MEDICINE REVISION

HYPERGLYCEMIA
SYMPTOM 1:
35 year old software ENGINEER with a RBC checked for insurance showing
235mg/dl and FBG of 133mg/dl
- Plasma glucose itself needed for diagnosis of diabetes, capillary blood
glucose levels are not sufficient

ADA recommendations for diagnosis of diabetes mellitus: (any 1 of the

following)
1) Fasting blood glucose > 126 mg/dl (with 8 hour of strict fasting with
water in between maximum) (or)
2) 2 hour post prandial blood glucose (after a glucose/ carbohydrate
meal) > 200 mg/dl (or)
3) Random blood glucose > 200 mg/dl + osmotic symptoms (or)
4) HbA1c > 6.5
- Hyperglycaemia is the phenotype
- Diabetes presents with the common phenotype of hyperglycaemia
- In this patient, FBG is 133 mg/dl which confirms the diagnosis of
diabetes mellitus

DIABETES MELLITUS
Diabetes is not a single organ disease, but is a complex component
consisting of 8 modalities called as the OMNIOUS OCTET OF DEFRONZO
(which was established by a type of DM) and the interaction between them

I) With respect to pancreas:

1) Impaired insulin secretion
2) Increased glucagon secretion

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Relation with pancreas is important due to Pancreatic diabetes – TYPE 3c
DM, causes:
- Chronic calcific fibrocalculous pancreatitis seen in young males and
tropical regions. (MOST COMMON CAUSE)
- Cystic fibrosis
- Hemochromatosis
- Pancreatic malignancy
Symptoms: - of malabsorption- weight loss, fatigue, anorexia,
steatorrhoea, diarrhoea)
- Recurrent abdominal pain – due to acute or chronic pancreatitis
- deranged blood glucose
- Microvascular complications are much common

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Question – lean, young, ketosis negative diabetes is:
a) Type I diabetes mellitus
b) Type Ib diabetes mellitus
c) Type I.5 diabetes mellitus
d) Type 3c diabetes mellitus
Answer – C) Type 3c DM

Justification – to increase glucagon, alpha cells should be working. In a

pancreatic disease, there is no insulin, no glucagon. Ketosis occurs due to
increase in glucagon and in pancreatic diabetes (type 3c), there is
deficiency of glucagon, resulting in ketosis negative diabetes
Diagnosis – ERCP is the gold standard

II) With respect to liver: increased gluconeogenesis (abdominal obesity

causes change in the abdominal receptors from alpha to beta3, which
in turn causes lipolysis and releases free fatty acids. These free
fatty acids enter the portal circulation freely and reach the liver,
where they act as the substrate for gluconeogenesis. Hence abdominal
obesity is very dangerous)

III) With respect to brain

Neurotransmission dysfunction in diabetes (cause type 3a diabetes,
which is similar to Alzhiemers disease which is now regarded as type
3a diabetes
IV) With respect to muscle: decreased glucose uptake

V) With respect to Adipose tissue : increased lipolysis (lipolysis releases

free fatty acids which increase glucose production. FFA cant go into
the mitochondria, because there is no carnitine palmitoyl transferase,
hence FFA is stored as fatty acyl coenzyme A that will promote
insulin resistance)
VI) With respect to Kidney: increases glucose resabsorption (lead to
edema, remodelling)

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VII) With respect to Intestine – decreased incretin effect (incretin
(hormone) endogenously stimulates insulin release)
(described in relation to type 2 DM)

Approach to the patient:

 Patient would have TYPE 1 DM, which is autoimmune destruction
where only after 70- 80% of beta cells are destroyed (as no osmotic
symptoms present)
 Patient could have had 1.5 diabetes
- KPD – ketosis prone diabetes, type 2 presenting as type 1 (since
patient dones present with ketosis, KPD is highly unlikely)
- LADA – type 1 which presents as type 2
 Patient could have had type II diabetes (but since no features of
insulin resistance, it isn’t type 2)
 Or type 3c – no features of pancreatic disease including malabsorption
issues or weight loss, abdominal pain (therefore not 3c)
 Or TYPE 4 – elderly disease, > 65 years, who have asymptomatic rise
in blood glucose. Due to T regulatory cells ) (due to age of the
patient is less, it cant be type 4)
 MODY

