Metabolism 2 –Type 1 and gestational diabetes, and metabolic syndrome Flashcards
What is Type 1 Diabetes
- T1D also known as autoimmune diabetes
- Previously juvenile diabetes, or insulin-dependent diabetes mellitus (IDDM)
- Polygenic disease
- Insulin hyposecretion: deficiency in insulin secretion owing to loss of pancreatic beta-islet cells
What is the difference between type 1a and type 1b diabetes
- Type 1a in most cases (70-90%): beta-cell loss consequence of T1D-related autoimmunity characterised by formation and detection of T1D associated autoantibodies
- Type 1b in rarer cases: Cause of beta-cell loss is unknown and autoantibodies are not detected. Often genetically linked.
Type 1 diabetes pathophysiology
beta-cell death can be driven by
- beta-cell autoimmunity
- Increased islet amyloid deposition
- Inflammatory cytokine signalling
- Endoplasmic reticulum stress
- Oxidative stress
- Elevated FFA and/or glucose concentrations
Explain Type 1beta-cell autoimmunity
Interactions between T and B cells (lymphocytes) trigger the production of islet-targeting autoimmune antibodies
- Activated B cells interact with CD4+and CD8+T lymphocytes as well as dendritic cells (DCs).
-Antigen presentation by B cells and DCs drives the activation of β-cell-specific (targeting) T cells.
- Additionally, exposure of B cells to β-cell autoantigens drives production of islet-targeting autoantibodies
- β-cell damage and destruction via activated CD4+ /CD8+ T cells and autoantibodies
- Autoantibodies classically target insulin, glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2) or zinc transporters (ZNT8)
What are some contributing factors for Type 1 Diabetes
- Carrying specific HLA genotypes HLA-DR and HLA-DQ (encode Major Histocompatibility Complex or MHC proteins). Major genetic risk if carrying HLA-DR3-DQ2 and HLA-DR4-DQ8 genetic variants
- Genome-wide association studies have also identified >50 non-HLA linked genetic variations that contribute to T1D risk.
- HLA class II and INS polymorphisms are suggested to influence immune tolerance processes
- Genetic risks are necessary but not sufficient for disease, environmental influences
- Various environmental factors influence development of T1D including: viral infections, timing of first introduction of foods (breast v cows milk), gestational events including gestational infections, and toxins (N-nitroso derivatives)
- NOTE T2D is not a risk factor for developing T1D
What are Major Histocompatibility Complex (MHC)
- HLA genes encode proteins in the Major Histocompatibility Complex (MHC)
‒ MHCs are cell surface proteins essential for adaptive immunity
‒ MHCs mediate interactions with leukocytes by presenting antigenic peptides
‒ Prevents the immune system from targeting its own cells (provides tolerance)
‒ 2 classes of MHCs that are expressed in different cell types and interact with different T-leukocytes
‒ Variations in MHC proteins can alter the adaptive immune response
What is the TD1 Disease progression
Progression from presymptomatic to symptomatic T1D is associated with the number of different autoantibodies detected and the age of seroconversion (the earliest age of detecting a particular antibody)
- Those with more autoimmune antibodies have a higher risk of reaching symptomatic disease
How do we manage T1D
- Treatment aimed to promote healthy living and glycaemic control in order to prevent severe hypoglycaemia, severe hyperglycaemia and ketoacidosis
Consensus target for T1D patients for HbA1c <7.5% (relative to healthy range of <5.7%) - Treatment involves insulin injections multiple times/day or insulin pump. Glucose levels continually monitored (before meals/exercise) via blood glucose monitor or continuous glucose monitor
- Insulin analogues with either short- or long-acting potential are also used
- Immunotherapies which prevent or delay beta-cell loss have been trailed since 1976, but yet to be successful
- Pancreatic transplantation can essentially cure type 1 diabetes but is generally reserved for those with more severe diabetic complications
What are some of the complications of Diabetes
- Diabetic kidney disease
- Retinopathy
- Peripheral neuropathy
- Coronary heart disease and heart failure
- Stroke
- Peripheral vascular disease
Explain how Retinopathy occurs in Diabetes
↑ BGL can damage the microvascular systems of the eye leading to blockage of blood vessels in the retina
In advanced disease, blood vessels in the retina bleed into the vitreous – resulting in vision impairments, and floating spots/streaks (like cobwebs/cotton wool)
