LADA & MODYPresented By

Sriloy Mohanty

LADA- Latent Onset Diabetes In Adult

Introduction

Latent Autoimmune Diabetes in Adults (LADA) is

a form of autoimmune (type 1 diabetes)

which is diagnosed in individuals who are older

than the usual age of onset of type 1 diabetes.

Often, patients with LADA are mistakenly

thought to have type 2 diabetes, based on

their age at the time of diagnosis.

Progress to insulin requirement within 6 years

Diabetes 1.5

History 1980s

San Raffaele Hospital

Milan (patient)

Stiff Mans Syndrome (SMS)

Type 1 DM

Anti GAD antibodies (Glutamic acid

decarboxylase)

GAD

Glutamic acid decarboxylase

Present in cytoplasm of the human beta cells

Catalyses the Conversion of glutamic acid to

GABA

GABA is involved in release of insulin from

secretory granules

Adults who should be considered for antibody testing*: age of onset <50 years acute symptoms BMI <25 kg/m2

personal or family history of autoimmune disease

C-Peptide test is positive

Symptoms Unusual thirst Frequent urination Weight loss despite an increase in appetite Blurred vision Nausea and vomiting Extreme weakness and fatigue Irritability and mood changes Frequent bladder and skin infections that don't

heal easily High levels of sugar in the blood when tested High levels of sugar in the urine when tested Dry, itchy skin Tingling or loss of feeling in the hands or feet

Diagnosis

C-peptide test (a measure of endogenous insulin)

If positive then….

GAD antibody test

Islet cell antibodies (ICA) are also common

HDL to triglyceride ratio- it exceeds 4 then insulin

resistance

If IR then no LADA

Rx for LADA LADA often does not require insulin

at the time of diagnosis and may be managed with diet and exercise

the avoidance of using metformin treatment

May require multiple daily Insulin injections(after 6 months)

Maturity-Onset Diabetes of the Young (MODY)

1975 Definition

Type-2 diabetes mellitus in the young plus

Autosomal dominant inheritance

Understanding MODY

Mutations in one of the 6 different

genes

Onset of diabetes type 2 early in life:

childhood, adolescence or young

adulthood

Primary defect in insulin secretion, and

IR

Maturity Onset diabetes of the young (MODY)

MODY 1 - Mutation in HNF-4-alpha (transcription factor), chromosome 20

MODY 2 - Mutation in glucokinase gene, chromosome 7

MODY 3 - Mutation in HNF-1-alpha (transcription factor), chromosome 12 (most common form)

MODY 4 - Mutation in insulin promoter factor-1 (IPF-1), chromosome 13

MODY 5 - Mutation in HNF-1-beta, chromosome 17 MODY 6 - Mutation in Neurogenic Differentiation

Factor-1 (NEUROD1) , chromosome 2

Heterozygous Gene Mutations Identified in MODY

Name (Year) GeneChromosome

MODY1 (1991) HNF-4a 20qMODY2 (1993) Glucokinase 7pMODY3 (1996) HNF-1a 12qMODY4 (1997) IPF-1 (PDX-1) 13qMODY5 (1997) HNF-1b 17qMODY6 (1999) Neuro-D1 / BETA-2 2q

HNF = Hepatocyte nuclear factorIPF = Insulin promoter factorPDX-1 = Pancreatic duodenal

homeobox-1

MODY-Related Proteins

Glucokinase

Expressed in b-cells and liver

GSK catalyzes the formation of glucose-6-phosphate

from glucose.

Liver – Helps in storage of glucose as glycogen

Mutation causes problem in conversion

Liver-enriched transcription factors HNF-1a, HNF-1b, and HNF-4a

Expressed in liver, pancreatic islets, kidneys and genitalia.

In Beta cells they regulate

The expression of the insulin gene

Proteins involved in glucose transport and metabolism.

Mutations results in defect of insulin secretion response to

glucose, leading to progressive decline in glycemic control.

Transcription factor IPF-1

Rare

Expressed in pancreatic islets

Central role in development of

pancreas.

Mediates glucose-induced

stimulation of insulin-gene

transcription

Transcription factor Neuro-D1 (BETA2)

Rare

Expressed in pancreatic islets

Activates the transcription of the

insulin gene

Required for normal development of

the pancreatic islets

Recognition at young age

1.Mild, asymptomatic increase in blood

glucose in a child, adolescent or young

adult(<25 years)

2. Prominent family history of diabetes

in 2-3 generations

3. Usually not associated with obesity

When to suspect MODY

a “type 1″ diabetes patient who has negative blood testing for autoantibodies.

a “type 1″ diabetes patient who generates a significant amount of insulin for years beyond diagnosis (detectable blood levels of c-peptide, proinsulin, and/ or insulin)

a “type 2″ diabetes patient who is normal weight and shows no signs of insulin resistance.

a diabetes with family history of early onset diabetes for 2-3 generations.

Diabetes paired with pancreatic insufficiency  Individual or family history of diabetes paired with

developmental kidney disease or kidney cysts

Rx for MODYRx depends on the involved gene and other factors

MODY 3 and 1 can be treated initially with sulfonylureas, prompts the body to produce insulin.

Usually GCK-MODY requires no treatment at all.

Other type of MODY Rx is unclear may require multiple daily Insulin injections.

Thank you…