Metabolic Disorders and Diabetes Mellitus
Metabolic Disorders
Diabetes Mellitus
A multifactorial disease.
Starve–Feed Cycle
The daily cycle of feeding passes through a series of states:
Fed (postprandial) state: 0-4 hours after a meal.
Early post-absorptive state: 4-16 hours after a meal.
Late post-absorptive (early fasting): Up to 3 days after a meal.
Refed state.
Fed State – Mixed Diet
Carbohydrate levels rise, causing an increase in insulin release from the β cells of the pancreas.
Hepatocytes increase glycogen synthesis; glucose is also converted into fatty acids.
GLUT4 transporters increase glucose uptake into muscle (increased glycolysis and glycogen synthesis) and fat cells (glycerol for TAG synthesis).
Reduces glucose concentration in the blood.
Glucose Uptake
Brought about by facilitated diffusion.
Family of transporters known as GLUT (tissue-specific):
GLUT3 (Brain, nerve tissue): Low K_m allows a relatively constant rate of glucose uptake.
GLUT2 (Liver, β-cells of pancreas): High K_m, rate of uptake is proportional to the extracellular glucose concentration.
Fed State – Mixed Diet (cont.)
Amino acids from protein in the diet are distributed to tissues for synthesizing new proteins; excess is degraded in the liver.
Fatty acids are transported to tissues via chylomicrons and taken up by the activation of lipoprotein lipase (ApoC-II).
Chylomicron remnants are transported to the liver for processing.
Excess fatty acids in the diet are taken to the liver, packaged into VLDL, and transported to adipocytes.
Distribution of Nutrients (Fed State)
Insulin is high, glucagon is low.
Glucose goes to the brain, adipose tissue, and muscle.
In the liver, glucose is converted to glycogen.
Amino acids are used for protein synthesis.
Fatty acids are converted to TAG and stored in adipose tissue.
Early Post-Absorptive State
Glucose levels begin to fall due to ongoing utilization, triggering glucagon release.
Hepatic glycogenolysis maintains blood glucose levels (major source up to 16 hours).
Lipolysis is initiated, releasing fatty acids from adipocytes.
Late Post-Absorptive State
The body becomes more reliant on hepatic gluconeogenesis for maintaining blood glucose as hepatic glycogen becomes depleted.
Cortisol, released due to increased stress, has a similar effect as glucagon, except it binds to muscle tissues to increase protein degradation.
Glucagon/cortisol stimulate the release of fatty acids from adipocytes.
Fatty acids are exported to the liver and other tissues for fuel; glucose is spared for the brain's use.
Fasting/Starvation State
As the fast continues, the body cannot continue to keep glucose levels constant.
Over time (2-3 days), the brain switches to utilizing ketone bodies as the main source of fuel (70-80%).
Allows reduction in gluconeogenesis (protein sparing) and stabilization of glucose levels.
The kidney becomes a major gluconeogenic tissue.
When fat stores are exhausted, protein is metabolized once more, causing irreversible damage to organs.
Fasting/Starvation State (cont.)
Glucose levels decrease, while glucagon and ketone body levels increase.
Free fatty acid levels also rise.
Fasting/Starvation State - Summary
Liver: Gluconeogenesis occurs; glycogen is converted to glucose; ketone bodies are produced.
Muscle: Proteins are broken down into amino acids.
Adipose tissue: TAG is broken down into fatty acids and glycerol.
Diseases Affecting Fuel Utilization
Defects in glycogen metabolism.
Hypoglycemia.
Defects in fatty acid oxidation.
Hypoglycemia.
Diabetes Mellitus.
Hyperglycemia and hypoglycemia.
Diabetes Mellitus
Most common metabolic disease in the world.
Over 5% of the population suffers from the disorder; it is becoming an increasing problem.
Types:
Type 1 (Insulin-dependent): About 10% of cases.
Type 2 (Non-Insulin-dependent): Remaining 90%.
Gestational Diabetes: Develops during pregnancy.
Glucose entry into cells is impaired.
Starvation in a sea of plenty.
Type 1 Diabetes
(Insulin-dependent Diabetes, aka Juvenile onset diabetes).
Mainly in the young, but can occur at any age.
Beta cell destruction rate is usually rapid, but can be slow, especially in adults (latent AI diabetes in adults; LADA).
Types:
Type 1A (immune-mediated):
Beta cell destruction with no evidence of autoimmunity.
Rare.
Mainly African or Asian descent.
Strongly inherited.
Episodic ketoacidosis due to varying degrees of insulin deficiency with periods of absolute insulin deficiency.
Type 1B (idiopathic).
