Endocrinology and metabolic diseases
1. Diabetes mellitus – etiology, pathogenesis, classification
Diabetes – spectrum of metabolic diseases characterized by chronic hyperglycemia
Type 1 DM – autoimmune destruction of B cell islets in the pancreas absolute
insulin deficiency
Type 2 DM – strong genetic component, associated with obesity and sedentary
lifestyle, characterized by insulin resistance and impaired insulin secretion due to
pancreatic B cell dysfunction relative insulin deficiency
Type 1
5-10% of total diabetes cases, most often onset <20 years, peak at 4-6 years and 10-
14 years
Autoimmune destruction of pancreatic B cells in genetically susceptible individuals
Associated with HLA-DR3 + HLA-DR4, and other autoimmune diseases hashimoto,
gastritis, celiac disease, primery adrenal insufficiency
Type 2
more common, adult onset typically >40 years, increasing incidence In younger
people, more common in men.
Hereditary + environment involved, associated with metabolic syndrome and central
obesity, risk factors: family history, race/ethnicity, inactivity, PCOS, hypertension,
dyslipidemia.
WHO and ADA (American diabetes association) classification
Type 1
o Autoimmune – type 1a
o LADA – latent autoimmune diabetes in adults, characterized by late onset
type 1 often mistaken for type 2
o Idiopathic – type 1b
Type 2
Gestational diabetes
Other types:
o MODY – maturity onset diabetes of the young – genetic defects beta cell
dysfunction - few subtypes, usually treated with sulfonylureas
o Pancreatogenic diabetes – after pancreas removal, hemochromatosis, cystic
fibrosis
o Due to endocrinopathies – chushing, acromegaly
o Drug induced – corticosteroids
o Infections -congenital rubella, parovovirus B19
,Pathophysio
Normal insulin physiology
Insulin synthesized in B cells of islets, cleavage of proinsulin produced c-peptide and
insulin, insulin is made up of 2 peptide chains (A and B chains.)
Insulin is an anabolic hormone with variety of metabolic effects on the body
cellular uptake and metabolism of nutrients and glycemic control
Insulin is the only hormone that directly lowers blood glucose, insulin inhibits
proteolysis, stimulates protein synthesis and stimulates cellular uptake of amino
acids, it also maintains fat depot and has antiketogenic effect, it also stimulates
intracellular potassium accumulation
Type 1 DM
Genetic susceptibility and environmental triggers (often viral infection)
autoimmune response with production of autoantibodies anti glutamic acid
decarboxylase antibody (anti-GAD) anti islet cell cytoplasmic antibody (anti-ICA)
destruction of B cells absolute insulin deficiency decreased uptake into
tissues hyperglycemia
Type 2 DM
Peripheral insulin resistance due to – central obesity (increased FFA impaired
glucose uptake into hepatocytes, myocytes and adipocytes.) increased serine kinase
activity phosphorylation of insulin receptor substrate decreased affinity of IRS-
1 for Pi3K decreased GLUT4 expression decreased cell glucose uptake
, Pancreatic B cell dysfunction accumulation of pro-amylin decreased
endogenous insulin production.
Initially, insulin resistance is compensated by increased insulin and amylin secretion,
but as insulin resistance progresses, simulatenously insulin secretion capacity
declines, at one point the insulin secretion can no longer overcome the resistance
and impaired glucose tolerance with postprandial hyperglycemia occurs.
2. Diabetes mellitus – clinical manifestations of type 1 and type 2 diabetes
Clinical Features of Diabetes
Type 1
o Often sudden onset
o Diabetic ketoacidosis is the first manifestation in 1/3 of cases
o Children often present with acute illness and classic symptoms of polyphagia,
polydipsia and polyuria
Type 2
o Typically gradual onset
o Majority of patients are without symptoms
o Some patients may present with hyperglyemic crises, older patients may
present with hyperosmolar hyperglycemic state, sometimes DKA results,
symptoms of complications are often the first sign of the disease.
Clinical Features – the same for both:
Polyuria which can secondary enuresis and nocturia in children
Polydipsia
Polyphagia
Unexplained weight loss, blurred vision, fatigue, pruritis
Poor wound healing, increased susceptibility to infections, cramps
Symptoms usually manifest when 80-85% of beta cells are destroyed.
Patients with type 1 are often thin, and patients with type 2 are often obese with benign
acanthosis nigricans or acrochordons (skin tags)
Diagnosis
All patients aged 35-70 who are overweight or obese should be screened for
diabetes, as well as any patient with symptoms, any patient over 45 with history of
prediabetes, gestational diabetes, and any other risk factors.
