A 45-year old gentleman admitted with polyuria and polydipsia.

His fasting blood sugar is 185

mg/dl.
a) What is the diagnosis?
b) Mention the important points in the history and examination of this patient?
c) How would you manage him?

You discharged him after starting appropriate treatment. 4 years later he presented with bilateral
lower limb swelling and reduced urine output. He also complains of poor vision and numbness of
his hands and feet. On examination he is pale and has bilateral pitting ankle oedema. His pulse rate
is 82/min, blood pressure is 174/98 mmHg and JVP is not elevated. His lungs are clear.
His investigations are:
Hb - 9.2 g/dl BU - 200 mg/dl (< 40)
MCV - 88 fl (80 - 96) Cr - 2.8 mg/dl (0.8 – 1.3)
WBC - 6800/mm3 Na⁺ - 142 mmol/dl
Platelets - 280000/mm3 K⁺ - 4.6 mmol/dl
UFR: ECG - Normal
Albumin ++
RBC – Nil
Pus cells – Nil RBS – 214 mg/dl

d) List the problems of this patient?

e) Write 5 other investigations with reasons?
Diabetes Mellitus
(DM)

Dr P Mayurathan
Senior Lecturer in Medicine
Honorary Consultant Physician
 Diabetes Mellitus in Sri Lanka
• Prevalence In 2005:
• Males – 14.2%
• Females – 13.5%
 Diabetes Mellitus in the world - WHO
• Number of people with diabetes rose from 108 million in 1980 to 422
million in 2014
• The global prevalence of diabetes among adults over 18 years of age
rose from 4.7% in 1980 to 8.5% in 2014
• Between 2000 and 2016, there was a 5% increase in premature
mortality from diabetes
• Diabetes prevalence has been rising more rapidly in low- and middle-
income countries than in high-income countries
• Diabetes is a major cause of blindness, kidney failure, heart attacks,
stroke and lower limb amputation
• In 2016, an estimated 1.6 million deaths were directly caused by
diabetes. Another 2.2 million deaths were attributable to high blood
glucose in 2012
Experts predicts

• Diabetes in urban population in developing countries is

projected to double between 2000 and 2030
 Definition
• It is defined as a syndrome of chronic hyperglycemia due to relative
insulin deficiency, resistance or both

• Chronic hyperglycaemia is associated with complications,

dysfunction and failure of various organs such as;
• Eyes
• Kidneys
• Nerves
• Heart
• Brain
• Blood vessels
Pancreas
Insulin
GLUT receptors
Classification

1. Type – 1 DM

2. Type – 2 DM

3. Type – 3 DM

4. Gestational Diabetes Mellitus (GDM)

5. Other causes
Type – 1 DM

• Due to autoimmune destruction of pancreatic β-cells

• Permanent destruction of β-cells of pancreas

• The pancreas cannot produce insulin.

Pathophysiology of Type 1 DM
 Type – 1 DM

• Type I diabetes usually starts in childhood

• But can occur in adults (30 to 40-year-olds) is known as LADA (Latent

Autoimmune Diabetes of Adults)

• It is associated with other autoimmune conditions

 Type – 1 DM

• 2 major autoantibodies play a major role

• Islet cell antibodies (ICA) - against cytoplasmic proteins in the beta

cells – 69-90%

• Antibodies to Glutamic Acid Decarboxylase (GAD-65) – 80%

• Other antibodies are Insulin AutoAntibodies (IAA – 70%) and IA-2A (to

protein tyrosine phosphatase – 54-75%)

•
 Type – 2 DM

• In type 2 DM, the pancreas is not destroyed and usually produces

insulin at the early phases of disease

• But they have insulin resistance

• Occurs due to genetic predisposition and lifestyle factors (lack of

exercise and improper dietary habits)

• Common among adults

Pathophysiology of type 2 M
What is Insulin Resistance?
Type 3 DM

Please remember only 3C is due to Pancreatic causes

Gestational Diabetes Mellitus (GDM)

• Women without past history of DM, presents with high blood

glucose levels during pregnancy

• It is caused by improper insulin responses

• Likely due to pregnancy-related factors such as the presence

of human placental lactogen

• Commonly occurs from 24-28 weeks of pregnancy

• It generally has few symptoms and it is most commonly diagnosed

by screening during pregnancy
 What is LADA and MODY?
• LADA – Latent Autoimmune Diabetes of Adults
• Due to autoimmune destruction of pancreatic beta cells
• But late onset

