Advanced Biochem 1: The Genetics of Diabetes

normal blood glucose levels

Fasting glucose: < 100 mg/dl

2-hour postprandial glucose (2-h PG): < 140 mg/dl

A1C: < 5.7%

pre-diabetes glucose levels

Fasting glucose: impaired, ≥ 100 - 125 mg/dl

2-hour postprandial glucose (2-h PG): impaired glucose tolerance, ≥ 140 - 199 mg/dl

A1C: 5.7% - 6.4%

diabetes glucose levels

Fasting glucose: ≥ 126 mg/dl

2-hour postprandial glucose (2-h PG): ≥ 200 mg/dl

Random PG: ≥ 200 + symptoms

A1C: ≥ 6.5%

Pathogenesis of Type 1 Diabetes Mellitus (T1DM)

Autoimmune disease (not metabolic)

• Slowly progressive disease - takes months to years

• Most common presentation is absolute insulin deficiency

→ Diabetic Ketoacidosis (DKA)

includes:

1. Autoimmune destruction of the pancreatic Beta cells

2. T cell mediated

3. Auto-antibodies bind the cellular proteins

T1DM: Autoimmune destruction of the pancreatic Beta cells

- takes months to years

- insulinitis from lymphocytic infiltration

- destruction of insulin granules

- cannot produce insulin → hyperglycemia

- 90% of β-cells are not functioning at the time of classic diagnosis

T1DM: T cell mediated

- cell invasion and apoptosis

- CD3 regulatory T cells

- CD8 natural killer T cells

- CD4 B cells

Diabetic Ketoacidosis (DKA)

body begins to break itself down to use ketones as an energy source

- because cells can no longer use the sugar in blood for energy and utilizes fats instead

- the process of burning fat produces ketones, which builds up in blood

Incidence of T1D

Dramatically Increasing Worldwide

- Projected increase in T1D in US from 1.7 in 2020 to 5 million by 2050

Other Laboratory Findings for T1D

Measurable autoimmune activity

• Glutamic acid decarboxylase autoantibodies (GADA)

• Insulin autoantibodies (IAA)

• Insulinoma-associated antigen-2 autoantibodies (IA-2A)

• Zinc transporter 8 autoantibodies (ZnT8A)

Evidence of insulinopenia

• C-peptide with normal to high glucose

→ endogenous insulin

• Low or undetectable levels indicate little or no insulin secretion

Pathogenesis of T1DM-A

Genetics of T1DM

MHC Susceptibility Genes

- Increased Risk of T1DM

- HLA DR3 & DR4 (most closely linked)

SNPs: Single Nucleotide Polymorphisms & T1DM

common type of genetic variation

- relative risk of getting T1DM can be assessed based on type of SNPs

- more susceptible to environmental triggers

- HLA Class II has the highest relative risk for autoimmunity

Functions of the SNP's Linked to Risk for T1DM

Familial Patterns in T1DM

• >90% of people with T1DM do not have a family history

• Spontaneous risk 0.4%

T1D Risk in Individuals Who Have an Affected Relative

Types of T1DM

Type 1A

Type IB

Latent Autoimmune Diabetes of Adults (LADA)

T1DM: Type 1A

presents with classic signs and symptoms of insulin deficiency

- Autoimmune response: markers of autoimmunity - GAD or ICA ATB

- Most common

T1DM: Type 1B

presents with classic signs and symptoms of insulin deficiency

- No autoimmune response no markers present

- Zinc transporter ATB are present

T1DM: LADA

slowly progressive T1DM

- Adult form of type 1

- affects people between 35-50

- Less likely to present initially with DKA

Patterns of ICA Antibody Titers Detected Over Time in the DAISY Study

Environmental triggers of T1DM

o Viruses - most common

- enteroviruses

o Timing of immunizations

o Peri-natal factors

- lack of passing on immune protection

o Cow's milk

o Environmental toxins

o Gut microbiome

Evidence for a Viral Etiology in Pathogenesis of T1DM

• Viral-specific antibodies are present in serum in patients with new-onset T1DM

• Enteroviral RNA has been isolated from pancreatic islets of patients with new-onset T1DM

• Children with congenital rubella developed T1DM within first 5 years of life

• Cytomegalovirus (CMV) outbreaks have been associated with clusters of subsequent T1DM

• Mice inoculated with CMVB4 (obtained from a young patient with new-onset T1DM).... developed the disease

Type IA stages

Stage 1 – Initiation of autoimmune response

- Environmental Trigger (virus)

- Detection of circulating autoantibodies (ICA, GAD65, IAA, IAA-2)

- Progressive loss of beta-cell mass induced by CD4+ & CD8+ cells

Stage 2 – persistent autoimmune response

- Glucose intolerance

Stage 3 – decreased β-cells

- clinical presentation of T1DM

- < 15-20 % of β-cells are “functional” remain

- Hyperglycemia

- Symptoms

- Insulin initiation

- Diabetes by standard criteria

Most Prevention Trials Focus on Individuals With?

