Diabetes Mellitus

By Dr. Adithya Polavarapu

Definition
• Diabetes mellitus (DM) refers to a group of common metabolic
disorders that share the phenotype of hyperglycemia.
• Several distinct types of DM are caused by a complex interaction of
genetics and environmental factors.
• factors contributing to hyperglycemia include reduced insulin secretion,
decreased glucose utilization, and increased glucose production
• DM is the leading cause of end-stage renal disease (ESRD),
nontraumatic lower extremity amputations, and adult blind- ness. It also
predisposes to cardiovascular diseases
Criteria for Diagnosis

• Symptoms of diabetes plus random blood glucose concentration ≥11.1

mmol/L (200 mg/dL) or
• Fasting plasma glucose ≥7.0 mmol/L (126 mg/dL) or
• Hemoglobin A 1c ≥ 6.5% or
• 2-h plasma glucose ≥11.1 mmol/L (200 mg/dL) during an oral glucose
tolerance test.
Criteria for Diagnosis
Classification
• DM is classified on the basis of the pathogenic process leading to
hyperglycemia, as opposed to earlier criteria such as age of onset or type
of therapy
• However, there is increasing recognition of other forms of diabetes in
which the molecular pathogenesis is better understood and may be
associated with a single gene defect. These alternative forms may share
features of type 1 and/or type 2 DM
Classification
Type 1 Immune mediated beta cell destruction leading to
diabetes absolute insulin deficiency

Ranges from predominantly insulin resistance with

Type 2 relative insulin deficiency to predominantly insulin
diabetes secretory defect with insulin resistanc.

Gestational Glucose intolerance developing during the second

or third trimester of pregnancy
diabetes

Include specific genetic defects in insulin secretion

Specific types of or action, metabolic abnormalities that impair
Diabetes insulin secretion, mitochondrial abnormalities.
 Specific types of DM
• Genetic defects of beta cell development or function characterized by
mutations in:
1. Hepatocyte nuclear transcription factor (HNF) 4α (MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1α (MODY 3)
4. Insulin promoter factor-1, HNF-1β, NeuroD1, and others leading to
other forms of MODY
5. Insulin, subunits of ATP-sensitive potassium channel leading to
permanent neonatal diabetes
6. Mitochondrial DNA
7. Other pancreatic islet regulators/proteins such as KLF11, PAX4,
BLK, GATA4, GATA6, SLC2A2 (GLUT2), RFX6, GLIS3
• Transient neonatal diabetes
• Infections—congenital rubella, cytomegalovirus, coxsackievirus
• Endocrinopathies—acromegaly, Cushing’s syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma
 Specific types of DM
• Diseases of the exocrine pancreas—pancreatitis, pancreatectomy,
neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous
pancreatopathy, mutations in carboxyl ester lipase
• Genetic defects in insulin action, including type A insulin resistance,
Rabson-Mendenhall syndrome, Lipodystrophy syndromes
• Drug- or chemical-induced—glucocorticoids, vacor (a rodenticide),
pentamidine, nicotinic acid, diazoxide, β-adrenergic agonists, thiazides,
calcineurin and mTOR inhibitors, hydantoins, asparaginase, α-interferon,
protease inhibitors, antipsychotics (atypicals and others), epinephrine
• Uncommon forms of immune-mediated diabetes—”stiff-person”
syndrome, anti-insulin receptor antibodies
• Other genetic syndromes sometimes associated with diabetes—
Wolfram’s syndrome, Down’s syndrome, Klinefelter’s syndrome,
Turner’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Laurence-
Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi
syndrome
 Epidemiology
• Diabetes is fast gaining the status of a potential epidemic in India with
more than 62 million diabetic individuals currently diagnosed with the
disease.
• In 2000, India (31.7 million) topped the world with the highest number
of people with diabetes mellitus followed by China (20.8 million) with
the United States (17.7 million) in second and third place respectively
40
32M • It is predicted that by 2030
32 diabetes mellitus may afflict
up to 79.4 million individuals
24 21M in India
18M
16

