Diabetes Mellitus

Definitions
o Diabetes – “Passing of large volumes of urine” from Greek physician Cappodicia
o Mellitus – “Honey” (1604)
o “A group of metabolic disorders of glucose regulation and utilization.”
o “A disease in which the body does not produce or properly use insulin.”

 DM is a group of diseases characterized by high levels of blood glucose resulting from

defects in insulin production, insulin action, or both .
 The term diabetes mellitus describes a metabolic disorder of multiple aetiology
characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin secretion, insulin action, or both.
 Diabetes Insipidus: Excessive urination & extreme thirst as a result of inadequate
output of the pituitary hormone ADH (antidiuretic hormone, also called vasopressin) or the
lack of the normal response by the kidney to ADH

Pathophysiology of DM  Plasma glucose is tightly regulated by hormones:

 Insulin Deficiency
o Insulin: ↓ plasma glucose
 Insulin Inefficiency (Insulin Resistance)
o Glucagon + Epinephrine + Cortisol + Growth
 A Combination with different degrees of
hormone: ↑ plasma glucose
each of them
 An internal piece of the
peptide is removed; resulting
in the mature insulin
molecule.
 The "a" chain contains 21
amino acids
 The "c" (removed) chain
contains 35 amino acids
 The "b" chain contains 30
amino acids
 Molecular weight 5743

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Symptoms
1. Polyuria / Nocturia
2. Excessive thirst and appetite
3. Weight Loss
4. Lethargy
5. Blurred Vision
6. Skin infections
7. Vaginal infections.
8. Tingling or numbness in hands or feet.
9. Cuts/bruises that are slow to heal

Classification

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 Type 1 DM
 Was previously called insulin-dependent DM (IDDM) or juvenile-onset diabetes.
 Develops when the body’s immune system destroys pancreatic beta cells, the only cells in
the body that make the hormone insulin that regulates blood glucose.
o Causes of this absolute insulin deficiency:
1. Genetic Element: Autoimmune attack of Beta cells (Islet cells antibodies are available in
the serum of patients)
2. Environmental Factor: Viral infection or toxin
 Type 1 DM is defined by the presence of 1 or more of these autoimmune markers:
1. Glutamic Acid Decarboxylase Autoantibodies (GADA)
2. Tyrosine phosphatases IA-2 and IA-2b
3. Zinc transporter (ZnT8)
4. Insulin Autoantibodies (IAA)
 This form of diabetes usually strikes children and young adults, although disease onset can
occur at any age. (Usually progresses over many months or years during which the subject is
asymptomatic and euglycemic.)
 The rate of progression is dependent on the age at first detection of antibody, number of
antibodies, antibody specificity, and antibody titer.
 Glucose and A1C levels rise well before the clinical onset of diabetes, making diagnosis
feasible well before the onset of DKA
 4 stages in the development of Type 1 DM
1. Preclinical period with positive b-cell antibodies
2. Hyperglycemia when 80-90% of the β- cells are destroyed.
3. Transient remission (honeymoon phase)
4. Establishment of the DM
 May account for 5-10% of all diagnosed cases of diabetes.
o In identical twins, if 1 sibling has T1DM, the other twin has 30-50% of developing DM.
o 80% of T1DM patients have no diabetic relatives, so genetic element is not strong in T1DM.
 Risk factors for type 1 diabetes may include
1. Autoimmune
2. Genetic
3. Environmental factors
 Sudden onset of severe symptoms occurs when 80-90% of B-cells have been destroyed.
 Characterized by rapid weight loss in relatively short period (muscle wasting)
 Commonly complicated by DKA
 Only treated by insulin (essential for life)

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 Type 2 DM
 Was previously called non-insulin-dependent DM (NIDDM) or adult-onset diabetes.
 May account for about 90-95% of all diagnosed cases of diabetes.
 Type 2 diabetes is increasingly being diagnosed in children and adolescents.
 It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly.
o The defective responsiveness of body tissues to insulin is believed to involve the insulin
receptor.
o At this stage, hyperglycemia can be reversed by a variety of measures and medications that
improve insulin sensitivity or reduce glucose production by the liver.
 As the need for insulin rises, pancreas graduallyloses its ability to produce insulin.
 Type 2 DM occurs when a diabetogenic lifestyle (excessive calories, inadequate caloric
expenditure and obesity) is superimposed upon a susceptible genotype
 Risk Factors
1. Age  45 years
2. Family history of diabetes
3. Lack of regular exercise regularly
4. Overweight
5. Gestational Diabetes
6. Low HDL cholesterol or high triglycerides or Impaired glucose metabolism
7. Certain racial and ethnic groups

o Insulin and
appetite interact in
the brain when
neurotransmitters
in the
hypothalamus
signal satiety in
response to
increased insulin.
o Adding brain and
neurotransmitter
dysfunction to the
pathogenic picture
of type 2 diabetes
gives us the

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 The pathophysiology of hyperglycemia in T2DM involves three main defects:
1. Insulin deficiency due to insufficient pancreatic insulin release;
2. Excess hepatic glucose output due to ↑ glucagon + insulin insufficiency + resistance
3. Insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat)
and the liver.
 Two pancreatic islet cell defects contribute to this pathology:
1. Beta cells produce insulin, which facilitates glucose entry into tissues.
o In type 2 diabetes mellitus, a decline in functional beta-cell mass causes insulin deficiency,
which in turn contributes to hyperglycemia.
2. Alpha cells produce glucagon.
o Elevated glucagon levels promote increased hepatic glucose output.

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 The horizontal axis in
the figure shows the
years before and after
diagnosis of diabetes.
 Insulin resistance
begins years before
diagnosis.
 Insulin resistance ↑
during disease
development and
continues to ↑ during
impaired glucose
tolerance (IGT).
 Over time, insulin
resistance remains
stable during the
progression of T2DM

 The insulin secretion rate ↑ to compensate for the ↓ in insulin effectiveness due to insulin
resistance.
 β-cell function can ↓ even as insulin secretion ↑.
 At the time of diagnosis of T2DM and 6 years afterwards about 50% and 73% of β-cell function
has been lost, respectively.
 Over time, β-cell compensatory function deteriorates and insulin secretion ↓. β-cell function
progressively fails.

 Initially, fasting glucose is maintained in near-normal ranges.

 The pancreatic β cells compensate by increasing insulin levels, leading to hyperinsulinemia.
 This compensation keeps glucose levels normalized for a time, but as β cells begin to fail, IGT
develops with mild postprandial hyperglycemia.
 As the disease progresses, the β cells continue to fail, resulting in higher PPG levels.
 With continued loss of insulin secretory capacity, fasting glucose and hepatic glucose
production ↑.
 Once β cells cannot secrete sufficient insulin to maintain normal glycemia at the fasting or
postprandial stage, T2DM (hyperglycemia) becomes evident.
 Insulin resistance and β-cell dysfunction are established well before T2DM is diagnosed.

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 T1DM T2DM
Prevalence ~10% ~90%
UK Prevalence 0.25% 5-7% (10% of those >65)
Onset Sudden Gradual
Age at Onset Mostly children Mostly adults
Peak Age of Onset 12 60
Family History Generally not strong Strong
Initial Presentation Polyuria, polydipsia, fatigue, Hyperglycemic symptoms often with
weight loss, ketoacidosis complications of diabetes
Etiology Autoimmune B-cell Insulin resistance + B-cell destruction + B-
destruction cell dysfunction
Presence of B-Cell >90% No
Antibodies
Insulin-Dependent Yes No
DKA Common Rare
Obesity Uncommon Common
Insulin Resistance Uncommon Common
Endogenous Insulin ↓ or absent Normal or ↓ or ↑
Concordance in 50% 90%
identical twins
Treatment Insulin from outset Diet + oral hypoglycemic agents + insulin

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 Other Types of DM
 Other specific types of diabetes result from specific genetic conditions (such as maturity-onset
diabetes of youth), surgery, drugs, malnutrition, infections, and other illnesses.
 Such types of diabetes may account for 1-5% of all diagnosed cases of diabetes.

MODY – Maturity Onset Diabetes of the Young

 MODY is a monogenic form of
diabetes with autosomal
dominant mode of inheritance.
o Mutations in any one of several
transcription factors or in
the enzyme glucokinase 
insufficient insulin release from
pancreatic ß-cells  MODY.
o Different subtypes of MODY
are identified based on the mutated gene.
 However, genetic testing has shown that MODY can occur at any age and that a family history
of diabetes is not always obvious.

