Diabetes Mellitus, Type I

Microscopic view of pancreatic islet cells. Courtesy Dr. José Sánchez Gonzales

What Is Type I Diabetes Mellitus?

Type 1 diabetes mellitus (T1DM), also termed type 1A, is an inherited autoimmune disorder in which anti-islet autoantibodies destroy the islet cells of the pancreas that secrete insulin hormone. Type 1 diabetes mellitus was formerly called juvenile diabetes because it usually afflicts persons under the age of 25 years.

Loss of insulin production results in failure to metabolize glucose. Glucose is a simple sugar that is a required source of energy for the body, especially the brain and muscles.

Type 1 diabetes mellitus is characterized by sustained fasting blood glucose levels above 126 mg/dL (hyperglycemia) with subsequent loss of glucose from the body by removal through the urine (glucosuria) as the body attempts to lower blood glucose, and cell starvation that follows.

That is, while glucose accumulates in blood, the body cannot access it. Without insulin treatment, this disorder quickly produces coma and ultimately results in death. In fact, it is 5th leading cause of death in the United States.

Q: How does insulin work?

A: Insulin moves glucose from the bloodstream into body cells where it is used or reformulated for high energy storage. For example, muscles can use glucose for immediate work or store it in the form of glygogen for later work, depending on need. Healthy insulin production keeps an 8 hour fasting blood glucose level to less than 100 mg/dL. Upon eating carbohydrate food, glucose is digested and absorbed from the small intestine into the bloodstream which then raises blood glucose levels. The elevated level is controlled by prompt action of insulin to lower it to below 140 mg/dL  within 2 hours of eating.

Insulin does not work alone. The islets of Langerhans manage glucose in the body. The islets are specialized formations located on the outer surface of the pancreas. The islets are composed of two different types of cells known as alpha and beta cells. These cells make the competing hormones that keep blood glucose within a healthy range.

Alpha cells secrete glucagon to raise blood glucose levels by triggering the body to release stored energy in the form of glycogen. In the opposite, beta cells secrete insulin to lower blood glucose by opening body cells so that glucose in blood can enter. Without insulin, glucose cannot enter cells but remains in the bloodstream where it accumulates.

Insulin is also needed to move magnesium into cells from the bloodstream. On the other side, magnesium is needed to produce insulin. Insulin has other functions such as building muscle and helping regulate cholesterol which directly impacts the sex hormones, estrogen, progesterone, and testosterone.

Onset of symptoms usually occurs over a period of days or weeks, although beta cell destruction can begin years earlier. The SEARCH for Diabetes in Youth multicenter study, funded by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), has determined that based on data from 2002 to 2003, a total of 15,000 youth in the United States were newly diagnosed with type 1 diabetes each year. Non-Hispanic white youth had the highest rate of new cases of type 1 diabetes according to NIH.

Type 1A diabetes mellitus has become one of the most intensively studied autoimmune disorders. It is now possible to predict its development, beginning with HLA-encoded genetic susceptibility, followed by the development of a series of anti-islet autoantibodies.1

What Is Type I Diabetes Mellitus In Celiac Disease and/or Gluten Sensitivity?

• Type 1 diabetes mellitus is an associated immune disorder of celiac disease.
• Patients with type 1A diabetes mellitus and their relatives inherit susceptibility to express multiple autoantibodies including celiac disease.2
• Celiac disease antibodies may be present before, at the same time as, or several years after diagnosis of type I diabetes mellitus. One third of diabetics with the celiac disease associated HLA DQ genotype tested serologically positive for celiac disease compared with greater than 2% of patients lacking DQ2.3
• Other autoimmune disorders are significantly more prevalent in diabetic patients with celiac disease than in those without celiac disease. Newly diagnosed patients showed excellent compliance with gluten free diet.4
• The association between celiac disease and other immune disorders may be due to the sharing of a common genetic background, such as HLA antigens. However, in a very large study, involving 909 patients with celiac disease, Ventura and his associates found that the development of immune disorders in celiac disease was clearly related to the duration of exposure to gluten.5
• A study involving 1000 adult patients with type 1 diabetes mellitus and undetected celiac disease found that these patients have worse glycemic control and a higher prevalence of retinopathy (eye disease) and nephropathy (kidney disease) than matched control subjects. “Improvement of these parameters after 1 year on a gluten free diet is encouraging and similar to that seen in newly diagnosed celiac disease without diabetes.”6

How Prevalent Is Type I DM In Celiac Disease and/or Gluten Sensitivity?

