normal.  All of these levels normalized after treatment with nedocromil.  This medication also prevented macrophage infiltration in the heart ventricle.  This finding indicates that mast cell signaling to macrophages is an important process in fibrosis.
Atherosclerosis is the accumulation of low density lipoprotein (LDL) cholesterol in the arterial wall.  Macrophages eat particles of LDL, and when they do, they turn into weird looking cells called foam cells.  Mast cells often live very close by foam cells, and many researchers think that mast cells help macrophages transform into foam cells. 
When mast cells release chemicals, chymase and carboxypeptidase A are bound to heparin.  After release, these components form insoluble granules called remnants.  When mast cells are activated, LDL uptake by macrophages rises by 7-24X.  Treatment with cromolyn has been shown to block mast cell dependent LDL uptake by macrophages. 
HDL passes from the bloodstream into the arterial wall.  When mast cells degranulate, those remnants degrade HDL components in the blood, peritoneal fluid and maybe also in atherosclerotic lesions.  Mast cell deficient mice have lower serum total cholesterol, triglycerides, phospholipids and a less atherogenic lipoprotein profile in general.
Mast cells are heavily involved in obesity, hypertension and atherosclerosis.  For this reason, many mast cell patients have these problems. 

Reference:

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Metabolic issues associated with MCAS

MCAS patients often have a whole host of metabolic irregularities.  Abnormal levels of electrolytes are very common, as are mild increases in liver function tests, including aspartate transaminase, alanine transaminase and alkaline phosphatase.  Magnesium levels low enough to cause symptoms is not common, although the reason for this is not known.
Vitamin D deficiency is often present in MCAS.  In one study looking at children with asthma, low vitamin D was correlated with decreased lung function and exercise sensitivity.  In MCAS patients, there is no obvious relation to osteoporosis.  Many people receive vitamin D supplements to correct low levels, but it is not clear if there is any benefit to this.

Hypothyroidism (including Hashimoto’s thyroiditis) and elevated levels of TSH are often seen in MCAS patients.  Previous studies have linked hypothyroidism to increased mast cells in bone marrow.  In mice, TSH has shown to increase both the mast cell population in the thyroid and to trigger degranulation.  Hyperthyroidism is sometimes seen in MCAS patients, but much less frequently.  Antithyroid antibodies (TPO) are often high, sometimes extremely high, and sometimes without obvious clinical thyroid disease.

Hyperferritinemia is not unusual in mast cell disease, including MCAS.  18% of ISM patients have high serum levels of ferritin.  It is often misinterpreted as hemochromatosis, even in the absence of the HFE mutation.  MCAS patients with a history of red cell transfusion are often told they have hemosiderosis, even when serum ferritin is much higher than to be expected from hemosiderosis.  High ferritin in MCAS patients is probably secondary to systemic inflammation.  The widely variable nature of the ferritin levels is indicative of inflammation.
MCAS is also associated with obesity and diabetes mellitus (types I and II), all of which are systemic inflammatory conditions.  MCAS patients often have lipid abnormalities.  Hypertriglyceridemia is the most common presentation, but there are many variations.  Lipid issues that have been resistant to treatment with statins are often reversed quickly when MCAS patients are effectively managing their mast cell issues. 
MCAS is also heavily associated with metabolic syndrome.  (There will be a full post on this tomorrow.)

References:
Afrin, Larry B.  Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
A Melander, C Owman, F Sundler.  TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid.  Endocrinology, 89 (1971), pp. 528–533

Siebler T, Robson H, Bromley M, Stevens DA, Shalet SM, Williams GR.  Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.  Bone. 2002 Jan;30(1):259-66.

Chinellato I, Piazza M, Sandri M, Peroni DG, Cardinale F, Piacentini GL, Boner AL.  Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.  Eur Respir J. 2011 Jun;37(6):1366-70. 

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.