Download Type 1 diabetes mellitus

TYPE 1 DIABETES MELLITUS
R A C H E L S TA H L
CHARACTERISTICS OF DIABETES TYPE 11
• autoimmunity against pancreatic β-cells
• T-cell mediated2
• loss of β-cells
• insulin deficiency
FUNCTIONS OF THE PANCREAS
• Exocrine3 –digestion
• Endocrine3 –glucose regulation
• Islets of Langerhans
• α-cell - glucagon
• β-cell - insulin
• δ-cell – somatostatin
Picture from: Lehninger Principles of Biochemistry
T1D DIFFERS FROM T2D IN:
• Time of onset4
• Target cell effect4
• Role of insulin4
• Associated genes4
• Diagnostic tests5
Picture from: Lehninger Principles of Biochemistry
EPIDEMIOLOGY OF T1D6
• Rising in industrialized areas
• Accounts for 7-12% of diabetic cases
• Affects ~29-50 million people worldwide (out of 300
million with DM overall)
• Affects ~1 million in US
• Most common metabolic children’s disease: 1 in ~500
• Patients with T1D have higher risk of cardiovascular
disease, renal disease, and heart attacks
STAGES OF DIABETES DEFINED BY AMOUNT
OF BETA CELLS AND BLOOD GLUCOSE7
Picture from Simmons et al.
Note: by the time symptoms are visible, ~80% of β-cells are destroyed
SYMPTOMS OF T1D ARE
DUE TO DYSGLYCEMIA8
• 4 T’s of diagnosis
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1. Toilet (excessive urination)
2. Thirsty
3. Tired
4. Thinner (weight loss)
• Diabetic ketoacidosis
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High glucose
Ketone production
Leading cause of mortality/ morbidity in T1D patients
Symptoms: Vomiting, Abdominal pain, Reduced consciousness
GENETIC AND GEOGRAPHIC FACTORS
LEAD TO T1D SUSCEPTIBILITY
• Genetic Factors1
• Immune-focused - HLA complex
• Hygiene hypothesis4
• Geographic Location1
• Industrialized countries
• Environment over genetics
T CELL AUTOIMMUNITY RESULT FROM
MULTIPLE FACTORS2
• Viral infections (e.g. mumps, congenital rubella,
coxsackievirus)
• T-cell response – more aggressive against islet cell
antigens
• Th1/ Th2 imbalance – Inflammatory response
• FasLigand expression – apoptosis
Picture from:
http://viviennebalonwu.tumblr.com/post/117643407703/rubella-
GLUTAMIC ACID DECARBOXYLASE IS
ONE AUTOANTIGEN OF TYPE 1 DIABETES
• Neurons and δ-cells make GABA9
• In pancreas, cleaved into peptides10
• Peptides presented on APC10
• T cell Activation10
picture from 11Boehmer and Sarukham
Picture from http://www.nara-wu.ac.jp/life/health/ueno/_src/sc516/gad_reaction.jpg
TYROSINE PHOSPHATASE IS ANOTHER
AUTOANTIGEN IN T1D11
• Islet cell Antigen (IA)-2 / IA-2β
• transmembrane protein
• Neurons, endocrine cells
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Highly conserved
IA-2 – secretory response
IA-2β – Islet development
Both - Insulin expression
Pictures from: Torii11
T1D PATIENTS HAVE INCREASED
ANTIBODIES AGAINST BOTH IA-2 AND
GAD12
SELF-MANAGEMENT EDUCATION
RECOMMENDED EARLY IN DIAGNOSIS13
• Glucose monitoring and Insulin injections
• Adolescence provides challenges to proper care
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Time constraints
Fear – self-injection
Peer pressure
Discipline
Picture from https://www.drugs.com/cg/how-to-give-aninsulin-injection.html
Picture from http://www.healthable.org/the-evolution-of-the-insulin-pump/
Β-CELL REPLACEMENT AS A NEW
TREATMENT TYPE14
• Turn Progenitor cells into β-cells
• Considerations:
• Viability of cells
• Increased tumor formation
• Access to blood vessels
• Sources of cells:
• Pluripotent from somatic
• Multipotent from bone marrow
• Non-β-endocrine cells (e.g. α to β)
Picture from Vieira et al.15
REFERENCES
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1 Needell
JC, Zipris D. 2016. The Role of the Intestinal Microbiome in Type 1 Diabetes Pathogenesis.
