DIABETES MELLITUS : FEATURES

DIAGNOSIS AND TREATMENT

BY
Dr. S.A. Onogwu
Consultant Physician/Endocrinologist
BSUTH, Makurdi
 OUTLINE
• INTRODUCTION
• EPIDEMIOLOGY
• NORMAL GLUCOSE AND FAT METABOLISM
• PATHOGENESIS
• CLASSIFICATION
• CLINICAL FEATURES
• DIAGNOSIS
• MANAGEMENT
• COMPLICATIONS
• TREATMENT
 INTRODUCTION
• Diabetes Mellitus (DM) is a chronic metabolic disorder
characterised by persistent hyperglycaemia due to absolute or
relative insulin deficiency, insulin resistance or both.
• Prediabetes (IFG and or IGT) is a state of abnormal glucose
regulation with plasma glucose higher than normal but not
high enough to be classified as diabetes mellitus.
• DM affects both gender
• It is a multisystem disorder
 EPIDEMIOLOGY
• Diabetes Mellitus is now a global epidemic
• Sedentary lifestyle, urbanization, increase in
consumption of high calorie diet and the ageing
population are partly responsible for the increasing
prevalence of DM
• 537 million adults (20-79 years) in the world were
living with DM in 2021 ---IDF
– 1 in 10 adults
• The number is projected to rise to 643 million (1 in 9
adults) by 2030 and 784 million (1 in 8 adults) by 2045
NORMAL GLUCOSE AND FAT METABOLISM

• Plasma glucose is normally regulated and

maintained within a narrow range.
• This is essential for ensuring a continuous
supply of glucose to the central nervous
system.
• The brain has little capacity to store energy in
form of glycogen or triglycerides and hence
depends on the liver for a constant supply of
glucose to generate ATP.
NORMAL GLUCOSE AND FAT METABOLISM

• Glucose homeostasis reflects a balance between:

- entry of glucose into the circulation from the liver.
- intestinal absorption of glucose after meals
- uptake of glucose by peripheral tissues especially
skeletal muscles and brain.
• Insulin is the primary regulator of glucose
metabolism and storage and is secreted by
pancreatic β cells into portal blood in response to a
rise in blood glucose.
NORMAL GLUCOSE AND FAT METABOLISM

• A number of other factors such as amino acids and

hormones like glucagon-like peptide 1 (GLP-1) &
gastrointestinal inhibitory peptide (GIP) released
from the gut after food intake can augment insulin
release.
• Hence insulin release is greater when glucose is
administered orally than when the same rise in
plasma glucose is achieved by intravenous
glucose infusion – this phenomenon is termed
‘incretin’ effect.
NORMAL GLUCOSE AND FAT METABOLISM

• The rise in portal vein insulin and glucose after

meals suppresses hepatic glucose production
resulting in net hepatic glucose uptake.
• Insulin also stimulates glucose uptake in skeletal
muscle and fat mediated by GLUT 4.
• When intestinal glucose absorption declines during
starvation, portal vein insulin and glucose
concentration falls and glucagon rises leading to
glycogenolysis, gluconeogenesis and increased
hepatic glucose output.
NORMAL GLUCOSE AND FAT METABOLISM

