Diabetes Mellitus – Treatment with diet, drugs and insulin Flashcards
Describe Type 1 Diabetes
- Autoimmune destruction of islet beta cells
- Insulin deficiency
- Ketosis-prone
- Seldom overweight
- Diagnosed young, median age 9
Describe Type 2 Diabetes
- Decreased beta cell mass and dysfunction of islets
- Insulin resistance
- Not ketosis-prone
- Often overweight
- Tends to be diagnosed in later life
What are the aims of diabetes treatment?
- To restore disturbed metabolism to near normal
- To prevent, or delay progression, of diabetic complications
- To educate people about diabetes and motivate them to achieve effective self-management
What are the aims of dietary management in diabetes?
- To achieve good glycaemic control
- To reduce hyperglycaemia and avoid hypoglycaemia
- To ensure adequate nutritional intake
- To assist with weight management
- To avoid aggravating diabetic complications
What are the calorific values of food constituents?
- Carbohydrate= 4 kcals
- Protein= 4 kcals
- Fat= 9 kcals
- Alcohol= 7 kcals
Describe a weight-reducing diet
-Reduce/ eliminate refined carbohydrates and saturated fat
-Restrict TOTAL caloric intake (portion size)
=Increase insulin sensitivity
=Lower blood glucose
=Lower triglycerides/ LDL-cholesterol
What is the Glycaemic Index?
-GLYCAEMIC INDEX (GI) is a measure of change in blood glucose following ingestion of a particular food
=Post-prandial rise in blood glucose is influenced by amount and source of carbohydrate
-Different carbohydrate-containing foods can be ranked by their effect on post-prandial glycaemia
=Low GI foods produce a slow, gradual rise in blood glucose after ingestion
=Low GI foods include starchy foods (rice, spaghetti, granary bread, porridge) and pulses like beans and lentils
What is the recommended composition of a healthy diet as % energy intake?
- Carbohydrate= 45-60% (unrefined, complex)
- Fat <35% (monosaturated 10-20%)
- Protein= 10-15% (do not exceed 1g/kg body wt)
- High intake of dietary fibre (fruit, vegetables), low intake of salt
Describe dietary treatment of Type 1 Diabetes
- At diagnosis insulin should be started immediately
- Dietary modification requires restriction of refined sugars and saturated fats
- Diet is weight-maintaining for most people
- Insulin dosage adjustment is based on carbohydrate content of meals
- Structured education programmes are available, e.g. DAFNE (Dose Adjustment For Normal Eating)
- Other lifestyle changes (regular exercise) are supplementary
What are the potential therapeutic targets in T2DM?
- Adipose deposition
- Liver (gluconeogenesis)
- B-cell (dysfunction)
- Kidneys= promote more release of glucose through urine
Describe the intensification of therapy in Type 2 Diabetes management
- Diet and exercise
- Oral monotherapy
- Oral combination
- Oral and insulin
- Insulin
What are the indications and contraindications for oral hypoglycaemic drugs?
-Indications= T2DM (if diet alone inadequate)
=Insulin sensitizers in combination with insulin Type 1
-Contraindications= ketoacidosis, severe intercurrent illness
Describe sulphonyreas (T2DM)
- stimulate secretion of endogenous insulin
- used in non-obese patients (may be insulin-deficient)
- used as monotherapy or in combination with metformin, glitazone or insulin
- Glipizide (intermediate duration of action), gliclazide (older patients as shorter duration)
- choice of sulfonylurea is based on duration of action and method of elimination
- promote weight gain
- main adverse effect is hypoglycaemia
Describe Biguanide/ Metformin (T2DM)
- decreases hepatic glucose production
- increases insulin sensitivity in muscle
- encourages weight loss
- effective as monotherapy or in combination with sulfonylurea, glitazone or insulin
- side-effects include nausea and diarrhoea
- contraindicated in renal impairment (risk of lactic acidosis)
Describe Glucose Prandial Regulators (Glinides)
- Repaglinide (MEGLITINIDE)
- Nateglinide (AMINO ACID DERIVATIVE)
- Insulin secretagogues – direct effect on beta cells
- Stimulate rapid endogenous insulin release when given with meals
- Side-effects include weight gain and hypoglycaemia
- Lower risk of hypoglycaemia than sulfonylureas
Describe a glucosidase inhibitors
-Acarbose, Miglitol
-Delay digestion of carbohydrate and slow down postprandial absorption of glucose
-Do not cause weight gain
Limited efficacy; can be used in combination
-Gastrointestinal side-effects are common, including bloating and flatulence
Describe how PPAR gamma works
-Work in fat (lipolysis reduced)
0-lower plasma free fatty acids, increases adiponectin
-increase insulin sensitivity/ reduces insulin resistance in liver and muscle
=reduces glucose output in liver
=Increases glucose uptake from muscle
Describe Thiazolidinedione
- Pioglitazone
- Slow onset of action - take 2-3 months to achieve maximal effect (works at level of nucleus)
- Promote weight gain - but redistribute body fat to reduce visceral depot
- Contraindicated in congestive cardiac failure; hepatic impairment (water retention) May cause vertebral fractures
What is the Incretin Effect?