Type 1 Diabetes (cont.)
Absolute failure of β-cells of the pancreas to produce insulin.
Autoimmune destruction of β-cells (85% have antibodies to pancreatic cells which may be detectable long before clinical presentation).
Antibody testing for GADA, ICA, and IAAs can identify 85% of cases of new or future type 1 diabetics (98% specificity).
The number of autoantibodies is related to the risk of developing type 1 diabetes; 10% of the population has one.
Type 1 Diabetes - Genetics and Triggers
Genetics:
Concordance rate of less than 40% between monozygotic twins.
Triggers:
Viral infection (Coxsackie B, congenital Rubella, COVID?).
Cow's milk (Bovine insulin).
Wheat (peptides).
Chemical (Nitrosamines).
Vitamin D deficiency.
Type 1 Diabetes - Mechanism
When blood glucose levels rise, insulin remains low.
Gluconeogenesis, glycogenolysis, and lipolysis continue inappropriately; glycolysis and glycogenesis are not stimulated in the liver, and there is limited uptake into muscle.
Excessive uptake into peripheral tissues.
Thus, the liver is contributing to the hyperglycemia.
Type 1 Diabetes - Effects
Protein degradation yields glucogenic amino acids.
Fatty acids are oxidized as fuel, producing acetyl-CoA.
Lack of oxaloacetate prevents acetyl-CoA entry into the citric acid cycle; acetyl-CoA accumulates.
Acetyl-CoA accumulation favors ketone body synthesis.
Ketone bodies are exported to the brain as fuel.
Type 1 Diabetes - Complications
As blood glucose levels rise and exceed the level the kidney is able to re-absorb, glucose enters urine and takes water with it by osmosis.
Excessive urine production leads to dehydration and increased thirst.
Muscle amino acids are degraded to feed gluconeogenesis, causing wasting.
Excess gluconeogenesis means the liver lacks oxaloacetate, so ketone bodies are produced.
The body is stuck in a state of “starvation”.
Excessive ketone body production leads to ketoacidosis, which can lead to coma and death.
Type 1 Diabetes - Diabetic Ketoacidosis
Increased gluconeogenesis.
Decreased glucose uptake.
Hyperglycemia.
Glycosuria.
Insulin lack.
Increased lipolysis.
Ketonuria.
Dehydration.
Increased ketogenesis.
Ketonemia.
Acidosis.
Compensatory hyperventilation.
Type 1 Diabetes - Treatment
Insulin injections are needed to lower blood glucose.
Constant monitoring of blood glucose is required to maintain glucose homeostasis.
Many patients monitor their own blood glucose concentrations using reagent strips (glucose oxidase) and a glucose meter.
Maturity Onset Diabetes of the Young (MODY)
Autosomal dominant, monogenic defect of insulin secretion occurring at any age.
Usually a mild form of type 1 DM.
Makes up approximately 1-2% of diabetics.
Impaired glucose-stimulated insulin secretion.
Transient hyperglycemia but without insulin resistance.
Due to defects in specific proteins regulating insulin synthesis and secretion (MODY 1-6).
MODY 1, 3, and 4 may be linked to decreased transcription of beta cell genes involved in insulin synthesis, storage, and secretion…
Rare Causes of Diabetes
Glucokinase (MODY 2):
Inactivating mutations.
↓ ATP produced.
↓ insulin release.
Hyperglycemia.
GLUT2 deficiency:
Less glucose enters the cell.
↓ ATP produced.
↓ insulin release.
Hyperglycemia.
Mutation in ATP K^+ channel causes neonatal diabetes.
Gestational Diabetes Mellitus (GDM)
A glucose intolerance that begins, or is first recognized during pregnancy (affects 3-5% of pregnancies).
Hyperglycemia becomes apparent around 24-28 weeks.
Increases the mother’s risk of pre-eclampsia, type 2 diabetes, and the requirement for a C-section.
Increases the child’s risk of:
Hypoglycemia at birth.
Increased laying down of fat.
Type 2 diabetes later on.
Gestational Diabetes Mellitus - Insulin Resistance
Insulin resistance is a normal phenomenon emerging in the second trimester and functions to:
Secure glucose supply to the developing fetus.
Avoid maternal hypoglycemia.
However, if insulin resistance is increased and is maintained throughout pregnancy, the mother develops GDM.
This is usually managed through diet control, exercise advice, and (as a last resort) anti-diabetic drugs.
Gestational Diabetes Mellitus - Pathophysiology
Maternal and placental hormones (e.g., human placental lactogen; HPL).
TNFα secretion by the placenta increases → insulin resistance (2nd and 3rd trimesters).
