Secondary Diabetes ________________________________ Nihal Thomas MD DNBEndo,MNAMS,FRACP Endo Sudeep

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Secondary Diabetes ____________________________
____Nihal Thomas MD DNB(Endo),MNAMS,FRACP
(Endo)Sudeep MD Dip DiabDepartment of
Endocrinology Christian Medical
College, Vellore,India

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1.What is the relative contribution of Fasting
hyperglycaemia and postprandial hyperglycaemia to
mean glycaemic values?
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• Glycaemic Control
• -relative contributions
• The contribution of Post prandial hyperglycaemia
  to Hba1C is upto 70
• in well controlled individuals
• The contribution of fasting hyperglycaemia
• to HbA1C is up 30 in those with poorly
  controlled diabetes mellitus
• -Diabetes Care 2003, Monnier L.

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2.How common is unrecognized hypoglycaemia in
the well controlled patient with diabetes
mellitus?
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• Hypoglycaemia is present in upto
• 7 of the time in a day in individuals
• with well controlled
• diabetes mellitus
• Diabetes Technology and Therapeutics
• Hay LG, Wilmhurst EG.

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Secondary Diabetes ...seems to be a
different ball game

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What is Secondary Diabetes? A Disorder of
Diabetes..other than Type 1 or Type 2 Diabetes

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• Classification
• Genetic defects of Beta cell function by
  mutation.
• Genetic defects in Insulin action.
• Exocrine pancreatic diseases.
• Endocrinopathies due to over production of
  counter regulatory hormones.
• Drugs or chemicals induced.
• Infectious diseases.
• Uncommon form of immune mediated diabetes.
• Other genetic syndrome with diabetes.

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• Classification
• Genetic defects of Beta cell function by
  mutation.
• Genetic defects in Insulin action.
• Exocrine pancreatic diseases.
• Endocrinopathies due to over production of
  counter regulatory hormones.
• Drugs or chemicals induced.
• Infectious diseases.
• Uncommon form of immune mediated diabetes.
• Other genetic syndrome with diabetes.

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Regulatory Hormones a Background
Proglycaemic Glucagon Catecholamines Growth
Hormone Glucocorticoids Somatostatin
Hypoglycaemic Insulin Glucagon-Like Peptide-1
Somatostatin
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Regulatory Hormones a Background
Proglycaemic Glucagon Catecholamines Growth
Hormone Glucocorticoids Somatostatin
Hypoglycaemic Insulin Glucagon-Like Peptide-1
Somatostatin
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Insulin - ve Glucagon
ve GLP-1 -ve
Somatostatin ve -ve

Cortisol ve Catecholamines ve


Liver
Growth Hormone ve
Pituitary
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Proglycaemic hormones
Glucagon..Ketogenic
CatecholaminesKetogenic Glucocorticoids.Ketogen
ic Increase in stress

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• 26 year old lady history of weight gain and
  hypertension.
• On Examination
• BP 170/120mmHg
• Obese,
• Pigmented.
• Severe Proximal Myopathy
• 800AM Cortisol 36ug/dl .
• Post Dexa 2mg 7ug/dl
• ACTH 60pg/dl (20-40pg/dl)

Case Number 1
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Microadenoma
Optic Chiasm
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Bilateral Adrenal Hyperplasia
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Glycaemic Profile-Preoperatively

• Fasting-
  240mg/dl
• 2hour post breakfast- 320mg/dl
• 2hour post lunch- 420mg/dl
• 2hour post dinner- 320mg/dl
• Mechanistic Viewpoint
• Reduced insulin post-receptor
  activity
• Inhibition of GLUT-4
  activity
• Increased gluconeogenesis (by activation
  of PEPCK)
• Increased production of
  glucagon

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Glycaemic Profile-Preoperatively

• Fasting-
  240mg/dl
• 2hour post breakfast- 320mg/dl
• 2hour post lunch- 420mg/dl
• 2hour post dinner- 320mg/dl
• Mechanistic Viewpoint
• Reduced insulin post-receptor
  activity
• Inhibition of GLUT-4
  activity
• Increased gluconeogenesis (by activation
  of PEPCK)
• Increased production of
  glucagon

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Iatrogenic Cushings- Subtle differences

• Dexamethasone
• Greater glycaemic disturbance
• -Longer action more area under the curve
• Deflazacort
• Less glycaemic disturbance

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• Trans-sphenoidal Surgery

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Glycaemic Profile -Postoperatively

• 1 week
• Fasting-
  140 mg/dl
• 2hour post breakfast- 330 mg/dl
• 2hour post lunch- 300 mg/dl
• 2hour post dinner- 280 mg/dl
• 6 weeks
• Fasting-
  120 mg/dl
• Post-prandial 2hour-
  240 mg/dl