 Osmotic symptoms if present – TYPE I DM

 Any features of insulin resistance – obesity, acanthosis nigricans,
hirusitism – TYPE II DM

Before branding for type II DM, check for fasting C-peptide which have to
be low to rule out type I DM
Give injection glucagon and then check for fasting C-peptide levels, as
glucagon directly stimulates insulin release and if it is < 1.8 ng/dl then it is
type I (therefore not type 2 not MODY)

LADA has variable levels of C-peptide levels

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 normal fasting C-peptide

LADA TYPE II MODY

asymptomatic, no
complications
as 1 presenting as
type 2 insulin resistance

strong family history

ANTI GLUTAMIC
ACID 25-30yrs, 3gen involved
DECARBOXYLAS
E POSITIVE C-peptide normal

no osmotic symptoms

Start will insulin

no insulin resitance

 rule out LADA after ruling out TYPE I

 Antibody profile for LADA:
1) Anti islet cell antibody
2) Anti GADA (most important)
3) Anti-Zn T8
 LADA ruled out – chances are type 2 DM or MODY
 Ask family history in MODY and diabetes
- One parent having diabetes – 25% chances, both parents – 40% for
TYPE 2
- No complications in family history – MODY

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SYMPTOM 1:
- 35 year old software ENGINEER with a RBC checked for insurance
showing 235mg/dl and FBG of 133mg/dl
- On examination had vitiligo
- No osmotic symptoms
- No obesity
Ans – do anti GAD to rule out LADA

LADA is sometimes misdiagnosed as T2DM

Some scientists have indicated that 1/10 to almost 1/3 of the people
diagnosed with T2DM are actually living with LADA

- Type 2 DM – insulin resistance, nothing to do with autoimmunity

- LADA – type 1 presenting as type 2

Non- insulin requiring diabetic patients at diagnosis especially when:

- lean patient, autoimmune illness, anti-GADA Ab - LADA

age 35-40
family history of type I DM or AID
lean body mass index

measurement of GADA Ab

if positive diagnosis of LADA

Evaluation of C-peptide (baseline and stimulated)

+ HLA DR-DQ typing + Measurement od other auto-Ab: ICA thyroid

definition of risk of preogression towards insulin dependency in LADA

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  Genetic association stronger for type 2, HLA association stronger for
type 1
 Type 1 – one parent 15% chances

For LADA:
 Age >30 years
 Family/ personal history of AI
 Reduced frequency of metabolic syndrome compared with T2DMover
HOMA, lower BMI, lower BP and normal HDL compared with T2D
 No disease specific difference in cardiovascular outcomes between
these patients and those with T2D
 C-peptide decrease more slowly than type I DM
 Positivity for GADA is the most sensitive marker, other auto-AB less
frequent (ICA, IA-2A,ZnT8A and tetraspanin 7 autoantibodies)
 Non-insulin requiring at onset of diabetes

GADA screening -ve T2D**

if +, Measure suspect LADA (ie lean or

serum/plasma C- other AI disease) action
peptide screen for IA-2A

>0/3 - <0.7
<0.3 nmol/l > 0/7 nmol/l
nmol/l

LADA algorithm T2D-ADA/EASD

applied guidelines applied

 HLA associations of type I and LADA are:

 HLA-DQ A1 05 01
 HLA-DQ B1 03 02
 HLA-DQ A1 03 01

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  HLA-DQ B1 02 01
 HLA-DR B1 03
 HLA-DR B1 04
CHARACTERS T1D LADA T2D MODY
Typical age All ages Usually age > Adults Usually age
of onset 30 <25
% of all 10% 10% 75% 5%
diabetes
Typical BMI Mostly normal Mostly normal Mostly Mostly normal
or thin or overweight overweight or
obese
Ethinicity All all All All
Progression Fast (days to Latent Slow (tears) Depends on
to insulin weeks) (months/ MODY type
dependence years)
Insulin Mostly no, some Yes Depends on
resistance approx. 10% MODY type
- yes
Antibodies Yes (ICA, Yes (mostly Some No
IA2, GAD65, GAD65),
IAA) some not
T cell Yes yes No No
response to
islet protein
Insulin/ C- Undectable or low Normal to Normal
peptide level extremely low high
at diagnosis
Ketoacidosis Yes Yes, many rare Rare
not all
Insulin Low/null Varies Varies Varies
secretion
Islet Chronic Chronic Chronic None
inflammation inflammation inflammation inflammation
HLA link High Low None None
TCFL2 link None In some 75% None
people
stronger