HPL increases in relation to fetus and placental growth.
Stimulates lipolysis.
Increases maternal blood glucose.
Increased nutrients to the fetus.
Gestational Diabetes Mellitus - Pathophysiology of Insulin Resistance
Anti-insulin properties decrease the body’s sensitivity to insulin and increase the mother’s blood glucose, making it available to the fetus.
Problems arise when there is excessive insulin resistance and not enough insulin produced to overcome the increased resistance.
Increased Human Placental Lactogen (HPL) and Increased TNFα
Type 2 Diabetes
(Non-Insulin-dependent Diabetes aka late onset diabetes).
Uncertain pathogenesis, but undoubtedly a heterogeneous disease.
Strong genetic link (concordance rate of >90% in monozygotic twins).
Predisposed β-cell dysfunction.
Insulin can be low, normal, or high but with a blunted response = INSULIN RESISTANCE.
Subacute onset may take months, years, or be asymptomatic.
In early stages, the pancreas may be slow to respond to increased blood glucose; delayed uptake into cells so it is excreted in urine.
Ketoacidosis is rare as there is usually enough insulin to prevent ketogenesis.
Type 2 Diabetes Mellitus (T2DM) - Epidemiology
Major contributing factors: age, obesity, ethnicity.
UK incidence rate approximately 6-10%.
Lifetime risk approximately 15-25%.
2-4 times more common in South Asian, African, and Caribbean people living in the UK.
Mainly adults over the age of 40 develop the disease.
Obesity increases the risk of type 2 DM by 80-100 fold.
Obesity, Diabetes, and CVD
T2DM occurs due to an inability to tolerate a glucose load (insulin resistance) and β-cell dysfunction.
T2DM risk factors: obesity.
T2DM develops in individuals genetically predisposed to impaired β-cell insulin secretion.
Obesity results in ectopic storage of lipids (e.g., liver, SKM) and activation of inflammatory pathways.
Leads to insulin resistance in obesity and chronic low-level inflammation (→ CVD).
Ectopic lipid (especially liver) leads to reduced HDL and increased TGs.
TG:HDL and total:HDL cholesterol show strongest correlations to insulin resistance.
Type 2 Diabetes Mellitus - Insulin Resistance
Blunted response by target tissues to insulin even though it is secreted in normal or supranormal amounts.
Genetic and environmental factors are involved.
Lifestyle and overeating are trigger events.
Central (abdominal) obesity is more closely linked with T2DM than subcutaneous – waist circumference / waist:hip ratio measures.
Diabesity.
Type 2- Insulin Resistance - Where Can Insulin Resistance Occur?
Pre-receptor resistance
Insulin autoantibodies
Mutant insulin structure
Insulin secretion defects
Receptor resistance
Decreased number
Decreased affinity (altered structure)
Post-receptor resistance
Impaired receptor tyrosine kinase activity
Post-receptor signalling (eg. IRS-1, PI3-kinase, Akt)
Down-regulation of GLUT4
Type 2- Insulin Resistance and Obesity
Often associated with obesity.
Overeating leads to constant high glucose so insulin levels raised.
Increased insulin downregulates receptors (endocytosis) leading to insulin resistance.
Obesity also results in ectopic storage of lipids and activation of inflammatory pathways.
Various molecules released from adipocytes have been implicated in glucose homeostasis.
Insulin Resistance - TNFα
Tumor Necrosis Factor (TNFα) is secreted from adipocytes, particularly visceral adipocytes.
In obesity, there is increased secretion of TNFα.
Insulin resistance leads to hyperglycemia.
TNFα inhibits IRS-1 activation (by insulin).
Thus, insulin-signal transduction is inhibited (insulin resistance).
↓ glycogen synthesis and ↓ GLUT4 transport to PM (skeletal muscle).
Adipose Tissue: Role of Adipokines
Adiponectin is a hormone secreted by adipose tissue that circulates in the blood.
Adiponectin activates signaling cascades that eventually increase glucose uptake by muscle, increase fatty acid oxidation by muscle and liver, and decrease gluconeogenesis in the liver.
Increased TNF in obesity reduces plasma adiponectin levels.
Decreased adiponectin in obesity leads to increased plasma FAs and glucose → insulin resistance & hyperglycemia.
Adiponectin - Genetics
Polymorphisms in the adiponectin gene (SNP 276 and SNP45) are linked to plasma levels of adiponectin, insulin resistance, and T2DM.
Currently, adiponectin is biochemically the strongest and most consistent predictor of T2DM.
Type 2 Diabetes Mellitus - Role of Obesity
↑ FFA.