Diagnostic criteria
Random blood glucose levels >200mg/dl in patients with symptoms
Or 2 or more abnormal tests showing hyperglycemia in asymptomatic patients
Random blood glucose, fasting blood glucose, OGTT and HbA1c are the main
methods of diagnostics
Diabetes can be diagnosed when:
Random blood glucose level measurement >11.0 mmol/dl (200mg/dl) OR
Blood glucose level >11.1 (200mg/dl) 2 hours after a 75g OGTT OR
Fasting plasma glucose >7.0 (126mg/dl) OR
HbA1c >48 mmol/mol
, The OGTT is the most sensitive test, but is less convenient and more expensive, however a
random fasting glucose cannot be used for diagnosis in hospitalized patients or patients who
are sick.
Other studies
C peptide – can help differentiate between types of diabetes
o Increased levels may indicate insulin resistance and hyperinsulinemia T2
o Decreased levels indicate absolute insulin deficiency T1
Urinalysis
o Glucosuria – non specific as can also occur if the renal threshold for glucose is
reached
o Ketone bodies diabetic ketoacidosis
o Micro albuminemia – early sign of diabetic nephropathy
Antibody testing – consider in patients with established diabetes, if there is suspicion
for type 1 DM
o Anti-glutamic acid decarboxylase antibodies – anti-GAD – 60-80% of people
with new onset T1DM
o Anti-tyrosine phosphate related islet antigen 2
o Islets cell antibody (ICA)
Differential Diagnosis
Glucagonoma and somatostatinoma
3. Chronic complications of diabetes mellitus
Complications of diabetes can occur in all patients (T1 + T2) with long standing diabetes, and
are more likely to be progressive and severe in patients with poor glycemic control.
The complications are divided into 2 broad categories:
Macrovascular complications
o Coronary artery disease
o Stroke
o Myocardial infarction
o Cardiac failure
o Peripheral artery disease
Microvascular complications
o Diabetic nephropathy renal failure
o Diabetic retinopathy retinopathy, impaired vision
o Diabetic neuropathy sensory loss, pain, weakness, delayed gastric
emptying postural hypotension
o Diabetic foot ulcer, gangrene, arthropathy, charcot foot
1. Diabetes mellitus – etiology, pathogenesis, classification
Diabetes – spectrum of metabolic diseases characterized by chronic hyperglycemia
Type 1 DM – autoimmune destruction of B cell islets in the pancreas absolute
insulin deficiency
Type 2 DM – strong genetic component, associated with obesity and sedentary
lifestyle, characterized by insulin resistance and impaired insulin secretion due to
pancreatic B cell dysfunction relative insulin deficiency
Type 1
5-10% of total diabetes cases, most often onset <20 years, peak at 4-6 years and 10-
14 years
Autoimmune destruction of pancreatic B cells in genetically susceptible individuals
Associated with HLA-DR3 + HLA-DR4, and other autoimmune diseases hashimoto,
gastritis, celiac disease, primery adrenal insufficiency
Type 2
more common, adult onset typically >40 years, increasing incidence In younger
people, more common in men.
Hereditary + environment involved, associated with metabolic syndrome and central
obesity, risk factors: family history, race/ethnicity, inactivity, PCOS, hypertension,
dyslipidemia.
WHO and ADA (American diabetes association) classification
Type 1
o Autoimmune – type 1a
o LADA – latent autoimmune diabetes in adults, characterized by late onset
type 1 often mistaken for type 2
o Idiopathic – type 1b
Type 2
Gestational diabetes
Other types:
o MODY – maturity onset diabetes of the young – genetic defects beta cell
dysfunction - few subtypes, usually treated with sulfonylureas
o Pancreatogenic diabetes – after pancreas removal, hemochromatosis, cystic
fibrosis
o Due to endocrinopathies – chushing, acromegaly
o Drug induced – corticosteroids
o Infections -congenital rubella, parovovirus B19
,Pathophysio
Normal insulin physiology
Insulin synthesized in B cells of islets, cleavage of proinsulin produced c-peptide and
insulin, insulin is made up of 2 peptide chains (A and B chains.)