≥2 Autoantibodies Endpoint → Development Stage 3 T1D

Summary of T1DM

Autoimmune

• Need both genetic risk by HLA typing and environmental exposure

• Then sustained immune response

• We can screen by genotype and by antibody presence

• Neither is predictive enough

• We have not yet found a reasonable way to stop immune mediated Beta cell destruction

USA Regional Screening Programs

Nationally Available Screening Programs

TrialNet

- T1D research-based screening and clinical trial program for individuals who have a higher risk of developing T1D based on family history or previous autoantibody testing

T1Detect

- Initiative to increase awareness and education about screening for risk of T1Din the T1D and healthcare provider communities and to provide the general population with access to in-home T1D risk screening

Latent Autoimmune Diabetes of Adults (LADA)

− Do not show insulin resistance

− Lack of diabetes dyslipidemia

− Have carbohydrate intolerance

− Have the polys and weight loss

− Do not have a family history of LADA or insulin resistance

o Personal history of autoimmunity

o Family history of autoimmunity

When to suspect LADA

- New T1DM diagnosis age 30-50

- No FH or T2DM or insulin resistance

- Personal or FH of autoimmune disorders

- BMI < 25

- Lack of diabetes dyslipidemia

- Previous episode of the "polys" and weight loss

- Carb intolerance

Screening tool for LADA

5 Key Features:

• Age Dx less than 50

• Classic poly symptoms

• BMI < 25

• Personal history of autoimmunity

• Family history of autoimmunity

- If person have more than 2 above: 90% sensitivity, 71% specificity

- If they have 1 or zero: 99% negative predictive value against LADA

Comparing T1, T2, LADA

Diabetes in the US

1. 37.3 million Americans with diabetes (11.3%)

- 90% have type 2 diabetes

- >1-2 million more per year

2. Estimated 25% of adults > 60 y/o have DM

3. Children can have type 2

- Rates as high as 40%

- PreDM in as many as 25% of adolescence

4. 1 in 5 US health care dollars spent on person with DM

PRE-Diabetes in the US

1. 100 million Americans have pre-DM (37%)

• 85% do not know they have it

2. CA– 55% of adults have DM or pre-DM

3. CDC predicts people born in 2000

• 1 in 3 will develop DM

• 40% risk in at risk populations

• 50% or 1 in 2 in Hispanic population

Type 2 Diabetes Mellitus (T2DM)

− Metabolic disease characterized by insulin resistance

− Individuals secrete insulin but cannot use it by cells → this is termed insulin resistance

Insulin resistance can be induced by?

a number of factors:

- increased weight

- increase caloric intake

- increased sedentary lifestyle

Natural History of Type 2 Diabetes

1. The pancreas compensates by producing more and more insulin in order to bring glucose into the cells

- however, sugar continues to build up in the blood

2. T2DM takes a long time to develop

- most of the time patient is unaware due to it being asymptomatic

3. Increased in insulin resistance leads to compensatory increases in circulating insulin

- prevents glucose levels from being too high

4. As time goes on, insulin resistance reaches a peak and plateaus

- compensatory release of insulin continues to prevent fasting glucose levels from being too high

5. β-cells reaches capacity and as the fasting glucose level remain normal, post-meal glucose level rises

- Insulin cannot keep up with β-cell dysfunction and both fasting and post-meal glucose levels rose over time.

Multiple metabolic defects for T2DM

1. Decreased insulin secretion

o Decreased sensitivity and years of resistance

2. Increased glucagon secretion

o Increased gluconeogenesis → hyperglycemia

3. Increased hepatic glucose production

o Liver makes glucose at night when fasting die to inability to detect glucose

4. Neurotransmitter dysfunction

o Either never satisfied or always satiated

5. Decrease glucose uptake

o Increase glucose in blood → hyperglycemia

6. Increase glucose reabsorption

7. Increase lipolysis

8. Decreased incretin effects

Type 2 Diabetes Genetics and Inheritance

1. Medically complex disorder

• >100 genetic alleles tied to T2DM

• 8+ Pathophysiologic mechanisms

2. Family History is a strong RF

• Risk T2DM is

• 1 in 7 if a parent dx before 50 years

• 1 in 13 if parent dx after age 50

• 1 in 2 if both parents have T2DM

3. Most people likely have pre-existing pre-diabetes

• Approximately 11%/ year progress

• 70% will progress over a lifetime

Who Should Be Tested for T2DM?

