Pathophysiology Of Diabetes Flashcards
What is Diabetes Mellitus (DM)?
A heterogenous complex metabolic disorder characterized by elevated blood [glucose] secondary to either resistance to the action of insulin, insufficient insulin secretion, or both
One end of a continuum of disordered glucose metabolism
How big a problem is the diabetes epidemic?
Worldwide = 415 million people expected to rise to 552 million people by 2030
UK prevalence = 3.7 million (85% type 2) including children but 850,000 estimated to be undiagnosed
Occupy 10% of NHS hospital beds
What is the function of glucose?
Main metabolic fuel for the brain normally
Why do we need glucose?
The body is unable to store or synthesize it, which is why we need a continuous steady supply
How can the body get glucose?
Dietary sources
Glycogenolysis (breakdown of glycogen stores)
Gluconeogenesis (formation of new glucose)
What are some important properties of glucose?
Hydrophilic so only diffuses slowly across the lipid cell membrane thus, it requires specific transport proteins (GLUT & SGLT) to move into cells
What type of transport to the GLUT family facilitate?
Facilitated diffusion (not energy dependent)
What are the functions of the different types of GLUTs?
1, 3 + 4: allow movement at low (basal) glucose levels
But 4 has a insulin dependent response in fat + muscle whilst 1, 2 + 3 are insulin independent
Where are the different GLUT transporters found?
1: ubiquitous so provide basal glucose to all cells
2: on β islet cells & tissues exposed to large glucose fluxes e.g. intestine, kidney + liver
3: mainly neurons
4: adipose tissue + muscles
What is the function of Sodium Dependent Glucose Transporters (SGLTs)? What are the different types?
Use Na to move glucose against concentration gradient
1: dietary uptake in intestines
2: major role in glucose reabsorption in kidneys
What does glucose homeostasis have to be able to cope with?
Changes in glucose delivery e.g. when fasted or after meals
Demand e.g. during exercise
What is involved in glucose homeostasis?
Inter-regulating hormones
Storage in excess (in fed state)
Release & production in deficit (in fasted state)
What is gluconeogenesis?
Production of glucose in the liver and kidneys from molecules (not carbohydrates) such as:
- Lactate (from non-oxidative metabolism i.e. Cori cycle)
- Glycerol (from fats)
- Glutamine + alanine (from protein)
What is glycogen?
A multi-branched polysaccharide that is a energy storage molecules in humans; primarily stored in liver + muscle cells
What happens if there is a defect in glycogen synthesis or breakdown?
A spectrum of diseases called glycogen storage diseases
What are the major hormonal players in glucose homeostasis? What do they do?
Insulin: decrease glucose production + lipolysis but increase glucose utilisation
Glucagon: increase glucose production + lipolysis but decrease glucose utilisation
What are the minor players in glucose homeostasis? What do they do?
Catecholamines (A/NA), GH & cortisol: increase glucose production + lipolysis but decrease glucose utilisation
FFA: increase glucose production but decrease glucose utilisation
Incretins (GLP-1): decrease glucose production + lipolysis but increase glucose utilisation
What isinsulin?
A 51 AA peptide (protein) hormone which 2 protein chains linked by disulphide bonds
Pancreatic origin; produced by β cells of Islets of Langerhans which provide endocrine function
What are the 3 major cell types of the pancreas? What do they do?
α: produce glucagon
β: produce insulin
δ: produce somatostatin (strong inhibitor of insulin + glucagon although exact role is unclear)
How does insulin secretion occur?
- EC glucose transported into β cell via GLUT 2
- Glucose metabolised increasing ATP:ADP ratio within cell
- ATP dependent K+ channels close
- Cell membrane depolarisation occurs
- Voltage gated dependent Ca channels open causing a Ca influx
- Exocytosis of stored insulin vesicles
Explain the concept of biphasic insulin secretion.
