FAR 381

Obesity and diabetes

Shamiso Mlambo
Department of Pharmacology
shamiso.mlambo@up.ac.za
 Obesity
• Mechanism resulting from evolution:
• Storage of excess energy latent in foodstuffs in adipose tissue as energy-dense
triglycerides
• easily mobilised when food is scarce

• Obesity: Abnormal or excessive fat accumulation that may impair health

• Multifactorial disorder
• Energy imbalance: long-term calorie intake ˃ energy output

• Generally accepted benchmark for classification (WHO):

• Body mass index (BMI) = mass (kg)/height (m)2
• Obesity: BMI ≥ 30
• BMI not a direct measure of adiposity
• Cannot distinguish lean mass from body fat
 Obesity
• Pathophysiology:
• Disturbance of homeostatic mechanisms controlling energy balance
• Genetic factors

• BMI guide:

BMI ˂ 18.5 kg/m2 : Underweight

BMI = 18.5 to 24.9 kg/m2: Acceptable/ “healthy”
BMI = 25.0 to 29.9 kg/m2: Overweight
BMI = 30.0 to 34.9 kg/m2: Grade 1 obesity
BMI = 35.0 to 39.9 kg/m2: Grade 2 obesity
BMI > 40.0 kg/m2: Grade 3 obesity/ morbidly obese
 Homeostatic Control of Energy Balance
• Leptin mRNA expressed in adipocytes
• Long-term regulation of food intake
• Secretion dependent on adiposity status
• Synthesis increased by glucocorticoids, insulin and oestrogen

• Hypothalamus
• Regulates appetite, feeding behaviour and energy status
• Receives signals from GI tract
• Contains receptors for leptin and other hormones
• Opposing neurons in arcuate nucleus
• Anorexigenic (appetite suppressing) and orexigenic (appetite promoting)
• Falling leptin levels vs rising leptin levels
 Causes and Risks of Obesity
Causes Risks

• Deficiencies in synthesis or response to • Type 2 diabetes

leptin
• Defects in hypothalamic neuronal systems’ • Cardiovascular diseases
response to adiposity signals
• Defects controlling energy expenditure • Osteoarthritis

• Decreased metabolic expenditure of • Hormone-dependent cancers (e.g colon,

energy breast, prostate cancer)

• Genetic contribution • Respiratory problems

 Approaches to The Problem of Obesity
• Diet and exercise
• Pharmacotherapy
• Indication:
• BMI ≥ 30
• BMI ≥ 27 with associated high blood pressure, type 2 diabetes or high
cholesterol
• Bariatric surgery
• Mechanical reduction in stomach size
• More effective than licensed drugs
• Indication: BMI > 40 or > 35 with comorbidities
 Pharmacotherapy
• Targeting different stages of the eating cycle
• Preventing over-eating
• Enhance satiety Anorexiants
Start
eating

Appetite
Total energy
suppressants Lipase inhibitors intake
approved for
short-term use
only
Stop eating
 Anorexiants
• Appetite suppressants
• Schedule IV medications
• Centrally-acting drugs
• Delay hunger signal
• Target Serotonin (5-HT), Noradrenaline (NA) and Dopamine (DA)
• 5-HT, NA and DA play a role in modulation of satiety signals

• Drugs:
• Phentermine + Diethylpropion - Pharmacology similar to amphetamines
(potential for abuse)
• Sibutramine – Withdrawn from market (cardiovascular events + strokes)
• Amphetamines, 2,4-Dinitrophenol, Fenfluramine, Rimonabant - Withdrawn
 Anorexiants: Mechanisms of action
Agent Releasing Inhibiting reuptake
5-HT NA DA 5-HT NA DA

Phentermine
*limited to 3 months
Teratogenic

Diethylpropion
*Extensive first pass metabolism
Sibutramine
*First pass demethylation to Mild
active metabolite activity
*Decrease triglycerides and VLDL

VLDL: Very low density lipoprotein

 Anorexiants
• Adverse effects
• Dry mouth, insomnia, constipation
• Increased heart rate and blood pressure
• Phentermine: CNS effects, heart valve disorders, pulmonary hypertension
• Sibutramine: Drug-drug interactions with CYP3A4 inhibitors

• Contraindications
• History of hypertension, CVD, arrhythmia, heart failure, stroke
• Sibutramine: avoid selective serotonin reuptake inhibitors (SSRIs)
 Anorexiant: Lorcaserin (BELVIQ®)
• FDA approval (May 2012) with restrictions and patient monitoring
• June 2013: classified under Controlled Substances Act

