Diabetes and hypoglycemia Flashcards
How are glucose levels maintained?
- dietary carbohydrate
- glycogenolysis
- gluconeogenesis
What metabolic changes occur in fed state?
- when you eat a meal
- insulin levels increase
- liver glucose production decreases
- peripheral catabolism decreases
- peripheral uptake increases
- liver nutrients uptake increases
- decrease in catabolism
What metabolic changes occur in fasting state?
- insulin levels decrease
- liver gluconeogenesis
- plasma glucose levels increase
- peripheral uptake decreases
- lipolysis/ proteolysis increases
- increase in catabolism
Why is it important to have plasma glucose regulation?
- enough glucose to fuel the body , specially the brain
- too high plasma glucose can cause pathological changes in cells
What happens at high glucose levels?
- promotes beta cells in pancrease to release insulin
- insulin stimulates glucose uptake from blood into muscle and adipose tissue
- this will lower blood glucose levels
- glucose -> glycogen for storage
What happens at low glucose levels?
- promotes glucagon release from alpha cells in pancreas
- Glucagon stimulates glycogen -> glucose breakdown in the liver
- this will increase blood glucose levels
What is the role of insulin in the adipose tissue?
- increase glucose uptake
- increase lipogenesis
- decrease lipolysis
What is the role of insulin in striated muscles?
- increase glucose uptake
- increase glycogen synthesis
- increase protein synthesis
What is the role of insulin liver?
- decrease glucogenesis
- increase glycogen synthesis
- lipogenesis
What is diabetes mellitus?
- a metabolic disorder characterised by chronic hyperglycemia, glycouria and associated abnormalities of lipid and protein metabolise,
Prevalence: - globally 422 million people have diabetes
-In UK 2018 ~ 3.8 million diagnosed with DM
What are classifications of diabetes?
- type 1 : deficiency in insulin secretion
- 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
Type 1 diabetes
- predominantly in children and young adults
- sudden onset
- appearance of symptoms may b preceded by ‘prediabetic’ period of several months
- 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.
What are pathogenesis of type 1 DM?
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.
How does destruction of pancreatic beta cell lead to hyperglycemia?
- destruction of pancreatic beta cell causes hyperglycemia due to absolute deficiency if both insulin and amylin.
- amylin is glucoregulatory peptide hormone co-secreted with insulin
- lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
what are metabolic complications of type I diabetes?
- insulin deficiency will lead to increased plasma glucose levels = hyperglycemia
- due to hyperglycemia polyphagia (excessively eating)
- glycosuria = due to there being excess glucose, kidney is not able to filter it all
- polyuria = more water gets into kidney
- volume depletion = due to polyuria
- polydipsia = body tries to compensate by drinking more water.
- diabetic coma
how does insulin deficiency lead to ketoacidosis?
- increased lioplysis
- increased free fatty acids (FFAs)
- increase FFA oxidation (liver)
- ketoacidosis
Type 2 diabetes
- slow onset
- patients middle aged/elderly prevalence
- strong familiar incidence
- pathogenesis uncertain - insulin resistance; beta cell dysfunction
What is pathophysiology of type 2 diabtetes?
- genetic predisposition and lifestyle factors can lead to insulin resistance
- compensatory eta cell hyperplasia
- beta cell failure (early) = impaired glucose tolerance
- beta cell failure (late) = diabetes.
What are metabolic complications of type 2 diabetes?
-low insulin leads to => increased gluconeogenesis =>glycogenolysis -this leads to hyperglycemia =>glucosuria =>osmotic diuresis =>loss of water and electrolytes (increased blood viscosity =thrombosis) => dehydration
how do you diagnose diabetes?
- In the presence of symptoms:
(polyuria, polydipsia, & weight loss for type 1)
=> random plasma glucose >/= 11.1 mmol/l(200mg/dl)
=> fasting plasma glucose >/= 7.0 mmol/l (126 mg/dl) fasting is defined as no caloric intake for at least 8 hrs
=>oral glucose tolerance test(OGTT) - plasma glu >/=11.1 mmol/l - In the absence of symptoms:
=>test blood samples on 2 separate days.
