Diabetes

• Type I (previously 'insulin-dependent')- autoimmune condition-->destruction of pancreatic beta cells ; body produces no insulin.
•Type II (previously 'non-insulin dependent')

- Family Hx
-Ethinicity: −Type I diabetes is more common in Northern European countries.
−Type II diabetes is more prevalent in South Asian (6x), African or Afro-Caribbean (3x) and Chinese populations.
-Age (Type II): > 40yrs

-Weight (T2): −Lose 5% weight à reduce risk of diabetes by 50%.
-Waist cirumference (T2)
-Sedentary lifestyle (T2)
-Social deprivation/low income

Often acute:
-2-4 week history of thirst, polyuria (increased urination), weight-loss, lethargy

More sub-acute and less marked:
-History of thirst, polyuria, lethargy, visual disturbances, infections, which occur over several months.

-Glucosoria: (excretion of glucose in urine)
-Hyperglycaemia (elevated blood glucose levels):
Elevated random plasma glucose (≥11.1mmol/L) & Elevated fasting plasma glucose (≥7mmol/L).
- Impaired glucose tolerance
- Complications of diabetes e.g. retionopathy

-Without insulin, cells cannot absorb glucose from the blood. The body switches to using other sources of fuel (glycogen, fats (can cause ketaacidosis) and proteins)

When blood glucose levels are elevated:
- increase in blood volume is countered by increased urinary output.
-increased osmotic pressure in the renal tubules --> reduced glucose and water reabsorption

−Detection of glucose in urine
−Random venous plasma glucose test
−Fasting venous plasma glucose test
−Oral glucose tolerance test
−Glycated haemoglobulin (HbA1c) levels of ≥6.5% (48mmol/mol) in some people with diabetes

-Oral glucose tolerancetesting (ogtt)
-Measure of how our bodies respond to glucose

- exposure of RBCs to glucose results in their haemoglobin (Hb) becoming irreversibly glycated --> HbA1c
- Increased blood glucose levels lead to increased HbA1c levels.
- If diabetic is not managing their diabetes --> then the HbA1c levels will be higher than normal

•Preserve life.
•Alleviate symptoms.
•Achieve good glycaemic control to avoid long-term complications.
•Avoid iatrogenic side effects (i.e. hypoglycaemia).

-Injected insulin
- Dietary modification: Low fat, high fibre, healthy diet that spreads nutrient load across day to avoid swings in blood glucose
- Monitoring
- Exercise, education

-Remission
-Hypoglycaemia
-Lipophypertrophy: accumulation of fat at injection sites due to local effects

- (HHS): a medical emergency involving hyperglycaemia, dehydration and uraemia.
-middle-aged, elderly and Afro-Caribbean at risk

-Lifestyle: 1st
-Education
-Drug treatments: Oral hypoglycaemic agents, Insulins

•Enhance the effect of endogenous insulin -->increasing the sensitivity of peripheral tissues to insulin and decreasing glucose production in liver

Biguanide, metformin, and thiazolidinediones ("glitazones")

Metformin
-reduce HbA1c by 1.5-2%
-Suppresses appetite, weight loss and reduces mortality and morbidity
-S/E --> abdominal pain, nausea, diarrhoea

-Insulin sensitizers
-Can take up to 3 months to see maximal effect
-Reduced availability of fatty acids in muscle improves insulin sensitivity
• Reduce hepatic glucose output

S/E: Increase risk of CV disease
-Induces weight gain but weight gain is limited to hips and thighs (a "lower risk" pattern of distribution) and intraabdominal fat is reduced.