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LADA – Latent Autoimmune Diabetes in Adults (Slow Onset Type 1 diabetes,
Late-onset Autoimmune Diabetes of Adulthood, Type 1.5)
 LADA is a form of autoimmune (T1DM) which is diagnosed in individuals who are older
than the usual age of onset of T1DM.
 Often, patients with LADA are mistakenly thought to have T2DM, based on their age at the time
of diagnosis.

Secondary DM:
2ry causes of DM include: Drug Induced Hyperglycemia:
1. Acromegaly 1. Atypical Antipsychotics: Alter receptor binding
2. Thyrotoxicosis characteristics  leading to ↑ insulin resistance.
3. Pheochromocytoma
4. Cushing syndrome
2. Corticosteroids: Cause peripheral insulin resistance
and gluconeogensis.
5. Chronic pancreatitis
6. Cancer 3. Beta-blockers: Inhibit insulin secretion.
4. Fluoroquinolones: Inhibits insulin secretion by
blocking ATP-sensitive K channels.
5. Thiazide Diuretics:
o Inhibit insulin secretion due to hypokalemia.
o ↑ insulin resistance due to ↑ free FA mobilization.

Ketosis Prone Diabetes

 A heterogenous condition characterized by presentation with DKA in patients who do not
necessarily fit the typical characteristics of autoimmune T1DM.
 KPD is characterized by severe B-cell dysfunction  DKA or unprovoked ketosis + variable
clinical course

Fulminant T1DM
 Presentation:
o Extremely ↑ glucose levels + DKA
o On average only 4 days of hyperglycemia
o Normal or near-normal A1C
 Often preceded by common cold-like & GIT symptoms
 Sometimes associated with pregnancy
 Pancreatic enzymes often ↑

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 Gestational Diabetes
Definition
 GDM is diabetes that is first diagnosed in the second or third trimester of pregnancy
that is not clearly either preexisting T1DM or T2DM.
 Women diagnosed with diabetes by standard diagnostic criteria in the first
trimester
should be classified as having preexisting pregestational diabetes

Classification
1. Pregestational
2. Gestational diabetes: carbohydrate intolerance that begin in pregnancy in the 2nd or 3rd
trimester

Risk Factors
1. Family history of diabetes
2. Past history of gestational diabetes.
3. Age >25 years.
4. Previous delivery of a baby > 4 kg.
5. Polycystic ovary syndrome
6. Current use of glucocorticoids.
7. Certain ethnic groups e.g., African-American, South or East Asian.
8. Pre pregnancy body mass index >30 kg/m2.

Effects of Pregnancy on Diabetic State

1. Hyperinsulinemia and ↑ insulin resistance due placental secretion of
diabetogenic hormones eg corticotropin releasing hormone, placental lactogen, and
progesterone, as well as ↓ exercise.
2. Diabetic retinopathy worsens.
3. Diabetic nephropathy: Pregnancy is not associated with permanent worsening of renal
function in the majority of diabetic women in absence of uncontrolled HTN or baseline serum
creatinine concentration > 1.5 mg/dL.
4. Pregnancy does not affect the course of somatic or autonomic neuropathy.

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Effects of Diabetes on Pregnancy
Fetal & Neonatal Complications Maternal Complications
1. Congenital malformations: eg 1. Spontaneous abortion.
congenital heart defects, caudal & NTDs. 2. HTN/preeclampsia.
2. Macrosomia with associated shoulder 3. Polyhydramnios.
dystocia and ↑ likelihood of cesarean
delivery.
4. Infections: eg urinary tract
infections
3. Neonatal: Hypoglycemia, erythrocytosis,
hyperbilirubinemia, prematurity with 5. Recurrence of GDM in subsequent
respiratory problems. pregnancies.
6. GDM increases risk of developing
T2DM
Whom and How to Screen? Universal screening for all pregnant women is better
than screening women who have at least 1 risk factor for development of gestational diabetes

24 to 28 weeks of Gestation
A. One Step Approach: B. Two Step Approach:
 75 gram two hour oral glucose tolerance  If one hour plasma glucose after a 50
test, a diagnosis of gestational diabetes can gram oral glucose ≥130 mg/dL go to
be made in women who meet either of the 100 gram two hour oral glucose
following criteria: tolerance test.
o Fasting plasma glucose ≥92 mg/dL but o Fasting : 95 mg%
<126 mg/dL o 1h : 180 mg%
o One hour ≥180 mg/dL o 2h: 155 mg%
o Two hour ≥153 mg/dL). o 3h: 140 mg%

Glycemic Targets in a Patient with Hyperglycemia during Pregnancy

Target Blood Glucose:
1. Fasting glucose concentrations ≤ 95 mg/dL.
2. Preprandial glucose concentrations ≤ 100 mg/dL.
3. One-hour postprandial glucose concentrations ≤ 140 mg/dL.
4. Two-hour postprandial glucose concentrations ≤ 120 mg/dL.
5. Glucose levels should not decrease to <60 mg/dL.

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Management
Diet Insulin Oral Medications
 Aim: To prevent excessive weight gain.  Regular insulin, NPH  Glyburide and
insulin, insulin aspart,
 For women who are at ideal body metformin can be given
insulin lispro and
weight during pregnancy, the caloric insulin detemir have if patient refuse taking
requirement is 30 kcal/kg/day. acceptable safety insulin.
 For women who are overweight & profiles.  Women with polycystic

obese, the caloric requirement is  However insulin ovary syndrome who

glargine has not get pregnant and taking
22-25 kcal/kg/day.
been studied metformin can
 For morbidly obese women, the
extensively in continue it during
caloric requirement is 12-14 pregnancy pregnancy.
kcal/kg/day

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Diagnosis of Diabetes

 Prediabetes: Impaired glucose tolerance and impaired fasting glucose

Prediabetes is a term used to distinguish people who are at increased risk of developing diabetes.
o IFG (Impaired fasting glucose): 100 to 125 mg/dl
o IGT (Impaired glucose tolerance): 140 to 199 mg/dL

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Complications
A. ACUTE (METABOLIC)
I. Diabetic Ketoacidosis (DKA)
II. Hyperosmolar non-ketomic Coma (HONK)
III. Hypoglycemia
B. CHRONIC (ANGIOPATHY)
I. Microvascular disease II. Macrovascular disease
1. Eyes  Retinopathy 1. IHD
o Cataract 2. Strokes
o Glaucoma 3. Peripheral vascular disease
4. Feet
2. Nerves  Neuropathy
o Peripheral
o Autonomic
3. Kidneys  Nephropathy
o Microalbuminuria
o Gross albuminuria
4. Feet

 Endothelial dysfunction is common to microvascular and macrovascular events

o Remodelling – hypertrophy  MI + HF
o Remodelling – plaque  PAD + TIA + Stroke + Aortic aneurysm
o Microalbuminuria/mild insufficiency  Overt proteinuria + ESRD
 Endothelial dysfunction drives atherosclerotic progression
o Atherosclerosis is accelerated in T2D by hyperglycaemia, insulin resistance, inflammation and
diabetic dyslipidaemia
 Diabetes is a Serious Chronic Disease: ~ 50 % of patients presented with complication
 Mechanisms of Hyperglycaemia Induced Damage
1. ↑ Polyol - sorbitol Pathway flux
2. ↑ AGES formation
3. ↑ Hexosamine pathway flux
4. Activation of protein kinase C
 Why does elevated glucose cause complications?
o Blood glucose/prolonged hyperglycaemia  Oxidative stress 
1. Impaired cardiovascular regulation
2. Structural changes to vessels
3. Insulin resistance and beta-cell failure

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Diabetic Retinopathy
 It is the leading cause of blindness in adult
 Approximately 5% of patients with diabetes progress to sever visual acuity loss
 In T1DM after 15 y the risk of having DR 98%.
o 1/3 macular edema 1/3 PDR
 In T2DM after 15 y 78% DR
 10-18% of NPRDR progress to PDR
 ½ of the patient with PDR progress to blindness in 5y time