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Other genes PTPN22,INS, PTPN22, INS PPARG, HNF4A, GCK,
involved STLA4 CCR5 JAZF1 HNF1A,
FOXP53 KCNJ11 IPF1,
CLEC16a IL6 NOTCH2 HNF1B,
UTPR3 OAS1 WFS1 FTO NEUROD1
SUMO4 HHEX
Early Insulin Non insulin or Non insulin Gene specific
treatment required, diet insulin, diet diet and
and exercise exercise increased
helpful activity
Late insulin, diet, insulin, diet, insulin, diet, Gene specific
treatment exercise exercise, pills exercise, pills

 Under 20 years – type 1 DM > ketosis prone diabetes

 20-30 years – type 1/ LADA/ MODY/ T2DM, 3c
 > 30 years – LADA, T1DM decreases, T2DM increases, MODY
chances decrease
 Overweight – T2DM > LADA (mostly normal weight)

MO GENE
DY
1 HNF4A (hepatocyte AD Adolescence or early Response well to
nuclear factor 4a) childhood small doses of
sulphonylureas
2 GCK (glucokinase) AD Mild hyperglycemia in lifestyle
(not a transcription early childhood, may measures, usually
fatcor) be present even at no drugs needed
birth
3 TCF1 (hepatocyte AD Adolescence or early Response well to
(MC) nuclear factor 1a) childhood small doses of
sulphonylureas
4 IPF1 (insulin AD Early childhood or Mostly
promotor factor 1a) later suphonylureas,
some may need
insulin
5 TCF2 (hepatocyte AD Adolescence or early Oral agents/
nuclear factor 1b) childhood insulin

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 Renal abnormalities
and genital anomalies
in females
6 NEUROD1 AD Fourth decade of life Insulin
(neurogenic Associated with
differentiation obesity
factor 1)
7 KFL11 AD Early adulthood rare

TYPE 3c Pancreatic diabetes:

 Fibrocalculous chronic pancreatitis
 Abdominal pain + steatorrhoe + DM
 Second to 3rd decade
 Nephropathy, macro rare, microvascular complications common
 Lean young ketosis negative diabetes
 ECRP gold standard
 Cf hemochromatosis

lean young pt with diabetes

insidiuod
acute onset
onset

without pancreatic calcification pancreatic calcification and ketosis

and ketosis positive negative

insulin resistant or sensitive usually insulin, partial

usually insulin sensitive do not
response to oral drugs, if underlying type 2 D
respond to oral drugs
present or in early FCPD

fibrocalculous pancreatic
type 1 DM
diabetes

CLASSIFICATION OF DIABETES
 TYPE 1 - normal AI
 TYPE 1.5:
- KPD

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 - LADA
 TYPE2
 TYPE 3a – neurotransmitter dysfunction – alzhiemers
- 3b –pancreatic diabetes
- 3d - drug induced
 TYPE 4 – T-reg dysfunction

New proposed classification of diabetes:

Type of diabetes Ab BMI Metabolic control Insulin
CLUSTER GAD deficiency or
resistance
1 SAID- severe AI + Low Poor Insulin
diabetes deficiency
2 SIDD severe - Low Poor Insulin
insulin deficiency deficiency
diabetes
3 SIRD – severe - High Poor Severe insulin
insulin resistance resistance
(T2DM)
4 MORD mild - High Modest Mild or no
obesity related metabolic insulin
diabetes dearrangements resistance
5 MARD - mild age - Variable Modest Mild or no
related diabetes metabolic insulin
(T4) dearrangements resistance

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