• MOA
• Selective 5-HT2C receptor agonist
• Decreased appetite

• Adverse effects
• Headache, dizziness, dry mouth, nausea, cough, constipation

• Contraindications
• Selective serotonin reuptake inhibitors and monoamine oxidase inhibitors
• Serotonin syndrome: high fever, muscle rigidity and confusion
 Lipase Inhibitors: Orlistat
• Only anti obesity drug licensed worldwide for long-term treatment of
obesity
• Safety not established in patients < 12 years
• Contraindicated in pregnancy
• MOA
• Irreversibly bind serine residues on gastric and pancreatic lipases
• Prevent breakdown of dietary fat to fatty acid and glycerol

• Adverse effects:
• Oily spotting, flatulence with discharge, faecal urgency, increased defaecation
• Reduces absorption of cyclosporine + contraceptive pills

• Interferes with absorption of fat soluble vitamins

• Multivitamin supplements: A, D, E, K
 Combination Drugs
• Phentermine and Topiramate
• Long-term treatment of obesity
• Topiramate: anticonvulsant with weight loss effects
• Phentermine: Stimulant to counteract the sedation of topiramate + additional weight loss
effects
• Step-dosing: dose escalated every two weeks
• Dependent on patient response
• Discontinued If a patient does not achieve a 5% weight loss after 12 weeks on the highest
dose
• Not to be stopped abruptly, should be tapered off Drug-drug interactions:
Topiramate:
• Adverse effects -Reduce efficacy of oral
• Topiramate: suicidal ideation, cognitive dysfunction contraceptives
• Phentermine: Increased heart rate -Hypokalaemia with use of non–
potassium-sparing diuretics
• Contraindicated in pregnancy Phentermine:
• Topiramate: Cleft palate -Serotonin syndrome with use of
MAOIs
 Newly-approved Anti-obesity Drugs

Date of FDA
Drug Mechanism of action Common adverse events
approval

Naltrexone/ Naltrexone (µ opioid Nausea, constipation, September 10,

Bupropion Contrave® receptor antagonist/ headache, vomiting, 2014
(Combination drug) Bupropion (NA + DA dizziness, insomnia, dry
reuptake inhibitor) mouth, diarrhoea
Liraglutide Glucagon-like Nausea, diarrhoea, December 23, 2014
(Victoza® or peptide-1 (GLP-1) constipation,
Saxenda®) agonist hypoglycaemia, decreased
appetite, pancreatitis,
kidney failure, gall bladder
problems, increased HR
 Questions???
1. Mr Smith suffers from hypertension and is also obese. The doctor
prescribes phentermine for his obesity. Comment on this prescription.
2. Kim is a pregnant newlywed and decides to get treatment for her
obesity, for the health of her baby. She is put on combination therapy for
obesity. What is the implication of this prescription?
Diabetes
 Pancreatic Islet Hormones
• Pancreatic Islet of Langerhans: 4 main cell types that secrete peptide
hormones
Cell type Peptide hormones Function

α-cells Glucagon Increase blood glucose

and protein breakdown
from striated muscle
β-cells Insulin Decrease blood glucose

δ-cells Somatostatin Inhibit secretion of

insulin and glucagon
PP cells Pancreatic polypeptide Function unknown
 Insulin
• Consists of 2 polypeptide chains
• Main hormone controlling intermediary
metabolism

Protease
• Preproinsulin
(Synthesized in • Proinsulin • Bioactive
rough ER) (Packaged Insulin
Signal in
peptidase secretory Stored in
vesicles) β-cells
 Function of Insulin
• Low basal levels of insulin maintained by constant secretion
• Stimulated by increased
blood glucose
• Glucose uptake by liver,
muscle and adipose cells
• Increases facilitated
transport of glucose via
Glut-4 transporter
• Liver: Glycogen
• Muscle: Glycolysis to
produce energy
• Adipose cells: Converted
to glycerol for fat synthesis
 Glucagon
• Single-chain, fuel-mobilising polypeptide
• Additional synthesis in upper GIT
• Little daily variation in plasma concentration
• Exerts effect on G-protein-coupled receptors
• Stimulate adenylate cyclase
• Glycogen breakdown and gluconeogenesis

• Secretion stimulated by decreased blood glucose

• Inhibited by opposite effect
• Release stimulated by sympathetic nerve activity and adrenaline via
β-adrenoceptors
 Blood Glucose Regulation
• Excess calories stored as glycogen or fat
• Mobilisation of energy stores regulated
• Insulin = important regulatory hormone
• Excessive insulin Hypoglycaemia Insulin secretion reduced
• Secretion of counter-regulatory hormones: Glucagon, adrenaline, glucocorticoids, growth
hormone

Glucose = Insulin = Glucose uptake = Glucose

Glucose = Glucagon = Glycogenolysis = Glucose

 Effects of hormones on Blood Glucose
Hormone Main action Main stimuli Main effect
Main regulatory hormone
Insulin Increase glucose uptake and Increased blood Decreased blood
glycogen synthesis glucose glucose
Decrease glycogenolysis and
gluconeogenesis
Main counter-regulatory hormones
Glucagon Increase glycogenolysis and
gluconeogenesis
Adrenaline Increase glycogenolysis
Increased blood
Glucocorticoids Decrease glucose uptake & Hypoglycaemia
glucose
utilisation
Increase gluconeogenesis
Growth hormone Decrease glucose uptake
 Diabetes Mellitus (DM)
• Combination of insulin deficiency (relative or absolute) and insulin
resistance

