Diabetes and hypoglycemia

Question 1

How are glucose levels maintained?

Answer 1

• dietary carbohydrate
• glycogenolysis
• gluconeogenesis

Question 2

What metabolic changes occur in fed state?

Answer 2

• 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

Question 3

What metabolic changes occur in fasting state?

Answer 3

• insulin levels decrease
• liver gluconeogenesis
• plasma glucose levels increase
• peripheral uptake decreases
• lipolysis/ proteolysis increases
• increase in catabolism

Question 4

Why is it important to have plasma glucose regulation?

Answer 4

• enough glucose to fuel the body , specially the brain

- too high plasma glucose can cause pathological changes in cells

Question 5

What happens at high glucose levels?

Answer 5

1. promotes beta cells in pancrease to release insulin
2. insulin stimulates glucose uptake from blood into muscle and adipose tissue
3. this will lower blood glucose levels
4. glucose -> glycogen for storage

Question 6

What happens at low glucose levels?

Answer 6

1. promotes glucagon release from alpha cells in pancreas
2. Glucagon stimulates glycogen -> glucose breakdown in the liver
3. this will increase blood glucose levels

Question 7

What is the role of insulin in the adipose tissue?

Answer 7

• increase glucose uptake
• increase lipogenesis
• decrease lipolysis

Question 8

What is the role of insulin in striated muscles?

Answer 8

• increase glucose uptake
• increase glycogen synthesis
• increase protein synthesis

Question 9

What is the role of insulin liver?

Answer 9

• decrease glucogenesis
• increase glycogen synthesis
• lipogenesis

Question 10

What is diabetes mellitus?

Answer 10

• 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

Question 11

What are classifications of diabetes?

Answer 11

1. type 1 : deficiency in insulin secretion
2. type 2: insulin secretion is retained but there is target organ resistance to its actions
3. secondary: chronic pancreatitis, pancreatic surgery, secretion of antagonists
4. Gestational: Occurs for first time in pregnancy

Question 12

Type 1 diabetes

Answer 12

• 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.

Question 13

What are pathogenesis of type 1 DM?

Answer 13

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.

Question 14

How does destruction of pancreatic beta cell lead to hyperglycemia?

Answer 14

• 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.

Question 15

what are metabolic complications of type I diabetes?

Answer 15

• 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

Question 16

how does insulin deficiency lead to ketoacidosis?

Answer 16

• increased lioplysis
• increased free fatty acids (FFAs)
• increase FFA oxidation (liver)
• ketoacidosis

Question 17

Type 2 diabetes

Answer 17

• slow onset
• patients middle aged/elderly prevalence
• strong familiar incidence
• pathogenesis uncertain - insulin resistance; beta cell dysfunction

Question 18

What is pathophysiology of type 2 diabtetes?

Answer 18

• 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.

Question 19

What are metabolic complications of type 2 diabetes?

Answer 19

-low insulin leads to 
=> increased gluconeogenesis 
=>glycogenolysis 
-this leads to hyperglycemia 
=>glucosuria
=>osmotic diuresis 
=>loss of water and electrolytes (increased blood viscosity =thrombosis)
=> dehydration

Question 20

how do you diagnose diabetes?

Answer 20

1. 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
2. In the absence of symptoms:
   =>test blood samples on 2 separate days.

Question 21

How do you diagnose pre-diabetes?

Answer 21

1. impaired glucose tolerance (IGT)

2. impaired fasting glycaemia (IFG)

Question 22

How is oral glucose tolerance test carried out?

Answer 22

1. 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
2. 75g oral glucose and test after 2 hour
3. blood samples collected at 0 and 120 mins after glucose.

Question 23

What are treatments for T2D stepwise?

Answer 23

1. diet and exercise
2. oral monotherapy
   - metformin
3. oral combination
   - sulphonylureas
   - gliptins
   - GLP- 1 analogues
4. insulin + oral agents.

Question 24

What is the aim of monitoring glycemia?

Answer 24

• 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

Question 25

What is the aim of monitoring glycemia?

Answer 25

- 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)

Question 26

What are long term complications of type 1 and type 2 diabetes?

Answer 26

1. occur in both T1D and T2D 2. micro-vascular disease - retinopathy - nephropathy - neuropathy 3. macro-vascular disease - related to atheroscelerosis heart attack/stroke 4. exact mechanisms of complications are unclear.

Question 27

Define hypoglycaemia

Answer 27

-plasma glucose <2.5 mmol/L in both diabetic and non diabetic patients.

Question 28

What are causes of hypoglycemia?

Answer 28

Drugs are most common cause | -more common in T1D than T2D

Question 29

What are some common insulin secretagogues used in sulfonylureas that cause hypoglycemia?

Answer 29

1. glyburide 2. glipizide 3. glimepiride => used to treat type 2 diabetes

Question 30

What causes hypoglycemia in patients without diabetes?

Answer 30

1. drugs such as alcohol - quinolone, quinine, beta blockers, ACE inhibitors and IGF-1 2. endocrine disease: eg. cortisol disorder 3. inherited metabolic disorders, eg: heriditary fructose intolerance 4. insulinoma (tumour)

Question 31

How does ethanol cause hypoglycemia?

Answer 31

- inhibits glucogenesis -but not glycogenolysis (several days of alcohol binge and limited food intake will result in hepatic depletion of glycogen)

Question 32

How does sepsis lead to hypoglycemias?

Answer 32

cytokines accelerated glucose utilisation and induced inhibition of gluconeogenesis in the setting of glycogen depeletion.

Question 33

How does CDK lead to hypoglycemias?

Answer 33

-mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal glucose production.

Question 34

What is reactive hypoglycemia (aka postprandial hypoglycemia)

Answer 34

=> 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.

Question 35

What is the counter-regulatory response to hypoglycemia?

Answer 35

1. brain : needs glucose for function so low levels are sensed by hypothalmus and activates the autonomic nervous system. 2. ANS stimulates b cells in pancreas to decrease insulin production to decrease glycolysis. 3. ANS stimulates alpha cells to increase glucagon production for glycogen -> glucose. 4. ANS causes the adrenal gland to increase cortisol levels and noradrenaline levels will stimulate gluconeogenesis and glycolysis in liver.

Question 36

What are signs and symptoms of hypoglycemia?

Answer 36

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

Question 37

What is neuroglycopenia and what are signs and symptoms?

Answer 37

- due to neuronal glucose deprivation symptoms: - confusion, difficulty speaking, ataxia, paresthesia, seizures, coma, death.