How do you diagnose pre-diabetes?
- impaired glucose tolerance (IGT)
2. impaired fasting glycaemia (IFG)
How is oral glucose tolerance test carried out?
- to check body’s ability of metabolising glucose
- in patients with IFG
- in unexplained glycosuria
- in clinical features of diabetes with normal plasma glucose values - 75g oral glucose and test after 2 hour
- blood samples collected at 0 and 120 mins after glucose.
What are treatments for T2D stepwise?
- diet and exercise
- oral monotherapy
- metformin - oral combination
- sulphonylureas
- gliptins
- GLP- 1 analogues - insulin + oral agents.
What is the aim of monitoring glycemia?
- to prevent complications or avoid hypoglycemia
1. self -monitoring to be encouraged: - capillary blood measurement
- urine analysis : glucose in urine gives indication of blood glucose concentration above renal threshold
What is the aim of monitoring glycemia?
- to prevent complications or avoid hypoglycemia
1. self -monitoring to be encouraged: - capillary blood measurement
- urine analysis : glucose in urine gives indication of blood glucose concentration above renal threshold
2. 3-4 months: blood HbA1c (glycated Hb; covalent linkage of glucose of residue in Hb.
others: urinary albumin (index of risk of progression to nephropathy)
What are long term complications of type 1 and type 2 diabetes?
- occur in both T1D and T2D
- micro-vascular disease
- retinopathy
- nephropathy
- neuropathy - macro-vascular disease
- related to atheroscelerosis heart attack/stroke - exact mechanisms of complications are unclear.
Define hypoglycaemia
-plasma glucose <2.5 mmol/L in both diabetic and non diabetic patients.
What are causes of hypoglycemia?
Drugs are most common cause
-more common in T1D than T2D
What are some common insulin secretagogues used in sulfonylureas that cause hypoglycemia?
- glyburide
- glipizide
- glimepiride
=> used to treat type 2 diabetes
What causes hypoglycemia in patients without diabetes?
- drugs such as alcohol
- quinolone, quinine, beta blockers, ACE inhibitors and IGF-1 - endocrine disease: eg. cortisol disorder
- inherited metabolic disorders, eg: heriditary fructose intolerance
- insulinoma (tumour)
How does ethanol cause hypoglycemia?
- inhibits glucogenesis
-but not glycogenolysis
(several days of alcohol binge and limited food intake will result in hepatic depletion of glycogen)
How does sepsis lead to hypoglycemias?
cytokines accelerated glucose utilisation and induced inhibition of gluconeogenesis in the setting of glycogen depeletion.
How does CDK lead to hypoglycemias?
-mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal glucose production.
What is reactive hypoglycemia (aka postprandial hypoglycemia)
=> drop in blood sugar are usually recurrent and occur within 4hrs after eating.
=> cause is unclear but could possibly be:
- benign tumour in the pancreas leading to overproduction of insulin
-too much glucose used up in tumour
- deficiencies in counter-regulatory hormones eg: glucagon.
What is the counter-regulatory response to hypoglycemia?
- brain : needs glucose for function so low levels are sensed by hypothalmus and activates the autonomic nervous system.
- ANS stimulates b cells in pancreas to decrease insulin production to decrease glycolysis.
- ANS stimulates alpha cells to increase glucagon production for glycogen -> glucose.
- ANS causes the adrenal gland to increase cortisol levels and noradrenaline levels will stimulate gluconeogenesis and glycolysis in liver.
What are signs and symptoms of hypoglycemia?
- neurogenic (autonomic)
- triggered by falling glucose levels
- activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
What is neuroglycopenia and what are signs and symptoms?
- due to neuronal glucose deprivation
symptoms:
- confusion, difficulty speaking, ataxia, paresthesia, seizures, coma, death.