Type I diabetes mellitus in celiac disease. The prevalence of type 1 diabetes mellitus found in patients diagnosed with celiac disease at a hospital endocrinology department was 25%.7

Celiac disease in type I diabetes mellitus.

• Prevalence of celiac disease was 33 per 1,000 subjects (3.3%) in adult patients with type I diabetes mellitus and newly diagnosed celiac disease.8
• Prevalence of silent celiac disease is 5.7% among patients with type 1 diabetes mellitus and 1.9% among their first-degree relatives.9
• Prevalence of celiac disease in children with juvenile diabetes mellitus in Wisconsin is at least 4.6% which is comparable to European and Canadian studies.10

What Are The Symptoms Of Type I Diabetes Mellitus?

Type 1 diabetes mellitus is marked by these symptoms:

• Frequent thirst.
• Frequent urination that lasts more than a day.
• Constant hunger.
• Weight loss.
• Blurred vision.
• Headache.
• Muscle aches.
• Extreme fatigue.

If not diagnosed and treated with insulin, a person with type 1 diabetes can quickly lapse into ketoacidosis. Ketoacidosis occurs when the body uses fat for energy because it cannot access glucose as a fuel source. When fat breaks down, acid waste products called ketones build up in the body and urine. In high levels, ketones are poisonous and may cause life-threatening diabetic coma.

Symptoms of ketoacidosis include:

• Deep, rapid breathing.
• Dry skin and mouth.
• Muscle stiffness or achiness.
• Headache.
• Flushed face.
• Fruity breath odor.
• Nausea or vomiting, inability to keep down fluids.
• Stomach pain11.

Complications include:

• Infections.
• Neuropathy (nerve damage).
• Retinopathy (retina damage) which is a leading cause of adult blindness.
• Blood vessel damage which can lead to hypertension.
• Nephropathy (kidney damage).
• Amputation.
• Heart attack.
• Stroke.

How Does Type I Diabetes Mellitus Develop In Celiac Disease and/or Gluten Sensitivity?

• Type 1 diabetes mellitus results from immune mediated, selective destruction of more than 90% of insulin secreting beta cells, sharing the same high-risk HLA DQ2 genotype as celiac disease.12.
• Genetics is a major factor in developing diabetes, but many people who have inherited the HLA DQ2 genes do not develop the condition. For people who develop diabetes, some trigger has caused the body to attack and destroy beta cells in their pancreas. Gluten appears to be a trigger for type 1 diabetes. Others may include rotaviruses, certain drugs, or some other autoimmune disease such as autoimmune thyroid disease.
• The combination of higher HbA_1c and lower HDL cholesterol, possibly secondary to underlying chronic inflammation, may be the mechanism. Improvement of these parameters after 1 year on a gluten free diet is encouraging and similar to that seen in newly diagnosed celiac disease without diabetes.13
• Magnesium deficiency produces insulin resistance.14

Does Type I Diabetes Mellitus Respond To Gluten-Free Diet?

Yes. While healthy eating, physical activity, and taking insulin are the basic therapies for type 1 diabetes mellitus, gluten free diet improves management of type 1 diabetes mellitus and reduces or eliminates risk of associated diseases.3 HbA_1c and HDL (good) cholesterol improves after 1 year on a gluten free diet.15

6 Steps To Improve Type I Diabetes Mellitus In Celiac Disease and/or Gluten Sensitivity:

• 1Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

• 2 Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

• 3 Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• 4 Manage Your Medications Safely:

• 5Nutritional Supplements To Help Correct Deficiencies:

• 6Manage Natural Remedies: 

What Do Medical Research Studies Tell About Type I Diabetes Mellitus In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies.” This study investigating the reported association between vitamin D deficiency and the risk of developing immune-mediated diseases showed that  patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases including diabetes mellitus, although  reverse causality or confounding cannot  be ruled out.