• Characterised by high blood glucose (Hyperglycaemia)

• Fasting blood glucose level > 7 mmol/l or oral glucose tolerance test > 11.1
mmol/l (2 hours post prandial)
• HbA1c: measures non-enzymatic glycation of haemoglobin (determine blood
glucose levels over time)

• Metabolic disorders
• Decreased carbohydrate metabolism
• Increased protein and lipid metabolism
 Clinical Classification of DM
• Type 1 DM
• Little to no production of insulin
• Can be caused by autoimmune destruction of pancreatic beta cells
• Triggered by invasion of viruses and chemical toxins
• Absence of exogenous insulin: Ketoacidosis
• Type 2 DM
• Characterized by insufficient insulin production or lack of response to insulin
• Associated with obesity
• More prevalent form of DM Insulin = gold standard
• Gestational for GDM
Oral hypoglycaemics with
• Carbohydrate intolerance in pregnant women
potential for use:
• Usually subsides after pregnancy term metformin and glyburide
• DM associated with:
• Disease, surgery, endocrinopathies, genetic syndromes, adverse effects of drugs
 Clinical Presentation of DM
• Uncontrolled hepatic glucose output and reduced uptake by cells
• Symptoms
• Exceed renal glucose threshold, glucose spill over into urine: glycosuria
• Osmotic diuresis: polyuria
• Dehydration thereby increasing drinking: polydipsia

• Amyotrophy: muscle wasting due to insulin deficiency

 Associated Complications
• Microvascular
• Retinopathy, nephropathy
• Macrovascular
• Atherosclerosis, hypertension, dyslipidaemia, stroke
• Neuropathic
• Peripheral neuropathy (Diabetic foot ulcers)
• Myocardial infarction
• Sorbitol-induced cataracts
• Reduction of glucose to sorbitol (change aldehyde to hydroxyl group)
• Sorbitol breaks down very slowly = accumulation in lens and attracts water
 Management of DM
Diet Pharmacological
• Low fat • Insulin
• Low Glycaemic index • Oral hypoglycaemics
• High fibre • Biguanides
• Sulfonylureas
• Calorie restricted • Thiazolidinediones (Glitazones)
• α- Glucosidase inhibitors
• Meglitinides
• Dipeptidyl peptidase-IV inhibitors
• Glucagon-like Peptide-1 agonists
(GLP-1)
 Insulin
• Exogenous insulin: porcine, bovine and recombinant
• Porcine and bovine insulin: differ by 1 and 2 amino acids respectively
• Possibility of immune response
• Polypeptide: degraded if taken orally

• Absorption dependent on
• Duration of action: ultra-short, short, intermediate and long-acting
• ROA: IM or SC
• Abdomen, buttock, anterior thigh, dorsal arm

• Indication
• Type 1 DM always
• Type 2 DM when uncontrolled by diet and oral hypoglycaemics
 Insulin
• Dosing: highly individualised
• Average daily requirement: 0.5-0.6 units/kg/day
• Short plasma half-life ~ 10 minutes
• Enzymatically inactivated in liver and kidney

• Combine with pramlintide (peptide amylin analogue)

• Aids glucose absorption by slowing gastric emptying

• Adverse effects:
• Hypoglycaemia (tachycardia, confusion, vertigo)
• Post hypoglycaemic hyperglycaemia (rebounding high blood sugar – avoid
increasing evening dose)
 Insulin Types
• Ultra-short and short-acting
• Insulin lispro, Insulin aspart, Insulin glulisine, regular insulin
• Mimic prandial release of insulin

• Intermediate-acting
• Crystalline insulin zinc suspension combined at neutral pH with protamine+
• Insulin isophane

• Long-acting
• Protamine combinations at decreased iso-electric point, precipitates slower
• Provide constant basal insulin supply
• Insulin glargine, Insulin detemir
 Classes of Oral Hypoglycaemics