• MODY – Maturity Onset Diabetes of Young

• Due to genetic and autosomal dominant disease
• Strong family history
• Young age of onset (< 25 years)
• No autoantibodies
 Other causes of DM
Chronic pancreatitis
Pancreatectomy
1. Pancreatic causes (3C) Pancreatic neoplasia
Cystic fibrosis
Hemochromatosis
Acromegaly Fibrocalculous pancreatopathy
2. Endocrine causes Cushing syndrome
Glucagonoma
Somatostatinoma
Hyperthyroidism
Pheochromocytoma Glucocorticoids
Thyroid hormone
3. Drugs/chemical induced (3E) β-adrenergic agonists
Statins

Maturity onset diabetes of the young (MODY)

4. Genetic factors Mitochondrial DNA mutations
Defects in proinsulin conversion
Insulin gene mutations
Insulin receptor mutations
Symptoms of DM

• Unexplained weight loss

• Excessive thirst (polydipsia)

• Excessive urination (polyuria)

• Excessive eating (polyphagia)

• Fatigue or feeling constantly tired

• Poor wound healing

• Infections

• Blurry vision

• Complications of DM
 How to diagnose DM?
Normal Pre-Diabetic Diabetes
Mellitus
FBS ≤ 99 100 - 125 ≥ 126
(mg/dl)
PPBS ≤ 139 140 - 199 ≥ 200
(mg/dl)
HbA1C ≤ 5.6 5.7 – 6.4 ≥ 6.5
(%)
75g OGTT – 2h ≤ 139 140 - 199 ≥ 200
BS (mg/dl)

If symptomatic patient: Need any one positive report

If asymptomatic patient: Need any two positive report
 How to diagnose GDM?

• Should be screened at 24 – 28 weeks of POA

• Several methods are available

 Diagnosis of GDM
1. One stage, non-fasting 75g OGTT

• 75g glucose dissolved in 300ml water is given over 3-5 minutes

• If 2hour glucose of more than 140mg/dl – It is GDM
Diagnosis of GDM

2. 1-hour 50-gram OGTT

• Glucose ≥140 mg/dL (≥7.8 mmol/L ) at 1 hour is a positive

screening test for GDM
 Diagnosis of GDM
3. Three point OGTT – (Most commonly done)
• At least 8 hours fasting
• Blood is drawn for Fasting plasma glucose (FPG)
• 75g glucose dissolved in 300ml water – to be taken within 10
minutes

• Then blood is drawn at 60 min and 120 min for plasma glucose
• FPG ≥ 92 mg/dl
• 60 minutes plasma glucose ≥ 180 mg/dl
• 120 minutes plasma glucose ≥ 153 mg/dl

One abnormal report is enough to make the diagnosis of GDM

 Diagnosis of GDM

4. 2 hour PPBS test

• Take average diet
• Diet should be completed within 15 minutes
• The 2 hour cut-off is calculated from the time of starting the
meal

• If ≥ 120mg/dl is GDM
 Pre-diabetic DM

Need only life style modification Always need life style

modification and
drug treatment
 Complications of DM

• Generally
• Complications develop about 5 - 10 years after diagnosis of type
1-DM

• But, type 2-DM can have complications even during the time of
diagnosis

• All need screening roughly 5 years after diagnosis

Complications of DM
Retinopathy

Microvascular Nephropathy

Neuropathy
Complications
Cerebrovascula
r

Macrovascular Coronary vascular

Peripheral vascular
Diabetic dermopathy
Complications of DM
AGE-RAGE: Advanced glycation endproducts-Receptor for Advanced Glycation Endproducts
 Diabetic Retinopathy
• Major cause for the blindness

• Blood sugar control plays an important role

• Others are:
• Growth hormone
• Platelets and blood viscosity
• Aldose reductase and vasoproliferative factors
• Macular oedema
• Hypoxia
• Neovascularization - VEGF
Stages of Diabetic Retinopathy
Diabetic Retinopathy
 Diagnosis of Diabetic Retinopathy

