Basal

secretion

Section 1 2nd Phase

Endocrinology
0-5
mins
Time

1. Diabetes Mellitus B The incretin effect

Endocrine pancreas cell types (Physiology)

Islets of Langerhans are collections of α, β, and δ endocrine After oral
cells. glucose

Insulin
Islets arise from pancreatic buds.
α = glucagon (peripheral)-20-30% of adult humans Islet Cell.
After
β = insulin (central)-60%
δ = somatostatin (interspersed)-10% intravenous
glucose
Insulin
1. Insulin secretion by Beta cell

Time

α cell
Insulin secretion in response to intravenous or oral glucose.
d cell
A. An acute first phase of insulin secretion occurs in
response to an elevated blood glucose,
B. This is followed by a sustained second phase.
β cell
C. The incretin effect describes the observation that insulin
secretion is greater when glucose is given by mouth
than when glucose is administered intravenously to
Capillaries achieve the same rise in blood glucose concentrations.
D. The additional stimulus to insulin secretion is mediated
by release of peptides from the gut and these actions
are exploited in incretin-based therapies
A. Glucose enters β cells by GLUT-2 ATP generated from 2. Synthesis
glucose metabolism closes K+ channels (target of
A. Preproinsulin → cleavage → proinsulin (stored in
sulfonylureas) and depolarizes β cell membrane . secretory granules)
B. Voltage-gated Ca2+ channels open Ca2+ influx B. Proinsulin → exocytosis of insulin and C-peptide
(equal amount of both).
C. This leads to stimulation of insulin exocytosis.
C. Insulin and C-peptide are ↑ in insulinoma and
D. Glucose acts like insulin secretogoue. sulfonylurea use, whereas exogenous insulin lacks
Insulin secretion C-peptide.
A
Glucose stimulus
C peptide

1st Phase Proinsulin s α-chain

s
s
s
s
s
Basal
secretion
β-chain
2nd Phase
3. Insulin metabolism
50% is metabolized in liver & 50% in kidney
4. Function
0-5 Time A. It Binds to insulin receptors (tyrosine kinase activity),
mins B. It inducing glucose uptake (carrier mediated transport)
into insulindependent tissue and gene transcription.

B The incretin effect 1

 2

Food Muscle
Amino acids
Gut -
Proteolysis
SECTION 1

Lactate Oxidation
Pyruvate +
Glucose
+

Glycogen

Glucose

+
Liver
Glucose
ENDOCRINOLOGY

Gluconeogenesis
-
- + Oxidation
Oxidation Glucose
- + - Ketone
Glycogen bodies FFAs
FFAs Ketogenesis FFAs Glycerol
Glycerol - +
Triglycerides

Adipose tissue

Major metabolic pathways of fuel metabolism and the actions of insulin.

A. Indicates stimulation and W indicates suppression by insulin.
B. In response to a rise in blood glucose, e.g. after a meal, insulin is released, suppressing gluconeogenesis and promoting
glycogen synthesis and storage. Insulin promotes the peripheral uptake of glucose, particularly in skeletal muscle, and
encourages storage (as muscle glycogen).
C. It also promotes protein synthesis and lipogenesis, and suppresses lipolysis.
D. The release of intermediate metabolites, including amino acids (glutamine, alanine), 3-carbon intermediates in oxidation
(lactate, pyruvate) and free fatty acids (FFAs), is controlled by insulin.
E. In the absence of insulin, e.g. during fasting, these processes are reversed and favour gluconeogenesis in liver from
glycogen, glycerol, amino acids and other 3-carbon precursors.