↑ Insulin secretion.
Visceral obesity.
Beta cell failure.
Hyperglycemia.
Insulin resistance (IRS1 serine phosphorylation).
↓ Adiponectin.
↑ TNF.
Binds TNF receptor.
↓ glucose uptake & glycogenesis.
Compensation.
Toxicity.
Type 2 Diabetes Mellitus - Role of Genetics and Lifestyle
Genetic predisposition.
Lifestyle.
Mild hyperglycemia (→ ↑insulin).
Insulin resistance (Obese).
Beta cell defects.
Faulty GLUT2 / K^+ channel.
Faulty insulin synthesis, release, or storage.
Faulty pre-receptor, receptor, or post- receptor signaling.
↓ insulin in muscle, adipose tissue, liver.
Type 2 Diabetes Mellitus - Pathophysiology – Key Points
On diagnosis, insulin resistance has been present for many years.
Stimulates secondary hyperinsulinemia.
When beta cells start to fail → hyperglycemia develops.
Thus, type 2 DM onset is usually slow.
Diagnosis:
Elevated fasting blood glucose.
Elevated random blood glucose.
Oral glucose tolerance test.
Elevated HbA1c (glycated hemoglobin).
Signs and symptoms.
Diagnosis - Random Plasma Glucose
Random plasma glucose ≥ 7.8 mmol/L requires checking fasting glucose levels.
Diagnosis - Oral Glucose Tolerance Test (OGTT)
Perform OGTT if fasting glucose is between 6.0 - 6.9 mmol/L.
Administer 75g anhydrous glucose or equivalent.
Repeat plasma glucose measurement after 2 hours.
Diagnosis - Fasting and 2-Hour Plasma Glucose Levels
Normal:
Fasting plasma glucose < 6.0 mmol/L and 2-hour plasma glucose < 7.8 mmol/L.
No follow up required.
Impaired Fasting Glycemia (IFG):
Fasting plasma glucose between 6.0 and 6.9 mmol/L and 2-hour plasma glucose < 7.8 mmol/L.
Annual fasting plasma glucose monitoring required.
Impaired Glucose Tolerance (IGT):
Fasting plasma glucose < 7.0 mmol/L and 2-hour plasma glucose between 7.8 and 11.0 mmol/L.
Annual fasting plasma glucose monitoring required.
Diabetes:
Fasting plasma glucose ≥ 7.0 mmol/L OR 2-hour plasma glucose > 11.1 mmol/L.
Oral Glucose Tolerance Test Results
Illustrates glucose level curves of Normal, IFG, IGT and Diabetic conditions.
Prediabetes
Two types:
Impaired fasting glycemia (IFG).
Impaired glucose tolerance (IGT).
Elevated blood glucose levels, but less than diabetics.
Increased risk of becoming type 2 diabetic.
Insulin resistance and CVD.
Mortality risk factor.
Exercise and Type II Diabetes
Increases expression of glucose transporter on muscle cells and helps reduce insulin resistance.
Helps with weight loss.
Improves blood lipid concentrations.
Lowers blood pressure.
Reduces other biochemical risk factors.
Comparison of Type 1 and Type 2 Diabetes Mellitus
Type 1:
Onset: usually below 20 years of age.
Insulin synthesis: absent; immune destruction of β-cells.
Plasma insulin concentration: low or absent.
Genetic susceptibility: yes, inheritance associated with HLA antigens.
Islet cell antibodies at diagnosis: yes.
Obesity: uncommon.
Ketoacidosis: possible after major stress.
Type 2:
Onset: usually over 40 years of age.
Insulin synthesis: preserved; combination of impaired β-cell function and insulin resistance.
Plasma insulin concentration: low, normal, or high.
Genetic susceptibility: not associated with HLA, important polygenic inheritance.
Islet cell antibodies at diagnosis: no.
Obesity: common.
Ketoacidosis: rare.
Acute Complications of Diabetes Mellitus
Ketogenic coma:
Mainly Type 1.
Often occurs prior to diagnosis.
Stress is a trigger (cortisol release).
HyperOsmolar Non Ketogenic coma (HONK):
Mainly Type 2.
Due to a combination of concurrent illness (e.g., stroke, MI etc.) and inability to take normal diabetic therapy.
Extreme dehydration (compounded by fluid intake).
Usually in elderly with high incidence of mortality (30%).
Hypoglycemic coma:
Insulin overdose (most common cause).
Sulphonylurea overdose (frequent cause in T2DM).
Alcohol (decreases gluconeogenesis).
Increased exercise (increased glucose uptake).
