Diabetes And Hypoglycaemia Flashcards
How are blood glucose levels maintained?
What role does the liver play at different points?
dietary carbohydrate
glycogenolysis- breakdown of glycogen store to glucose
gluconeogenesis-making glucose from non-glucose sources, e.g. lactate, alanine, fatty acids
Liver’s role:
after meals - stores glucose as glycogen
during fasting - makes glucose available through glycogenolysis and gluconeogenesis
Why should glucose levels be regulated?
Brain and erythrocytes require continuous supply: – therefore avoid deficiency.
High glucose causes pathological changes to tissues; e.g. micro/macro vascular diseases, neuropathy: – therefore avoid excess.
What is Diabetes Mellitus?
…..a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism:
the hyperglycaemia results from increased hepatic glucose production and decreased cellular glucose uptake
blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria
How can Diabetes be classified?
Type 1:
Insulin secretion is deficient due to autoimmune destruction of beta-cells in pancreas by T-cells
Commonest cause is autoimmune destruction of B-cells;
interaction between genetic and environment factors.
strong link with HLA genes within the MHC region on chromosome 6.
Environment: viruses (CMV, mumps, Rubella, EBV), drugs, stress. Can all cause destruction of beta-cells
Certain human leukocyte antigen (HLA)-DR/DQ gene polymorphisms, particularly HLA-DR and HLA-DQ alleles, increase susceptibility to, or provide protection from, the disease. In susceptible individuals, environmental factors may trigger the immune-mediated destruction of pancreatic beta cells
Type 2:
Insulin secretion is retained but there is target organ resistance to its actions
Secondary:
chronic pancreatitis, pancreatic surgery, secretion of antagonists
Gestational:
Occurs for first time in pregnancy
Describe the pathogenesis of Type 1 Diabetes Mellitus
Destruction of B-cells starts with autoantigen formation
Autoantigens are presented to T-lymphocytes to initiate autoimmune response
There would be circulating autoantibodies to various -cell antigens against glutamic acid decarboxylase
tyrosine-phosphatase-like molecule
Islet auto-antigen
The most commonly detected antibody associated with type 1 DM is the islet cell antibody
More than 90% of newly diagnosed persons with type 1 DM have one or another of these antibodies.
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
Amylin, a glucoregulatory peptide hormone co-secreted with insulin.
lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
Further details any extra info etc:
The destruction of insulin-producing beta cells in the pancreas starts with the formation of autoantigens. These autoantigens are ingested by antigen-presenting cells which activate T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. Activated Th1 lymphocytes secrete interluekin-2 (IL-2) and interferon. IL-2 activates autoantigen-specific T cytotoxic lymphocytes which destroy islet cells through the secretion of toxic perforins and granzymes. Interferon activates macrophages and stimulates the release of inflammatory cytokines (including IL-1 and tumour necrosis factor [TNF]) which further destroy beta cells (McCance & Heuther, 2014).
Activated Th2 lymphocytes produce IL-4 which stimulates B lymphocytes to proliferate and produce islet cell autoantibodies (ICAs) and anti-glutamic acid decarboxylase (antiGAD65) antibodies.
What do metabolic complications of Type 1 DM include?
Insulin deficiency leads to:
increased hepatic output and impaired glucose uptake – hyperglycaemia
Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse
Increased lipolysis blood level of ketone bodies formation (DKA) and metabolic acidosis.
How can Type 2 Diabetes Mellitus present?
Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age
Strong familiar incidence
Pathogenesis uncertain – insulin resistance; β-cell dysfunction:
may be due to lifestyle factors - obesity, lack of exercise
What 2 main things make up the pathophysiology of Type 2 Diabetes?
Genetic predisposition and Obesity/lifestyle factors
What do metabolic complications of Type 2 Diabetes include?
Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemic State (HHS)]
Development of severe hyperglycaemia
Extreme dehydration
Increased plasma osmolality
Impaired consciousness
No ketosis
Death if untreated
How would you look to diagnose DM?
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ). OR
Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
OR
HbA1c test (>48mmol/l (6.5%) is a diagnostic of diabetes in most situations (2 tests)
OR
Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
In the absence of symptoms:
test blood samples on 2 separate days
What would you look at when testing for pre-diabetes?
Impaired Glucose Tolerance (IGT)
Fasting plasma glucose >7mmol/L** and
OGTT value of 7.8 – 11.1 mmol
Impaired Fasting Glycaemia (IFG)
Fasting plasma glucose 6.1 to 6.9 mmol/L, and
OGTT value of < 7.8mmol/L
** OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.
When should the oral glucose tolerance test(OGTT) be carried out?
12
When should the oral glucose tolerance test(OGTT) be carried out?
OGTT should be carried out:
in patients with IFG
in unexplained glycosuria
in clinical features of diabetes with normal plasma glucose values
for the diagnosis of acromegaly
75g oral glucose and test after 2 hour
Blood samples collected at 0 and 120 mins after glucose
Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate
What can drug treatment entail for Diabetes?
Metformin: Decreases gluconeogenesis
Sulfonylureas: bind and close KATP channels, depolarize B cell releasing insulin
Glitazones: activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
SGLT2 inhibitors: promote glucose excretion via kidney
Incretin targeting drugs: potentiate insulin release in response to rising plasma glucose
DPP-4 inhibitors (prevent breakdown of natural incretins)
Synthetic GLP-1 analogues
Bit of extra detail on the above:
Metformin helps the body to control blood sugar in several ways. Metformin exerts its effect mainly by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose.
Sulphonylureas - they work mainly by stimulating the cells in the pancreas to make more insulin.
Dipeptidyl peptidase inhibitor (DPP-4; Gliptins): inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed.
What are some long term complications of Diabetes?
Occur in both type 1 and type 2 DM
Micro-vascular disease:
retinopathy, nephropathy, neuropathy
Macro-vascular disease:
related to atherosclerosis heart attack/stroke
Exact mechanisms of complications are unclear
What is hypoglycaemia in diabetes and what are some causes of it?
Defined as plasma glucose < 2.5 mmol/L
Hypoglycaemia in diabetes
Hypoglycaemia in patients without diabetes
Causes of hypoglycaemia
Drugs are the most common cause;
common in type 1 diabetes
Less common in type 2 diabetes taking insulin & insulin secretagogues
uncommon in patients who do not have drug treated DM:
In these patients hypoglycaemia may be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx.
Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the more commonly used sulfonylureas.
Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation
Among drugs used to treat type 2 diabetes earlier in the disease, insulin sensitizers (metformin, Glitazones); glucosidase inhibitors; glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors should not cause hypoglycaemia.