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Case Number 2

• 46 year old lady, presented with headache,
  vomiting, sudden loss of conciousness.
• Brought to emergency department.
• GCS 8/15 . Temperature 100degrees F .
• Blood Pressure 80/60mmHg.
• Complete 3rd nerve palsy on left side, with
  pupillary involvement. Neck stiffness.
• Physical Examination otherwise normal.
• Known case of diabetes mellitus for 5
  years
• Additional History
  Amenhorrea-5months

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3rd Nerve Palsy
Acromegalic Features
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Pituitary Adenoma-
Standard histopathology
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Apoplectic tissue
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Glycaemic Profile -Pre-apoplexy

• Fasting-
  160 mg/dl
• 2hour post breakfast-
  260mg/dl
• On glipizide 10mg twice
  daily
• and metformin 1g twice daily
• Growth Hormone 24ng/dl post 100g
  glucose
• (normal lt 2.5
  ng/dl)
• Mechanistic Viewpoint for Hyperglycaemia in
  growth hormone excess
• Insulin Resistance due to
  IGF-I excess

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Glycaemic Profile -Post-apoplexy

• Fasting-
  80 mg/dl
• 2hour post breakfast- 60mg/dl
• 2hour post lunch- 40mg/dl
• 2hour post dinner- 130mg/dl
• Mechanistic Viewpoint
• 
  Hypocortisolemia
• Reduction in growth hormone
  levels

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Glycaemic Profile -Post-apoplexy

• Fasting-
  80 mg/dl
• 2hour post breakfast- 60mg/dl
• 2hour post lunch- 40mg/dl
• 2hour post dinner- 130mg/dl
• Mechanistic Viewpoint
• 
  Hypocortisolemia
• Reduction in growth hormone
  levels

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Glycaemic Profile -Post-apoplexy

• Fasting-
  80 mg/dl
• 2hour post breakfast- 60mg/dl
• 2hour post lunch- 40mg/dl
• 2hour post dinner- 130mg/dl
• Mechanistic Viewpoint
• 
  Hypocortisolemia
• Reduction in growth hormone
  levels
• Diabetes Cures
  itself!

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Case Number 3

• 16-year old boy presents with recurrent attacks
  of fainting.
• Fasting Plasma glucose 40mg/dl

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Fathers Height 152cm
Height 128cm
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Calcified Craniopharyngioma
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• Spontaneous Hypoglycaemia due to Growth hormone
• 
  and Cortisol deficiency
• Initiated on Growth Hormone Therapy
• - following appropriate stimulatory tests
• Growth hormone therapy may increase
• the risk if type 2 diabetes mellitus
  6-fold
• by the 4th decade in those who are NOT
  growth
• hormone deficient.

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Physiology of Case 1 and 2
Hypothalamus
GHRHGrowth hormone releasing hormone GHRP-6Gr
owth Hormone Releasing Peptide-6

GHRHve
GHRP-6
Growth Hormone
Liver
Pituitary
Somatostatin-ve
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Growth factors
IGF-I Insulin Growth Factor I IGFBP-6IGF
Binding Protein-6
Growth Hormone

Liver
ALS
IGFBP-3
IGF- I
GHBP GH
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Growth factors
IGF-I Insulin Growth Factor I IGFBP-6IGF
Binding Protein-6
Growth Hormone

Liver
ALS
IGFBP-3
IGF- I
GHBP GH
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Case Number 4
Symptoms sweating, prominence of eyes tremors,
palpitations. T4 24ug/dl
TSH lt0.001
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Symmetrical enlargement uniform uptake 2 hours
40, 6 hours 54, 24Hours 80
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Glycaemic Profile in thyrotoxicosis (Off
medications)

• Fasting-
  50 mg/dl
• 2hour post breakfast- 260 mg/dl
• 2hour post lunch- 240
  mg/dl
• 2hour post dinner- 210
  mg/dl
• Mechanistic Viewpoint
• Increased/ More rapid Postprandial
  absorption
• Glycogenolysis/ gluconeogenesis
  increased

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Glycaemic Profile in thyrotoxicosis (Off
medications)

• Fasting-
  50 mg/dl
• 2hour post breakfast- 260 mg/dl
• 2hour post lunch- 240
  mg/dl
• 2hour post dinner- 210
  mg/dl
• Mechanistic Viewpoint
• Increased/ More rapid Postprandial
  absorption
• Glycogenolysis/ gluconeogenesis
  increased

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Glycaemic Profile (Off medications)

• Fasting-
  50 mg/dl
• 2hour post breakfast- 260 mg/dl
• 2hour post lunch- 240
  mg/dl
• 2hour post dinner- 210
  mg/dl
• Mechanistic Viewpoint
• Increased/ More rapid Postprandial
  absorption
• Glycogenolysis/ gluconeogenesis
  increased
• But..glycogen storage is reduced
  markedly

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Glycaemic Profile (On medications)

• Fasting-
  111 mg/dl
• 2hour post breakfast- 160 mg/dl
• 2hour post lunch- 24mg/dl
• 2hour post dinner- 35 mg/dl
• On Neomercazole 30mg per day.
• Mechanistic Viewpoint
• 1) Thionamides (Neomercazole) may have
  an affinity for the sulphonylurea receptor
• 2) Autoimmune hypoglycaemia
• (antibodies to the insulin
  receptor)