Any patient with BMI ≥ 25 and a risk factor:

• Physical inactivity

• First-degree relative with DM

• High-risk race/ethnicity: African American, Latino, Native American, Asian American, Pacific Islander

• History of Gestational Diabetes

• Hypertension

• HDL < 35 or Triglycerides > 250

• History of Polycystic Ovarian Syndrome (PCOS)

• HgbA1c ≥ 5.7 or fasting glucose > 100

• Acanthosis nigricans

• History of CVD

Who Should Be Tested for T2DM? No Risk Factors + Normal BMI

• Begin testing at age 35

• Repeat testing every 3 years if normal

• Annually if pre-diabetes

US Preventive Services Task Force:

• Screen asymptomatic patient for DM if BP > 135/80

Diabetes Prevention Program

1. NIH Diabetes Prevention Program (DPP) Study

2. Nationwide clinical study

• 3000 adults at high risk for developing T2DM across 27 different centers

3. Intervention methods

• Routine care

• Metformin (titrated gradually)

• Lifestyle intervention:

- Reduction in fat & calorie intake

- Physical activity of 150 minutes per week (minimum)

- Weight loss of ≥ 7% body weight and maintained of weight loss

Interventions and Reduced Risk of T2DM

Prevention of T2D: Selected Lifestyle Modification Trials

T2D Clinical Presentation

Most often asymptomatic

• Found at routine testing

• Found at time of diagnosis of complication

• Found at other medical care

T2D Symptoms

not specific

• Tiredness

• Blurred vision

• Headaches

- "polys" and weight loss represent decompensation from long term abnormalities

Monogenic diabetes of young (MODY)

characterized by:

- non-insulin dependent diabetes diagnosed at a young age (<25 yrs)

- lack of autoantibodies

- Phenotypically, people with MODY appear like T1DM patients

- Clinically heterogeneous disorder

MODY Inheritance

Clinically heterogeneous disorder:

- autosomal dominant transmission

- Not metabolic abnormality or autoimmune

- Very strong family history is expected

- Caused by a single genetic abnormality:

o Impaired glucose sensing

o Impaired insulin secretion with minimal or defect in insulin action

o defect in the way insulin is packaged, made, or secreted

MODY Treatment

includes a drug that forces insulin to be secreted more quickly

- they do not need to be given insulin

MODY - form of monogenic diabetes

1. 500,000 in US (compared to 2 million T1DM)

2. Autosomal Dominant

- Each child of a parent with MODY has 50% chance of inheriting the disease

3. Collection of β-cell defects from gene mutations

- Genes control β-cell development, function and regulation

- Mutation in genes → impaired glucose sensing, insulin secretion with minimal or defect in insulin action

Monogenic Diabetes Pathogenesis

Pancreatic beta cell: coupling of:

- glucose sensing via GLUT-2 transporters

- generation of ATP

- membrane depolarization by closing potassium channels

- entering of calcium ions

- exocytosis of insulin

Location in the pancreatic beta cell of the:

1. gene mutations

2. affected proteins

- MODY(red)

- mitochondrial diabetes (blue)

- neonatal diabetes (green)

MODY Diagnosis

Diagnosis most often made by history

• Age is less predictive

• Can present early in life

• Can be missed till middle age

Genetic testing possible

• Clinical testing

• Research testing

MODY 3

Most common form 50-60%

• HNF Alpha defect

• Post prandial hyperglycemia

Treatment: low dose sulfonylurea

MODY 2

15 – 31%

• Glucokinase defect

• Mild, stable fasting hyperglycemia

• Not progressive, often diagnosed on routine screening

Treatment: diet (low carb)

MODY 1

Less common 10%

• Defective gene HNF-4

• High post prandial blood glucose is most commonly seen

Treatment: typically responds to SU

MODY 5

• Early diabetes +/- renal disease (cysts)

• HNF-1-β defect

MODY 8

Exocrine pancreatic insufficiency

Other Types of MODY

- MODY 4 (IPF 1)

- MODY 6 (NERUOD1)

- MODY 7 (KLF 11)

- MODY9 (PAX4)

- MODY 11(BLK) - very rare

Comparing Types of Diabetes

Other diabetes mellitus types

• Ketosis prone diabetes

• Secondary Diabetes

- (type 3c or pancreatogenic)

- Steroid induced

• Type 5 Diabetes mellitus