Insulin secretions occurs in 2 phases:
1) 1st phase - rapid onset + lasts 10 minutes when there is release of pre-docked & primed vesicles
2) 2nd phase - prolonged plateau lasting as long as hyperglycaemia persists because release of insulin from granules is complex (involves transport -> docking -> priming -> fusion)
How much stored insulin is released when stimulated? Why?
Only a portion, even under max stimulation implying that insulin levels are regulated by release rather than synthesis
What are the actions of insulin?
Predominantly anabolic:
- Activate insulin receptor on target cell membrane (outcome depends on 2ndary pathway activated e.g. gluconeogenesis inhibition)
- Glucose transport
- Glycogen synthesis
- Other
How insulin facilitate glucose transport into cells?
Promotes fusion of IC vesicles containing predominantly GLUT4 + transporter insertion into cell walls
How does insulin stimulate glycogen synthesis?
Promotes activation of glycogen synthase
What are the other actions of insulin?
Promotes protein synthesis + inhibits protein breakdown
Promotes lipogenesis + inhibits lipolysis (via hormone sensitive lipase)
Promotes mitogenesis (induces cell division) via insulin-like GH homology
Suppress ketogenesis
What is glucagon? When is it secreted?
Major counter-regulatory hormone produced by pancreatic islet α cells
Secretion regulated primarily by blood glucose levels (released in hypoglycaemia) & suppressed by insulin
What are the actions of glucagon?
Stimulates gluconeogenesis & glycogenolysis
Stimulate proteolysis
Increase hepatic FA oxidation & ketone formation
Stimulates lipolysis in adipose cells, increases circulating FFA & reduce adipocyte glucose uptake
What is the post-absorptive (fasted) state?
14-16 hours fast where glucose levels are relatively stable because balance of glucose entrance & utilisation is equal
How is glucose entering the system in a post-absorptive (fasted) state?
80% from liver: 50% glycogenolysis + 50% gluconeogenesis -> proportion shift to 90% gluconeogenesis by 48hrs as fast progresses + glycogen stores deplete
Kidneys contribute primarily via gluconeogenesis (contain little glycogen) with output of this process comparing to the liver
In the post-absorptive (fasted) state, what does the insulin:glucagon ratio look like?
Favours glucagon because its a primarily catabolic state
Loss of insulin action to supress lipolysis + proteolysis so there is production of precursors of gluconeogenesis + production of other fuels e.g. ketones
What happens in the post-prandial (fed) state?
Insulin responds to rising glucose levels & acute exposure to FFA so insulin:glucagon ratio favours insulin as this is a primarily anabolic state
What is the entero-insular axis?
L-cells of SI produce GI insulinotropic polypeptides such as Glucagon-Like Peptide (GLP) + Gastric Inhibitory Peptide (GLP) which augment insulin secretion in response to oral glucose load
Enzymes rapidly degraded by Dipeptidyl Peptidase 4 (DPP4)
How is the autonomic nervous system involved in glucose homeostasis?
ANS directly innervates the pancreatic islets:
Sympathetic response releases A/NA which inhibit insulin + promotes glucagon secretion
Parasympathetic response has opposite action
How are cortisol and Growth Hormone (GH) involved in glucose homeostasis?
Take several hours to have effect but promote gluconeogenesis + inhibit glucose transport into cells
Cortisol also directly inhibits insulin secretion (important when considering prescribed steroids, syndromes of cortisol or GH excess)
What are the 4 stages of diabetes mellitus (DM)?
- Normal
- Impaired fasting glycaemia
- Impaired glucose tolerance
- Diabetes
How is diabetes mellitus (DM) classified?
MAINLY into type 1 + type 2 by underlying pathogenesis
Other types + causes: monogenic, gestational, genetic, pancreas, endocrine or drugs
What is type 1 diabetes mellitus (T1DM)?
Autoimmune disease with selective destruction of β cells resulting in complete insulin deficiency - associated with other autoimmune conditions e.g. thyroid disorders, coeliac disease
Accounts for 5-10% of DM
What are the important features of type I diabetes mellitus (T1DM)?