Classification
Non Proliferative DR Proliferative DR
1. Increased capillary permeability 1. New vessels
2. micro aneurysms 2. Vitreous hemorrhage
3. Retinal hemorrhage (dot & blots) 3. Retinal detachment
4. Hard exudates 4. New viscualization of the iris (Rubeosis iridis)
5. Diabetic macular edema 5. Scar (retinitis proliferanse)

Background Retinopathy
 Micro aneurisms
 Scattered exudates
 Hemorrhages(flame shaped, Dot and Blot)
 Cotton wool spots (<5)
 Venous dilatations

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Diabetic Neuropathy
A. Sensorimotor neuropathy (acute/chronic)
B. Autonomic neuropathy
C. Mononeuropathy
1. Spontaneous
2. Entrapment
3. External pressure palsies
D. Proximal motor neuropathy
Screening for Neuropathy: The main reason is to identify patients at
risk for development of diabetic foot
1. 128 Hz tuning fork for testing of vibration perception
2. 10g Semmers monofilament: A standardized filament is pressed against
part of the foot. When the filament bends, its tip is exerting a pressure of 10
grams (therefore this monofilament is often referred to as the 10gram
monofilament). If the patient cannot feel monofilament at certain specified sites
on foot, he has lost enough sensation to be at risk of developing a neuropathic
ulcer. Monofilament has the advantage of being cheaper than a biothesiometer,
but to get results which can be compared to others, the monofilament needs to
be calibrated to make sure it is exerting a force of 10 grams

A. Sensorimotor Neuropathy
 Patients may be asymptomatic / complain of numbness, paresthesias, allodynia or pain
 Feet are mostly affected, hands are seldom affected
 In Diabetic patients sensory neuropathy usually predominates
 Complications of Sensorimotor neuropathy
1. Ulceration (painless)
2. Neuropathic edema
3. Charcot arthropathy
4. Callosities

B. Autonomic Neuropathy
Symptomatic Subclinical Abnormalities
1. Postural hypotension 1. Abnormal pupillary reflexes
2. Gastroparesis 2. Esophageal dysfunction
3. Gustatatory sweating 3. Abnormal cardiovascular reflexes
4. Neuropathic bladder 4. Blunted counter-regulatory responses to hypoglycemia
5. Neuropathic edema 5. ↑ peripheral blood flow
6. Charcot arthropathy
7. Diabetic diarrhea
8. Erectile dysfunction

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C. Mononeuropathies
1. Cranial nerve palsies (most common are n. IV,VI,VII)
2. Truncal neuropathy (rare)

Entrapment Neuropathies
1. Carpal tunnel syndrome (median nerve)
2. Ulnar compression syndrome
3. Meralgia paresthetica (lat cut nerve to the thigh)
4. Lat Popliteal nerve compression (drop foot)
 All the above are more common in diabetic patients

D. Proximal Motor Neuropathy

 Amyotrophy – most common proximal neuropathy, affects the Quadriceps muscles with
weakness and atrophy
o (synonym: Diabetic Femoral radiculo-neuropathy)

Diabetic Amyotrophy Thoracoabdominal Sudomotor Dysautonomia

This syndrome is known by several
names, including diabetic proximal
motor neuropathy and diabetic
polyradiculoneuropathy. Patients
typically present with pain and
weakness in the proximal large
muscles of the legs and pelvic area.
Muscle wasting may be unilateral
or bilateral, but is usually
asymmetric with bilateral
involvement.4 Patients complain of
severe pain in the lumbar and
sacral regions. Many patients
report a loss of appetite and
depression as well. Improvement
may take from 6 months to 2 years.
Immunotherapy may be beneficial
and
accelerate
recovery.11
Radiculopathy
Truncal radiculopathies are rare but Patients often complain of
can present at the initial diagnosis hyperhidrosis or anhidrosis of the
of diabetes.2 Nerve roots T8 extremities, venous congestion,
through T12 are commonly pain and redness of the feet, and
affected. Patients complain of a gustatory sweating.5 Gustatory
tight bandlike or constricting pain sweating is common in patients
in the chest or abdomen. The chest with cervical sympathetic
or abdominal wall skin becomes denervation, demonstrated by
sensitive to the touch.2 Motor profuse sweating of the face, neck,
involvement may lead to abdominal and upper trunk while eating.12
muscle weakness, which may lead
to herniation and an asymmetric
bulge in the abdominal wall.3
Examination of spinal fluid may
show an increase of protein.4
Prognosis is generally good; most
patients
recover within
several months.

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Diabetic Nephropathy
Epidemiology of DKD
 Occurs in 20-40 % of patients with diabetes.
 DKD typically develops after diabetes duration of 10 years in T1DM, but may be present at
diagnosis of T2DM.
 Has an exaggerated cardiovascular risk.
 Both T1DM and T2DM have equal risk.

Definition of DN
 A microvascular complication of diabetes ch` by
o Persistent albuminuria (confirmed at least 2 out of 3 consecutive urine collection 3-6
months apart)
o Declining renal function ( GFR)
o Hypertension .
(With absence of clinical & lab evidence of other kidney or urinary system disease)
 Albuminuria:
o 30- 300 mg/24h or 20 - 200μg/min “Microalbuminuria”
o 300mg/24h or 200μg/min “Macroalbuminuria”

Pathogenesis of DN
 Initial (Functional) Changes  Glomerular Hyperfilteration & Hyperperfusion.
 Pathological Phases: Early endothelial cell dysfunction & podocyte injury followed by
extracellular matrix (ECM) deposition at (GBM) & mesangium.

Which is assessed histologically as

1. Diffuse GBM thickening.
2. Mesangial expansion.
3. Glomerular hypertrophy  sclerosis.

 Progressive fibrosis in the glomerular & tubular compartments is a hallmark feature of

advanced DN

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Diagnosis of DN
1. Spot Urinary Albumin creatinine Ratio (UACR) in 1st pass morning or in a spot urine sample.
2. Serum creatinine & estimated glomerular filtration rate (eGFR)

Causes of Transient Proteinuria

1. UTI
2. Heavy exercise
3. Fever
4. Uncontrolled diabetes
5. Pregnancy
6. Menstruation

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3. Ophthalmologic examination: To detect presence of diabetic retinopathy
4. Renal ultrasound: In DN, kidney size is normal
5. Indication of renal biopsy:If there is Features that point to non-diabetic kidney disease instead
of DN

When to Refer to Nephrologists??

1. Uncertain about the etiology of renal disease (heavy Proteinuria, active urinary sediments,
hematuria).
2. Resistant HTN despite treatment.
3. Advanced kidney disease (Stage 4-5 CKD).
4. Absence of retinopathy.
5. Rapid decline in GFR.
6. Abnormal ultrasound .

Screening of DN: Screening for nephropathy in diabetics prevents progression of kidney disease.
When to Screen?
1. T2DM  At diagnosis and early follow up
2. T1DM  5y after diagnosis
 Measurement of urinary Albumin /creatinine ratio (UACR)
 Abnormal results must be confirmed twice within 3-6 months before diagnosis of albuminuria
is made

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Management of DN
Targeting hemodynamic factors: Targeting metabolic factors:
A. BP control (ACEIs, ARBs) A. Control of hyperglycemia
B. Low Protein Diet B. Control of dyslipidemia
C. Low Salt Diet C. Control of Proteinuria

BP CONTROL
 ↓ BP is important in preventing progression of DN irrespective of the used agent.
 Start antihypertensive if BP is >140/90 mmHg
 Target BP <130/80mm Hg
 ACEIs & ARBs are the 1st line antihypertensive caused 60% reduction of
macroalbuminuria and ↑ chance of regression of albuminuria.

Inhibition of RAAS in DN
 ACEIs have Reno-protective effects
 Therefore, ACEIs & ARBs should be used in all patients with DN, regardless of BP (i.e even
normotensive patient).
 Repeat renal function 1 w after introduction of ACEIs If S.cr > 30% rule out renal artery stenosis

GLYCEMIC CONTROL
1. Prevent progression of microalbuminuria macroalbuminuria.
2. Prevent deterioration of kidney function in macroalbuminuric patients.
3. Prevent cardiovascular complications

 Glycemic control aims for  A1c level <7% (can be > 7 with comorbidities, limited life
expectancy &  risk of hypoglycemia).
 Adjust the dose of anti-hyperglycemic drugs If albuminuria & reduced kidney function
 When eGFR is < 60 mL/min/1.73 m2, evaluate and manage potential complications of CKD

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DIET MODIFICATION o Sodium < 2.4 g/d (< 100 mmol/d)
o ↑ Fibres improves lipid profile. o Protein < 0.8 mg/kg /day .
o ↓ Salt diet reduces blood pressure. o potassium > 4 (g/d)
o ↓ Phosphorus. o Calcium and magnesium
o ↓ Protein diet. supplements
 Dietary recommendations depend on the stage of CKD
o Phosphorus < 1.7 (g/d).