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Glycaemic Profile (On medications)

• Fasting-
  111 mg/dl
• 2hour post breakfast- 160 mg/dl
• 2hour post lunch- 24mg/dl
• 2hour post dinner- 35 mg/dl
• On Neomercazole 30mg per day.
• Mechanistic Viewpoint
• 1) Thionamides (Neomercazole) may have
  an affinity
• for the sulphonylurea receptor
• 2) Autoimmune hypoglycaemia
• (antibodies to the insulin
  receptor)

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Case Number 5

• 27 year old lady, presents with
• Palpitations, headache and weight
  loss of 8 kg
• over a period of 6 months.
• On examination
• Weight 40 kg Height
  152 cm
• Blood pressure 240/130mmHg
• Optic Fundus Grade III hypertensive
  changes
• 24 Hour Urinary VMA 22mg in 24 hours (N7mg)

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Extra-adrenal Phaeochromocytoma
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Glycaemic Profile

• Fasting-
  110mg/dl
• 2hour post breakfast- 200 mg/dl
• 2hour post lunch- 230mg/dl
• 2hour post dinner- 264
  mg/dl
• On Amlodipine 10mg/ day and Losartan 50mg
  twice daily
  
• Mechanistic Viewpoint
• Excessive Catecholamines
  cause
• 1) Alpha adrenergic effect-reduced insulin
  secretion
• 2) Beta adrenergic effect-increased hepatic
  glycogenolysis
• 3) Increased circulating fatty acids insulin
  resistance

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Glycaemic Profile- on modified therapy

• Fasting-
  110mg/dl
• 2hour post breakfast- 134 mg/dl
• 2hour post lunch- 110mg/dl
• 2hour post dinner- 192
  mg/dl
• On Amlodipine 10mg/ day and Losartan 50mg
  twice daily
  Prazocin XL 10mg tid
• Mechanistic Viewpoint
• Alpha adrenergic blocking effect
• - increased insulin
  secretion
• Oral Hypoglycaemic agents not used.

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Glycaemic Profile- Post-operative tumour excision

• 6 hours postoperatively 54
  mg/dl
• Mechanistic Viewpoint
• 1) Sudden catecholamine withdrawal
• 2) Depleted Hepatic glycogen storage

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Summarizing, The Endocrine Causes .

• 1. Growth Hormone - Acromegaly
• 
  -Treatment
• 2. Corticosteroid Excess -Exogenous
• 
  -Endogenous
• 3. Hyperthyroidism
• 4. Phaeochromocytoma
• 5. Glucagonoma Syndrome
• 6. Somatostatinoma Syndrome

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Summarizing.

• 1. Post-prandial hyperglycaemia is a dominant
• phenomenon in Endocrine disorders for secondary
  diabetes.
• 2. Reversal of hyperglycaemia- as a natural
  phenomenon or as a post-therapeutic adjunct is a
  common occurrence.
• 3. Spontaneous Hypoglycaemia due to various
  mechanisms may occur.

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Disease of exocrine pancreas

• Chronic Pancreatitis
• Fibrocalculous pancreatic diabetes
• Acute pancreatitis
• Malnutrition related diabetes mellitus
• Pancreatectomy
• Cystic fibrosis
• Hemochromatosis

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Chronic Pancreatitis

• 75 have intolerance-
• 40 - 50 have frank diabetes while
• 25 - 30 have impaired glucose tolerance
• Diet
• Alcohol
• Enzymes

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Fibrocalculous pancreatic diabetes

• Ketosis resistant
• Low BMI
• Recurrent abd pain
• Other clinical features
• Radiology
• OHA? Which?
• Complicationas

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Drugs and chemicals induced diabetes

• Diuretics
• Phenytoin
• Nicotinic acid
• ACTH
• Cyclosporin
• Opiates

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Genetic defects of beta-cell function

• Mutations in islet cell transcription factors /
  glucokinase
• MODY

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MODY

• Three generations
• Younger
• Milder

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Genetic defects in insulin action

• Genetic defects in Insulin Receptor / Post
  Receptor Signaling defect -Type A
• Circulating Autoantibodies to Insulin Receptor-
  Type B

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Genetic defect

• Two main types
• Glucokinase gene defect
• very young subjects,
• managed with diet and OHAs
• Transcription factor defects (HNF 1A, HNF 1B,
  HNF 4A)
• onset adolescent,
• disease progressive requiring OHA and insulin

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Salient features

• Monogenic form of insulin defect
• Autosomal dominant mode of inheritance where
  glucose intolerance is seen in atleast 3
  successive generations
• Patients usually are at 3rd decade of life
• Glucose intolerance is mild

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Management

• Diet
• Exercise
• Oral Hypoglycaemic Agents

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THANK YOU