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[MBD] NoNa > Diabetes and Hypoglycaemia > Flashcards

Diabetes and Hypoglycaemia Flashcards

1
Q

What is Glucose and how is the blood glucose level maintained ?

A

Glucose is a major energy substrate

Blood glucose levels are maintained through :

  • Dietary Carbohydrate
  • Glycogenolysis - liver breaks down glycogen -> glucose
  • Gluconeogenesis - non-carbohydrate sources produce glucose
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2
Q

What is the role of the liver ?

A

Following Meals - Stores glucose as glycogen

During Fasting -Makes Glucose available through glycogenolysis (break down of glycogen ) and gluconeogenesis (production of glucose from non-glucose sources )

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3
Q

Why is it important to regulate blood glucose level ?

A

Brain and erythrocytes require continuous glucose supply therefore must avoid glucose deficiency

High glucose can cause pathological changes to tissues:
e.g. micro/macro vascular diseases, neuropathy

At high blood glucose, blood passes pancreas. pancreatic beta cells release insulin, which stimulates glucose uptake from blood into liver, muscles, adipose tissue = reduces blood glucose. Insulin: glucose ➔ glycogen for storage.
At low blood glucose, blood passes pancreas. pancreatic alpha cells secrete glucagon, which stimulates breakdown of glycogen to glucose to increase blood glucose

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4
Q

What is the function of insulin in the liver, striated muscle and adipose tissue?

A

Insulin release is induced by high blood glucose to reduce blood glucose level

Liver :
Decreases gluconeogenesis
Increases glycogen synthesis
Increases lipogenesis (lipid synthesis)

Striated Muscle:
Increases glucose uptake into muscle
Increases glycogen synthesis
Increases protein synthesis

Adipose tissue :
Increases glucose uptake into adipose tissue
Increases lipogenesis
Decreases lipolysis

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5
Q

What are the counter-regulatory hormones to insulin and what are their functions ?

A
  1. Glucagon -Mobilises fuels, maintains blood glucose in fasting
    - Activates gluconeogenesis /glycogenolysis and activates fatty acid release
  2. Epiniphrine -Mobilises fuels in acute stress
    - Stimulate glycogenolysis and stimulate fatty acid release
  3. Cortisol -Changing long term
    - Amino acid mobilisation and gluconeogenesis

4.Growth Hormone

see slide 7

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6
Q

Define Diabetes Mellitus

A

This is a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism

Hyperglycaemia due to ⬆ hepatic glucose production + ⬇ cellular glucose uptake
Glycosuria (glucose in urine) as blood glucose exceeds renal threshold

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7
Q

What is classified as glycosuria?

A

Glycosuria = excess sugar in the urine

Blood glucose>10mmol/L = exceeds renal threshold

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8
Q

What are the different classifications of Diabetes ?

A

Type 1: Deficiency in Insulin secretion due to autoimmune destruction of beta-cells of the pancreas by T-cells

Type 2: Insulin secretion is retained but target organ resists its actions

Secondary: Due to Chronic pancreatitis, pancreatic surgery, secretion of insulin antagonists.
pancreas removed = lack of insulin production

Gestational - Pregnancy

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9
Q

Describe Type 1 DM

A

Predominantly in children + young adults

Sudden onset (days/weeks)

Appearance of symptoms may be preceded by prediabetic period of several months.

Cause - Autoimmune destruction of B-cells of pancreas by T-cells:

  • Due to Interaction b/w genetic/environmental factors
  • Strong link with HLA genes within the MHC region on chromosome 6, ⬆susceptibility/protect against disease

In susceptible individuals, environmental factors may trigger immune-mediated destruction of pancreatic B-cells

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10
Q

Pathogenesis of Type 1 DM

A

1.Destruction of B-cells starts with autoantigen formation

2.Autoantigens are presented to T-lymphocytes to initiate autoimmune response (secrete toxins to destroy pancreatic B-cells)
(Autoantigens are ingested by APCs which activate T-helper1+2 lymphocytes. Activated T-helper1 lymphocyte secretes IL2 + interferon. But IL2 then activates autoantigen which is specific to T-cytotoxic lymphocytes which then secrete toxins to destroy islet cells. + Activated TH2 lymphocyte produces IL4 = stimulates B-lymphocytes to proliferate + produce islet cell autoantibodies)

  1. = Circulating autoantibodies to various cell antigens against:
    - Glutamic acid decarboxylase
    - Tyrosine-phosphatase like molecule
    - Islet auto-antigen

Most commonly detected antibody of T1DM = islet cell antibody

see notebook for clear process

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11
Q

How do both genetic predisposition and environmental factors link when it comes to pathogenesis of Type 1 DM ?