LIPID CONTROL May  proteinuria & preserve GFR (Keep LDL <100)

TREATMENT OF ADVANCED DN (CKD STAGE 3 OR MORE)

A. Monitoring renal function:
Contrast Induced
 Measure serum creatinine, eGFR:
Nephropathy (CIN)
o Every 6 months (if eGFR <60)
 Def: Impairment of renal function
o Every 3 months (if eGFR <45)
+2 and measured as 25% ↑ in
 Monitor electrolytes, bicarbonate, Ca , PO4,
S.cr from baseline within 48-
PTH, hemoglobin, albumin, weight: 72 hrs of IV contrast
o Every year (if eGFR <60) administration.
o Every 3-6 months (if eGFR <45)  CIN is one of the leading causes of
B. Glucose control: Anti-diabetic drugs may need to be hospital acquired acute
modified acc. to eGFR kidney injury (AKI).

55 ys old diabetic patient with Hx. Of cancer bladder and CT urography is planned for further evaluation
and you are asked for advice on minimizing risk of contrast induced nephropathy(CIN). His medication
was glimipride 3mg/d, metformin 850mg/twice daily
 What is your advice to prevent CIN in this patient???
1. Stop metformin 2days before contrast CT (to avoid lactic acidosis)
2. IV hydration with saline o.9% (diuresis)
3. Bicarbonate therapy 150mEq before &after contrast.
4. Oral N-acetyl cysteine 1200mg twice/d for 48 hrs

A 58-year-old man with a 7-year history of T2DM a walk-in clinic due to increasing swelling in his LL that
began about 6m previously and has worsened over the past 6w. The patient’s medical Hx. is significant
for HTN, T2DM. His medications include gliclazide 80 mg twice/d, metformin 500 tds, amlodipine 10
mg/d, and ibuprofen occasionally. **Examination: NAD apart from pallor & G2 pitting oedema LL.
**Lab: S.cr: 3.7 mg/dl, S.Albumin: 3 gm/dl, Urine analysis: prot. ++++ ,CBC: Hb: 10 (NNA)
 Is previous medication suitable for patient & why? NOT suitable d.t decline of renal function(GFR)
 What will happen if the patient continue on this medication??? Hypoglycemia (clearance of Sus) +
Lactic acidosis (clearance of metformin)
 Stop Metformin when eGFR < 30 ml/min/1.73 m2

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 Acute Complications
I. Diabetic Ketoacidosis (DKA)
Who gets DKA?
 Hallmark of T1DM (insulin insufficiency)
 Previously undiagnosed DM (about 25 – 30%)
 Interruption to normal insulin regime
 Intercurrent illness - usually infection
 Loss of beta cell function is gradual over time “Honeymoon period”
Pathophysiology
1. Insulin deficiency *lack of glucose in muscle
2. Glucagon excess *increase in gluconeogenesis
3. Rapid lipolysis  free FA + ketone bodies release of Beta-hydroxybutyrate .. Ketones resoposible
for all s&s
4. Hypovolaemia – vomitting + osmotic diuresis …..Increases concentration of ketones + glucose
 2ry to insulin deficiency + action of counter-regulatory hormones  blood glucose ↑ 
hyperglycemia and glucosuria.
o Glucosuria causes an osmotic diuresis  water & Na loss.
 In the absence of insulin activity  body fails to utilize glucose as fuel and uses fats instead.
o This leads to ketosis.
 The excess of ketone bodies  metabolic acidosis, the later is also aggravated by Lactic
acidosis caused by dehydration & poor tissue perfusion.
 Vomiting due to an ileus, plus ↑ insensible water losses due to tachypnea will worsen
the state of dehydration.
 Electrolyte abnormalities are 2ry to their loss in urine & trans-membrane alterations
following acidosis & osmotic diuresis.
 Because of acidosis  K ions enter the circulation leading to hyperkalemia, this is aggravated
by dehydration and renal failure.
 So, depending on the duration of DKA, serum K at diagnosis may be high, normal or low, but
the intracellular K stores are always depleted.
 Phosphate depletion will also take place due to metabolic acidosis.
 The dehydration can lead to decreased kidney perfusion and acute renal failure.
 Accumulation of ketone bodies contributes to the abdominal pain and vomiting.
 The increasing acidosis leads to acidotic breathing and acetone smell in the breath and
eventually causes impaired consciousness and coma.

26
Precipitating Factors Symptoms and Signs
1. New onset of T1DM: 25% 1. Nausea
2. Vomiting
2. Infections (the most common cause): 40% 3. Abdominal pain
3. Drugs: e.g. Steroids, Thiazides, Dobutamine 4. Often preceding polyuria, polydipsia,
& Turbutaline. weight loss
4. Omission of Insulin: 20%. This is due to: 5. Drowsiness/confusion/coma (severe)
o Non-availability (poor countries) 6. Kussmaul respiration - hyperventilation
o Fear of hypoglycemia
7. Sign of associated systemic illness
o Rebellion of authority
o Fear of weight gain (MI, infection, etc)
o Stress of chronic disease

Diagnosis  To diagnose DKA, the following criteria must

 You should suspect DKA if a diabetic patient be fulfilled :
presents with: 1. Hyperglycemia: of > 300 mg/dl &
1. Dehydration. glucosuria
2. Acidotic (Kussmaul’s) breathing, with a
fruity smell (acetone). 2. Ketonemia and ketonuria
3. Abdominal pain &\or distension. 3. Metabolic acidosis: pH < 7.25,
4. Vomiting. serum bicarbonate < 15 mmol/l.
5. An altered mental status ranging from  This is usually accompanied with severe
disorientation to coma.
dehydration and electrolyte
imbalance.
Management: The management steps of DKA includes:
 Assessment of causes & sequele of DKA by taking a short history & performing a scan examination.
 Quick diagnosis of DKA at the ER.
 Baseline investigations.
 Treatment, Monitoring & avoiding complications.
 Transition to outpatient management.

Replacing Fluids
 Initial management: 1 L 0.9% NaCl ….30 mins*…….1hr……2hr ……4 hr
o Then continue NaCl 0.9% as dictated by fluid status
o *Beware of elderly patients
 Later: Once blood glucose <250 mmol/L – give 10% dextrose alongside 0.9% Normal Saline at
125ml / hour

27
Insulin Infusion
 50units short acting regular made to 50ml with NaCl 0.9%
 Rate: 0.1 units/kg/hour
o 70kg = 7 units/hour
 Aim for:
o Fall in serum ketone of 0.5 mmol/L per hour
o OR rise in serum HCO3- by 3 mmol/hr
o OR reduction of Blood glucose by 50mg/dl/hr
 Increase rate of insulin by 1 unit per hour if above not achieved
 Continue infusion until blood ketones <0.3 or –ve urine ketone, venous pH >7.3 and/or HCO3- >18

Replace Electrolytes: K+ is most important (Insulin shifts K+ into cells therefore K+ will fall as
rehydrate)
≥ 5.5 3.5 - 5.4 <3.5
 No  Add 20mmol per  Add 40mmol per litre
potassium litre  Hyponatraemia may occur due to osmotic
supplement effect of glucose - it will correct with treatment of
DKA

Monitoring
 Monitor urine output and vital signs closely…… catheterize
 Repeat glucose, VENOUS bicarbonate – ABG …….2 – 4 hours, 6 - 8 hours, 12 hours, 24 hours
 Repeat ABG at 2 hours if not improving……….? Alternative cause for acidosis e.g. lactate

Pitfalls in DKA
1. High WCC: may be seen in the absence of infections.
2. BUN: may be elevated with prerenal azotemia secondary to dehydration.
3. Creatinine: some assays may cross-react with ketone bodies, so it may not reflect true renal
function.
4. Serum Amylase: is often raised, & when there is abdominal pain, a diagnosis of pancreatitis
may mistakenly be made.
5. Do not stop insulin even if the blood glucose is normal
Complications
1. Cerebral Edema
2. Intracranial thrombosis or infarction.
3. Acute tubular necrosis.
4. Peripheral edema.