5. Anabolic effects of insulin: F. MNEMONIC: BRICK L (insulin-independent glucose

A. ↑glucose transport in skeletal muscle and adipose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver.
tissue G. Brain utilizes glucose for metabolism normally and
B. ↑glycogen synthesis and storage ketone bodies during starvation.
C. ↑triglyceride synthesis 8. Regulation
D. ↑protein synthesis (muscles) A. Glucose is the major regulator of insulin release.
E. ↑cellular uptake of K+ and amino acids
B. Insulin response with oral vs IV glucose because of
F. Unlike glucose, insulin does not cross placenta. incretins such as glucagon-like peptide 1 (GLP-1),
6. Insulin-dependent glucose transporters: which are released after meals and increased β cell
GLUT-4: adipose tissue, striated muscle sensitivity to glucose.
(Exercise can also increase GLUT-4 expression) 9. Local forces regulating insulin secretion from beta cells.
7. Insulin-independent transporters: A. Glucose enters the beta cell via the GLUT-2 transporter
protein, which is closely associated with the glycolytic
A. GLUT-1: RBCs, Brain, Cornea, Placenta enzyme glucokinase.
B. GLUT-2 (bidirectional): β islet cells, Liver, Kidney, Small B. Metabolism of glucose within the beta cell generates
Intestine ATP.
C. GLUT-3: Brain, Placenta C. ATP closes potassium channels in the cell membrane
D. GLUT-5 (fructose): spermatocytes, GI tract. D. Effect of sulfonylurea binds to this receptor, and this
E. RBCs always utilize glucose because they lack also closes potassium channels.
mitochondria for aerobic metabolism. E. Closure of potassium channels predisposes to cell
membrane depolarization,
 3

F. This allows calcium ions to enter the cell via calcium 5

channels in the cell membrane ATP-sensitive k+
k channels close
G. The rise in intracellular calcium triggers activation of
6

SECTION 1
calcium-dependent phospholipid protein kinase which, Depolarization
via intermediary phosphorylation steps, 4 7
H. This leads to fusion of the insulin-containing granules ↑ATP/ADP ratio↑ intracellular
Ca2+8
with the cell membrane and exocytosis of the insulinrich 3
Glucolysis Exocytosis
GLUT-2 Insulin
granule contents. Glucose of insulin
Glucose granules
I. Similar mechanisms produce hormonegranule
secretion in many other endocrine cells.

ENDOCRINOLOGY
Insulin
Blood
vessel
Insulin secretion by pancreatic β cells

Tyriosine 1 Glucagon
phosphorylation 1. Source
Made by α cells of pancreas.
2. Function Catabolic effects of glucagon:
A. Glycogenolysis, gluconeogenesis
B. Lipolysis and ketone production
Phosphoinositide-3 RAS/MAP 3. Regulation
kinase pathway kinase A. Secreted in response to hypoglycemia.
pathway
B. Inhibited by insulin, hyperglycemia, and somatostatin.
GLUT-4
Glucose Definition Of Diabetes Mellitus (DM)
Glycogen,
lipid, protein DM includes a group of metabolic disorders that share the
synthesis phenotype of chronic hyperglycemia
Diagnosis:
2 Diabetes is diagnosed by any of the following criteria.
1. Symptoms of DM plus RBS > 200mg/dl.(> 11.1 mmol/L)
Vesicles Celll growth,
containing Dna synthesis 2. FBS > 126mg/dl (>7 mmol/L). (It should be checked twice)
GLUT-4 3. Plasma glucose > 200mg/dl (> 11.1 mmol/L) 2hrs after
OGTT with 75gm of glucose
4. HBA1C > 6.5%
Insulin dependent glucose uptake
Golden line to remember :
Strongest indication for screening for diabetes is HT
Insulin signalling in peripheral cells (e.g. muscle and adipose
Diagnostic criteria for evaluation of standard GTT
tissue).
Normal Impaired Glucose DM
1. The insulin receptor consists of α- and β-subunits tolerance
linked by disulphide bridges (top right of figure). (Prediabetic)

2. The β-subunits straddle the cell membrane.

FBS <100 mg% 100-125 mg% ≥ 126 mg%
3. The transporter protein GLUT-4 (bottom left of figure) is (<5. 6 mmol/L) (5.6 -6.9 (>7 mmol/L)
mmol/L)
stored in intracellular vesicles.

4. The binding of insulin to its receptor initiates many Two hrs <140 mg% 140 -199 mg% ³200 mg%
after 75 gm (<7.8 mmol/L) (7.8-11 mmol/L) ( >11.1 mmol/L)
intracellular actions including translocation of these glucose
vesicles to the cell membrane, carrying GLUT-4 with
HBA1c <5.7% 5.7 to 6.4% > 6.5%
them; this allows glucose transport into the cell.
 4

Oral glucose tolerance test (OGTT) 3. In standardized assays, the HBA1C approximates the
1. Diagnostic Test for Diabetes mellitus in border line cases following mean plasma glucose values:
HBA1C (%) to eAG (mg/dl)
Golden lines to remember :
A. 6.0% = 126 mg/dl B. 6.5% = 140 mg/dl
SECTION 1