-Plasma insulin response to oral and IV insulin
=Secretion of insulin is greater in response to oral than IV
=Promoted by release of GI hormones “incretins”
Describe Glucagon-like peptide (GLP-1)
- Potent insulinotropic hormone (incretin) is released in response to meals
- Rapidly degraded in plasma by enzyme Dipeptidyl Peptidase 4 (DPP- 4)
- Plasma GLP-1 is lower in people with impaired glucose tolerance (IGT) and type 2 diabetes compared to healthy non-diabetic subjects
What are the physiological effects of GLP-1?
-Upon ingestion of food, GLP-1 is secreted from the L-cells of the intestine
=Stimulates glucose-dependent insulin secretion
=Suppresses glucagon secretion
=Slows gastric emptying
=Reduces food intake
=Improves insulin sensitivity
What are the therapeutic forms of GLP-1?
- Incretin mimetic, synthetic exendin-4 (Exenatide)
- GLP-1 analogue (Liraglutide)
- DPP- 4 inhibitors (Gliptins)
- EXENATIDE: synthetic form of Exendin-4
Describe incretin mimetics
- Exenatide, Liraglutide
- Act like a GLP-1 peptide
- Have to be given by injection
- Promote weight loss
- Given in combination with either metformin or sulfonylurea
- Main side-effect is nausea
- Hypoglycaemia rare except when given with SU
Describe gliptins
- Sitagliptin, vildagliptin
- DPP-4 inhibitors – inhibit degradation of incretin hormones and enhance their actions
- Oral route of administration
- Taken in combination with metformin
- Produce modest reduction in HbA1c so less effective
- Weight neutral
- Few side-effects, with minimal hypoglycaemia
Describe SGLT2 inhibitors
-Sodium-glucose Cotransporter-2 inhibitors
-acts as a glucuretic to remove glucosethat would otherwise be reabsorbed
=Lowers blood sugar
=canagliflozin, dapagliflozin, andempagliflozin
=Reduction in cardiovascular events?
What are the mechanisms and sites of actions for anti-diabetic drugs?
-Augment supply of insulin, pancreatic beta cell
=Sulfonylureas
=Prandial glucose regulators (glinides)
=Incretin mimetics
-Enhance insulin action and reduce resistance, liver fat and muscle
=Metformin
=Thiazolidinedione
-Delay carbohydrate absorption, gut
=a glucosidase inhibitors
=Incretin mimetics
What are the indications for insulin therapy in T2DM?
- Persistently elevated blood glucose and HbA1c on maximum doses of anti-diabetic drugs (secondary failure to anti-diabetes drugs)
- Symptoms of hyperglycaemia and/or infections (e.g. candidiasis)
- Non-fasting ketonuria
- Severe intercurrent illness
- Metabolic complications (hyperosmolar states)
What are the problems with insulin therapy?
- Insulin has to be given by injection
- Biological action is variable as insulin absorption is influenced by many factors (site of injection, ambient temperature, exercise, etc.)
- Insulin has to be given several times daily
- Insulin regimens are often complicated
What are the types and formulations of insulin?