Researchers analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts.

After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema.18

“Endocrine manifestations of celiac disease.” This study investigating the prevalence of endocrinopathies in 36 patients who were diagnosed with celiac disease at a hospital endocrinology department found type-1 diabetes mellitus in 25% of these patients.

Other conditions found include short stature (58%), delayed puberty (31%), elevated alkaline phospahatase (67%), low calcium (22%), X-rays suggestive of osteomalacia or rickets (8%), carpopedal spasm (6%), and night blindness (6%). Anti-TPO antibody positivity was found in 53%, hypothyroidism in 28%, and subclinical hypothyroidism in 17%. A total of 14% patients had no GI symptoms.7

“High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease.” This case-control study investigating 1000 patients with type 1 diabetes aged older than 16 years who were assessed for celiac disease against matched control subjects found that adults with undetected celiac disease and type 1 diabetes have worse glycemic control and a higher prevalence of retinopathy and nephropathy.

HbA_1c, lipid profile, quality of life, retinopathy stage, nephropathy stage, and degree of neuropathy before and after 1 year on a gluten free diet were assessed in order to better understand the implications of celiac disease in adult patients with type 1 diabetes with respect to diabetes-related outcomes including glycemic control, lipids, microvascular complications, quality of life, and the effect of a gluten-free diet.

In this study, the prevalence of celiac disease was 33 per 1,000 subjects (3.3%). Compared with the population control group, in which the prevalence of celiac disease was 1% (12 of 1,200), there was an increased prevalence of celiac disease in people with type 1 diabetes. At diagnosis of celiac disease, adult type 1 diabetic patients had worse glycemic control (8.2 vs. 7.5%), lower total cholesterol (4.1 vs. 4.9%), lower HDL cholesterol (1.1 vs. 1.6%), and a higher prevalence of retinopathy (58.3 vs. 25), nephropathy (41.6 vs. 4.2%), and peripheral neuropathy (41.6 vs. 16.6%). There was no difference in quality of life. After 1 year on a gluten free diet, only the lipid profile improved overall, but in individuals who adhered to the gluten free diet HbA_1c and markers for nephropathy improved. Treatment with a gluten free diet for 1 year is safe in adults with type 1 diabetes and does not have a negative impact on the quality of life.

Researchers state, “The mechanism by which celiac disease increases the risk of microvascular disease is unclear and is likely to be multifactorial. Unrecognized celiac disease is associated with raised homocysteine levels, which is probably a result of deficiency in folic acid and other B vitamins, which is a risk factor for endothelial dysfunction. In the current study, the combination of higher HbA_1c and lower HDL cholesterol, possibly secondary to underlying chronic inflammation, may be the mechanism. Improvement of these parameters after 1 year on a gluten free diet is encouraging and similar to that seen in newly diagnosed celiac disease without diabetes.”13

“Celiac disease in adult patients with type 1 diabetes mellitus in Tunisia.” This study confirmed that celiac disease is prevalent in adults with type 1 diabetes mellitus in Tunisia and serological screening for celiac disease in type 1 diabetes mellitus is important because many patients are asymptomatic and most are detected by the screening.19

“Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.” This study evaluating the role of autoantibody tests for autoimmune diseases in children with newly diagnosed type 1 diabetes mellitus demonstrated that the most accurate test for celiac disease is the IgA anti-endomysium. The IGA tissue transglutaminase is accurate for screening.20

“Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: clinical and genetic characteristics.” This observational study investigating clinical and genetic characteristics of 118 patients with both celiac disease and adult type 1 diabetes mellitus diagnoses so as to lead to better detection of celiac disease in adult patients with T1 diabetes mellitus found that a delay of celiac disease diagnosis is frequently found in adult type 1 diabetes mellitus patients.