1. Glycosuria + Ketonuria is seen only in diabetes. C. 7.0% = 154 mg/dl D. 7.5% = 169 mg/dl
2. Only glycosuria (without diabetes) is seen in E. 8.0% = 183 mg/dl F. 8.5% = 197 mg/dl
A. Normal young adult G. 9.0% = 212 mg/dl H. 9.5% = 226 mg/dl
B. Pregnancy I. 10.0% = 240 mg/dl
C. Hyperthyroid (Alimantry glycosuria) LMRP
3. Only ketonuria is seen in prolong starvation. 1. Diagnosis
4. Renal glycosuria A. RBS ≥ 200 mg/dl
A. It is a benign condition B. FBS≥ 126 mg/dl
B. Found in some young adults.
ENDOCRINOLOGY

C. HBA1C>6.5%
C. Blood sugar is normal.
D. No treatment required. 2. Triad Polyuria, Polydipsia, Weight loss
E. It is self-limiting. 3. Glycosuria + Ketonuria is seen only in diabetes.
4. Only glycosuria (without diabetes) is seen in
Alimantry glycosuria
A. Normal young adult
1. It is seen in
B. Pregnancy
A. Hyperthyroid C. Hyperthyroid (Alimantry glycosuria)
B. Cases where a part of the stomach is surgically removed
5. Only ketonuria is seen in prolong starvation
2. It is a temporary condition, when a high amount of
carbohydrate is taken, it is rapidly absorbed. 6. Fructosamine
3. The excessive glucose appears in urine producing 7. eAG = HBA1c
glycosuria
Types of Diabetes
Monitoring glycemic control Two main types of diabetes
Glycated haemoglobin (= HBA1c) 1. Type-1
1. HBA1c is produced by nonenzymatic condensation of
2. Type-2
glucose molecules with HB molecule.
2. In a normal adult HbA1c constitutes <5.6% of the total adult
haemoglobin. Golden line to remember :
3. Levels relate to mean glucose level over previous 8-12 wks The ratio of patients of type 1(5%) and type 2(95%)
(i.e RBC half-life).
4. HBA1c is the single best parameter to know about long
↑ Glucose ↑ Ketones
term diabetic control.
Conditions affecting HBAIC
Falsely elevated HbA1c Falsely decreased HbA1c Hyperglycaemia
Glycosuria Acidosis
1. Iron Deficiency Anemia 1. Hemolytic Anemia
2. Post Splenectomy 2. Acute or Chronic blood loss
3. Uremia 3. Pregnancy
4. Chronic Aspirin Therapy
Osmotic diuresis Vomiting
Fructosamine (glycated plasma protein)
1. Levels reflect diabetic control over previous 2-3 wks
2. Is used in pregnancy and pre conception to assess shorter Fluid and electrolyte depletion
term control
3. Also used in patients with hemoglobinopathies and
hemolytic anemia which interfere with HbA1C tests.
eAG (Estimated Average Glucose) Renal hypoperfusion

1. Postprandial and nocturnal hyperglycemia may not be

detected by the SMBG of fasting and preprandial capillary
plasma glucose but will be reflected in the HBA1C.
Impaired excretion of ketones
2. Recent intercurrent illnesses may impact the SMBG and hydrogen ions
measurements but not the HBA1C.
Pathophisiology of Dehydration in DM
 5

Golden lines to remember : Autoantibodies in type 1 Diabetes

1. Dehydration occurs during ketoacidosis as a consequence 1. Insulin Auto antibodies ( IAA)
of two parallel processes. 2. Islet cell Autoantibody ( ICA)
3. Anti-GAD – 65 (Glutamic acid decarboxylase)
2. Hyperglycaemia results in osmotic diuresis, and

SECTION 1
4. Tyrosine Phosphatase ( IA -2 )
hyperketonaemia results in acidosis and vomiting. 5. Zinc transporter 8 (ZnT8)
3. Renal hypoperfusion then occurs and a vicious circle
is established as the kidney becomes less able to Islet cell autoantibodies
compensate for the acidosis.
1. Islet cell antibodies are detected by a fluorescent antibody
Features of Type – 1 DM technique which detects binding of autoantibodies to islet
cells.
1. Age – below 30 years
2. Much of this staining reaction is due to antibodies specific
2. Patient has normal Weight or underweight for glutamic acid decarboxylase (GAD) and protein tyrosine
3. Presence of autoantibodies: phosphatase – IA-2.