Decreased glucose delivery to the brain causes changes in neural firing rates, leading to headache, dizziness, irritability, fatigue, confusion, blurry vision, hunger, seizures, and coma.
Long Term Complications
Fall into 2 categories:
Macrovascular: linked to insulin resistance; related to atherosclerosis/CHD/stroke/PVD.
Microvascular: directly linked to hyperglycemia – Nephropathy, Neuropathy, and Retinopathy.
The prevalence of all complications increases with the duration of the disease.
All are related to hyperglycemia.
Significant source of morbidity and mortality.
Microvascular Complications
Linked to prolonged exposure to high glucose concentrations but not fully understood; a mixture of ROS, AGE, and redox imbalance.
Excess glucose overwhelms normal pathways (e.g., glycolysis in non-insulin-dependent cells) so shunted down the polyol pathway.
Decreased NADPH (due to aldol reductase, polyol pathway) so decreased reduced glutathione → increased ROS damage.
Decreased Nitric oxide so decreased blood flow through capillaries.
Increased sorbitol (osmotic pressure) and Fructose (AGE).
Diabetes Mellitus - Glucotoxicity (Intracellular)
Increased Glucose leads to increased Glucose-6-P, Fructose-6-P, Fructose 1,6-bisP, and Glyceraldehyde-3-P.
This increases Krebs/TCA cycle and ETC, leading to ROS.
The Polyol pathway increases Sorbitol and Fructose.
AGE (Advanced glycation endproduct) formation.
Long Term Complications - Basement Membrane
Many chronic complications are related to changes in the walls of arteries, arterioles, and capillaries.
The basement membrane is a thin sheet of fibers that lines the endothelium of blood vessels and underlies the epithelium.
It acts as a barrier and anchors epithelium to connective tissue.
DM causes biochemical and structural changes to endothelial cells, the basement membrane, and the ECM of blood vessels.
Diabetic Retinopathy
Proliferative retinopathy:
Blood supply to the retina greatly decreases.
Damaged blood vessels begin to leak and burst, whilst others become blocked.
They are very fragile and may bleed further obscuring vision.
Extensive haemorrhages lead to scar tissue forming which pulls and distorts the retina → retina can become detached.
In response, growth factors are released which stimulate the synthesis of new blood vessels.
Laser surgery is used as a treatment.
Diabetic Nephropathy
Basics:
Diabetic renal disease is the leading cause of end-stage renal failure in the western world.
The leading cause of premature death in young diabetics.
40% of diabetics will develop nephropathy.
Hyperglycemia causes damage to small blood vessels supplying the kidney → decreased GFR & renal failure.
Diabetic Neuropathy
Blood vessels depend on neural regulation for normal function.
Neurons depend on capillaries for nutrients.
Chronic high blood glucose damages blood vessels.
Lack of blood leads to ischemia and damage to nerves.
Blood vessels also leak causing further damage to nerves.
Diabetic Neuropathy (cont.)
Most common complication of Diabetes.
Progressive damage to nerves leads to pain, numbness, and muscle spasms.
Damaged capillaries lead to damaged nerves (lack of nutrients etc.).
Peripheral Neuropathy: Loss of temperature, pain, and touch sensation.
Autonomic Neuropathy: Defects in vasomotor responses.
Hyperglycemia - Macrovascular Disease - Pathophysiology
Atherosclerosis.
↑ Intra- and extracellular AGE formation.
Bind and modify LDL receptor.
↓ LDL taken up by systemic cells.
↑ LDL taken up by mØ.
Damage to endothelium & BM.
Vasculature becomes leaky.
Invasion by inflammatory cells and lipids.
↑ Proinflammatory & profibrotic molecules.
ROS.
Macrovascular Disease - Plaque Formation
Exposure of matrix to platelets and mural thrombus formation.
Endothelial cell destruction.
Active macrophages secrete metalloproteinase enzymes weakening plaque cap.
Fibrous cap formation.
Matrix synthesis.
Smooth muscle cells migrate and replicate due to cytokines secreted by the endothelium and macrophages.
Cell necrosis.
Lipid pool.
Rupture of the plaque cap.
Macrovascular Disease - LDL Involvement
Damage to endothelium allows LDL entry into intima.
LDL oxidation due to foam cell involvement.
Oxidized LDL is taken up by macrophages through scavenger receptors.
Monocyte attachment, transmigration, activation, and transformation into macrophage due to expression of adhesion molecules.
Treatment of Diabetes Mellitus
Type 1:
Diet.
Insulin.
Pancreas Transplant.
Type 2:
Diet.
Exercise.
Drugs (hypoglycemic drugs).