Researchers retrospectively collected data on sex distribution, age of onset of type 1 diabetes mellitus, age of celiac disease diagnosis, celiac disease complaints, duration of celiac disease complaints before celiac disease diagnosis, family history of celiac disease or type 1 diabetes mellitus, comorbidity and HLA-DQ type. Results show that thirty-three percent of type 1 diabetes mellitus + celiac disease patients reported celiac disease related complaints for at least 5 years before celiac disease diagnosis. Two peaks in the age of celiac disease diagnosis in T1 diabetes mellitus patients were observed: around 10 and 45 years of age. Women were diagnosed with celiac disease at a younger age than men (median 25 years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). This observational study emphasises that more frequent screening for celiac disease in particularly adult T1 diabetes mellitus patients is required, preferably by a 5 years interval.21

“Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type 1 diabetes mellitus.” This study investigating silent celiac disease in type 1 diabetes mellitus confirmed high prevalence of undiagnosed celiac disease among diabetic patients and their relatives and that other autoimmune disorders are significantly more prevalent in diabetic patients with celiac disease than in those without celiac disease. Newly diagnosed patients showed excellent compliance with gluten free diet.4

“Magnesium deficiency produces insulin resistance and increased thromboxane synthesis.“ This study investigating the effects of a magnesium infusion and dietary-induced isolated magnesium deficiency on the production of thromboxane and on angiotensin II-mediated aldosterone synthesis in normal human subjects found that magnesium deficiency may be a common factor associated with insulin resistance and vascular disease.

Because insulin resistance may be associated with altered blood pressure, researchers also measured insulin sensitivity using an intravenous glucose tolerance test with minimal model analysis in six subjects. The magnesium infusion reduced urinary thromboxane concentration and angiotensin II-induced plasma aldosterone levels.

The low magnesium diet reduced both serum magnesium and intracellular free magnesium in red blood cells as determined by nuclear magnetic resonance (186 +/- 10 [SEM] to 127 +/- 9 mM, p < 0.01). Urinary thromboxane concentration measured by radioimmunoassay increased after magnesium deficiency. Similarly, angiotensin II-induced plasma aldosterone concentration increased after magnesium deficiency. Analysis showed that all subjects studied had a decrease in insulin sensitivity after magnesium deficiency (3.69 +/- 0.6 to 2.75 +/- 0.5 min-1 per microunit per milliliter x 10(-4), p < 0.03). We conclude that dietary-induced magnesium deficiency 1) increases thromboxane urinary concentration and 2) enhances angiotensin-induced aldosterone synthesis.22

CASE REPORT SUMMARIES

“Celiac crisis in an adult type 1 diabetes mellitus patient: a rare manifestation of celiac disease.” This case report describes celiac crisis, an acute severe onset of celiac disease, is a rare and life-threatening manifestation, in a 30-year-old woman with type 1 diabetes mellitus with one-month history of severe acute watery diarrhea associated with nausea, vomiting, abdominal pain, and weight loss of 9 kg. The diagnostic hypothesis of celiac crisis was reached based on profuse diarrhea leading to dehydration, severe metabolic and electrolyte abnormalities, and subsequent improvement after introduction of a gluten-free diet.23

“Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus.” This case report describes the effect of a gluten free diet in a 5-year and 10-month old boy who was diagnosed with classical type 1 diabetes mellitus (T1DM) without celiac disease. He started on a gluten-free diet after 2-3 week without need of insulin treatment. At the initiation of gluten-free diet, HbA1c was 7.8% and was stabilised at 5.8%-6.0% without insulin therapy. Fasting blood glucose was maintained at 4.0-5.0 mmol/l. At 16 months after diagnosis the fasting blood glucose was 4.1 mmol/l and after 20 months he is still without daily insulin therapy. There was no alteration in glutamic acid decarboxylase positivity. The gluten-free diet was safe and without side effects. The authors propose that the gluten-free diet has prolonged remission in this patient with type 1 diabetes mellitus and that further trials are indicated.24

