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SECONDARY DIABETES UPDATE
Dr.V.Mohan., MD., Ph.D., D.Sc., D.Sc (Hon. Causa),
FRCP (London, Edinburgh, Glasgow & Ireland), FNASc., FASc., FNA, FACE, FTWAS, MACP
PRESIDENT & DIRECTOR
MADRAS DIABETES RESEARCH FOUNDATION,
SIRUSERI, CHENNAI
CHAIRMANDR.MOHAN’S DIABETES SPECIALITIES CENTRE,
GOPALAPURAM, CHENNAI
WHO COLLABORATING CENTRE FOR
NONCOMMUNICABLE DISEASES
ICMR CENTRE FOR ADVANCED
RESEARCH ON DIABETES IDF CENTRE OF EXCELLENCE IN
DIABETES CARE
Dr. Satish Garg,Professor of Medicine and Pediatrics
University of Colorado Denver
Editor-in- Chief, Diabetes Technology & Therapeutics
& Organizing Committee of
Declaration of potential conflict of
interest
I have no conflict of interest to declare
Definition : These are forms of diabetes where a definite cause for the
diabetes is known. This is in contrast to ‘primary’ forms of diabetes like
type 1 and type 2 diabetes.
Depending on the disease process involved (eg. destruction of
pancreatic beta cells or development of insulin resistance) clinically,
these types of diabetes may behave similar to type 1 or type 2
diabetes.
SECONDARY DIABETES
1. Endocrine diseases associated with diabetes
2. Drug induced diabetes (eg. glucocorticoids)
3. New Onset Diabetes After Transplantation (NODAT)
4. Diabetes Secondary to Pancreatic Diseases
CAUSES OF SECONDARY DIABETES
Endocrine diseases associated with diabetes
1. Acromegaly
2. Cushing Syndrome
3. Pheochromocytoma
4. Glucagonoma
5. Thyroid disorders
6. Polycystic ovary syndrome (PCOS)
ACROMEGALY
Jennings RE, Hanley NA. Textbook of Diabetes. 2017;272-290
Clinical features
Protruding mandible (prognathia)
Big tongue (macroglossia)
Enlarged forehead (frontal bossing)
Large hands and feet (carpal tunnel syndrome, tight rings, increasing shoe size)
Osteoarthritis from abnormal joint loading
Increased stature (gigantism; if GH excess occurs prior to epiphyseal closure)
Thickened, greasy (increased sebum production) skin
Excessive sweating
Diabetes develops if β cells fail to compensate for the increased demand for insulin. IGT, impaired
glucose tolerance; NEFA, non-esterified fatty acid.
Mechanisms of hyperglycemia and diabetes in acromegaly
Cushing Syndrome
Easily bruised, thin skin; poor wound
healing
Striae (purple or “violaceous”
rather than white)
Thin (osteoporotic) bones that
easily fracture
Central obesity, characteristic rounded
facies, “buffalo” hump
Mood disturbance (depression, psychosis)
Clinical features
Mechanisms of hyperglycemia and diabetes in Cushing syndrome
NEFA, non-esterified fatty acids; PEPCK, phosphoenolpyruvate carboxykinase
1. Endocrine diseases associated with diabetes
2. Drug induced diabetes
3. New Onset Diabetes After Transplantation (NODAT)
4. Diabetes Secondary to Pancreatic Diseases
COMMON CAUSES OF SECONDARY DIABETES
MECHANISMS
Increased insulin resistance
STEROIDS, Beta agonists, Growth Hormones
Decreased insulin production
Pentamidine, L-asparaginase, Phenytoin, Beta-blockers, Diazoxide
Both insulin secretory defect & increased resistance
Diuretics, Cyclosporine
Induces diabetes independent of insulin
Nicotinic acid, Total parenteral nutrition
Mohan LR, Mohan V. JAPI. 1997;45:876-879
Drug induced diabetes
1. Endocrine diseases associated with diabetes
2. Drug induced diabetes
3. New Onset Diabetes After Transplantation (NODAT)
4. Diabetes Secondary to Pancreatic Diseases
COMMON CAUSES OF SECONDARY DIABETES
New Onset Diabetes After Transplantation
(NODAT)
New Onset Diabetes Mellitus After Transplantation (NODAT)
occurs in 2% to 53% of all solid organ transplants.
Kidney transplant recipients most commonly develop NODAT
Liver, heart and lung transplants also occasionally develop
NODAT.
