Diabetes and Hypoglycaemia

Question 1

How are blood glucose levels maintained

Answer 1

dietary carbohydrate
glycogenolysis
gluconeogenesis

Question 2

Liver’s role in regulating glucose

Answer 2

after meals - stores glucose as glycogen

during fasting - makes glucose available through glycogenolysis and gluconeogenesis

Question 3

Insulin function in adipose tissue

Answer 3

↑Glucose uptake
↑Lipogenesis
↓Lipolysis

Question 4

Insulin function in liver

Answer 4

↓Gluconeogenesis
↑Glycogen synthesis
↑Lipogenesis

Question 5

Insulin function in striated muscle

Answer 5

↑Glycogen synthesis
↑Glucose uptake
↑Protein synthesis

Question 6

Diabetes Mellitus - define

Answer 6

…..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

Question 7

Diabetes Mellitus - type I vs type II

Answer 7

Type 1:
Insulin secretion is deficient due to autoimmune destruction of β-cells in pancreas by T-cells

Type 2:
Insulin secretion is retained but there is target organ resistance to its actions

Question 8

Diabetes Mellitus - secondary vs gestational

Answer 8

Secondary:
chronic pancreatitis, pancreatic surgery, secretion of antagonists

Gestational:
Occurs for first time in pregnancy

Question 9

Type 1 DM - cause

Answer 9

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

Question 10

Type 1 DM - onset

Answer 10

Sudden onset (days/weeks)

Appearance of symptoms may be preceded by
‘prediabetic’ period of several months

Question 11

In type I DM circulating autoantibodies to various -cell antigens against:

Answer 11

glutamic acid decarboxylase
tyrosine-phosphatase-like molecule
Islet auto-antigen

Question 12

HLA class II in type I DM

Answer 12

HLA class II cell surface present as foreign and self antigens to T-lymphocytes to initiate autoimmune response

Question 13

Most common antibody in type I DM

Answer 13

The most commonly detected antibody associated with type 1 DM is the islet cell antibody

Question 14

Destruction of pancreatic ß-cell causes

Answer 14

Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.

Question 15

Amylin - function

Answer 15

Amylin, a glucoregulatory peptide hormone co-secreted with insulin.

lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.

Question 16

Effect of insulin deficiency in type I DM

Answer 16

INSULIN
DEFICIENCY → Hyperglycemia (leads to glycosuria) → Glycosuria → Polyuria → Volume depletion (polydipsia) = diabetic coma

INSULIN DEFICIENCY → Increased
lipolysis → Increased free fatty acids (FFA) → Increased FFA oxidation (liver) → Ketoacidosis
(DKA) = diabetic coma

Question 17

Type 2 DM- Presentation:

Answer 17

Slow onset (months/years)

Patients middle aged/elderly – prevalence increases with age

Strong familiar incidence

Question 18

Type 2 DM - pathogenesis

Answer 18

Pathogenesis uncertain – insulin resistance; β-cell dysfunction:

may be due to lifestyle factors - obesity, lack of exercise

Question 19

Metabolic complications of Type 2 DM

Answer 19

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 20

Diagnosis, Type 2 DM, in presence of symptoms

Answer 20

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
Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l

Question 21

Diagnosis, Type 2 DM, in absence of symptoms

Answer 21

In the absence of symptoms:

test blood samples on 2 separate days

Question 22

Compare IGT vs IFG classification

Answer 22

IGT – impaired glucose tolerance
IFG – impaired fasting glycaemia

If impaired fasting glycaemia = increased risk of developing diabetes + developing cardiovascular disease is also increased

but this seems to be lower than if you have pre-diabetes (impaired glucose tolerance)

Question 23

OGTT should be carried out when

Answer 23

OGTT should be carried out:

in patients with IFG

in unexplained glycosuria

in clinical features of diabetes with normal plasma glucose values

Question 24

OGTT - process

Answer 24

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 25

Metformin - type II DM treatment ↑ ↓

Answer 25

↓ gluconeogenesis and ↑ peripheral utilisation of glucose; effective if residual functioning beta cells as acts only in presence of insulin Helps respond better to own insulin, lower the amount of sugar created by the liver, and decreasing the amount of sugar absorbed by the intestines.

Question 26

Sulphonylureas - type II DM treatment

Answer 26

Stim the cells in the pancreas to make more insulin They also help insulin to work more effectively in the body. Dipeptidyl peptidase inhibitor (DPP-4; Gliptins): inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

Question 27

Incretins - type II DM treatment

Answer 27

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

Question 28

Monitoring glycaemic control - aim

Answer 28

Aim: to prevent complications or avoid hypoglycaemia

Question 29

Self-monitoring - describe types

Answer 29

Capillary blood measurement Urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold

Question 30

Long term complications in DM

Answer 30

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 31

Hypoglycaemia - define

Answer 31

Defined as plasma glucose < 2.5 mmol/L

Question 32

Causes of hypoglycaemia + prevalence in types of DM

Answer 32

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:

Question 33

Why hypoglycaemia uncommon in pt w/DM that is not drug treated

Answer 33

In these patients hypoglycaemia may be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx.

Question 34

Sulfonylureas - examples

Answer 34

Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the more commonly used sulfonylureas.

Question 35

Stimulation of endogenous insulin - effect

Answer 35

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

Question 36

List type II DM drugs that should not cause hypoglycaemia

Answer 36

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 37

Drugs that cause hypoglycaemia

Answer 37

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

Question 38

Hypoglycaemia in patients without diabetes - list

Answer 38

Endocrines disease; e.g. cortisol disorder Inherited metabolic disorders, e.g. hereditary fructose intolerance. Insulinoma Others: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination).

Question 39

Ethanol effect on glucose regulation

Answer 39

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.

Question 40

Sepsis effect on glucose regulation

Answer 40

Sepsis: relatively common cause of hypoglycaemia. Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion

Question 41

CKD effect on glucose regulation

Answer 41

CKD: mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.

Question 42

Reactive hypoglycaemia - define

Answer 42

Also known as postprandial hypoglycaemia, drops in blood sugar are usually recurrent and occur within four hours after eating..

Question 43

Reactive hypoglycaemia - can occur in who

Answer 43

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.

Question 44

Reactive hypoglycaemia - cause

Answer 44

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 45

Explain effect of plasma glucose level decline in fast state

Answer 45

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

Question 46

Counter-regulatory hormones function in response to hypoglycaemia

Answer 46

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.

Question 47

Epinephrine effect

Answer 47

Epinephrine has similar hepatic effect as glucagon; inhibits insulin secretion..

Question 48

Signs & Symptoms of hypoglycaemia - categories

Answer 48

Neurogenic (autonomic) | Neuroglycopaenia

Question 49

Neurogenic (autonomic) symptoms - describe characteristics

Answer 49

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

Question 50

Neuroglycopaenia symptoms - describe characteristics

Answer 50

Neuroglycopaenia: Due to neuronal glucose deprivation. ``` Sign & symptoms include: confusion, difficulty speaking, ataxia, paresthesia, seizures, coma, death ```