1. Liu E, Eisenbarth GS. Type 1A diabetes mellitus-associated autoimmunity. Endocrinology and Metabolism Clinics of North America. Jun 2002;31(2):391-410, vii-viii. [↩]
2. Liu E, Eisenbarth GS. Type 1A diabetes mellitus-associated autoimmunity. Endocrinology and Metabolism Clinics of North America. Jun 2002;31(2):391-410, vii-viii. [↩]
3. Book LS. Diagnosing celiac disease in 2002: who, why, and how? Pediatrics. May 2002;109(5):952,3p. [↩] [↩]
4. Not T, Tommasini A, Tonini G, et al. Undiagnosed doeliac disease and risk of autoimmune disorders in subjects with Type 1 diabetes mellitus. Diabetologia. Feb 2001;44(2):151-5. [↩] [↩]
5. La Villa G, Pantaleo P, Tarquini R, Cirami L, Perfetto F, Mancuso F, Laffi G. Multiple immune disorders in unrecognized celiac disease: a case report. World J Gastroenterol. 2003;9(6):1377-1380, Available at: http://www.wjgnet.com/1007-9327/9/1377.asp. Accessed Jan 3, 2005. [↩]
6. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care. 2011 Oct;34(10):2158-63. doi: 10.2337/dc11-0149. Epub 2011 Sep 12. [↩]
7. Philip R, Patidar P, Saran S, Agarwal P, Gupta K. Endocrine manifestations of celiac disease. Indian J Endocrinol Metab. 2012 December; 16(Suppl 2): S506–S508. [↩] [↩]
8. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care. 2011 Oct;34(10):2158-63. doi: 10.2337/dc11-0149. Epub  2011 Sep 12. [↩]
9. Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type 1 diabetes mellitus. Diabetologia. Feb 2001;44(2):151-5. [↩]
10. Aktay AN, Lee PC, Kumar V, Parton E, Wyatt DT, Werlin SL. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. Journal of Pediatric Gastroenterology and Nutrition. Oct 2001;33(4):462-5. [↩]
11. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001363/ [↩]
12. Book LS. Diagnosing celiac disease in 2002: who, why, and how? Pediatrics. May 2002;109(5):952,3p [↩]
13. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newlydiagnosed celiac disease. Diabetes Care. 2011 Oct;34(10):2158-63. doi: 10.2337/dc11-0149. [↩] [↩]
14. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 1993 Jun;21(6 Pt 2):1024-9. [↩]
15. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newlydiagnosed celiac disease. Diabetes Care. 2011 Oct;34(10):2158-63. doi: 10.2337/dc11-0149. Epub 2011 Sep 12. [↩]
16. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
17. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩] [↩]
18. Ramagopalan SV, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies. BMC Med. 2013 Jul 25;11:171. doi: 10.1186/1741-7015-11-171. [↩]
19. Bouguerra R, Salem B, Chaabouni H, et al. Celiac disease in adult patients with type 1 diabetes mellitus in Tunisia. Diabetes and Metabolism. Feb 2005;31(1):83-6. [↩]
20. Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus. Health Technology Assessment: HTA. Jun 2004;8(22):iii-xi,1-183. [↩]
21. Bakker SF, Tushuizen ME, Stokvis-Brantsma WH, Aanstoot HJ, Winterdijk P, van Setten PA, von Blomberg BM, Mulder CJ, Simsek S. Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: clinical and genetic characteristics. Eur J Intern Med. 2013 Jul;24(5):456-60. doi: 10.1016/j.ejim.2013.01.016. Epub 2013 Feb 12. [↩]
22. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 1993 Jun;21(6 Pt 2):1024-9. [↩]
23. Toyoshima MT, Queiroz MS, Silva ME, Corrêa-Giannella ML, Nery M. Celiac crisis in an adult type 1 diabetes mellitus patient: a rare manifestation of celiac disease. Arq Bras Endocrinol Metabol. 2013 Nov;57(8):650-2. [↩]
24. Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012. pii: bcr0220125878. doi: 10.1136/bcr.02.2012.5878. [↩]