- Short acting= soluble (actrapid, Humulin-S)
- Intermediate-acting= isophane (NPH)= Insulatard, Humulin-I
-Fixed mixtures are available containing combinations of soluble and isophane insulins e.g. 30% soluble with 70% isophane (Humulin M3)
What are insulin analogues?
- Substitution of single amino acid in insulin chain
- Alters absorption characteristics of insulin
- Time-action profile is modified by minor changes in amino acid sequence of insulin molecule
What are the types of insulin analogues?
- Fast-acting= insulin lispro (Humalog), aspart (Novorapid), glulisine (Apidra)
- Long-acting= insulin glargine (Lantus), detemir (Levemir)
-Fixed mixtures include Humalog Mix 25 (25% fast-acting) and Novomix 30 (30% fast-acting)
What are the time-action characteristics of insulins?
- Soluble= 30 mins onset, 1-2hrs peak effect, 7 hr duration
- Fast-acting analogue= 5-10 mins onset, 30-60 mins peak effect, 3 hours duration
- Isophane= 3hr onset, 7hr peak, 12-14hr duration
- Long-acting analogue= 1hr onset, no peak effect, 19-32 hr duration
What does insulin regime choice depend on?
- Targets for glycaemic control
- Time-action profile of insulins
- Ease and convenience of administration
- Flexibility of regimen
- Practical issues (e.g. disability, supply, species preference)
What are the different insulin regimens for treating diabetes?
- BASAL-BOLUS (Multiple injection): Short-acting or fast-acting insulin before meals; intermediate-acting or long-acting insulin once daily
- TWICE DAILY: Soluble or fast-acting and isophane (NPH) insulins combined; free-mixing or fixed mixture
- ONCE DAILY: Intermediate-acting or long-acting insulin, combined with anti-diabetic drugs (Type 2 diabetes)
What are the routes of administration for insulin?
-SUBCUTANEOUS - =syringes, pens, pumps -intrapulmonary - =inhaler (historical) -intravenous, intramuscular =injection (emergency use) -intraperitoneal - =dialysate (renal failure) -transplanted islets =pancreatic islets
Describe lipohypertrophy at insulin injection sites
- Unsightly
- Slows insulin absorption
- Resolves if site avoided
What are the side effects of insulin therapy?
- HYPOGLYCAEMIA
- WEIGHT GAIN
- lipodystrophy at injection sites
- peripheral oedema (salt & water retention)
- insulin antibody formation (animal insulins)
- local allergy (rare)
What are the signs and symptoms of hypoglycaemia?
-Blurred vision
-Sweating
-Hunger
-Dizziness
-Trembling
-Palpitations
=Low blood glucose (below 4 mmol/L)
What are the causes of insulin-induced hypoglycaemia?
-Administration of too much insulin
-Inadequate consumption of food
-Increased physical exercise
-Alcohol (without food)= switches off gluconeogenesis
=Mismatch occurs between plasma insulin and glucose concentrations
What are the risk factors for severe hypoglycaemia in Type 1 Diabetes?
-Duration of diabetes; Age (older); Gender (female)
-Impaired awareness of hypoglycaemia
=can’t sense symptoms
-History of previous severe hypoglycaemia
-Strict glycaemic control
=rate of hypoglycaemia increases
-Sleep
What is the treatment for hypoglycaemia?
MILD (self-treated) -Oral fast-acting carbohydrate (10-15g) =glucose drink =glucose tablets, confectionery -Oral supplementary snack (starch)
SEVERE (external help required) -Parenteral therapy =i.v. 20% dextrose (25-50g) =i.m. glucagon (1mg) -Oral therapy =buccal glucose gel; jam, honey
Describe morbidity associated with hypoglycaemia
-CNS =Coma, convulsions =Vascular events (stroke, transient ischaemia) =Cognitive impairment (young children) =Brain damage (rare) -Cardiac =Arrhythmias =Myocardial ischaemia/ infarct -Other =Accidents (including driving), injuries -Acquired syndromes =Impaired awareness of hypoglycaemia =Counterregulatory hormonal deficiencies
What are the reasons for difficulty achieving target HbA1c in T1DM?
- hypoglycaemia
- inadequate fasting or post-prandial glycaemic control
- wide glucose excursions
- weight gain