A. Islet cell antibodies (lCA)
B. Anti-glutamic acid decarboxylase (GAD) antibodies;
4. Family history of DM may or may not be positive
5. Other autoimmune diseases (Grave Disease, Hashimoto
Thyroiditis, Pernicious Anaemia, Addison Diseases, Celiac
disease) may be there (Schmidt syndrome or polyglandular
failure syndrome)
6. Serum insulin levels are low
ENDOCRINOLOGY
3. Not all the staining seen with ICA is due to these
two autoantibodies, so it is assumed that other islet
autoantibodies are also involved.
Insulin autoantibodies also appear in the circulation but do
not contribute to the ICA reaction.
II. Idiopathic (Type I B)
1. Some cases of Type 1 DM are idiopathic i.e. they have
beta cell destruction without antibodies.

7. HLA - DR3, DR4 2. Acute Fulminant diabetes mellitus

8. Main treatment is insulin
9. Latent autoimmune diabetes of adults (LADA)
A. It is a form of Type 1 DM, with slower progression to
insulin dependence in elderly person.
B. So in this case also serum insulin level is reduced &
auto antibodies are there.
Pathogensis of Type I diabetes-
I. Autoimmune. Destruction of Beta cells. (Type 1A)
1. Absolute deficiency of insulin (Pancreas devoid of
β-islet cells)
2. Insulitis:
A. T-cell cytokine destruction (type IV HSR)
HSR = Hypersensitivy Reaction
B. Autoantibodies against β-islet cells (>80%) and
insulin (>50%) (Type II HSR)
3. Triggers for destruction—e.g., viruses
A. It is acute onset diabetes
B. Can occur in any age
C. Occurs after viral infection.
D. Serum insulin level are reduced but there are no
antibodies against insulin or beta cell.
E. The viral infections associated with diabetes
are : Mumps, Measles, Coxsackie virus,
Cytomegalovirus, Rubella, EB virus
Clinical characteristics of fulminant type 1 DM
1. 20% of acute- onset type 1 diabetes
2. Duration of the disease <7 days.
3. High plasma glucose levels with near normal (HbA1c)
4. Disease onset may be accompanied by ketoacidosis
5. Elevated serum pancreatic enzyme levels
6. Negative anti- islet autoantibodies
Progession of type 1 diabetes mellitus

4. Infiltration of islets cells by inflammatory cell 100%

Serum insulin autoantibodies
Functioal beta-cell mass

50%

Islet cell antibodies (ICA)

0%
IA-2/ICA512 GAD65
Genetic Environmental Dysglycemia and Diabetes
suscepti- events trigger presence of auto mellitus
bility autoimmune antibodies
response against
? beta cells
Time years
Autoantibodies in type 1 DM
 6

Mauriac syndrome Genetic defects associated with MODY

1. Seen in children with poorly controlled type1 DM Genetic Defect

2. Characterized by MODY 1 HNF 4a
SECTION 1

A. Short Stature
MODY 2 Glucokinase
B. Delayed Puberty
MODY 3 HNF 1a
C. Hepatomegaly ( Due to increased Glycogen deposition
in the lever) MODY 4 IPF - 1
D. Cushingoid features MODY 5 HNF 1β
E. Obesity
MODY 6 NDF – 1
3. Pathogeneses
Difference between Type 1 diabetes and MODY
ENDOCRINOLOGY

A. Not Fully known

Type 1 DM MODY
B. Could be due to high blood Glucose level promoting the
flow of glucose into hepatocytes & hyperinsulinemia 1. Age < 40 <25
stimulate the conversion of glucose to glycogen. 2 Family history +/– +++
4. Treatment – Strict glycemic Control
3 Autoimmune +++ –
Features of Type - II DM 4 Body weight Normal/ Normal
1. Age, usually > 40 years under
2. Patient are overweight 5 Beta cell sensitivity to glucose Normal Reduced

3. No autoantibodies
6 Serum insulin level ↓ ↓
4. Ketosis is uncommon.
7 Insulin antibody +++ –
5. Non ketotic hyper osmolar coma is common.
8 Treatment Insulin SU (Low dose)
6. Family history strongly positive.
9 Insulin resistance No No
7. Insulin resistance is the main cause
Cause of Hyperglycemia in Type II Diabetes
8. Initially Serum insulin levels are very high (hyper insulinemia)
9. Treatment: weight loss, oral drugs & insulin 1. ↑Glucose from liver (glycogenolysis, gluconeogenesis)
2. ↓Peripheral utilization of sugar
Maturity onset diabetes of the young (MODY) 3. ↓Release of insulin from pancreas.