28
 Cerebral Edema
 Clinically apparent cerebral edema occurs in 1-2% of children with DKA.
 It is a serious complication with a mortality of > 70%.
 Only 15% recover without permanent damage.
 Typically it takes place 6-10 hours after initiation of treatment, often following a period of
clinical improvement.

Causes of Cerebral Edema: The mechanism of CE is not fully understood, but many factors
have been implicated:
1. Rapid and/or sharp decline in serum osmolality with treatment.
2. ↑ initial corrected serum Na concentration.
3. ↑ initial serum glucose concentration.
4. Longer duration of symptoms prior to initiation of treatment.
5. Younger age.
6. Failure of serum Na to raise as serum glucose falls during treatment.
Presentations of C. Edema
1. Deterioration of level of consciousness.
2. Lethargy & decrease in arousal.
3. Headache & pupillary changes.
4. Seizures & incontinence.
5. Bradycardia. & respiratory arrest when brain stem herniation takes place.

Treatment of C. Edema
1. Reduce IV fluids
2. Raise foot of Bed
3. IV Mannitol
4. Elective Ventilation
5. Dialysis if associated with fluid overload or renal failure.
6. Use of IV dexamethasone is not recommended.

Discharge, Prevention & Prognosis

 How do you stop IV insulin? Overlap with regular insulin
 Prevention : Diabetic nurse + docs can use opportunity for patient education about insulin
regime
 Mortality is < 5%: Patients with frequent episodes are at increased risk of dying and diabetic
complications
29
II. Hyperosmolar Non-Ketotic Hyperglycaemic State /
Hyperosmoler Hyperglycemic State (HONK/HHS)
 Hallmark of T2DM
 May occur in:
1. New diagnosis
2. Poor compliance with treatment
3. Intercurrent illness – especially MI, Infection, CVA
4. Drugs- Steroids
5. Sugary drinks

Importance: Mortality markedly higher compared to DKA

 Co-morbidities, longer time to diagnosis, electrolyte disturbances
 Cerebral oedema and Pulmonary Embolism more common

Clinical Presentation
1. Possibly osmotic symptoms
2. Dehydration around 10L deficit
3. ↓ level of conciousness
4. Signs of underlying infection in up to 50%
5. +/- thrombo-embolism in up to 30%
6. 2/3 cases previously undiagnosed
7. As high as 50% mortality

How Do I Recognize It? Diagnosis requires ALL of the following:

1. Raised blood glucose (usually >600 mg/dl
2. Absence of ketones
3. Serum osmolality >350mmol
 How do you calculate osmolality? 2(Na+K) + urea + glucose/18

Is the Treatment the Same as DKA? Insulin

 Fluid replacement – SLOWER (may be a marker of population  50units actrapid made to 50ml
not pathology) with NaCl 0.9%
 Electrolyte replacement  Rate: 0.1 units/kg/hour
 Insulin – ‘slower’ scale – normally very responsive to IV insulin o 70kg = 7 units/hour
 Search for cause  More insulin sensitive
 ANTICOAGULATION + Monitor  Stop when patient is recovered

30
III. Hypoglycemia
Definition
 “Any abnormally low plasma glucose concentration that exposes the subject to potential harm”
 Plasma glucose alert value <70
mg/dL (<3.9 mmol/L), with or without symptoms.
 To diagnose hypoglycemia, Whipple triad is present.
1. Documentation of low blood sugar,
2. Presence of symptoms,
3. Reversal of these symptoms when the blood sugar level is restored to normal

Classification

Risk Factors
1. Use of insulin and sulfonylureas
2. Older people
3. Long duration diabetes
4. Irregular eating habits
5. Exercise
6. Have lower HbA1c
7. Periods of fasting e.g. Ramadan
8. Prior hypoglycemia
9. Hypoglycemia unawareness
10. Alcohol

31
Causes: Drugs are the most common cause
A. IN DIABETES: Exogenous insulin & insulin secretagogues (sulfonylureas)
1. Patient, doctor or pharmacist error
2. Deliberate overdose for suicide attempts
3. Unpredictable insulin absorption
4. Altered insulin clearance in renal failure
5. Decreased insulin requirements: missed meal, vomiting, exercise
6. Recurrent hypoglycemia unawareness
 NB: Insulin sensitizers (metformin , thiazolidinediones), (GLP-1) receptor agonists, and DPP4I are
much less common causes hypoglycemia.

B. HYPOGLYCEMIA IN PATIENTS WITHOUT DIABETES

1. Drugs 2. Endocrine 3. Tumours
1. Insulin, sulfonylureas, 1. Hypopituitarism 1. Mesenchymal tumors,
2. Alcohol,-others 2. ACTH deficiency fibromas, carcinoid,
 N.B. Factitious hypoglycemia: 3. Addison’s disease 2. Myelomas, lymphomas,
3. Hepatocellular, and
Measurement of C-peptide levels colorectal carcinomas.
during hypoglycaemia should identify
patients who are injecting insulin.

4. Critical Illness or Organ Failure 5. Endogenous Hyperinsulinism

1. Sepsis: Because of cytokine induced inhibition 1. A beta cell secretagogue, such as a
of gluconeogenesis in the setting of glycogen sulfonylurea
depletion. 2. Insulin autoimmune
2. Chronic kidney disease: Impaired hypoglycemia
gluconeogenesis, reduced renal clearance of
insulin, and reduced renal glucose production.
3. Insulinoma: Pancreatic islet cell tumour
that secrete insulin
3. Fulminant liver failure:
o Diagnosed by Whipple’s triad +
Gluconeogenesis is also impaired.
Measurement of overnight fasting (16
4. Malnourishment: As a result of substrate hours) glucose and insulin levels, C-
limitation of gluconeogenesis and glycogenolysis peptide or proinsulin during a
in the setting of glycogen depletion. spontaneous episode of hypoglycaemia.

32
Pathogenesis of Symptoms
1. Insulin secretion declines as the glucose declines to low-normal levels, around 80 mg/dl in
venous blood.
o Low insulin levels stimulate increases in hepatic and renal glucose production
2. Epinephrine is released by the adrenal medulla at mild levels of hypoglycemia ( 65–70
mg/dl) and stimulates hepatic and renal glucose production and decreases glucose utilization by
peripheral tissues
3. Glucagon release: At glucose (65–70 mg/dl ) Increases hepatic glucose production via
glycogenolysis and gluconeogenesis.
4. Cortisol and growth hormone release: Contribute only if the hypoglycemia persists for
several hours.
5. Neuroglycopenic symptoms: Develop If glucose levels to decline into the mid-50 mg/dl
range.

Symptoms
Autonomic = Neurogenic Symptoms Neuroglycopenic Symptoms
(Warning Symptoms) Caused by sympathetic neural 1. Bad concentration
response (↑ catecholamines) to lowering blood glucose 2. Confusion
1. Sweating 3. Weakness
2. Palpitations 4. Drowsiness
3. Trembling 5. Vision changes
4. Tingling 6. Difficulty speaking
5. Anxiety 7. Headache
6. Hunger 8. Dizziness
7. Nausea 9. Tiredness

Signs
1. Diaphoresis and pallor .
2. Heart rate and systolic blood pressure are raised.
3. Neuro- glycopenic manifestations.