• Adipocytes in the liver synthesize triglycerides

form FFA and glycerol.
• Insulin is the major regulator of fatty acid
metabolism and lipogenesis.
• In the fasting state low insulin levels promote
lipolysis.
 CLASSIFICATION OF DM
• Old classification
– Type 1 DM (β- cell destruction, mostly immune
mediated with absolute insulin deficiency; onset mostly
in childhood and early adulthood)
– Type 2 DM (most common type of DM. Associated with
obesity and overweight)
– Other specific types (monogenic forms of DM,
endocrinopathy, infections, disorders of the exocrine
pancreas, drugs and genetic disorders )
– Gestational diabetes (hyperglycaemia first detected in
pregnancy)
 2019 WHO classification
• Type 1 DM
• Type 2 DM
• Hybrid forms of DM
– Slowly evolving, immune-mediated diabetes of adults
– Ketosis-prone T2DM
• Other specific types of DM
• Unclassified DM (use temporarily until a class is assigned)
• Hyperglycaemia first detected in pregnancy
– DM in pregnancy
– GDM (Gestational diabetes mellitus)
 PATHOGENESIS
• Type 1 – autoimmune T cell destruction of β cells. Marked
hyperglycemia results when 80 – 90% of β cells are destroyed.
The destructive process is β cell specific.
• Islet cell antibodies are present before the disease presents
clinically and they are confirmatory when detected.
• There is association with other autoimmune disorders.
• Genetic predispositon account for 1/3rd of cases. The HLA
haplotypes DR3 and/or DR4 are associated with increased
susceptibility.
• Environmental factors like viruses (coxackie, EBV,mumps),
nitrosamines and bovine serum albumin have also been
implicated.
 PATHOGENESIS
• Type 2 – primarily due to insulin resistance.
• Presence of hyperinsulinaemia at the onset
• Associated with obesity/overweight and
dyslipidaemia in most people
• Obesity is a major cause of increased insulin
resistance - especially central obesity.
• Physical inactivity also promotes insulin
resistance.
 CLINICAL FEATURES
Features Type 1 Type 2
Typical age at onset < 40 years× > 40 years×
Classical symptoms Yes. Presents classically Not always.
with Polyuria, polydipsia,
weight loss.
Duration of symptoms Weeks Months to years
before presentation
Body weight Normal or low Obese
Ketonuria Yes No
Rapid death without Yes No
treatment with insulin
Autoantibodies Positive in 89 – 90% of Negative
cases. (Islet cell antibodies)
Diabetic complications at No ±
diagnosis
Family history of DM Uncommon Common
Other autoimmune Common Uncommon
diseases.
 Diagnosis
• FBG:
– ≥ 7.0 mmol/l
• RBG:
– ≥ 11.1 mmol/l
• N.B two abnormal values on two different days
without symptoms or single abnormal value with
symptoms is diagnostic of DM
• FBG:
– 6.1 mmol/l—6.9 mmol/l IFG (WHO)
– 5.6 mmol/l---6.9 mmol/l IFG (ADA)
 Diagnosis
• Oral glucose tolerance test (OGTT). Done after
8-12 hours over night fasting
– For non- pregnant adults:
• 0 hour: ≥ 7.0 mmol/l
• 2 HPP: 7.8 mmol/l---11.0 mmol/l (IGT)
• 2 HPP: ≥ 11.1 mmol/l
– GDM (any one abnormal value is diagnostic of GDM)
• 0 hour: ≥ 5.1 mmol/l
• 1 hour: ≥ 10.0 mmol/l
• 2 hour: ≥ 8.5 mmol/l
 Diagnosis
• HbA1c
– < 5.7 % (normal)
– 5.7%--- 6.4% (prediabetes)
– ≥6.5% (DM)
 MANAGEMENT OF DM
• The goal of management is to minimise
complications, improve quality of life, and
prolong life. This is achieved through:
1. Lifestyle modifications alone
2. Lifestyle and oral antidiabetic drugs
3. Lifestyle, oral antidiabetic and/or injected
therapies.
 LIFE STYLE MODIFICATION
1. Regular physical exercises eg brisk walking,
cycling, swimming 4-5 times per week.
2. Healthy diet
• High fibre diet
• Less refined food
3. Reducing alcohol consumption
4. Quit smoking
 DIET THERAPY
• Avoid refined sugar and sugary drinks
• Complex Carbohydrates: 45 – 60% of diet
• Fat: < 35% of diet
– Omega 6 Polyunsaturated (10%)
– Omega 3 polyunsaturated 1 portion with oily fish
– Monounsaturated (10-20%)
– Saturated (<10%)
• Protein: 10 – 15% of diet
• Plenty of vegetables.
 DRUG TREATMENT
• CLASSIFICATION OF ORAL ANTI DIABETIC AGENTS:
1. Biguanides
2. Sulphonyl ureas
3. Meglitinides
4. Alpha glucosidase inhibitors
5. Thiazolidinedione
6. Incretin based therapies
7. The Sodium and glucose transporter 2 (SGLT2)
inhibitors
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
1. Biguanides – Metformin
• Mechanism of action – Reduces hepatic glucose production
- Increases insulin mediated glucose uptake
- Increases gut glucose uptake and utilization
- Other Amp mediated metabolic benefits
2. Sulphonylureas – Glimepiride, Glibenclamide, Glipizide,
Tolubutamide
• Mechanism of action- Insulin secretagogues (promote
pancreatic β cell insulin secretion)
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
3. Meglitinides – repaglinide, nateglinide
• Mechanism of action – Insulin secretagogues
(promote pancreatic B cell insulin secretion)
4. Alpha - glucosidase inhibitors – Acarbose, miglitol
• Mechanism of action – Delay carbohydrate
absorption in the gut by inhibiting disaccharidases.
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
5. Thiazolidinediones – Pioglitazone, Rosigltazone (withdrawn in
2010)
• Mechanism of action – bind and activate peroxisome
proliferator activated receptor-Ꝩ (PPARꝨ) – a nuclear
receptor present mainly in adipose tissue that regulates the
expression of several genes involved in metabolism
- Enhance the action of endogenous insulin
- directly – In adipose cells
- Indirectly – by altering release of adipokines such as
adiponectin which alter insulin sensitivity in the liver.
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
6. Incretin – based therapies: The incretin effect is the
augmentation of insulin secretion seen when a glucose
stimulus is given orally rather than intravenously. It
reflects release of incretin peptides from the gut.
• The incretin hormones are primarily glucagon-like
peptide 1 (GLP -1) and gastric inhibitory polypeptide
(GIP). These are rapidly broken down by the
peptidase DPP -4 (dipeptidyl peptidase 4).
• The incretin effect is diminished in type 2DM.
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
• Incretin based therapies include:
a. Gliptins or DPP-4 inhibitors
Enhance concentrations ie prevent breakdown of GLP1 and
GIP. Examples include Sitagliptin, Vildagliptin, Saxagliptin,
Linagliptin.
b. GLP-1 receptor agonists – have a similar structure to GLP-1.
Resists breakdown by DPP-4 enzyme. Delays gastric emptying.
Inhibits appetite →↓appetite → weight loss
• Examples include Exenatide, exenatide MR
• Liraglutide (once daily)
 ORAL ANTIDIABETIC AGENTS AND THEIR
MECHANISM OF ACTION
7. SGLT2 Inhibitors
• The sodium and glucose transporter 2 (SGLT2)
Inhibitor
- Dapagliflozin
• Mechanism of action-
•Inhibits the reabsorption of glucose in the proximal
tubules with consequent glycosuria.
•The SGLT2 inhibitors are now part of the current
guideline for the management of Heart failure.
 INSULIN THERAPY
1. Rapid acting insulin: insulin analogues - lispro,
aspart, glulisine
2. Short acting: soluble or regular insulin
3. Intermediate acting: isophane (NPH)
4. Long acting: insulin analogues – glargine,
detemir and degludec.
Insulin is usually injected subcutaneously into the
anterior abdominal wall, upper arms, outer
thighs and buttocks.