• HbA1C

• Imaging

• Fluorescein angiography

• Optical coherence tomography scanning

• B-scan ultrasonography
 Treatment of Diabetic retinopathy
• General:
• Control obesity
• Blood sugar control
• Stop smoking
• Controlling the blood pressure
• Treatment for high cholesterol
• Pharmacologic therapy
• Triamcinolone (intravitreally) - Corticosteroid for macular oedema
• Bevacizumab (intravitreally)
• Ranibizumab (intravitreally) Monoclonal antibody that can help to reduce
diabetic macular oedema and
neovascularization of the disc or retina
• Laser photocoagulation
• Vitrectomy
• Cryotherapy
 Other ocular complications

• Specific to progression of the ocular disease

• e.g. - cataract, rubeosis ridis

• Non-specific recognized associations of diabetes in the eye

• e.g. - glaucoma, retinal vein occlusion/optic disc swelling
 Diabetic Nephropathy
• DM is a major cause of renal morbidity and mortality

• Diabetic nephropathy is one of the leading causes of CKD worldwide

• 40% of Diabetic patients develop advanced or ESKD (End stage kidney disease)

• Clinically they present as three glomerular syndromes:

• non-nephrotic range proteinuria
• nephrotic syndrome
• CKD

• The morphological changes of diabetic nephropathy are identical in both

types of DM
Natural History of Diabetic
Nephropathy
 Diabetic Nephropathy

• Most common lesion involves the glomeruli and arterioles

• Increases the susceptibility of pyelonephritis

• Increases papillary necrosis

• Causes variety of tubular lesions

• Initial change is enlargement of the kidneys due to tubular hypertrophy and

hyperplasia in response to hyperglycaemia
 Pathogenesis of Diabetic
Nephropathy
 2 processes play an important role in diabetic glomerular lesions

1. Haemodynamic effects – increased GFR, increased glomerular capillary

pressure, glomerular hypertrophy and increased glomerular filtration area
Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion)
2. Metabolic defect – insulin deficiency and hyperglycaemia
Glycosylation end products leads to thickened GBM and increased mesangial
matrix (↑type IV collagen, ↑fibronectin and ↓heparan sulfate
proteoglycan)

 Both contribute to the loss of podocytes from the filtration barrier due to either
apoptosis or detachment and podocyturia
 Ultimately glomerular capillaries become sclerosed and non-functioning
 Activation of RAAS
 Later all these changes are associated with heavy proteinuria
Pathogenesis of Diabetic Nephropathy
The Kimmelstiel-Wilson lesion of diabetes mellitus. Nodules of pink
hyaline material form in regions of glomerular capillary loops in the
glomerulus. This is due to a marked increase in mesangial matrix from
damage as a result of non-enzymatic glycosylation of proteins. This is one
form of chronic kidney disease (CKD) with loss of renal function over
time.
Proteinuria

• Urine albumin <30mg/24 hours is normal

• Microalbunimuria is defined as 30 – 300mg/day

• Microalbunuria can not be detected with normal UFR

• Need to do urine albumin: creatinine ratio

 Management of Diabetic
Nephropathy
• Cessation of smoking

• Increase physical activity

• Control blood sugar

• Control hypertension - < 130/80 mmHg

• Control hyperlipidaemia

• Start ACEI or AIIRB

Diabetic Neuropathy
Diabetic Neuropathy
Peripheral Neuropathy

• Symmetrical sensorimotor neuropathy is most commoner

than Pure sensory neuropathy

• First affects the proprioception and vibration sensation

• Later other modes of sensory loss and absent distal reflexes

What is Mononeuritis Multiplex?
Treatment
 Diabetic Dermopathy

• Signifies other microvascular

complications
 Macrovascular complications
• Atherosclerosis is the main mechanism

• There is strong evidence of increased platelet adhesion and

hypercoagulability

• Impaired nitric oxide generation and increased free radical formation in

platelets, as well as altered calcium regulation, may promote platelet
aggregation

• Elevated levels of plasminogen activator inhibitor type 1 may also impair

fibrinolysis in patients with diabetes

• The combination of increased coagulability and impaired fibrinolysis

likely further increases the risk of vascular occlusion and cardiovascular
 How to control all of these
complications?
• Cessation of smoking

• Weight control – Proper diet and exercise

• Sugar control – there are target HbA1C levels depending on the

age, co-morbidities and complications

• BP control < 130/80mmHg

• Cholesterol control
• LDL < 100mg/dl if no macrovascular complication
• LDL < 70mg/dl if there is macrovascular complications
Treatment
 Oral hypoglycaemic agents
• Biguanide – Metformin