Complications: The vast majority of episodes are reversed after the glucose level is raised to
normal.Prolonged untreated hypoglycemia can lead to:
1. Transient neurological deficits , but Permanent neurological damage is rare.
2. Loss of consciousness, Coma & Death
3. Increased risk of seizures, dementia, & car accident
4. CVS complications
5. Weight gain be defensive eating
6. Reduced quality of life + Hospitalization costs

33
Diagnosis
1. Clinical Evaluation 2. Lab Testing 3. Determination of Cause
 History including :  Fasting or  Lab and Radiologic studies
1. Timing of symptoms (particularly Postprandial
in relationship to meals), evaluation for :
2. Underlying illnesses or conditions 1. Glucose
3. Medications taken by the 2. Insulin
individual by family members, 3. C-peptide
and Social history. 4. Sulfonylurea +
meglitinide screen
 Clinical exam: may explore cause
Treatment Examples of 15g of Carbohydrate
 In adults, mild to moderate hypoglycaemia should be for Treating Mild-Moderate
treated by the oral ingestion of 15g of carbohydrate,
Hypoglycemia
preferably as glucose or sucrose tablets or solution.
o 15 g of glucose in the form of
o These are preferable to orange juice and glucose gels.
glucose tablets
 Patients should be encouraged to wait 15 minutes, o 15 ml (3 teaspoons) or 3 packets of
retest BG and retreat with another 15g. of carbohydrate if table sugar dissolved in water
the BG level remains <70 mg/dl. o 175 ml (3/4 cup) of juice or regular
 If >70 mg/dl a snack is allowed soft drink
o 6 Life Savers™ (1 = 2.5 g
 Treatment of severe hypoglycaemia
carbohydrate)
1. In the community: 1mg glucagon IM and long acting o 15 ml. (1 tablespoon) of honey
carbohydrate on recovery
2. Hospital options-
o I.M. glucagon 1mg
o I.V. 20ml of 50% dextrose*
 Treatment of the underlying cause
1. Adjust dose of anti-diabetics
2. Surgical removal of the insulinoma, oral glucocorticoids, diazoxide and octreotide, glucagon.
3. Replacement therapy for Addison disease.
Prevention
1. Patient Education 2. Hypoglycemia Awareness
1. Keeping a diary of low blood sugar symptoms Avoidance of hypoglycemia for several weeks
2. Regular check of blood sugar may help to improve it.
3. Modifying 4. Nocturnal Hypoglycemia
1. Diet (what, when, and how much you eat). 1. Bedtime snacks
2. The dosage or types of medicines. 2. ↓ dose of soluble insulin before supper
3. The timing and level of physical activity 3. Changing to a rapid-acting insulin analogue
4. Glycemic targets for individual patients.

34
Special Types of Hypoglycemia
1. Hypoglycemia Unawareness 2. Nocturnal Hypoglycemia
 Occurs in T1DM with frequent episodes of mild-  Can lead to disruption of sleep and
moderate hypoglycemia delays in correction of the hypoglycemia.
 It is an impairment of counter regulatory response  If high morning sugars preceded by an
to hypoglycemia (epinephrine and glucagon), episode of Nocturnal hypoglycemia=
o So many patients will develop neuroglycopenic (Somogyi effect).
symptoms, without warnings symptoms of
hypoglycemia which is dangerous.
3. Reactive Hypoglycemia:
 Blunted autonomic reflex responses to
 More common in overweight and
hypoglycemia  Only neuroglycopenic
symptoms occur obese people who are insulin-resistant
 Inability to think clearly (judgment is the  May be a frequent precursor to T2DM
first to go) leads to inappropriate, ineffective or no
 Possible higher risk in patients with a
response
 Greatly increased risk of death family history of T2DM or insulin-
 Absolute avoidance of hypoglycemia for several resistance syndrome
months restores responsiveness  TTT:
 N.B. may occur also in the following o Dietary therapy (restriction of
conditions: refined carbohydrates, avoidance of
1. During night. simple sugars, increased meal
2. BB frequency, increased protein and
3. Old age fiber);
4. Recurrent hypoglycemia o Alpha-glucosidase
inhibitors

35
 Management of Diabetes Mellitus
Goals of Treatment Specific Goals in Management
1. Complete elimination of overt clinical manifestation of Diabetes
2. Prevention of Acute diabetic complications.
1. Fasting <100 mg/dL
3. Prevention and treatment of hypoglycemia
4. Maintainance of high levels of physical fitness 2. Post-meal <140 mg/dL
5. Achievement of normal growth including proper 3. A1C <7%
timing of puberty.
4. Blood Pressure <130/80
6. Encourage the patient for full participation in all
activities appropriate for his age. 5. LDL <100 mg/dL; HDL >45 mg/dL
7. Education of patient and his families regarding 6. Triglycerides <150 mg/dL
diabetic process

36
Diet
Nutrition Assessment
1. Type of diabetes, any complications 7. Dietary 24 hour recall (meals, snacks, and
2. Blood sugar control beverages)
3. Past medical history 8. Favorite foods
4. Anthropometrics- height, weight, BMI, body 9. Food allergies
composition 10. Eating patterns and habits
5. Biochemical- labs 11. Physical activity
6. Medications, including supplements 12. Readiness to change
13. Attitude

Most Common Least Common

1. Diabetes 1. Underweight
2. Overweight/Obesity 2. Gastrointestinal issues
3. Hypertension 3. Celiac disease
4. High Cholesterol 4. Food allergies
5. Renal Disease 5. Eating disorders
6. HIV/AIDS 6. Sports nutrition
7. Pregnancy 7. Vegetarianism
8. Emotional eating 8. Bariatric surgery

MNT Goals for Diabetes

1. Achieve and maintain:
o Blood glucose levels in the normal range
o Lipid profile that reduces risk for cardiovascular disease
o Blood pressure levels in the normal range
2. To prevent (or slow) the rate of development of chronic complications by
modifying nutrient intake and lifestyle
3. To address individual nutrition needs, taking into consideration personal and cultural
preferences and willingness to change
4. To maintain the pleasure of eating by only limiting food choices when indicated by
scientific evidence

MNT Recommendations
1. Monitor carbohydrate intake for glycemic control
2. Include a variety of carbohydrates from fruit, vegetables, whole grains, legumes, and fat-free/low-
fat dairy products
3. The use the glycemic index may provide a modest benefit
4. Avoid excess energy intake

37
Special Considerations
1. Weight loss
 Weight loss has been shown to improve insulin resistance
 Encourage dietary changes, increased physical activity, and behavior modification
 Weight loss medications may be considered and can help with an additional 5-10% weight loss with
lifestyle modifications
 Bariatric surgery
2. Type 1 Diabetes
 Insulin therapy may be integrated into an individual’s dietary and physical activity pattern
 Adjust rapid-acting insulin doses based on carbohydrate content in meals and snacks
 When on fixed daily insulin doses keep carbohydrate content consistent with respect to time and
amount
 Adjust insulin for planned exercise. For unplanned exercise, extra carbohydrate may be needed
3. Type 2 Diabetes
 Encourage lifestyle modifications to improve glycemia, dyslipidemia, and blood pressure
 Reduce caloric intake, saturated and trans fats, cholesterol, and sodium
 Increase fiber, nutrient-rich foods
 Increase energy expenditure
4. Pregnancy
 Adequate caloric intake and nutrients needed to provide appropriate weight gain for mother and
fetus
 Focus on food choices for a healthy and steady weight gain, glycemic control, and absence of
ketones
 Aim to develop healthy habits and lifestyle modifications (diet and exercise) for after delivery

Meal Planning Strategies

 Timing of meals
 Healthy choices and balanced
meals
 Variety including nutrient-rich
foods and high-fiber foods
 Moderation using portion control
 Limit refined sugars
 Carbohydrate counting
1. Prescribed meal plan
2. Exchange system
3. Carbohydrate servings
4. Label reading
5. Glycemic index
6. Insulin to carbohydrate ratio + correction factor (if
applicable)

Breakdown of Macronutrients
 Total carbohydrate: 45-65% of total calories
 Total Protein: 10-35% of total calories
 Total fat: 20-35% of total calories

38
Nutrition Counseling
1. Patient’s lifestyle
2. Work schedule
3. Family life
4. Support system
5. Education level
6. Knowledge about diabetes and nutrition
7. Record keeping abilities
8. Attitude
9. Ability to adapt to change
10. Reaction to advice
11. Goal setting

Doctor’s Advice
 “Nutrition is an important part of taking care of your diabetes”
 Avoid telling patients to diet and lose weight without resources
 Do not recommend fad diets, try to encourage healthy lifestyle changes instead
 Be specific- “try to be active at least 30 minutes most days of the week”
 Keep it positive

Basic Nutrition Advice

 Timing of meals and snacks (no more than 4 hours without eating)
 Get a variety of healthy, high-fiber foods
 Limiting refined carbs and added sugars
 Watch portion sizes and read labels
 Keep a food journal
 Learn to make lifestyle changes and not diet for a short period of time