A

In a susceptible individual a environmental factor such as an infection by Epstein-Barr virus / CMV this will cause autoantigens to form on insulin-producing beta cells and circulate in the blood stream and lymphatics.

This will then be processed and presented as autoantigen by antigen presenting cells.

Activation of T helper 1 lymphocytes which will secrete interferon gamma and interleukin 2.
Interferon gamma will activate macrophages by releasing interleukin 1 and tumour necrosis factor alpha.

Interleukin 2 will activate autoantigen specific T cytotoxic cells.

Activation of T helper cell 2 will secrete IL-4 which will lead to activation of B lymphocytes which produces islet cell autoantibodies and antiGAD antibodies.

This will destroy beta cells with decreased insulin secretion

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12
Q

What is the most common antibodies found in Type 1 DM ?

A

Islet cell auto antibody
anti-glutamic acid dicarboxylic antibody.

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13
Q

Type 1 diabetes causes ……….glycaemia - How?

A

T1DM causes hyperglycaemia (⬇ insulin, ⬇ amylin)
Amylin = glucoregulatory peptide hormone, cosecreted w insulin. ⬇ blood glucose by slowing gastric emptying = suppresses glucagon secretion by pancreatic a-cells

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14
Q

What is amylin?

A

This is a glucoregulatory peptide hormone which is co-secreted with insulin.
It lowers blood glucose by slowing gastric emptying and supressing glucagon output from pancreatic cells

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15
Q

What are the metabolic complications of Type 1 DM?

A

Slide 14 + notebook
polyuria (osmotic diuresis)

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16
Q

What is the presentation of Type 2 DM ?

A
  1. Slow onset (months/yrs)
  2. Patients middle aged/elderly. Prevalence ⬆ with age
  3. Strong familiar incidence
  4. Pathogenesis is uncertain - insulin resistance, pancreatic Beta-cell dysfunction (insufficient insulin secretion)

Due to lifestyle factors, obesity ,lack of exercise

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17
Q

Pathophysiology of Type 2 DM ?

A

Insulin resistance

Genetic predisposition (family member has T2DM) + lifestyle factors = target organs insulin resistance.
= Compensatory Beta-cell hyperplasia as they try to produce sufficient insulin to ⬇ blood glucose. Eventually , there is beta-cell failure (early) and impaired glucose tolerance.
Further beta-cell failure (late) which leads to diabetes.

In cases where there is primary beta-cell failure, there will be diabetes straight away

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18
Q

What are the metabolic complications of Type 2 -DM

A

Pathogenesis of HONK state
Hyperglycaemic, Hyper-osmolar Non-Ketotic (HONK)

Insulin resistance of target cells = body thinks there is low blood glucose level bc low glucose uptake into cells
= ⬆ gluconeogenesis, ⬆ glycogenolysis
= develop Severe hyperglycaemia

= glycosuria
= osmotic diuresis = water moves from EC space into blood vessels = loss of water + electrolytes
= Extreme dehydration (= cardiovascular collapse)

loss of water + electrolytes = Increase plasma osmolality (blood becomes viscous) = thrombosis

hyperglycaemia = ⬆ plasma osmolarity = cerebral dehydration = Impaired consciousness

No ketosis

Death if untreated

19
Q

Describe the pathogenesis of the HONK state

A

Low insulin will lead to increased gluconeogenesis and glycogenolysis which both lead to hyperglycaemia .
This leads to glycosuria (sugar in urine ), this leads to osmotic diuresis which is the loss of water thus dehydration through loss of water and electrolytes.

The loss of water and electrolytes can also lead to thrombosis.

Hyperglycaemia also increases plasma osmolarity which can cause increased blood viscosity and thrombosis as well as cerebral dehydration

20
Q

How can HONK be diagnosed ?

A

⬆ glucose
⬆ osmolarity
⬆ pH (no ketones = alkaline. ketones are acidic)

21
Q

How is Diabetes diagnosed? what are the symptoms

A

Type 1 :
presence of symptoms - polyuria, polydipsia, weight loss(forT1)
and weight loss

-Random plasma glucose>11.1mmol/l
Fasting plasma glucose >7.0mmol/l.
(FASTING = No calorific intake for more than 8h)

HbA1c (haemoglobin ) test > 48mmol/l - two tests

Oral glucose tolerance test
(plasma glucose >11.1 mmol/l

Where there are no symptoms :
Test blood samples on 2 separate days

22
Q

What is the IGT and IFG (Pre-diabetes - at risk of developing diabetes + CVS disease) ?