-Sulphonylureas
-meglitinides

•i.e. short-acting gliclazide or tolbutamide or long-acting glibenclamide
-S/E: weight gain, sustained hypoglycaemia

i.e. nateglinide, repaglinide
-Less marked effect on glycaemic control
-S/E: short-acting so reduced risk of hypoglycaemia and reduced need to snack, less weight gain

i.e acarbose
-MOA: Slows digestion and absorption of glucose after a meal, reducing the post-pranial peak in blood glucose, stabilising blood glucose levels throughout the day

-stimulates insulin release from b-cells and suppresses glucagon release from alpha-cells
-It slows gastric emptying, slowing digestion and absorption of nutrients
•Reduces appetite

-i.e. Saxagliptin, sitagliptin, vildagliptin (oral route)
- Inhibits DDP4, GLP-1 degradation decreases which leads to increased insulin secretion and decreased glucagon secretion

-exenatide, dulaglutide, liraglutide, semaglutide
- used in combo with metformin, a sulfonylurea or pioglitazone or insulin (sitagliptin)

-sodium-glucose co-transporter-2 inhibitors
-located in the proximal tubules inhibition --> decrease in blood glucose by increasing renal glucose excretion

-i.e. canaglifozin, dapagliflozin, empagliflozin (oral route)
-Used as a monotherapy if diet and exercise fail and metformin is inappropriate/contra-indicated or as an add-on therapy with other glucose-lowering medicines to help establish good glycaemic control

Treated with insulin
- tends to be given aloongside oral hypoglycaemic drugs

-Diabetes occurring for the first time during pregnancy
-Increases risk of miscarriage, congenital malformations, still birth or baby dying in first year of life

-lifestyle modification: diet withh low fat, high in carbs, exercise.

insulin is drug of choice for gestational diabetes, some oral hypoglycaemic drugs might be considered (i.e. metformin or glibenclamide after 11 weeks gestation

-gene therapy: nucleic acids
- proteins & peptides: polypetides e.g INSULIN
-MABs: polypeptides
-Vaccines:

It is a protein;
Would be digested by gastric and intestinal componenets

- Purified animal insulin: can be derived from pig/cow
- recombinant DNA technology:

when injected subcutaneously, a 'depot' is formed:
-Lowest Mwt monomeric insulin is most rapidly released
•Dissociation of aggregates/crystals/complexed insulin results in slow release of active therapeutic

1. One, two or three insulin injections per day
2. Multiple daily injections
3. Continuous sub-cutaneous insulin infusion

Pre-filled injectors or
Solution for injection plus
- syringe and needle
- Injectors, autoinjectors
- Needle-free injectors
- Pumps

Protein solutions not stable at elevated temperatures

Hypoglycaemia
Diabetic ketoacidosis (KDA)
Hyperglycaemic hyperosmolar state (HHS)

•when blood glucose levels fall below 4mmol/L.

- oral glucose
- IM or S/C glucagon or IV glucose (dextrose) if unconscious or unable to swallow

diabetic ketoacidosis: uncontrolled hyperglycaemia--> lack of insulin, glucose cannot be used as an energy source so alternatives such as fats, and frre fatty acids are used --> build up of ketones

−IV rehydration (IV 0.9% saline).
−Insulin infusion (to correct hyperglycaemia).
− correction of electrolyte balance (potassium may be low: hypokalemia).

HHS: •very high blood glucose levels, often as a result of both illness and severe dehydration.
- Often occurs in T2D

−Anti-coagulant prophylaxis with low molecular weight heparins
−Prevention of foot ulceration

•Cardiovascular disease.

•Neuropathy (nerves)

•Retinopathy (eyes)

•Renal disease (nephropathy).

•Extremities (i.e. feet).

