A detailed overview of diabetes mellitus and its diagnostic criteria along with pathogenesis of its complications

1. Diabetes Mellitus and it’s complications
Dr. Abhra Ghosh

2. Diabetes Mellitus - Definition
A chronic disease primarily due to disorder of carbohydrate metabolism,
cause of which is deficiency or diminished effectiveness of insulin,
resulting in hyperglycemia and glycosuria.
Secondary changes may occur in the metabolism of proteins, fats, water and
electrolytes and in tissues/organs sometimes with grave consequences

3. Types of Diabetes Mellitus
Classified into 4 general categories:
1. Type 1 diabetes [aka. Juvenile diabetes*] (due to autoimmune β-cell
destruction, usually leading to absolute insulin deficiency)
2. Type 2 diabetes (due to a progressive loss of adequate β-cell insulin secretion
frequently on the background of insulin resistance)
3. Gestational diabetes mellitus (diabetes diagnosed in the second or third
trimester of pregnancy that was not clearly overt diabetes prior to gestation)

4. 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes
syndromes (such as neonatal diabetes and maturity-onset diabetes of the
young*), diseases of the exocrine pancreas (such as cystic fibrosis and
pancreatitis), and drug- or chemical-induced diabetes (such as with
glucocorticoid use, in the treatment of HIV/AIDS, or after organ
transplantation)
Types of Diabetes Mellitus

5. Recent advances – Excerpts*
1. Immune markers of IDDM:
• GAD – Glutamic acid decarboxylase is of potential significance
• Anti-GAD antibodies is seen in Type I diabetes with age of onset >35 years
• So, anti GAD helps in differentiating Type 1 and Type 2 DM

6. Recent advances – Excerpts*
2. Genes of DM – MODY
• Few genes have been discovered –
MODY1 (HNF4⍺)
MODY2 (GCK)
MODY3 (HNF1⍺)
MODY5 (HNF1β)
• Contributes to 2-5% of diabetes
• Inheritable
• Mutation of these genes increase the susceptibility to NIDDM

7. Clinical features
• Polyuria
• Polydipsia
• Polyphagia
• Generalized weakness, tiredness
• Loss of weight
• Dehydration
• Hypercholesterolemia
• Acidosis

8. Type 1 diabetes mellitus - Pathogenesis
Exposure to a virus or toxin start the process of β cell destruction
Infiltration of the β cells by lymphocytes - insulitis
Cells are destroyed – decrease in production of insulin
When the insulin secretory capacity falls below a threshold, symptoms of type 1
diabetes appear

9. Type 2 diabetes mellitus - Pathogenesis
Points to remember –
• Metabolic alternations observed in T2D are milder
• Reason is – Though inadequate, there is insulin secretion in T2DM
• Acute complications are less compared to T1DM

10. Type 2 diabetes mellitus - Pathogenesis
Obesity
Increase in secretion of proinflammatory cytokines, leptins, decreased
secretion of adiponectin
Decrease in insulin receptor by internalization
Insulin resistance and hyperinsulinemia
Exhaustion of beta cells of pancreas
Decrease in insulin secretion  T2DM

11. Metabolic changes
Intestine
Amino acids Chylomicrons
Glucose
Release into
Adipose tissue
Lipo. lipase
Accumulation
in blood
Protein synthesis
Neoglucogenesis
Amino acids from
muscle breakdown Mobilization of TAG
Glycerol + FA
Liver
Acetyl CoA
Ketone bodies
VLDL

12. Progression of T2DM
Insulin
resistance
Hyper
insulinemia
Impaired
glucose
tolerance
Decline
in beta
cell func
T2DM
Microvascular complications
Macrovascular complications

13. Diagnosis
The ADA recommends that the following people be screened for diabetes:
• Anyone with a body mass index higher than 25 (23 for Asian Americans),
regardless of age
• Anyone older than age 45
• Women who have had gestational diabetes
• Anyone who has been diagnosed with prediabetes

14. • Random blood sugar test – ≥ 200mg/dL
• Fasting blood sugar test – <100 mg/dL - Normal
100 to 125 mg/dL - Prediabetes
>126 mg/dL - Diabetes
• Oral glucose tolerance test – 140 mg/dL - Normal
140 to 199 mg/dL - IGT
>200 mg/dL - Diabetes
Diagnosis

15. Glycated hemoglobin (A1C) test:
• Below 5.7%  normal
• 5.7% to 6.4%  prediabetes
• 6.5% or higher on two separate tests  diabetes
• An A1C level of less than 7%  common treatment target for adult
diabetic
Diagnosis

16. Treatment
• Weight reduction
• Exercise
• Dietary modification
• Drugs – Oral hypoglycemic agents
• Insulin

17. Complications
Complications due to DM
Acute
1. Diabetic ketoacidosis
2. Coma
Chronic
Involvement of small vessels
1. Retino, nephro, neuropathy
2. Diabetic gangrene
3. Skin lesions
Involvement of
large vessels
1. Atherosclerosis
2. Myocardial
infarction
3. Stroke

18. Increased influx through polyol pathway
Toxic aldehydes Inactive alcohols
Aldose reductase
Increased glucose Sorbitol
NADPH NADP+
GSH
GSSG

19. Intracellular production of AGE precursors
• Excess glucose causes alteration of proteins involved in gene
regulation
• AGE diffuses out of cells and modify extracellular matrix proteins
• AGE binds with albumin  bind with AGE receptors  production
of inflammatory markers

20. PKC activation
Hyperglycemia
↑ DAG
↑ PKC
Vascular
occlusion ↑ Vascular
permeability
↑ Collagen
formation
Capillary
occlusion
Proinflamma
tory gene
expression
↑ ROS
formation

21. Increased hexosamine pathway activity
Fructose – 6 – phosphate
Glucosamine – 6 – phosphate
GFAT
UDP – N – acetyl glucosamine
Attach with serine and threonine residues of transcription factors
Altered gene expression and vascular pathology

22. Inhibition of glyceraldehyde – 3 – phosphate dehydrogenase
↑ Glucose
↑ Glucose – 6 - phosphate
↑ Fructose – 6 – phosphate
Glyceraldehyde – 3 phosphate
1,3 - bisphosphoglycerate ROS from mitochondria
Poly ADP ribose
↓ GADPH
PKC pathway
AGE pathway
Hexosamine pathway
Polyol pathway

23. DKA

24. Complications in T1DM vs T2DM