Insulin is an anabolic hormone with variety of metabolic effects on the body
cellular uptake and metabolism of nutrients and glycemic control
Insulin is the only hormone that directly lowers blood glucose, insulin inhibits
proteolysis, stimulates protein synthesis and stimulates cellular uptake of amino
acids, it also maintains fat depot and has antiketogenic effect, it also stimulates
intracellular potassium accumulation
Type 1 DM
Genetic susceptibility and environmental triggers (often viral infection)
autoimmune response with production of autoantibodies anti glutamic acid
decarboxylase antibody (anti-GAD) anti islet cell cytoplasmic antibody (anti-ICA)
destruction of B cells absolute insulin deficiency decreased uptake into
tissues hyperglycemia
Type 2 DM
Peripheral insulin resistance due to – central obesity (increased FFA impaired
glucose uptake into hepatocytes, myocytes and adipocytes.) increased serine kinase
activity phosphorylation of insulin receptor substrate decreased affinity of IRS-
1 for Pi3K decreased GLUT4 expression decreased cell glucose uptake
, Pancreatic B cell dysfunction accumulation of pro-amylin decreased
endogenous insulin production.
Initially, insulin resistance is compensated by increased insulin and amylin secretion,
but as insulin resistance progresses, simulatenously insulin secretion capacity
declines, at one point the insulin secretion can no longer overcome the resistance
and impaired glucose tolerance with postprandial hyperglycemia occurs.
2. Diabetes mellitus – clinical manifestations of type 1 and type 2 diabetes
Clinical Features of Diabetes
Type 1
o Often sudden onset
o Diabetic ketoacidosis is the first manifestation in 1/3 of cases
o Children often present with acute illness and classic symptoms of polyphagia,
polydipsia and polyuria
Type 2
o Typically gradual onset
o Majority of patients are without symptoms
o Some patients may present with hyperglyemic crises, older patients may
present with hyperosmolar hyperglycemic state, sometimes DKA results,
symptoms of complications are often the first sign of the disease.
Clinical Features – the same for both:
Polyuria which can secondary enuresis and nocturia in children
Polydipsia
Polyphagia
Unexplained weight loss, blurred vision, fatigue, pruritis
Poor wound healing, increased susceptibility to infections, cramps
Symptoms usually manifest when 80-85% of beta cells are destroyed.
Patients with type 1 are often thin, and patients with type 2 are often obese with benign
acanthosis nigricans or acrochordons (skin tags)
Diagnosis
All patients aged 35-70 who are overweight or obese should be screened for
diabetes, as well as any patient with symptoms, any patient over 45 with history of
prediabetes, gestational diabetes, and any other risk factors.
Diagnostic criteria
Random blood glucose levels >200mg/dl in patients with symptoms
Or 2 or more abnormal tests showing hyperglycemia in asymptomatic patients
Random blood glucose, fasting blood glucose, OGTT and HbA1c are the main
methods of diagnostics
Diabetes can be diagnosed when:
Random blood glucose level measurement >11.0 mmol/dl (200mg/dl) OR
Blood glucose level >11.1 (200mg/dl) 2 hours after a 75g OGTT OR
Fasting plasma glucose >7.0 (126mg/dl) OR
HbA1c >48 mmol/mol
, The OGTT is the most sensitive test, but is less convenient and more expensive, however a
random fasting glucose cannot be used for diagnosis in hospitalized patients or patients who
are sick.
Other studies
C peptide – can help differentiate between types of diabetes
o Increased levels may indicate insulin resistance and hyperinsulinemia T2
o Decreased levels indicate absolute insulin deficiency T1
Urinalysis
o Glucosuria – non specific as can also occur if the renal threshold for glucose is
reached
o Ketone bodies diabetic ketoacidosis
o Micro albuminemia – early sign of diabetic nephropathy
Antibody testing – consider in patients with established diabetes, if there is suspicion
for type 1 DM
o Anti-glutamic acid decarboxylase antibodies – anti-GAD – 60-80% of people
with new onset T1DM
o Anti-tyrosine phosphate related islet antigen 2
o Islets cell antibody (ICA)
Differential Diagnosis
Glucagonoma and somatostatinoma
3. Chronic complications of diabetes mellitus
Complications of diabetes can occur in all patients (T1 + T2) with long standing diabetes, and
are more likely to be progressive and severe in patients with poor glycemic control.
The complications are divided into 2 broad categories:
Macrovascular complications
o Coronary artery disease
o Stroke
o Myocardial infarction
o Cardiac failure
o Peripheral artery disease
Microvascular complications
o Diabetic nephropathy renal failure
o Diabetic retinopathy retinopathy, impaired vision
o Diabetic neuropathy sensory loss, pain, weakness, delayed gastric
emptying postural hypotension
o Diabetic foot ulcer, gangrene, arthropathy, charcot foot
