secondary diabetes update dr.v.mohan., md., ph.d., …...tetracyclines valproate didanosine...

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.