- Tricyclic ADs (TCA): amittriptyline
-Serotonin-noadrenaline reuptake inhibitors (SNRI): duloxetine
- VGCC alpha 2 delta subunit ligands: pregabalin, gabapentin

-Sildenafil (PDE5 inhibitor) for erectile dysfunction (autonomic neuropathy).
-Antiemetics for nausea and vomiting

-Anti-vascular endothelial growth factor (VEGF) intra-ocular injection
- Intra-ocular corticosteroid implant

-ACE inhibitors and angiotensin II (AII) receptor antagonists can be used to prevent further kidney damage and control blood pressure (BP)

- Air embolism
-Thrombosis; formation of a clot in a blood vessel
-Phlebitis; inflammation of the vein
-Extravasation/leakage of the injection into surrounding tissue

-Quite slow and unpredicatable

-Bolus is time and amount given is based upon on food take
-basal; provides steady dose throughout day and night

Solubility
-Co-solvents can be used such as ethanol, PEG, glycerine
-Surfactants: sorbitan
Preservatives (should be avoided in single dose IV)
-phenol
Osmolarity and pH
-Buffers: sodium acetate

-DESMOND
-X-PERT
-DAFNE

•Reinforce diet and lifestyle advice
•Offer support through locally commissioned services e.g weight management programmes, blood pressure monitoring
•NMS and MUR (until phased out, then through new consultation services run by GP pharmacists)
•Ensure patients receive NICE-recommended care processes:
e.g. HbA1c measurement, with a suggested target of 48 mmol/mol (6.5%)

-Hypo/hyperglycaemia
-Blood glucose: ( 4-9mmol)

T1D: Insulin
TD2: Diet, metformin (especially if overweight) or sulphonylurea
•Other newer drugs
•Insulin

- •Insulin passports and patient information booklets should be offered to patients receiving insulin
•Insulin passport - credit-card sized record of the patient's current insulin preparations and has a section for emergency information

<4mmol/L glucose

-The immediate treatment is to have some sugary food
-between 3 and 5 dextrose tablets
-a handful of sweets
-Avoid fatty foods & drinks: chocolate and milk

Patient may be advised to:
•increase the dose of insulin
•change their diet - for example, avoid foods that cause glucose levels to rise, such as cakes or sugary drinks
•get more exercise
•monitor glucose levels
-For extreme hyperglycaemia --> diabetic ketoacidosis --> A&E

•Illness generally increases physiological insulin requirements and will affect blood sugars
•While unwell it is VERY likely that blood glucose will increase even if you are eating less than usual

-Staying hydrated: 100ml every hours
-Not fasting
-Continuing to take tablets and/or insulin as normal
-•Patients on insulin: test for ketones (e.g Ketostix)
-Type 1 - more monitoring of blood glucose (every 4 hours) and urinary ketones
-Type 2 - monitoring of blood glucose.

-metformin
-Sulfonylureas
-GLP-1 analogues e.g. exentatide
-SGLT2 inhibitorss: canagliflozin
-ACEi/ARBs
-diuretics
-NSAIDs

-Eye (retinopathy)
-Neuropathy- •sensory loss in hands and feet
-nephropathy

•Plan ahead and follow general travel advice
•Diet - still eat healthily, take some healthy snacks whilst travelling as well as fast-acting carbohydrates
•Medicines and travel vaccines - carry insulin passport, take x2 the quantity of medical supplies normally used
•Travel insurance
•Air travel - a letter from the GP explaining the need to carry syringes or injection devices and insulin.

-Energy balance: BMR & Weight loss
-Foetal programming
-Genetics of obsesity
-Appetite regulation

obese: 30-34.9
severe: 35- 39.9

•Under-nutrition in gestation induces programming of the pancreatic beta cells, muscle, liver, adipose tissues and neuroendocrine axis
-Increases risk of obesity, glucose tolerance

•Thrifty metabolism gene allows for fat storage to protect against famine
-Cycle and feast and famine

-Insulin
-Leptin

Peptide hormone secreted by gastric mucosa
-Levels rise just before meals and falls after
-Increases food intake

-diabetes
-Gall bladder disease
-HT
-Dyslipidaemia
-Sleep apnoea
-Breathlessness
-Nonalcoholic fatty liver disease

Active endocrine

Orlistat/Alli
•Reduce fat absorption
•Eating fat causes anal leakage

-Vertical sleeve gastrectomy
-Adjustable gastric band
-Gastric bypass