0
India China USA
Epidemiology 1

• It is predicted that by 2030 diabetes mellitus may afflict up to 79.4

million individuals in India.
• There are, however, patterns of diabetes incidence that are related to the
geographical distribution of diabetes in India. Rough estimates show that
the prevalence of diabetes in rural populations is one-quarter that of urban
population for India and other Indian sub-continent countries such as
Bangladesh, Nepal, Bhutan, and Sri Lanka
• Preliminary results from a large community study conducted by the
Indian Council of Medical research (ICMR) revealed that a lower
proportion of the population is affected in states of Northern India
(Chandigarh 0.12 million, Jharkhand 0.96 million) as compared to
Maharashtra (9.2 million) and Tamil Nadu (4.8 million).
• A suggested explanation for this difference is that the north Indians are
migrant Asian populations and south Indians are the host populations,
however this possible cause-and-effect has not been corroborated through
further research.
[1] Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in
Epidemiology
• The National Urban Survey conducted across the metropolitan cities of
India reported similar trend: 11.7 per cent in Kolkata (Eastern India), 6.1
per cent in Kashmir Valley (Northern India),6 11.6 per cent in New Delhi
(Northern India), and 9.3 per cent in West India (Mumbai) compared with
(13.5 per cent in Chennai (South India), 16.6 per cent in Hyderabad
(south India), and 12.4 per cent Bangalore (South India).
21.3

17 17
14
12.8 12 12 12
9
8.5

4.3

0
Kashmir Delhi Mumbai Chennai Hyderabad Bangalore
 Pathogenesis of Type 1 DM
• Type 1 DM is the result of interactions of multiple factors which lead to
Immune mediated destruction of pancreatic beta cells & insulin deficiency

Genetic Factors

Destruction of
pancreatic Beta cells

Environmental Immunologic
Factors Factors

Insulin Deficiency
 Insulitis;
The Major Susceptibility gene is located in
HLA region on chromosome 6. Halotypes -Islet cell autoantibodies
include HLA DR3 &/OR DR4 -Activated lymphocytes in
islets, peripancreatic LN &
blood.
Genetic Factors - T lymphocytes that
proliferate when stimulated
with islet proteins
- Cytokines { TNF- α, IL-
1}

Environmental Immunologic
Factors Pancreatic islet molecules
Factors
targeted are;
Proinsulin, insulin, glutamic
acid decarboxylase, ICA-
Coxsackie, rubella, enteroviruses 512/IA2 & beta cell specific
Bovine milk proteins,Nitrosourea compounds zinc transporter ZnT-8
,Vit D deficiency, environmental toxins
 Pathogenesis of Type 1 DM
• The temporal decline of beta cell function
& mass preceding the development of type
1 DM is show schematically below.
• Initial triggering event
• Antibodies appear after event
• Progressive loss of insulin
secretion.
• Features of diabetes do not
become evident until a
threshold loss of insulin
secretion & beta cell mass
occurs.
• “Honeymoon” Phase is seen
in first 1 or 2 yrs after initial
presentation during which
glycemic control is achieved
with modest doses of insulin.
 Pathogenesis of Type 2 DM

• There are 2 major mechanisms :

• Peripheral insulin resistance
• Pancreatic β-cell Dysfunction
• Type 2 DM is characterized by impaired insulin
secretion, insulin resistance, excessive hepatic glucose
production, abnormal fat metabolism & systemic low
grade inflammation.
 Peripheral insulin resistance
Numerous Genetic & environmental factors

Central obesity Increased serine kinase activity in

liver,fat & skeletal muscle cells

Increased plasma lvls of

Phosphorylation of insulin
free fatty acids
receptor substrate (IRS)-1
Impaired insulin-dependent
glucose uptake into hepatocytes, Decreased affinity of
Myocytes & adipocytes IRS-1 for PI3K
Absence of insulin dependent
inhibition of hepatic Decreased expression of GLUT-4
glycogenolysis & glucose o
genesis further promotes
hyperglycemia Decreased cellular glucose uptake
 Pancreatic β cell dysfunction
Peripheral insulin resistance creates huge
demand for glucose lowering agents

Increased production of pro-insulin & pro-amylin.