A

Impaired glucose tolerance (IGT)

  • Fasting plasma glucose >7mmol/l, then
  • do OGTT to check if b/w 7.8-11.1mmol = IGT = pre diabetic

Impaired Fasting glycaemia (IFG)

  • Fasting plasma glucose 6.1-6.9 mmol/L +
  • OGTT value <7.8mmol/L

** OGTT used in individuals with fasting plasma glucose‹7.0 mmol/L to determine glucose tolerance status.

23
Q

When should the oral glucose tolerance test be carried out ?

A

OGTT should be carried out to check body’s ability to metabolise glucose - clear glucose from blood

  • In patients with IGT,IFG
  • In unexplained glycosuria
  • In clinical features of diabetes with normal plasma glucose values
  • For the diagnosis of acromegaly (excess growth hormone )

75g oral glucose and test after 2 hours
Blood samples collected at time0 before giving glucose + 120 mins after administering glucose to check body’s ability to metabolise glucose

Subjects tested fasting after 3 hours of normal diet containing at least 250 g carbohydrate.

24
Q

Treatment of T1DM

A

Treatment of T1DM = Insulin therapy

25
Q

Outline the treatment of T2DM

A
  1. Lifestyle changes - Diet and exercise
  2. Oral monotherapy - Metformin
  3. Oral combination of drugs - Sulphonylureas,Gliptins,GLP-1 analogues
  4. Insulin + oral agents
26
Q

Describe the drug treatment of Type 2 diabetes mellitus

A
  • *Metformin:** Decreases gluconeogenesis + increases peripheral use of glucose
  • *Sulfonylureas:** bind and close KATP channels, depolarize B cell releasing insulin
  • *Thiazolidinediones:** reduces insulin resistance
  • *Glitazones:** activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
  • *SGLT2 inhibitors:** promote glucose excretion via kidney. prevents glucose reabsorption in 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 - prevent breakdown of natural incretins

Incretin aids insulin production + reduces liver glucose production

27
Q

How does Sulphonylurea work ?

A

It works by stimulating pancreatic beta cells to secrete insulin = ⬇ blood glucose
causes hypoglycaemia if patient hasn’t eaten

28
Q

Outline the mechanism of Gliptins ?

A

This is a peptidyl-peptidase inhibitor which works by blocking peptidyl-peptidase 4 which is an enzyme which destroys the hormone incretin. Incretin helps the body produce more insulin and reduces the amount of glucose being produced by the liver when not needed.

Gliptins will block the enzyme which destroys incretin.

29
Q

What are GLP-1 analogues ?

A

Anatagonist which mimics the actions of nitra-incretin hormones to help lower the blood glucose levels after a meal.

30
Q

How are glycaemic levels monitored?

A

monitor glycaemic levels to prevent complications + avoid hypoglycaemia

Self-monitoring is encouraged:

  • Capillary blood measurement (home)
  • Urine analysis: glucose in urine indicates that blood glucose concentration is above renal threshold

3-4 months: Blood HbA1c (glycated Hb; covalent linkage of glucose to residue in Hb)

Urinary albumin = kidney damage (index of risk of progression to nephropathy)

31
Q

What are the long term complications of Type 1/2 diabetes?

A

Microvascular disease:
Retinopathy, Nephropathy (kidney damage), Neuropathy (diabetic foot ulcer which cannot heal = amputate leg). hyperglycaemia = protein glycation = increase sorbitol = thickens basement membrane + loss of pericytes

Macrovascular disease:
Related to atherosclerosis, heart attack/stroke. hyperglycaemia = endothelial damage, platelet adhesion, plaque formation

Exact mechanisms of complications are unclear

32
Q

Define Hypoglycaemia and causes

A

Hypoglycaemia: plasma glucose <2.5 mmol/L

  • Hypoglycaemia in diabetes
  • Hypoglycaemia in non-diabetic patients

Causes:
Drugs
-Common in type 1 diabetes
-Less common in type 2 diabetes taking insulin +insulin secretagogues (substance which promotes secretion)

Uncommon in patients who do not have drug-treated DM

In these patients hypoglycaemia may be caused by :

  • Alcohol
  • Critical illness (hepatic disease, renal disease ,cardiac failure,sepsis, insulinoma, hormone deficiency, inherited metabolic dx)
33
Q

What are some commonly used sulfonylureas?

A
  • Exogenous insulin
  • Insulin secretagogues - glyburide, glipizide, glimepiride

cause hypoglycaemia

Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increases glucose utilisation

34
Q

What drugs are used to treat type 2 diabetes earlier in the disease ?