39
Exercise
What Can Physical Activity Do ?
1. Increase flexibility and strength  Physical activity lowers blood glucose in T2DM by
2. Slow bone loss helping:
3. Provide better quality of life 1. Muscle cells become more sensitive to insulin
4. Help lose weight and keep it off 2. Keep the liver from producing too much glucose
5. Give more energy 3. Build more muscle
6. Build muscle 4. You lose weight and keep it off
7. Improve sex life
 Physical activity helps heart by:
8. Lift mood
9. Treat depression 1. Strengthening heart muscle
10. Reduce stress and anxiety 2. Lowering resting heart rate
11. Improve blood glucose control 3. Lowering blood pressure
(lowers A1C) 4. Improving cholesterol
12. Keep heart healthy 5. Reducing risk of heart attack and stroke
 “Sitting” through life increases risk of:
1. Heart disease
2. High blood pressure
3. High cholesterol
4. Overweight
5. Type 2 diabetes
Getting Started
 Check :  Resistance Activities
o Are over age 35 1. “Push, Pull, and Lift” Activities
o Have had diabetes more than 10 years 2. increase muscle strength
o Have high blood pressure, heart disease, 3. prevent falls
poor circulation, or other diabetes 4. increase mobility
complications 5. improve blood glucose control
 Aerobic Activity 6. Stretching
o Walking briskly 7. Improves balance and coordination
o Dancing 8. M more flexible
o Bicycling 9. Reduces stiffness
o Hiking 10. Reduces risk of injury
o Jogging/running
o Skating
o Stair climbing
o Swimming
o Water exercise

40
How Can Patient Begin?
 Choose activity (example: brisk walking)
 Set a long-term goal - at least 30 minutes a day, 3-5 days a week
 Buy comfortable walking shoes + Get a partner
 Start Slowly: Set short-term goal for one week
 Gradually Increase Activity: Beginning Exercisers:
o First Week - 3 times a week
o Morning: Walk 5-10 minutes
o Lunch: Walk 5-10 minutes
o After dinner: Walk 5-10 minutes
 Keep track of how long and how far pt walk each day
 Keep Track of Steps: Use a pedometer
o Keep track of how many steps you normally take in a day for one week
o Gradually add 500-1,000 steps a day  Set a goal of at least 3,000 to
o 4,000 steps more than baseline
 Vary pt Activities + Keep A Record of Physical Activity
 Beginning A Physical Activity Plan:
o Type of activities + List long-term goal + List goal for first week

Effect of Physical Activity on Blood Treatment for Low Blood Glucose:

Glucose Equal to about 15 grams of carbohydrate:
 Depends on:  ½ cup fruit juice
1. Blood glucose level before exercise  ½ cup soft drink (not diet)
2. Diabetes medication  3 glucose tablets
3. Physical fitness  8 Lifesavers
4. Type of activity Physical Activity and Hypoglycemia
 Blood glucose checks before and after  More common after physical activity
exercise are the key  Body is replenishing stored carbohydrate
 Physical activity usually lowers blood (glycogen)
glucose  Check blood glucose after exercise
 Physical activity can raise blood glucose if: How to Prevent Low Blood Glucose
o BG is >250 mg/dl before exercise and Next Time?
have ketones
 Adjust Insulin: For planned, regularly
o Starting a new vigorous exercise program
scheduled physical activity
 Low blood glucose can result from
exercise only if pt take:
 Eat Snack:
o insulin o For unplanned physical activity
o oral diabetes medication (pills) o When exercising for an extended period
o sulfonylureas e.g Amaryl, of time
o repaglinide  Check blood glucose before, during,
and after exercise

41
 Examples of 15 gram carbohydrate snacks
o 6 saltine-type crackers
o 1 cup yogurt
o 2 fig bars
o 1 ounce sport or energy bar
o 8 ounces sports drink - ideally with less than 8% carbohydrate
 Beware of Too Many Snacks
o Avoid routinely eating extra food if pt trying to lose weight
o ask about adjusting medication dosages
o change the time of day exercise

Exercising With Diabetes Complications: If you have diabetes complications:

 An exercise stress test is recommended + Don’t consider diabetes a barrier to exercise
o Most moderate lifestyle activities are safe + Some activities may need to be modified

Caution
Heart  Very strenuous activity
Disease  Heavy lifting or straining
 Exercise in extreme cold or heat
Hypertension  Very strenuous activity
 Heavy lifting or straining
Retinopathy  Strenuous exercise
 Heavy lifting and straining
 High-impact aerobics, jogging
Nephropathy  Strenuous activity
Neuropathy  Weight-bearing, high impact,
strenuous, or prolonged exercise:
o jogging/running + step exercise
o jumping + exercise in heat/cold
Choose
 Moderate activity such as walking,
swimming, biking, gardening
 Moderate lifting, stretching
 Moderate activity like:
 Walking + stretching
 weight lifting with light weights
 Moderate, low-impact activities:
walking, cycling, water exercise
 Light to moderate activity like
walking, light housework, gardening,
water exercise
 Low impact, moderate activities:
o Biking + swimming
o chair exercises + stretching
o light to moderate daily activities

Exercise Safely
 Check blood glucose before and after exercise
 Don’t exercise if blood glucose is too high or too low
 Carry carbohydrate to treat low blood glucose if pt are at risk
 Stop exercising if pt feel pain, lightheaded, or short of breath
 Avoid strenuous activity in extremely hot, humid, or cold weather
 Wear proper shoes for the activity to reduce the risk of injury
 Wear diabetes identification
 Include warm-up and cool-down sessions
 Drink plenty of fluid
42
Insulin
 Made in betacells of the pancreas
 Moves glucose into cells
 Moves potassium into cells
Indications:
 T1DM
 T2DM in special circumstances
o Absolute: Pregnancy, DKA
o Relative:
1. Uncontrolled by diet or oral drugs
2. Diabetic complications : renal failure
3. Intercurrent events: TB - infections -
trauma – operations
 Non diabetic use :
o TTT of hyperkalemia,
o Combined insulin tolerance test for
hypopituitarism, schizophrenia,
o Gastric function tests
 Must never be frozen
Source of Insulin: animal + human insulin by 
recombinant DNA technique  If refrigeration not available – Frio bags
Timing
 Soluble insulin: 30-45 minutes pre-meal
 Short-acting insulin analogues: no
more than 15 minutes pre-meal and can be
given post-meal
 Intermediate- or long-acting
insulins do not have to be given in relation
to a meal
Calculation of Insulin Dose:
1. Sliding scale technique: Start with 10
units Regular insulin before every meal and T
dose by 5 units every day, then calculate the
total daily dose.
2. Trial & Error: Then calculate the total daily
dose.
Route of Administration:
1. SC injection
2. lntraveous: regular insulin
3. Insulin pump: insulin through a catheter in
abdominal fat
o Given in severe cases, children, pregnant
and renal transplant patient
Storage
 One month in fridge or at room
temperature once the vial has been opened
Store away from source of heat
available
 May be damaged by direct sunlight or
vigorous shaking
Normal Pancreatic Function
 Basal: Beta cells secrete small amounts of
insulin throughout the day.
 Bolus: At mealtime, insulin is rapidly
released in response to food.
 Expected insulin changes during the day for
individuals with a healthy pancreas.
43
Insulin Preparations

Type Preparation Onset Peak Duration

Rapid Acting Lispro (Humolog, 15-30 min (may 1 - 2 hours 3 – 4 hours
Insulin Novolog Aspart) come on in 5 min)
Short Acting Regular (clear so 0.5 to 1 hour 2 – 4 hours 6 – 8 hours
Insulins can be given IV)
Intermediate NPH, Lente 1 – 4 hours 4 – 12 hours 18 – 24 hours
Acting Insulins (chemicals added.
Cloudy)
Once a day Glargine/Lantus or  Cannot be diluted or mixed in syringe with any other
Insulin detemir/levemir insulin
and Degludec  Slow, steady release
(Tresiba )  Daily dosing [usually at bedtime]
 Refrigerated or tosses every 14 days
Combination 70/30 (70% NPH  Fewer injections
Insulins and 30% regular)  Rotate sites to decrease lipodystrophy