Typically rapid but can be a honeymoon period
Only treated with insulin
Typically seen in younger, lean patients
What are the symptoms of type 1 diabetes mellitus (T1DM)?
Hyperglycaemia Polyuria Polydipsia Weight loss Fatigue Ketoacidosis
What is the normal blood glucose concentration?
< 7.8 mmol/L
Why do patients with type 1 diabetes mellitus (T1DM) experience hyperglycaemia?
There is loss of insulin secretion so an inability to uptake glucose into cells or store it as glycogen
Also, unopposed glucagon action (as in a fasted state) causes glycogenolysis + gluconeogenesis
Why do patients with type 1 diabetes mellitus (T1DM) experience polyuria?
Hyperglycaemia results in glycosuria which exceeds the renal capacity to reabsorb glucose so patients urinate more often to rid the body of glucose
Glucose in urine also inhibits concentrating ability of kidney
Why do patients with type 1 diabetes mellitus (T1DM) experience polydipsia?
Physiological response to dehydration to maintain fluid balance
High blood [glucose] directly stimulates thirst response too
Why do patients with type 1 diabetes mellitus (T1DM) experience weight loss?
Unopposed lipolysis + proteolysis for gluconeogenesis precursors
When are ketones produced? What are the 3 types?
Product of FA metabolism produced as an alternative energy source
- Acetone
- Acetoacetate
- β-hydroxybutyrate)
What is diabetic ketoacidosis (DKA)?
When ketone production leads to acidaemia -> medical emergency seen almost exclusively in T1DM patients (can be 1st presentation in undiagnosed T1DM often preceded by other acute illness due to stress hormone release or insulin omission)
How does diabetic ketoacidosis (DKA) present?
Signs of shock from severe dehydration
High RR (to blow off acid)
Abdominal pain (can be severe)
What is type 2 diabetes mellitus (T2DM)?
Heterogenous condition characterized by insulin resistance + initially hyperinsulinaemia
Loss of 1st phase insulin response + β cell exhaustion occurs over time
What are the symptoms of type 2 diabetes mellitus (T2DM)?
Indolent; often asymptomatic at presentation
What are the modifiable risk factors associated with type 2 diabetes mellitus (T2DM)?
Overweight/obesity (BMI > 25kg/m^2) Central/visceral obesity Lack of physical activity Smoking Poor diet (high saturated fat, low fibre, dyslipidaemia) Low socioeconomic status
What are the non-modifiable risk factors associated with type 2 diabetes mellitus (T2DM)?
Age > 40yrs (>25 if South Asian origin) FH Ethnicity (Black African, South Asian) History of gestational diabetes/baby > 4.5kg at birth Impaired glucose regulation (prediabetes or non-diabetic hyperglycaemia) Mental health/antipsychotic use history HTN, CVD or stroke history Low birth weight POS
What waist circumference indicates central obesity?
Men: >94cm
South Asian men: >90cm
Women: >80cm
What is the treatment for type 2 diabetes mellitus (T2DM)?
Diet, exercise + lifestyle measures
Oral hypoglycaemic agents
Injectable agents
What oral hypoglycaemic agents exist? What do they do?
Biguanides (e.g. metformin): decrease hepatic gluconeogenesis
Sulfonyureas: increase insulin secretion
Thiazolidinediones: reduce insulin resistance
α-glucosidase inhibitor: decrease carb absorption
DPP-4 inhibitors: prevent breakdown of GLP
SGLT2 inhibitors: promote glycosuria
What injectable agents exist for type 2 diabetes mellitus (T2DM)?
GLP-1 analogues
Insulin
What are some complications of diabetes mellitus (DM)?
Hypoglycaemia of treatment
Microvascular: nephropathy, retinopathy or neuropathy
Macrovascular: IHD, cerebrovascular disease or PVD
What are the symptoms of hypoglycaemia?
Sweats Illness Agitation Aggression Irrationality Memory loss
