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/ DIABETES MELLITUS

Complex disorder of carbohydrate and fat metabolism

ETIOLOGY:-

Signaling defects :-

LEPRECHAUNISM:

- Dec. tyrosine kinase activity


- hepatic nuclear factor abnormality
- Zinc transport problem in cell
- Non- immune in nature
- Characterized by ear defects, lean body habitus and alphine facies.
- No age limit
- Can take place b/w 7-72 yrs of age

RABSON MANDERHALL SYNDROME:-

- Insensitive receptor and transporter


- Mitochondrial abnormality
- Tyrosine kinase induced desensitization of enzyme
- DM + precocious puberty.

WOLFRAM SYNDROME:-

- DM , DI, optic atrophy, and deafness (mitochondrial problem).

SECONDARY CAUSES OF DM:-

- Friedrick ataxia :- inc. gluconeogenesis


- Myotonic dystrophy – inc. gluconeogenesis.
- Pancreatits – damage pancreas
- Cystic fibrosis
- PCO
- Acromegaly – glycogenolysis + inc. gluconeogenesis
- Cushings
- Pregnancy
- pentamidine – damage pancreas and B cells
- thiazide
- valproate
- OCPS
- hemochromatosis
- thyrotoxicosis
- stress
- pheochromocytoma

PRIMARY DIABETES:-

INSULIN DEPENDENT (JUVENILE, TYPE 1, LADA):-

- familial
- HLA DR3- DR4
- requires insulin for management
- non- obese
- ketoacidosis
- brittle DM (recurrant hyper and hypoglycemia)
- type 1 DM anti GAD AB  LADA
- type 1 DM anti IA2 AB, anti zinc transportor AB, anti amylin ab , juvenile DM
- Genes:- PTEN , PTPN, CTLA4.
- Anti GAD, IA2,AMYLIN AB are (destructive ab)
- Anti zinc transportor ab (blocking ab)

 starvation, alcohol(hypoglycemia with mild stress)  thiolase  -ve insulin

acetoacetate

B-hydroxybutyrate acetone

Here check BI:- B-hydroxybutyrate

Acetone in breath

Blood glucose

PATHOLOGY:-

Type 2 HS and T cell abnormality.

- May lead to APS 2, hypogonadism, addisons, M. gravis, Hashimoto thyroiditis, celiac disease.
- Here pancreas are being destroyed and fibrosed.

TYPE 2 DM (INSULIN NON-DEPENDENT):-

- Obese and stressful conditions


- No HLA , autoimmunity, genetically predisposed
- Onset after 30 yrs of age
- Latinos, Spanish , argentines, Mexicans, Asians and blacks.
- 30% of of B cells reductions and < 30% of insulin sensitivity.
- Environmental factors ( stress, poverty, cytokines) play a role.
- Insulin resistance at its receptor present
- Hepatic gluconeogenesis >70% of expected is abnormal
- Phenylalanine , isoleucine, tyrosine plays role for FFA
- IRS and MAP kinase pathway is affected
- 25%of DDP4 catabolizes GLP
- Calpain:- salvage protein of insulin metabolism (abn. In type 2)
- Dec. in GLP
- Type 2 B can be autoimmune.
- Insulin, C- peptide, and pre-pro-insulin, all are raised

Type 2 DM

A B
- obese - obese
- inc. androgen - inc. androgen and inc. insulin receptor ab

COMPLICATIONS:-

Inc. in AIPP deposition in B cells.

MODY:- (MATURE ONSET DIABETES OF YOUNG)

- Hexokinase abn—no glycolysis


- Glucokinase abn
- Hepatic nuclear factor defect

MITOCHONDRIAL:-

 Myotonic dystrophy
 Friedrick ataxia

TERMS AND DEFINITIONS:-

Honenymoon period :- period before complete B cells failure from beta cell defect to beta cell
decompensation , presents with DKA for the first time.
 During honey moon period , normal insulin levels maintained till the time of overt diabetes.
 This phenomena is only applied to type 1 DM.
 It is not applied to chronic pancreatits, type 2 DM , or any other sec. diabetes.

Somogyi effect:- hyperglycemia following an episode of hypoglycemia inc. in cortisol, GH & glucagon
late in night resulting in hyperglycemia in early morning hrs.
Dawn’s effect:- due to somogyi effect early morning insulin requirements are high .

C/F:-

- Polyuria
- Polydipsia
- Polyphagia
- UTI
- Carbuncle
- Paronychia
- Granuloma anulare
- Necrobiosis lipoidica
- Hyperglycemia
- Dec. wound healing

PATHOGENESIS OF DM:-

 Hyperglycemia
 Hyper lipidemia
 Inc. LDL
 Low HDL
 Dec. in linker breaker protein protein ALT 711 and AG with inc. in sorbitol.
 Non-enzymatic glycosylation of protein
 Inc. gluconeogenesis Amino acids in circulation
 Fructose amine, glycosylated hb, amodari product , Schiff bases and inc. in cytokine
 Inc. uptake of glucose and gluconeogenic A.A from PCT and intestinal villi
 Prognostically the pathogenesis is guided by EGDR and IEMD.
 EGDR (estimated glucose disposal rate):- 9-10 in body
- 7 in Asians, 6 in Caucasians 5 in Africans
 IEMD ( intra epidermal nerve fiber density)

Points:-

- Linker breaker protein prevents from non-enzymatic glycosylation.


- Check nerve density...