Explain how diabetes can cause Peripheral Neuropathy
Peripheral neuropathy is a common complication of diabetes mellitus that is associated with increased mortality, neuropathic pain, foot ulceration and lower-limb amputation
Persistent hyperglycaemia and dyslipidaemia in diabetes can cause neuronal inflammation, oxidative stress, mitochondrial dysfunction and cell death
Damages motor, sensory and autonomic nerves impairing sensation, movement, gland and organ function
Involves damage to Schwann-cells, altered protein expression in the dorsal root ganglia (DRG) and demyelination/degeneration
What are two other serious eye diseases that can be caused by diabetes
Diabetic macular edema - blood vessels in the retina leak fluid into the macula, causing blurred vision
Neovascular glaucoma - abnormal blood vessels grow out of the retina and block fluid from draining out of the eye – causes glaucoma which can lead to vision loss and blindness
Explain how diabetes can cause Ketoacidosis
Ketoacidosis is a metabolic state associated with uncontrolled production of ketone bodies that cause metabolic acidosis (change in blood pH)
Diabetic ketoacidosis occurs at frequency of up to 8 episodes/1000 diabetic patients and in 11% of T1D patients - accounts for 2% of all diabetic fatalities
Diabetic ketoacidosis occurs as result of chronic insulin deficiency AND corresponding elevation in glucagon
→ drives glucose production in liver (via glycogenolysis and gluconeogenesis) AND release of FFA from fat (via lipolysis)
→ FFAs converted to acetyl CoA in the liver (via -oxidation in mitochondria)
→ Acetyl CoA metabolised to ketone bodies via ketogenesis
Acetoacetic acid and β-hydroxybutyrate are the most abundant circulating ketone bodies – both have low pKa so at high doses turn blood acidic
Initially body buffers pH change via bicarbonate buffering system but the system can be easily overshot
Compensatory hyperventilation (respiratory alkalosis) occurs to lower CO2 levels, and in severe cases, Kussmaul respiration can result
Kussmaul respiration – deep and laboured breathing pattern, or hyperventilation
Goals is to ↓ CO2 levels in the blood via increased rate and depth of respiration
One of most serious diabetic complications – severe metabolic and electrolyte derangements can result in hypokalaemia, hypomagnesemia, and hypophosphatemia – leads to failure of respiratory muscles
Treatment of diabetic ketoacidosis involves IV fluids and insulin therapy
What is Gestational Diabetes (GDM)
Hyperglycaemia during pregnancy that resolves after birth
GDM occurs in an estimated 1 in 8 pregnancies in Australia
Generally detected late in 2nd trimester (13-26 wks) or early in the 3rd trimester (27-40 wks)
Risk factors include maternal overweight/obesity (BMI ≥25), older age at gestation (>40 years), multiparous pregnancies, carrying male foetus, history of GDM or T2D, and ethnicity
GDM increases the risk of complications for both the mother (esp hypertension disorders of pregnancy) and the foetus (esp excess foetal growth and adiposity)
Also increases risk of mother and offspring developing obesity, diabetes, and early CVD long-term
45% of GDM cases are predicted to be preventable via modification of lifestyle prior to conception
Explain the GDM Pathophysiology
During pregnancy numerous physiological adaptations take place in the mother to provide adequate resources to support embryo development
In healthy pregnancy women, increased (fasting) energy demands place additional stress on beta-cells:
- 30% ↑ in basal glucose production (primarily hepatic) despite substantial ↑ in fasting insulin levels
- BGL ↓decrease owing to ↑ plasma volume in early pregnancy AND ↑ glucose uptake in late gestation by fetal unit
- 50% ↓ in peripheral insulin sensitivity (in muscle/fat) by late gestation, which drives ↑ insulin secretion to maintain euglycemia (attributed to reduced IR mediated glucose uptake)
Most often mothers with GDM display evidence of metabolic dysfunction prior to conception (insulin resistance, beta-cell defects) – often asymptomatic
Early gestation: can sustain normoglycaemia as beta-cells can produce sufficient insulin
Mid-Late gestation: as insulin resistance ↑ insulin production is insufficient
Thus, glucose suppression is reduced in GDM women, resulting in hyperglycaemia
Changes to glucose metabolism during pregnancy also linked to altered ovarian and placental hormone and inflammatory cytokine levels – later upregulated in obese mothers