Complications of Insulin:
1. Hypoglycemia & hypoglycemic coma
2. Insulin resistance :
o Definition : ↑↑ daily insulin
requirements > 200 IU in absence of
conditions ass. with ↑↑ insulin demand
(infection – pregnancy…)
o Causes:
1. Obesity : commonest cause for mild
resistance
2. Antibodies against insulin preparations
3. Antibodies against insulin receptors
o Treatment: MC or human insulin,
cortisone, plasma exchange
3. Insulin edema : mild LL edema (salt & water
retention)
4. Insulin lipgdystrophy:
o Insulin lipoatrophy : change to purified
or human insulin
o Insulin lipohypertrophy: (insulin
tumor): change site of injection
5. Insulin Allergy : use monocomponent or
human insulin
6. Acute neuropathy, Blurring of vision &
Weight gain
7. Smoggy effect:
o Nocturnal hypoglycemia: (night
sweats, night mares & morning headache)
o This causes rebound morning
hyperglycemia
o Tills by ↓ insulin dose

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Types of Insulin Regimens
 Exact duration depends on insulin 1. Requires only one injection per day
Once-  Insulin analogues may provide 24-
2. May help overcome resistance to
Daily hour cover
starting insulin injections
 Intermediate human insulin
Basal 3. Particularly useful when patient’s blood
preparations may only be active
Insulin for ~8 hours and have a more glucose is high overnight and in the
pronounced peak activity morning
 Contains: 1. Targets mealtime glucose
Premixed o Basal component 2. Suited to people with fairly regular
Insulin – o Short-acting component
lifestyles, who eat similar amounts at
Once,  Possible regimens: similar times each day
Twice Or o Once daily with largest daily
3. Can be initiated as one injection per
Three- meal (usually dinner)
Times o Twice daily with dinner and day to familiarise patient with injecting*
Daily
breakfast (figure) o Second or third injections of
o Three-times daily, with each same insulin in same device can be
meal added if necessary to optimise control
Basal– 1. Produces insulin profile that is closest to natural insulin production by body
Bolus 2. Offers greater flexibility over type of food and when it can be eaten
Therapy 3. Suited to those who are highly motivated

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46
Oral Antibiabetics

I. INSULIN SECRETAGOGUES: Sulfonylureas II. INSULIN SENSITIZERS: Biguandies

1. Promote release of insulin from β – cells 1. ↓ hepatic glucose production
2. ↓ appetite & glucose absorption from the gut
o Sulphonylureas bind to the sulphonlyurea receptors
3. ↑anaerobic glycolysis ( T lactic acid formation from
on the surface of the pancreatic β cell  closure of the K
glucose)
channel and inhibition of efflux of K in β cell 
4. ↑ sensitivity of insulin receptor
depolarization of β cell membrane and opening of voltage-
Action

5. Beneficial effect on lipid profile.

dependent Ca channel  exocytosis of insulin from the
vesicles  ↑ risk of hypoglycemia
o In order to avoid hypoglycemia, patients may indulge in
defensive eating which results in weight gain
2. ↓ hepatic glucose production
3. Insulin sensitizing effect
Classification Indications
 Used alone in obese type 2 DM not controlled by diet alone
 Combined with sulphonyl urea or insulin to achieve control

Preparation & dosage: Metformine : 500 mg t.d.s

after meal up to 2-3gm/d

Efficacy: High Efficacy: High

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 1. Extensive experience 1. Extensive experience
Advantage
2.  Microvascular risk (related to glucose control) 2. No weight gain
3. Low cost 3. No hypoglycemia
s

4. Likely ↓ CVD events (UKPDS)

5. Low cost

1. Hypoglycemia 1. GI side effects ( reduced by initiating treatment at a

Side Effect

2. Wight gain low dose and gradually titrating )

3. B Cell Exhaustion
4. Chloretic jaundice 2. Lactic acidosis (extremely rare)
5. Hypersensitivity reactions 3. Contraindications CKD and Heart failure

Drug Interaction Benefits Risks

1. A1C ↓ 1–1.5% 1. GI side effects in up
↑ Hypoglycemia ↓ Action 2. No weight gain to 50%
1. Anticoagulants 1. BB, Diuretics, 3. Rare hypoglycemia
2. Salicylates 2. Corticosteroids, 4. Favourable lipid profile 2. Not tolerated in up to
3. Sulfonamides 3. Estrogens, Thyroid 5. ↑ initial response rate 20%
4. MAO Inhibitors 4. Hormones 6. Established safety profile 3. Caution or
5. Tricyclic antidepressants 5. Sympathomimetics,
6. Azole antifungals 6. Phenothiazines
contraindication if
Creatinine Clearance < 60
7. Isoniazid, Phenytoin,
mL/min
8. Nicotinic Acid
4. Lactic acidosis: very
rare
5. Discontinued at or
prior to IV contrast and
withheld for 48 hours post
IV contrast

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 V. Phenylalinine
III. Thiazolidinedione IV. α-Glucosidase Inhibitors
Derivatives
 Preparation : pioglitazone  Preparation: Acarbose  Preparation:
 Action: insulin sensitizer (PPAR -γ agonist)  Action: Competitive inhibitor of α- Repaglinide
1. ↑ peripheral Insulin action on Skeletal glucosidase enzymes in small intestines  ↓ (Novonorm)
Muscle absorption of starches and sugars. o Short pulse
2. ↓ hepatic Glucose production o Taken before meals duration of action
 Indication: T2DM (Obese &Insulin resistance)  Effects: o Give after meal
 Contraindication: 1. ↓ fasting plasma glucose 20-30 mg/dl with capricious
1. Decompensated liver disease, 2. ↓ peak postprandial glucose 40-50 mg/dl appetite
2. CHF (NYHA 3,4) 3. ↓ HbA1c 0.5-1.0% o Full dose
4. No specific effect on lipids or blood range (0.5-4 mg)
pressure with meals taken
5. Abdominal discomfort
6. Contraindicated with inflammatory bowel
disease or cirrhosis
Efficacy: High Efficacy: Modest
1. No hypoglycemia 1. No Body weight gain
Side Effect Adva.

2. Durability 2. No hypoglycemia
3. ↓TGs,↑HDL-C 3. ↓Post-prandial glucose

1. Edema ,  Gastrointestinal upset (Flatulence)

2. Weight Gain,
3. Bone fracture,
4. ↑ risk of CHF,
5. ↑ risk of bladder cancer.
6. ↑ cost

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VI. Incretin-Based Therapies (DPP4 Inhibitors + GLP1 Agonists)
 Incretin Hormones are hormones produced in GI tract in response to nutrients which in turn stimulates insulin secretion
 Predominant Hormones are: GLP-1 and GIP
 In patients with T2DM, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to
the inability of these patients to adjust their insulin secretion to their needs

Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes

 GLP-1 secretion is impaired in Type 2 diabetes + Natural GLP-1 has extremely short half-life
o Add GLP-1 analogues with longer half-life: exenatide, liraglutide
o Block DPP-4, the enzyme that degrades GLP-1: Vildagliptin, sitagliptin

GLP-1 Analogues DPP4I

1. Activates GLP-1 receptor 1. Inhibits DPP-4
2. ↑Insulin, ↓glucagon 2. ↑ GLP-1, GIP
Action 3. ↑satiety
4. ↓ gastric emptying
High Moderate to High
Efficacy (Glucose Dependent Manner)
1. Weight loss 1. No hypoglycemia
2. ↓ risk of hypoglycemia but 2. Well tolerated
Advantages relatively higher than DPP-4I
3. ? ↑ Beta cell mass
4. ? CV protection
1. GI 1. ? Pancreatitis
2. ?↑ Pancreatitis 2. ↑ cost
Disadvantages
3. Injectable
4. ↑ cost

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VII. SGLT2 Inhibitors

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Potential Clinical Benefit in T2DM
1. Glucose lowering
o Prevention of microvascular morbidity1
o Decrease in glucotoxicity2
o Urinary glucose excretion decreases as
hyperglycemia decreases, resulting in a low risk
of hypoglycemia2
2. Insulin-independent mechanism3
o Ability to work at all stages of disease
o Ability to combine with other classes of
antihyperglycemics2
o Stable control in combination with insulin and
insulin secretagogues2
3. Osmotic diuresis
o Initial weight loss2
o Decrease in blood pressure
4. Loss of excess calories in the urine2,3
o Sustained weight loss2
o Mitigation of weight gain from other classes of
antihyperglycemics2

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