1. It is an autosomal dominant form of diabetes affecting Pathophysiology of Type II Diabetes.

young people with a definite positive family history. It is due to receptor / post receptor problems / GLUT – 4 Defect
2. There is impaired glucose – induced secretion of insulin. ß 1. ↓ Receptors due to adipose tissues (Down and Up regulation
cell can not sense glucose, so reduced Insulin release. of receptors)
3. There is no peripheral resistance to insulin 2. Post receptor defect: most important is tyrosine kinase
defect (normally is acetylated when insulin attaches to
4. Several types of MODY have been described. receptor muscle/ adipose).
3. GLUT-4 defect: normally moves from cytosol to cell
5. Except for MODY 2, in which a glucokinase gene is membrane to attach to glucose and bring glucose in cell
defective, all other types involve mutations of a hepatocyte
nuclear transcription factor (HNF) that regulates islet gene Other features contributing to insulin resistance
expression.
1. Amyloid deposition in beta cell
6. MODY 3 is the most common form – accounts for two-
thirds of all MODY cases. It is due to HNF- 1 alpha mutation 2. Increase free fatty acid
Differences Between Different Types of Diabetes Mellitus
7. Features of MODY:
A. Definite family history B. No antibodies Parameter Type 1 DM Type 2 DM
C. No obesity D. DKA uncommon 1. Age at onset - usually young Adults

E. Insulinopenia F. No hypertension 2. HLA association DR3, DR4 No HLA association

G. No Insulin resistance H. No Hyperlipidemia 3. Body weight- Normal or Obese

underweight
I. Treatment of MODY is low dose of sulphonylurea
 7

Parameter Type 1 DM Type 2 DM Golden lines to remember :

4. Family h/o May or may not be Strongly +ve (but 1. Type 1 DM
there always positive)
A. Low-carbohydrate diet

SECTION 1
5. Presentation - Usually (Abrupt) Gradual or
asymptomatic B. Insulin replacement
6. Insulin Absolute, but drugs OHA, later insulin. 2. Type 2 DM
requirement like AGI, Pramlintide A. Dietary modification and exercise for weight loss
can be given
B. Oral agents
7. Serum insulin Low High C. Non-insulin injectables
level-
D. Insulin replacement
8. Etiology Autoimmune, Insulin resistance,
impaired insulin Other types of Diabetes
Secretion

