Diabetes and hypoglycaemia

Question 1

How are blood glucose levels maintained?
What role does the liver play at different points?

Answer 1

→ 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:
1. after meals - stores glucose as glycogen
2. during fasting - makes glucose available through glycogenolysis and gluconeogenesis

Question 2

Why should glucose levels be regulated?

Answer 2

→ 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.

Question 3

What is Diabetes Mellitus?

Answer 3

→ Ametabolic disorder characterised by:
1. chronic hyperglycaemia
2. glycosuria and associated abnormalities of lipid
3. protein metabolism

→ the hyperglycaemia results from increased hepatic glucose production and decreased cellular glucose uptake blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria

Question 4

How can Diabetes be classified?

Answer 4

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, disappears after childbirth

Question 5

Describe the pathogenesis of Type 1 Diabetes Mellitus

Answer 5

→ 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.

Question 6

What do metabolic complications of Type 1 DM include?

Answer 6

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.

Question 7

How can Type 2 Diabetes Mellitus present?

Answer 7

→ 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

Question 8

What 2 main things make up the pathophysiology of Type 2 Diabetes?

Answer 8

Genetic predisposition and Obesity/lifestyle factors

Question 9

What do metabolic complications of Type 2 Diabetes include?

Answer 9

→ 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

Question 10

How would you look to diagnose DM?

Answer 10

→ 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 8h)
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, a blood test sample taken on 2 separate days

Question 11

What would you look at when testing for pre-diabetes?

Answer 11

→ 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.

Question 12

When should the oral glucose tolerance test(OGTT) be carried out?

Answer 12

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

Question 13

What can drug treatment entail for Diabetes?

Answer 13

→ Metformin: Decreases gluconeogenesis
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.

→ Sulfonylureas: bind and close KATP channels, depolarize B cell releasing insulin. They work mainly by stimulating the cells in the pancreas to make more 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)
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.

→ Synthetic GLP-1 analogues

Question 14

What are some long term complications of Diabetes?

Answer 14

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

Question 15

What is hypoglycaemia in diabetes and what are some causes of it?

Answer 15

→ 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.

Question 16

What do we know about hypoglycaemia in patients without diabetes and what are some causes of this?

Answer 16

→ Drugs such as alcohol may cause hypoglycaemia;
→ Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1
→ Endocrines disease; e.g. cortisol disorder
→ Inherited metabolic disorders, e.g. hereditary fructose intolerance

Insulinoma:
→ Rare tumours that start in the insulin making cells of the pancreas.
→ These cells are called pancreatic islet cells.
→ Insulinomas are also called islet cell tumours
→ Metabolic acidosis interferes with your body’s ability to maintain normal functions of your endocrine system (the collection of glands that produce hormones).
→ This can cause your body to build a resistance to insulin.
→ If left untreated for too long or not corrected in time, it can lead to diabetes.

Others:
1. Severe liver disease
2. Non-pancreatic tumours (beta cell hyperplasia)
3. Renal disease (metabolic acidosis, reduced insulin elimination).

Causes of hypoglycaemia in patients without diabetes:
1. Ethanol: inhibit gluconeogenesis, but not glycogenolysis.
→ The hypoglycaemia will typically follow several days alcohol binge with limited food intake; resulting in hepatic depletion of glycogen.

2. Sepsis: relatively common cause of hypoglycaemia.
   → Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion
3. CKD: mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.

Question 17

What is reactive hypoglycaemia? (Hypos After Eating)

Answer 17

Also known as postprandial hypoglycaemia;
→ drops in blood sugar are usually recurrent and occur within four hours after eating..
→ can occur in both people with and without diabetes,
thought to be more common in overweight individuals or those who have had gastric bypass surgery.
→ Cause is unclear
→ possibly a benign (non-cancerous) tumour in the pancreas may cause an overproduction of insulin,
too much glucose may be used up by the tumour itself.
deficiencies in counter-regulatory hormones: e.g. glucagon.

Question 18

What is the typical response to hypoglycaemia in normal subjects?

Answer 18

1. When plasma glucose level decline in fast state pancreatic beta-cells secretion of insulin is decreased (1st defence);
   → hepatic glycogenolysis and gluconeogenesis is increased
   → there is reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis
2. Counter-regulatory hormones are released:

→ 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 and limit utilisation.
→ Since the brain is permanently dependent on glucose, strong counter-regulatory mechanisms exists to quickly increase glucose levels to protect the human body from the negative consequences of hypoglycemia.
→ Counter-regulatory response to hypoglycemia (Figure1) includes inhibition of the endogenous insulin secretion and stimulation of glucagon, catecholamines (norepinephrine, epinephrine), cortisol and growth hormone secretion, which all together stimulate hepatic glucose production and cut down glucose utilization in peripheral tissues, increasing in this way plasma glucose levels.

Question 19

What are some signs and symptoms of hypoglycaemia?

Answer 19

1. Neurogenic (autonomic):
   → triggered by falling glucose levels
   → activated by ANS & mediated by sympathoadrenal
   → release of catecholamines and Ach

Symptoms of hypoglycemia are divided into two categories.
1= Neurogenic (autonomic) symptoms are triggered by a falling glucose level and cause patients to recognize that they are experiencing a hypoglycemic episode.
Neurogenic symptoms and signs associated with elevated adrenaline levels include shakiness, anxiety, nervousness, palpitations, sweating, dry mouth, pallor, and pupil dilation

2. Neuroglycopaenia: due to neuronal glucose deprivation.

Sign & symptoms include:
1. confusion
2. difficulty speaking
3. ataxia,
4. paresthesia
5. seizures
6. coma
7. death

Question 20

In summary…

Answer 20

→ Homeostatic mechanisms ensure maintenance of blood glucose levels within a narrow range, fed or fasting
→ DM is characterised by hyperglycaemia due to absolute or relative deficiency of insulin.

→ Monitoring is aimed at controlling of glycaemia and reducing complications

Different causes of hypoglycaemia:
→ in infants may result from inherited metabolic disease;
→ in adults – drugs or may be due to insulinoma.