Pham PT, et al. Chapter 12. In :After the Kidney Transplant - The Patients and
Their Allograft. 2011
1. Endocrine diseases associated with diabetes
2. Drug induced diabetes
3. New Onset Diabetes After Transplantation (NODAT)
4. Diabetes Secondary to Pancreatic Diseases
COMMON CAUSES OF SECONDARY DIABETES
Pancreatic diseases associated with glucose intolerance and diabetes
Unnikrishnan R, Mohan V. Textbook of Diabetes . 2017;291-305
Inflammatory
Acute pancreatitis
Chronic pancreatitis (including Fibrocalculous
Pancreatic Diabetes & Alcoholic Pancreatitis)
Infiltration
Hereditary hemochromatosis
Secondary hemochromatosis
Very rare causes: sarcoidosis, amyloidosis, cystinosis
Neoplasia
Adenocarcinoma of the pancreas
Surgical resection or trauma
Cystic fibrosis
Causes of Acute PancreatitisCommon (75% of cases) Uncommon
Alcohol abuse
Gall stone disease
Hypertriglyceridemia
Drugs
Sulfonamides
Tetracyclines
Valproate
Didanosine
Estrogens
Metabolic disorders
Hypercalcemia
Diabetic ketoacidosis
Infections
Mumps, Coxsackie, and HIV viruses
Mycoplasma pneumoniae
Trauma
Abdominal injury
Surgery, including ERCP
Miscellaneous
Hereditary relapsing pancreatitis
Pancreatic cancer
Connective tissue diseases
Pancreas divisum
ERCP, endoscopic retrograde cholangiopancreatography Unnikrishnan R, Mohan V. Textbook of Diabetes . 2017;291-305
Rarely produce
permanent
diabetes. Usually
transient
hyperglycemia.
Pancreatic diseases associated with glucose intolerance and diabetes
Unnikrishnan R, Mohan V. Textbook of Diabetes . 2017;291-305
Inflammatory
Acute pancreatitis
Chronic pancreatitis (including Fibrocalculous
Pancreatic Diabetes & Alcoholic Pancreatitis)
Infiltration
Hereditary hemochromatosis
Secondary hemochromatosis
Very rare causes: sarcoidosis, amyloidosis, cystinosis
Neoplasia
Adenocarcinoma of the pancreas
Surgical resection or trauma
Cystic fibrosis
Causes of Chronic Pancreatitis
Common (90% of cases) Rare
Alcoholic Pancreatitis
Tropical Chronic
Pancreatitis (&
Fibrocalculous
Pancreatic Diabetes)
Idiopathic Pancreatitis
Hereditary Pancreatitis
Obstructive Pancreatitis
Unnikrishnan R, Mohan V. Textbook of Diabetes . 2017;291-305
Alcoholic Chronic Pancreatitis (ACP)
Most of the cases of chronic pancreatitis (>85%) in
European and North American populations.
Alcohol alters the composition of pancreatic secretions,
leading to the formation of proteinaceous plugs that
block the ducts and act as foci for calculi formation.
Unnikrishnan R, Mohan V. In Pickup’s Textbook of Diabetes. 2017;291-305
Differences between Alcoholic Chronic Pancreatitis and
Tropical Chronic Pancreatitis
Alcoholic chronic
Pancreatitis (ACP)
Tropical chronic
Pancreatitis (TCP)
Demographic features
Male : female
Peak age at onset (years)
Socioeconomic status
Alcohol abuse
90 : 10
30–50
All groups
Present
70 : 30
20–30
Poor > affluent
Absent
Pancreatic morphology
Prevalence of calculi
Features of calculi
Ductal dilatation
Fibrosis
Risk of pancreatic cancer
50–60%
Small, speckled; in small Ducts
Usually moderate
Variable
Increased
>90%
Large; in large ducts
Usually marked
Heavy
Markedly increased
Diabetes
Prevalence
Time course
50%
Slower evolution
>90%
Faster evolution
Unnikrishnan R, Mohan V. In Pickup’s Textbook of Diabetes. 2017;291-305
Large calculi in a patient with TCP
Small speckled calcification
characteristic of ACP
Chari S, Jayanthi V, Mohan V, Malathi S, Madanagopalan N, Viswanathan M.
Journal of Gastroenterology and Hepatology. 1992;7:42-44.