• Sulphanylureas – Tolbutamide, Glibenclamide, Gliclazide, Glipizide,

Glimepride

• Metiglinides – Repaglinide, Nateglinide

• Thiazolidinediones – Pioglitazone

• Intestinal enzyme inhibitors – Acarbose

• Lipase inhibitors - Orlistat

 Oral hypoglycaemic agents
• GLP-1 (Glucagon-Like Peptide-1) agonists – Exenatide, Liraglutide

• DPP-4 (Dipeptidyl Peptidase-4) inhibitors – Sitagliptin, Linagliptin,

Saxagliptin, Vidagliptin

• SGLT-2 (Sodium-Glucose Transport protein-2) inhibitors

(Gliflozins) – Canagliflozin, Dapagliflozin, Empagliflozin,
Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflon
Sergliflozin, Sotagliflozin, Tofogliflozin

• Bile acid sequestrants - Colesevelam

 What is Incretin?

• Incretins:
• GLP-1 (Glucagon-Like Peptide-1)

• GIP (Gastric Inhibitory Peptides)

• These incretins are rapidly inactivated by the

enzyme called DiPeptidyl Peptidase-4 (DPP-4)
GLP-1 agonists
DDP-4 (DiPeptidyl Peptidase-4)
inhibitors
What is SGLT-2?
Effects of SGLT-2 inhibitors
 What is Colesevelam?

• Bile acid sequestrants and reduce LDL cholesterol

• It reduces blood glucose by

• Increase GLP-1

• Increase Insulin secretion

• Suppression of Glucagon

• Increase splanchnic glucose utilization

Types of Insulin

1. Rapid-acting – Insulin lispro, Insulin aspart, Insulin glulisine

2. Short-acting – Soluble insulin

3. Intermediate-acting
– NPH (Neutral Protamine Hagedorn),
Isophane, Lente
Mixed Insulin( eg: 70% NPH with
30% Soluble – Mixtard Insulin)
4. Long-acting
– Insulin glargine (Lantus/Toujeo), Insulin determir
(Levemir), Insulin degludec (Tresiba)
 A 45-year old gentleman admitted with polyuria and polydipsia. His fasting blood sugar is 185
mg/dl.
a) What is the diagnosis?
b) Mention the important points in the history and examination of this patient?
c) How would you manage him?

You discharged him after starting appropriate treatment. 4 years later he presented with bilateral
lower limb swelling and reduced urine output. He also complains of poor vision and numbness of
his hands and feet. On examination he is pale and has bilateral pitting ankle oedema. His pulse rate
is 82/min, blood pressure is 174/98 mmHg and JVP is not elevated. His lungs are clear.
His investigations are:
Hb - 9.2 g/dl BU - 200 mg/dl (< 40)
MCV - 88 fl (80 - 96) Cr - 2.8 mg/dl (0.8 – 1.3)
WBC - 6800/mm3 Na⁺ - 142 mmol/dl
Platelets - 280000/mm3 K⁺ - 4.6 mmol/dl
UFR: ECG - Normal
Albumin ++
RBC – Nil
Pus cells – Nil RBS – 214 mg/dl

d) List the problems of this patient?

e) Write 5 other investigations with reasons?
• A 17-year old student presents with abdominal pain and vomiting for 1 day
duration. He also complains of fever, dysuria and loin pain for 3 days duration.
On examination he is febrile and dehydrated. His pulse rate is 116/minute,
blood pressure is 88/56 mmHg and respiratory rate is 32/minute. All other
examinations are normal except right renal angle tenderness.
His RBS is 350 mg/dl. Arterial blood gas shows pH of 7.20.
a) What is your most likely diagnosis?
b) What are your next important investigations?
c) What is the precipitating event for above (a) condition?
d) Explain the pathophysiology of condition (a)?
e) How would you manage him?
f) What are the important advices on discharge?
• Type 1DM
• Urine ketonebody and serum ketonebody *CBS > 200 mg/dl *pH < 7.3 or HCO₃⁻
< 15 mmol/l *Urine ketone bodies > ++ or S.Ketone > 3 mmol/l
• DKA
What are the diabetic emergencies with
high blood sugar?