A
  • Insulin sensitisers (Metamorfin, Glitazones)
  • Glucosidase inhibitors
  • glucagon-like peptide-1 (GLP-1) receptor antagonist
  • DPP-4 inhibitors

These drugs should not cause hypoglycaemia

T2DM drugs increase risk of hypoglycaemia if used together with insulin secretagogues

35
Q

What can cause hypoglycaemia in non-diabetic patients?

A

-Alcohol causes hypoglycaemia
-Drugs causing hypoglycaemia:
Quinolone
Quinine
Beta blockers
ACE inhibitors
IGF-1 - Insulin Growth Factor 1

Endocrine disease - cortisol disorder = hypoglycaemia

Inherited metabolic disorders - hereditary fructose intolerance = hypoglycaemia

Insulinoma (tumour) - beta cells of pancreas = excess insulin = hypoglycaemia

severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metabolic acidosis, reduced insulin elimination) = hypoglycaemia

36
Q

How does ethanol lead to hypoglycaemia ?

A

Alcohol inhibits gluconeogenesis but not glycogenolysis

The hypoglycaemia will follow several days alcohol binge with limited food intake

This results in hepatic depletion of glycogen

37
Q

How does Sepsis cause hypoglycaemia ?

A

Common cause

Releases cytokines

= Cytokine-accelerated glucose utilisation + induced inhibition of gluconeogenesis in the setting of glycogen depletion

38
Q

How does CKD cause hypoglycaemia ?

A

Unclear mechanism

Impairs gluconeogenesis + reduced renal clearance of insulin + reduced glucose production

39
Q

Outline reactive hypoglycaemia and the cause

A

Reactive hypoglycaemia aka postprandial hypoglycaemia

-Drops in blood sugar are usually recurrent and occur within four hours after eating

Reactive hypoglycaemia due to excessive pancreatic insulin production following carb-rich meal. excess insulin production continues after glucose from meal is digested = blood glucose level drops

Can occur in both diabetic +non diabetic patients

More common in overweight individuals/ gastric bypass surgery

The actual cause of reactive hypoglycaemia is unclear:

  • benign tumour in the pancreas causing overproduction of insulin
  • Too much glucose may be used up by the tumour itself after eating
  • Deficiencies in counter-regulatory hormones e.g. glucagon
40
Q

What is the normal counter-regulatory response to hypoglycaemia ?

A

brain requires glucose = strong counter-regulatory mechanisms to swiftly increase blood glucose.

  1. When plasma glucose level declines in fast state , pancreatic beta cells secretion of insulin will decrease
    + stimulate glucagon secretion by pancreatic alpha cells = + hepatic glycogenolysis and gluconeogenesis are increased
    + reduced glucose utilisation of peripheral tissue , inducing lipolysis and proteolysis

2.Counter regulatory hormones are released.

= stimulates adrenal gland to release cortisol + adrenaline. adrenaline stimulates hepatic glycogenolysis + gluconeogenesis.

  • Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence)
  • Epinephrine release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis
  • If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production + limit peripheral utilisation.
41
Q

Outline the counter-regulatory respone to hypoglycaemia

A

Look at slide

cortisol, adrenaline and glucagon reduce peripheral glucose utilisation + increase glucose production (gluconeogenesis,glycogenolysis) to meet body demands

42
Q

What are the signs and symptoms of hypoglycaemia ?

A
  1. Neurogeneic (Autonomic)
    - Triggered by falling glucose levels
    - Activated by ANS + mediated by sympathoadrenal release of catecholamine (adrenaline, noradrenaline) + ACh from postsyn sym. nerve endings

⬆ adrenaline - trembling, pale, sweating, mood changes, blurred vision (pupil dilate), headache, hunger, dry mouth, palpitation

2.Neuroglycopaenic
-Due to neuronal glucose deprivation
-Sign and symptoms:
Confusion
Difficulty speaking
Ataxia-degenerative disease of the nervous system
Paraesthesia-abnormal sensation of the skin
Seizures
Coma
Death

43
Q

Fed state

A

plasma glucose ⬆ = insulin release = ⬇ liver glucose production = inhibition of glycogenolysis + inhibition of gluconeogenesis + ⬆ glucose uptake into liver to convert it to glycogen for storage
⬆ peripheral uptake of glucose into muscle + adipose tissue
⬇ peripheral catabolism (⬇ lipolysis + proteolysis) to reduce glucose in bloodstream

44
Q

Fasting state

A

⬇ blood glucose level
⬇ insulin production by pancreas
⬆ gluconeogenesis - liver produces glucose from non-carb sources (lactate, aa’s) to ⬆ plasma glucose
⬇ peripheral uptake of glucose into muscles + adipose tissue
⬆ catabolism - breakdown of lipids (lipolysis) + proteins (proteolysis) to release glucose into bloodstream

[MBD] NoNa (28 decks)

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