Immune-Mediated

Diabetes (Juvenile-onset Diabetes)

Pathophysiology:

Diagnosis:

Autoimmune DestrucAon of Insulin-Producing -cells

1) Loss of insulin
2) Loss of regula-on: Cant sense rise in glucose and give perfect amt of insulin
3) Lose inhibi-on of Alpha cells: Glucagon
- Childhood and adolescence but can occur at any age. Adults lack obesity, present with
ketoacidosis/drama-c hyperglycemia
- Risk: Graves disease, Hashimotos, Addisons

Idiopathic Type 1 Diabetes

Diagnosis:

- No known e-ology (permanent

insulinopenia, prone to ketoacidosis
but have no evidence of -cell
autoimmunity). More common in
African or Asian ancestry

- No autoimmune markers
- Episodic ketoacidosis and varying
degrees of insulin deciency
between episodes

- Repeat without delay using new blood sample

- Fas-ng and 2-Hour Plasma Glucose
- A1C
- Blood glucose rather than A1C should be used to diagnose acute onset of type
1 diabetes in individuals with symptoms of hyperglycemia
- Markers: Islet cell autoan-bodies and autoan-bodies to insulin (ICA, IAA),
glutamic acid decarboxylase (GADAb), tyrosine phosphatase IA-2 Ia2, ZnT8

Type 1 Diabetes

Type 2 Diabetes

Type 2 Diabetes
Pathophysiology:
1) Insulin Resistance: Impaired capacity to
ac-vate glucose uptake and block lipolysis
2) Uncontrolled hepa-c glucose
produc-on/impaired hepa-c glucose
uptake
3) -cell failure, increased basal insulin
secre-on to compensate, but failure to
respond to normal metabolic cues. Then
lose -cell func-on and mass
- Risk increases with: age, obesity, lack of
physical ac-vity

Diabetes Mellitus

25 year old male pa-ent is diagnosed with

DM, fas-ng blood glucose 12 mmol/L

Diagnosis:
- Test for adults overweight or obese, test
fas-ng plasma glucose, 2h plasma glucose
a[er 75g oral glucose tolerance test, A1C
- Overweight or obese (BMI>25kg/m2)
- Ketoacidosis is rare, unless with infec-on
- Risk: glucocor-coids, thiazide, atypical
an-psycho-cs

Diagnosis:

- More suscep-bel to ketoacidosis

without any precipita-ng cause

- Younger pt, strong

family hx of
diabetes, low
prevalence of
autoimmune
markers

- -cell func-on improves

signicantly with
aggressive glycemic
control and insulin
therapy may be
discon-nued

Diagnosis:

Other causes

- Onset of hyperglycemia at early age

(before age 25)
- Impaired insulin secre-on with
minimal or no defects in insulin
ac-on. Autosomal dominant

Exocrine pancreas disease

(related to CysAc brosis)
- 20% adolescents and 40-50% of
adults with CF, due to insulin
suciency

Drug/chemical-induced Diabetes
- Glucocor-coid use

- Should consider in individuals with mild stable

fas-ng hyperglycemia and mul-ple family member
with uncharacterised DM (eg non-obese, low-risk
ethnic group), nega-ve diabetes autoan-bodies
- MODY 3 (most common): chromosome 12
Hepatocyte nuclear factor HNF-1a)
- MODY 2 (2nd most commong): muta-ons in
glucokinase gene on chromosome 7p, results in
defec-ve glucokinase molecule (converts glucose
to G6P > s-mulates insulin secre-on by -cell)
- Other mutaitons; HNF-4a, HNF-1, insulin
promoter factor-1, NeuroD1

Diagnosis:

Treatment:

- Oral glucose tolerance test

- A1C not recommended

- Insulin, prandial insulin therapy to

maintain weight

Lifestyle + Metformin
+ Basal insulin

Lifestyle + Metformin
+ Intensive insulin

At diagnosis:
Lifestyle
+ Metformin
STEP 1

Treatment:

Ketosis prone diabetes

Monogenic diabetes syndromes

(MODY. maturity-onset diabetes
of the young)

Tier 1: Well-validated
core therapies

Tier 2: Less wellvalidated

therapies

Lifestyle + Metformin
+ Sulfonylureaa
STEP 2

STEP 3

Lifestyle + Metformin
+ Pioglitazone

Lifestyle + Metformin
+ Pioglitazone
+ Sulfonylureaa

Lifestyle + Metformin
+ GLP-1 agonistb

Lifestyle + Metformin
+ Basal insulin

Also, weight loss (5% body weight), calorie intake, exercise to prevent onset of early peripheral
neuropathy, avoid smoking, phsycosocial care
Approved oral agents
- Insulin secretagogues include sulphonylureas (tolbutamide, glibenclamide, glipizide, gliclazide,
glimepiride) or non-sulphonylureas (nateglinide, repaglinide) s-mulate pancrea-c insulin release
- Biguanides (mebormin) decrease hepa-c glucose release, enhance peripheral glucose disposal and
delay glucose absorp-on
- Alpha-glucosidase inhibitors (acarbose) slow the diges-on and absorp-on of starch and sucrose in
the gut, thereby reducing the increase in postprandial blood glucose
- DPP-4 inihibitors prevent the breakdown of glucagon-like pep-de-1 (GLP-1) and glucose-dependent
insulinotropic polypep-de (GIP) and enhance glucose-s-mulated insulin secre-on (incre-n ac-on)
- GLP-1 and GIP act on the pancrea-c -cell to increase insulin release, and GLP-1 also acts on the cell to suppress glucagon release and hepa-c glucose produc-on
- Thiazolidinediones (rosiglitazone and pioglitazone) enhance -ssue sensi-vity to insulin in muscle
and liver through ac-va-on of intracellular receptors
- Sulphonylureas may increase the risk of hypoglycaemia
- Hypoglycaemia is not commonly seen with mebormin, alpha-glucosidase inhibitors or DPP-4
inhibitors unless combined with insulin or sulphonylureas. B Long-ac-ng sulphonylureas e.g.,
chlorpropamide and glibenclamide, carry a high risk of hypoglycaemia and are not recommended.