• Diabetic Ketoacidosis (DKA)

• Hyperglycaemic Hyperosmolar State (HHS)

• Lactic Acidosis
 What is DKA?
Criteria:
1. CBS > 200 mg/dl

2. pH < 7.3 or HCO₃⁻ < 15 mmol/l

3. Urine ketone bodies > ++ or S.Ketone > 3 mmol/l

• Need all 3 features for diagnosis

• A 17-year old student presents with abdominal pain and vomiting for 1 day
duration. He also complains of fever, dysuria and loin pain for 3 days duration.
On examination he is febrile and dehydrated. His pulse rate is 116/minute,
blood pressure is 88/56 mmHg and respiratory rate is 32/minute. All other
examinations are normal except right renal angle tenderness.
His RBS is 350 mg/dl. Arterial blood gas shows pH of 7.20.
a) What is your most likely diagnosis?
b) What are your next important investigations?
c) What is the precipitating event for above (a) condition?
d) Explain the pathophysiology of condition (a)?
e) How would you manage him?
f) What are the important advices on discharge?
 Diagnosis
Possible DKA associated with right sided pyelonephritis
 What are the immediate
investigations ?
1. Urine for ketone bodies

2. UFR and Urine culture and ABST

3. Blood culture and ABST

4. FBC

5. ESR/CRP

6. BU/SE/Cr

7. Urgent USS abdomen

Pathophysiology
 Management
• Principles of management:

1. Correct dehydration (Fluid management)

2. Correct hyperglycaemia (Sugar management)
3. Correct hypokalaemia
4. Correct acidosis
5. Treat the precipitating causes

• Admit to ETU

• Get two IV access

 Fluid Management
• Can follow this fluid regime: Normal saline
• 1 L for 30 minutes
• 1 L for 1 hour
• 1 L for 2 hours Usually they need about 6 – 8 L/24 hrs

• 1 L for 4 hours
• 1 L for 6 hours

• Insert urinary catheter and monitor UOP

• Check the renal functions

• Look for features of fluid overload

 Sugar Management
• Always with Soluble Insulin

• IV infusion (better) or hourly IM

• Check hourly CBS

• Give IV - 10 u as a bolus OR IM – 20 u as a bolus

• Then 0.1u/kg/hr (6u/hr) infusion (fixed dose)

• Until CBS around 200mg/dl and ketone bodies become negative

 When CBS around 200mg/dl

• Change the Normal saline to 10% Dextrose

• Continue the rate of 1 L over 6 hours

• Monitor CBS – hourly

• Give Soluble Insulin hourly according to the CBS (Variable Rate

Intravenous Insulin Infusion - VRIII)

• (please see the VRIII regime on the next slide )

• Continue this regime until patient looks well and take adequate
oral intake
VRIII (Variable Rate Intravenous
Insulin Infusion )
CBS (in mg/dl) Dose of Soluble Insulin hourly intravenously
(in Units)
< 70 No insulin
71 - 89 0.5
90 - 179 1
180 - 269 2
270 - 359 3
> 360 4
 Then
• Change the Soluble Insulin infusion to subcutaneous TDS regime
(Dose: Total 1u/kg/day – 3 divided doses)

• Start subcutaneous Soluble Insulin at least 30 min before stopping the

IV infusion

• Monitor pre-meal CBS TDS

• If blood sugar is under control with TDS regime (target pre-meal CBS
140 – 180 mg/dl), change the soluble insulin to Mixtard insulin BD
dose or Basal Bolus Regime
 Management of Hypokalaemia

• Add IV KCI into the Normal saline bottle from 2nd L onwards

• Later when replace N.saline to dextrose, add KCl into the dextrose

• Dose of KCl is based on the S. K⁺ report as follows:

• Do SE – 2 to 4 hourly at least initially

 Management of Acidosis
• As a last option

• Usually when you correct dehydration and hyperglycaemia,

acidosis will be corrected automatically

• If pH ≤ 6.9: Give NaHCO3 IV infusion

(Dose: 100 mmol in 400ml NS over 2 hours )
 In addition;

• After sending blood and urine culture start antibiotics to

cover pyelonephritis (suspected clinically on admission)

Diabetic emergencies with low blood
sugar?
• Hypoglycaemia

• What is hypoglycaemia?

 CBS < 70 mg/dl (< 4 mmol/l)

 Symptoms of Hypoglycaemia
• Sweating or cold
• Tremor
• Dizziness
• Headache
• Palpitation
• Change of behavior - confusion, irritability
• Slurring of speech
• Problems with vision
• Loss of consciousness
• Seizures/Fits
Management of
hypoglycaemia
What else you can give to treat the
hypoglycaemia?
• Glucagon