• Biguanides • Sensitizers: Increase peripheral

• Thiazolidinediones glucose uptake
• Sulfonylureas • Secretagogues: Increase insulin
• Meglitinides secretion (Considered short acting)
• α- Glucosidase inhibitors • Delay carbohydrate digestion
• Dipeptidyl peptidase-IV inhibitors • Incretin mimetics: peptide
• GLP-1 agonists analogues
 1. Biguanides
• Drugs:
• Metformin
• MOA
• Reduce hepatic glucose production
• Increase intestinal anaerobic glycolysis
• Increase glucose uptake and utilisation in skeletal muscle
• Reduce LDL and VDL
• Prevents hyperglycaemia, minimal hypoglycaemia
• Combination with sulfonylureas or insulin
• Adverse effects
• Dose dependent GI disturbances
• Anorexia, metallic taste, lactic acidosis (rare)
 2. Thiazolidinediones (Glitazones)
• Drugs:
• Pioglitazone
• MOA
• Bind peroxisome proliferator activated receptor gamma (PPARG)
• Adipocytes, myocytes and hepatocytes
• Enhance fatty acid and glucose uptake
• Reduce resistance, enhance glycaemic control
• Highly plasma protein bound (99%), extensive metabolism by CYP450
• Combination with metformin, sulfonylureas or insulin
• Adverse effects
• Peripheral oedema, increase subcutaneous fat, water retention
• Reduce concentration of oestrogen-containing contraceptives
• Troglitazone & Rosiglitazone withdrawn due to toxicity
 3. Sulfonylureas
• Drugs:
• First generation: Tolbutamide, chlorpropamide, tolazamide, acetohexamide
• Second generation: Glipizide, glyburide, glimepiride
• More potent

• Glyburide: minimal transfer across placenta

• MOA
• Bind sulphonylurea receptor on beta cell membrane
• Blocking KATP depolarises cell membrane, Ca2+ entry and insulin release
• Maintain high insulin: glucagon ratio = enhance glucose uptake into cell
• Reduce hepatic glucose production
 3. Sulfonylureas
• Drug interactions
• Bind strongly to plasma albumin (90-95%)
• DDI when competing for binding sites: salicylates, sulphonamides
• DDI resulting in sever hypoglycaemia
• NSAIDs, Uricosuric drugs, alcohol, Monoamine oxidase inhibitors (MAOIs)
• Adverse effects
• Hypoglycaemia, weight gain, rash, fever Age-related impaired renal
• GI disturbances, allergic reaction function: avoid long acting SUs
• Hyponatraemia (potentiate ADH action) (glyburide) in elderly; short-
acting glipizide preferred.
• Jaundice, haematopoietic changes
• Disulfiram-like reaction with alcohol: Additive effects in combination
• Tachycardia, Flushing, nausea, vomiting with biguanides
 4. Meglitinides
• Drugs
• Repaglinide, nateglinide
• MOA
• Short-acting secretagogues: act on same KATP channels as sulfonylureas
• Different binding site without sulfonylurea moiety
• Taken shortly before meals (skip meal, skip dose): reduce postprandial rise
in glucose
• Not as effective as sulfonylureas
• Combined with metformin or glitazones
• Adverse effects: Hypoglycaemia, weight gain
• Drug interaction
• Metabolized by CYP3A4
• Inhibited by some azoles and macrolide antibiotics
 5. α-Glucosidase Inhibitors
• Drugs
• Arcabose
• MOA
• Reversibly inhibit intestinal α-glucosidase
• Responsible for hydrolysis of oligosaccharides to glucose
• Delays carbohydrate and starch digestion in small intestine
• Taken prior to meal to blunt postprandial rise in glucose
• Combination with sulfonylurea or insulin
• Potential to develop hypoglycaemia
• Adverse effects
• Fermentation of starches: flatulence, abdominal distension
• Loose stool or diarrhoea
 6. Dipeptidyl Peptidase Inhibitors (DPP-IV)
• Drugs
• Sitagliptin, saxagliptin, linagliptin
• MOA
• Inhibit dipeptidyl peptidase-IV (DPP-IV)
• DPP-IV inactivates incretin hormones
• Incretins:
• Glucagon-like peptide (GLP), glucose-dependent insulinotropic polypeptide (GIP)
• Increased incretin: inhibit glucagon, increase insulin
• Decrease gastric emptying and blood glucose
• Taken alone, with metformin, a sulfonylurea or pioglitazone
• Adverse effects
• Nasopharyngitis, headache
 7. Glucagon-like Peptide-1 (GLP-1)
• Drugs
• Exenatide, liraglutide: incretin mimetics
• 60 minutes before first and last meal
• If glucose level is elevated
• Increase insulin secretion, inhibit glucose release
• Rapidly inactivated by DPP-IV, require long-acting derivatives
• Liraglutide: C16 fatty acid side chain – prolong action (Once daily)
• Long-acting release (LAR) exenatide (once weekly)
• Adverse effects
• GI disturbances
• Liraglutide: high risk of thyroid c-cell tumors
 Questions??
1. Explain why Insulin is the preferred anti-diabetic drug for pregnant
women.
2. Long-acting sulfonylureas should be avoided in geriatrics. Why is
this? Give an example of a long-acting SU that should not be
prescribed to geriatrics.
3. Explain why flatulence would be a possible side effect of α-
Glucosidase inhibitors.