Current Diabetes Reports 16: doi: 10.1007/S11892-016-0781-2
2 Devendra D, Liu E, Eisenbarth GS. 2004. Type 1 diabetes: recent developments. British Medical Journal
328: 750-754.
3Nelson DL, Cox MM. 2013. Principles of Biochemistry. New York (NY): W. H. Freeman and Co; 1340p.
4Paun A, Danska JS. 2016. Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome.
Pediatric Diabetes 17: 469-477
5Turner J. 2016. Common Diabetes Dilemmas. Pulse: 70-75.
6Leung SS, Forbes JM, Borg DJ. 2016. Receptor for Advanced Glycation end Products (RAGE) in type 1
Diabetes Pathogenesis. Current Diabetes Reports 16: doi: 10.1007/S11892-016-0782-y
7Simmons KM, Gottlieb PA, Michels AW. 2016. Immune Intervention and Preservation of Pancreatic Beta
Cell Function in Type 1 Diabetes. Current Diabetes Report 16: doi: 10.1007/S1 1892-016-0739-8.
8Dowling L. 2013. The 4 ‘Ts’ – aiding prompt diagnosis of Type 1 diabetes in children. Practice Nurse 43:
18-21.
9Franklin IK, Wollheim CB. 2004. GABA in the Endocrine Pancreas: Its Putative Role as an Islet Cell
Paracrine-Signalling Molecule. The Journal of General Physiology 123: 185–190.
10Boehmer H, Sarukhan A. 1999. GAD, a Single Autoantigen for Diabetes. Science 284: 1135-1137
11Torii S. 2009. Expression and Function of 1A-2 Family Proteins, Unique Neuroendocrine-specific
Protein-tyrosine phosphatases. Endocrine Journal 56: 639-648.
12Borg H, Fernlund P, Sundkvist G. 1997. Protein tyrosine phosphatase-like protein IA2-antibodies plus
glutamic acid decarboxylase 65 antibodies (GADA) indicates autoimmunity as frequently as islet cell
antibodies assay in children with recently diagnosed diabetes mellitus. Clinical Chemistry 43: 2358-2363.
13Abualula NA, Jacobsen KH, Milligan RA, Rodan MF, Conn VS. 2016. Evaluating Diabetes: Educational
Interventions With a Skill Development Component in Adolescents With Type 1 Diabetes. The Diabetes
EDUCATOR 42: 515-528.
14Vieira A, Courtney M, Druelle N, Avolio F, Napolitano T, Hadzic B, Navarro-Sanz S, Ben-Othman N,
Collombat P. 2016. β-cell replacement as a treatment for type 1 diabetes: an overview of possible cell
sources and current axes of research. Diabetes, Obesity and Metabolism 18: 137-143.
SHORT ESSAY
1.The 4 T’s of T1D are Tired (lethargy), Thirsty
(dehydration), Toilet (urination), and Thinner (weight
loss). Explain why each of these symptoms occur in
diabetic patients, focusing on the role of insulin and how
body processes are altered when it is no longer produced.
MC QUESTIONS
1. What are the characteristics of Stage 2 Diabetes?
1.
2.
3.
4.
Increased urination and weight loss with hyperglycemia
Presence of islet autoimmunity, asymptomatic, and normal blood glucose levels
Human Leukocyte Antigen genes identifiable with normal levels of β-cells
Dysglycemia, antibodies against islet cell antigens present but no symptoms visible
2. Which is not true of IA-2β?
1.
2.
3.
4.
It is a transmembrane protein found in both endocrine and neuronal cells
Functions include secretion responses, islet development, and insulin expression
Antibodies against IA-2β can be detected as early as stage 1 Diabetes
Along with GAD, it is an autoantigen that is attacked by T-cells in T1D
3. What is the function of the β-cell?
1.
2.
3.
4.
Secrete insulin and somatostatin in response to low levels of glucose
Participates in the exocrine response by secreting digestive enzymes in response to food intake
In the endocrine response, secretes insulin in order to promote uptake of glucose from the blood
Regulates immune response to insulin by deactivating B cells
4. T1D and T2D differ in all these ways except?
1. T1D arises predominantly in early life, and T2D arises predominantly in adulthood
2. T2D is caused by environmental factors, but T1D is determined only by genetics
3. T1D is diagnosed by high levels of islet cell antibodies, whereas T2D results in high C-peptide
concentration
4. T2D-associated genes control cell cycle regulation; T1D-associated genes control immune response