Pancreatic proteolytic enzymes that convert pro-insulin & pro-amylin into

insulin & amylin are not able tp keep up with high levels of secretion

Accumulation of pro-amylin (Islet amyloid

Polypeptide) in pancreas

Decreased endogenous insulin production

 Pathogenesis of Type 2 DM

• Initially, Insulin resistance is compensated by increased

insulin and amylin secretion
• Over the course of the disease, insulin resistance
progresses, while insulin secretion capacity declines.
• After a period of impaired glucose tolerance with
isolated postprandial hyperglycemia, diabetes manifests
with fasting hyperglycemia.
Pathogenesis of Type 2 DM
Risk factors
• Family history of diabetes (i.e., parent or sibling with type 2 diabetes)
• Overweight or obese (BMI ≥25 kg/m2, ≥23 kg/m2 in Asian Americans,
or other ethnically relevant definition for overweight)
• Physical inactivity
• Race/ethnicity (e.g., African American, Latino, Native American, Asian
American, Pacific Islander)
• Previously identified with IFG, IGT, or an hemoglobin A1c of 5.7–6.4%
• History of GDM
• Hypertension (blood pressure ≥140/90 mmHg)
• HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride
level >250 mg/dL (2.82 mmol/L)
• Polycystic ovary syndrome or acanthosis nigricans History of
cardiovascular disease
 Clinical evaluation of type 1 & type 2
History Type 1 diabetes Type 2 diabetes

Gradual; the majority of patients are

Sudden; diabetic ketoacidosis is often the
asymptomatic
first manifestation
Hyperosmolar hyperglycemic state (in
Onset Alternatively, children may present with
elderly especially, signs of dehydration)
acute illness and classic symptoms (see
Symptoms of complications may be the first
“Characteristic features” below)
clinical sign of disease

Classic
Polyuria
Secondary enuresis and nocturia in children
Polydipsia
Polyphagia
Nonspecific
Characteristic Fatigue
features Visual disturbances: blurred vision
Calf cramps
Poor wound healing
Pruritus

Weight loss; a thin appearance is typical for

Benign acanthosis nigricans
type 1 diabetic patients
Clinical evaluation of type 1 & type 2

Physical Examination
• Weight & BMI
• Retinal examination
• Orthostatic blood pressure ( normal BP > 130/80 is high in DM pts)
• peripheral pulses
• Insulin injection sites
• Teeth & gums for periodontal teeth
• Foot examination ( Annual examination includes
• Pedal pulses, Vibration sense, Sense of touch with monofilament,
Pinprick sensation, Ankle reflexes, nail care
• Foot deformities ( hammer or claw toes & Charcot foot )
• Sites of potential ulceration
Diagnostics
Diagnostics
Additional tests
• Specific autoantibodies for diabetes mellitus type 1
- Anti-GAD antibodies
- Anti-tyrosine phosphatase-related islet antigen (IA-2)
- Islet cell surface antibody (ICSA; against ganglioside)
• C-peptide
- ↓ C-peptide levels indicate an absolute insulin deficiency → type 1
diabetes
- ↑ C-peptide levels may indicate insulin resistance and
hyperinsulinemia → type 2 diabetes
• Urine analysis
- Microalbuminuria: an early sign of diabetic nephropathy
- Glucosuria: Testing urine for glucose does not suffice to establish
the diagnosis of diabetes mellitus.
- Ketone bodies (usually accompanied by glucosuria): positive in
acute metabolic decompensation in diabetes mellitus (diabetic
Acute Complications

• Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes

mellitus may result in severe hyperglycemia, potentially culminating in a
coma
• Hyperosmolar hyperglycemic state (HHS)
• Diabetic ketoacidosis (DKA)
• Life-threatening hypoglycemia: secondary to inappropriate insulin
therapy
 Long term Complications
Macro vascular
• More common in patients with type 2 diabetes
• Pathophysiology: The major determinants are metabolic risk factors,
which include obesity, dyslipidemia, and arterial hypertension.
Hyperglycemia may be less related to the development of macrovascular
disease.
• Manifestations
• Coronary heart disease (CHD)
• Cerebrovascular disease
• Peripheral artery disease (PAD)
• Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD)
• PAD diagnostic tools are unreliable in patients with Mönckeberg's
arteriosclerosis
 Long term Complications
Micro vascular
• Onset: typically arises 5–10 years after onset of disease
• Pathophysiology: Chronic hyperglycemia is the primary factor
influencing the development of microvascular disease; results in
glycation of proteins and lipids with subsequent impaired protein and
cell membrane function and tissue damage
• Manifestations
• Diabetic nephropathy
• Diabetic retinopathy
• Diabetic neuropathy
• Diabetic foot
Long term Complications