Natural history of tropical calcific pancreatitis (TCP) and
fibrocalculous pancreatic diabetes (FCPD)
IGT: impaired
glucose
tolerance
Unnikrishnan R, Mohan V. In Pickup’s Textbook of Diabetes. 2017;291-305
DIAGNOSTIC CRITERIA FOR FCPD (MOHAN et al, 1985)
Occurrence in tropical country
Diabetes (WHO criteria)
Evidence of chronic pancreatitis
Pancreatic calculiOR
ERCP evidence of CP
OR Ultrasound/CT featuresPlus h/o abd. Pain / steatorrhoea
Plus abnormal pancreatic function
Absence of other causes of CP (eg. alcoholism)
Mohan V et al. Diabetologia. 1985;28:229-232.
Classical triad of FCPD
DiabetesPancreatic calculi
Abdominal pain
FCPD
CLINICAL SPECTRUM OF FCPD
KETOSIS RESISTANCE KETOSIS
PRONE
Mohan V et al, Journal of Applied Medicine. 1996;883-887.
0
0.5
1
1.5
2
Pan
crea
tic B
cel
l fu
nct
ion
C-p
eptid
e l (
pm
ol/m
l)
NON DIABETIC
SUBJECTS
TYPE 2 DM FCPD TYPE 1 DM
C-PEPTIDE LEVELS IN DIFFERENT GROUPS OF DIABETES
Mohan V et al, Metabolism. 1983;32:1091-1092.
WHAT IS THE EXPLANATION FOR
KETOSIS RESISTANCE?
PROTECTION FROM
KETOSIS
Partial presentation of
beta cell function
(insulin reserve)
Pancreatic alpha cell
(glucagon) deficiency
Low adipose mass/
decreased supply of
non-esterifeid fatty acids
Carnitine deficiency
FCPD AND KETOSIS RESISTANCE
ULTRASOUND IMAGE OF PANCREAS IN A FCPD PATIENT
Calcite stones of various sizes removed from the pancreas of a
person with fibrocalculous pancreatic diabetes
Unnikrishnan R, Mohan V. In Pickup’s Textbook of Diabetes. 2017;291-305
ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAM (ERCP) OF FCPD PATIENT
Histopathology of pancreas in FCPD
Dense fibrosis entirely replacing exocrine tissue
FCPD
DO MICROVASCULAR
COMPLICATIONS OCCUR?
MICROVASCULAR COMPLICATIONS DO NOT OCCUR IN
SECONDARY FORMS OF DIABETES
Harrison’s Textbook of Diabetes (1981)
* p = 0.04 compared to Type 2 diabetes Mohan V et al. Journal of Diabetes and its Complications. 2004;18:264-270.
Prevalences of Microvascular and Macrovascular diabetic
complications in subjects with FCPD compared with NIDDM patients
Percentage of subjects with complications
Type 2 Diabetes (n = 277) FCPD (n =277)
Retinopathy 37.2 36.1
Non-proliferative 31.4 32.9
Proliferative 5.8 3.6
Nephropathy 15.0 10.1
Peripheral neuropathy 25.3 20.9
Macrovascular disease
Infarction 5.4 2.2
Ischaemia 6.5 2.5 *
DIABETES CARE, VOLUME 19, NUMBER 11, NOVEMBER 1996
Genetic alterations in the trypsinogen pathway
Serum protease inhibitor Kazal type 1 (SPINK1)
Cationic trypsinogen (PRSS1)
Anionic trypsinogen (PRSS2)
Chymotrypsinogen C (CTRC)
Alteration in other genes
Cystic fibrosis transmembrane conductance regulator (CFTR)
Regenerating islet-derived genes 1α (REG1A & REG1B)
Cathepsin B (CTSB)
Angiotensin converting enzyme (ACE)
Calcium-sensing receptor (CASR)
GENE MUTATIONS ASSOCIATED WITH FCPD
MANAGEMENT OF DIABETES SECONDARY TO
CHRONIC PANCREATITIS
Treatment of abdominal pain
Use of pancreatic enzymes
Management of diabetes
MANAGEMENT OF DIABETES IN SECONDARY TO CHRONIC
PANCREATITIS
Diet
Insulin
Principles similar to that of other types of diabetes
More liberal calorie Intake
High protein intake
Would be needed in majority of the cases to achieve glycemic control
Oral Hypoglycaemic drugs
Sulphonyureas can be used if cell function is good
Biguanides usually not used
TAKE HOME MESSAGES
Secondary Diabetes comprises a list of conditions where the
diabetes is specific to another primary disease or due to a
drug.
Accurate diagnosis of Secondary Diabetes will help in better
management of the condition.
Clinicians must have a high index of suspicion to diagnose
Secondary Diabetes.