• Diabetic cardiomyopathy
• Diabetic fatty liver disease
• Hyporeninemic hypoaldosteronism
• Limited joint mobility (formerly
known as diabetic cheiroarthropathy)
• Sialadenosis
• Increased risk of infection
Management
Management of Diabetes mellitus includes the
following aspects
• Individual treatment targets
• Life style modification
• Self management education
• Medical treatment
• Monitoring complications
Individual Treatment Targets
• Blood glucose control and regular glycemic monitoring: A1C values
• Weight loss : Type 2 diabetic patients with a BMI of 27–35 benefit from
a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight
reduction of > 10% is recommended.
• Blood pressure control ( Type 2: < 140/90 mm Hg )
• Improved blood lipid profile with statin therapy ( type 2: LDL < 100
mg/dL (2.6 mmol/L)
• Low dose aspirin for men > 50 years and women > 60 years with
cardiovascular risk factors
Lifestyle Modifications
• ↑ Physical activity → ↓ blood glucose and ↑ insulin sensitivity
• Smoking cessation
• Balanced diet and nutrition
• Small, frequent meals
• Diet: ∼ 55% carbohydrates (replace simple carbohydrates such as
glucose and sucrose with complex carbohydrates), 30% fat, 15%
protein
• High-fiber diet
• Alcohol should (if possible) be consumed with carbohydrates to
avoid hypoglycemia.
Self-management Education
• Education topics important for optimal diabetes self-care include
• self-monitoring of blood glucose (SMBG);
• urine ketone monitoring (type 1 DM);
• insulin administration;
• guidelines for diabetes management during illnesses;
• prevention and management of hypoglycemia (Chap. 399);
• foot and skin care;
• diabetes management before, during, and after exercise; and
• risk factor-modifying activities.
• The focus is providing patient-centered, individualized education.
Medical Treatment
Oral Anti-Diabetic Drugs
• HbA1C target for adults: < 7% (53 mmol/mol)
• The guidelines for the treatment of DM recommend an individualized treatment
strategy.
• If the target A1C is not reached within 3 months with conservative measures (e.g., diet,
exercise), the next step in the therapeutic algorithm should be initiated.
Weight reduction, exercise , medical nutrition therapy, self-management
General measures
education

Monotherapy The drug of choice is metformin. ( also insulin or sulfonylureas )

Metformin +
A second oral antidiabetic drug: dipeptidyl peptidase-4 inhibitor,
sulfonylureas, thiazolidinedione, meglitinides, SGLT-2 inhibitors, alpha-
Dual therapy
glucosidase inhibitors, amylin analogs
GLP-1 receptor agonists (incretin mimetics)
Basal insulin
Add a third oral antidiabetic drug, nightly basal insulin, or injectable
Triple therapy
GLP-1 receptor agonist

Combination
Metformin + basal insulin + mealtime insulin or GLP-1 receptor agonist
injectable therapy
Medical Treatment - Insulin Therapy
On average, the body requires 40 USP units of insulin daily.
Total daily requirement
20 units for basic metabolism → basal insulin
of insulin
20 units for calorie consumption → bolus insulin

1 unit of insulin lowers the blood glucose level by 30–40 mg/dL (1.7–2.2
Insulin correction factor
mmol/L)
10 g of carbohydrates increases the blood glucose level by 30–40 mg/dL
Carbohydrate counting
(1.7–2.2 mmol/L).

On average, 1 unit of insulin is required for 15 g carbs = 1 carb serving

(carb unit); however, this varies greatly from patient to patient.
Insulin-to-carbohydrate
Insulin sensitivity fluctuates over the course of a day → Insulin-to-
ratio
carbohydrate ratio changes over the course of a day.
Morning hours: 2 units insulin, lunchtime: 1 unit, evening hours: 1.5 units

Insulin replacement therapy: The exogenous insulin requirement depends

on the residual insulin production of the pancreas.
Type 1 diabetes The initial total daily dose (TDD) of insulin should be 0.6–1.0 U/kg.
After beginning insulin treatment, there is often a temporary reduction in
exogenous insulin demand.

Residual endogenous insulin production is augmented with exogenous

insulin, depending on the extent of insulin resistance (which in turn
Type 2 diabetes
depends on the level of obesity).
The TDD of insulin should be 0.1–0.2 U/kg.
Monitoring complications
• Regular monitoring of weight, abdominal circumference, blood
pressure, blood lipids, renal retention parameters (creatinine,
electrolytes), injection site in patients receiving insulin therapy
• Yearly eye exam (type 1: after 5 years with diabetes mellitus or after the
age of 11 years); more frequently in patients with abnormal findings or
diagnosed retinopathy
• Annual urine testing for microalbuminuria
• Foot exam for neuropathy and ulcers; advise patients to wear
appropriate footwear and avoid injury
• Routine screening for psychosocial problems, including signs of
depression and cognitive impairment
• Pneumococcal vaccines
Thank You