ENDOCRINOLOGY
Downregulation and Upregulation of Insulin Receptors: I. Diabetes in Pregnancy
Diabetes in pregnancy is divided into two categories:
Basic concept
I. Pregestational:
1. It is seen in Type-2 diabetes
1. Onset is prior to pregnancy.
2. Downregulation is the process by which a cell decreases the
2. If the woman has risk factors for DM, screen with
quantity of a cellular component, such as RNA or protein, in
fasting glucose or HBA1c;
response to an external variable.
3. An increase of a cellular component is called upregulation. A. eg, BMI > 25 kg/m2 (> 23 kg/m2 for Asians), first-
degree relative with DM,
4. Mechanism: The Insulin Receptor
B. high-risk ethnicity (black, Asian, Hispanic, Native
A. The process of downregulation occurs when a person
American),
is obese.
B. There are elevated levels of the hormone insulin in the C. Polycystic ovary syndrome,
blood. D. Prior delivery of baby > 4.1 kg (9 lb)
C. At high plasma insulin levels, the number of surface
E. Previous HbA1c > 5.7% or impaired glucose
receptors for insulin is gradually reduced by the
tolerance or impaired fasting glucose,
accelerated rate of receptor internalization and
degradation brought about by increased hormonal F. HDL-C < 35 mg/dL or triglycerides > 250 mg/dL
binding. II. Gestational Diabetes Mellitus (GDM)
5. Reversal 1. Occurs in 3–5% of all pregnancies, usually diagnosed in
A. The process of downregulation can be counteracted by the third trimester (24–28 weeks).
weight loss, which leads to increase insulin receptors. 2. Glucose intolerance develops during pregnancy.
B. This is also known as Up regulation of receptors A. Antiinsulin effect of human placental lactogen
(HPL), cortisol, and progesterone
Thrifty Genes
B. Increased risk for GDM in future pregnancies
1. Thrifty genes are genes which enable individuals to History
efficiently collect and process food to deposit fat during
periods of food abundance. 1. Typically asymptomatic.
2. According to the hypothesis, the ‘thrifty’ genotype would 2. May present with, polyhydramnios, or a large-for-GA
have been advantageous for hunter-gatherer populations, infant (> 90th percentile).
especially child-bearing women, because it would allow
them to fatten more quickly during times of abundance of Diagnosis
food. 1. Screen with a 1-hour 50-g glucose challenge test:
3. Fatter individuals carrying the thrifty genes would thus
better survive times of food scarcity. A. Venous plasma glucose is measured 1 hour later.
4. In modern societies with a constant abundance of food. B. Performed at 24–28 weeks.
5. The result is widespread chronic obesity and related health
problems like type II diabetes. C. Values ≥ 140 mg/dL are considered abnormal.
2. Confirm with an oral 3-hour (100-g) glucose tolerance
Golden lines to remember : test (GTT) showing any two of the following:
1. Type – I DM: Autoimmune / Idiopathic A. Fasting: > 95 mg/dL.
2. Type – II DM: Overweight / Insulin resistance
3. MODY: autosomal dominant B. 1 hour: > 180 mg/dL.
4. LADA: Type – I DM in elderly person C. 2 hours: > 155 mg/dL.
5. Downregulation and Upregulation of Insulin Receptors D. 3 hours: > 140 mg/dL.
6. Thrifty Genes OR
 8

75gm OGGTT 4. Other Endocrine Conditions causing hyperglycemia:

1. Fasting > 92 A. Cushing’s disease B. Acromegaly
2. 1Hr > 180 C. Pheochromocytoma D. Glucagonoma
SECTION 1

3. 2 Hr > 153 E. Somatostatinoma

GDM is diagnosed when any one value is abnormal (Note = In Addison disease hypoglycemia occurs)
Treatment 5. Potential Diabetes : Person himself at present is non-
1. Mother: diabetic but has a strong family history of type 2 diabetes.

A. Start with the controlled diet, regular exercise, and strict 6. Latent Diabetes:
glucose monitoring (four times a day). A. A person becomes diabetic under stressful conditions
like pregnancy.
B. Tight maternal glucose control (fasting ≤ 95 mg/dL; 1
hour postprandial ≤ 140 mg/dL and 2-hour postprandial B. Person again becomes nondiabetic when stress is
removed.
ENDOCRINOLOGY

≤ 120 mg/dL) improves outcomes.

C. Add insulin if dietary control is insufficient. 7. Malnourished diabetes
D. Give intrapartum insulin and dextrose to maintain tight A. It is seen in malnourished children.
control during delivery. B. Serum insulin level are reduced but there are no
antibodies against insulin or beta cell.
2. Fetus:
C. In these patients DKA is uncommon.
A. Obtain periodic ultrasonography and Fetal nonstress
D. These patients should be given good calories diet.
test (NSTs) to assess fetal growth and well-being.
B. It may be necessary to induce labor at 39–40 weeks 8. Brittle Diabetes:
in patients poorly controlled on insulin or an oral A. It is seen in children with type 1 diabetes.
hypoglycemic agent B. He has wide fluctuation in line blood sugar level.
Complications C. Sometimes patient’s sugar becomes very high leading
to DKA,
1. More than 50% of patients go on to develop glucose
intolerance and/or type 2 DM later in life. D. Sometimes patient goes into hypoglycemia
2. At 6–12 weeks postpartum, screen for DM (75 g 2-hour 9. Tropical diabetes:
GTT) and repeat testing every 3 years if normal results
A. Diabetes mellitus associated with chronic pancreatitis.
3. Newborn risks
B. Chronic pancreatitis patient are usually in Africa where
A. Macrosomia: Hyperglycemia in the fetus causes release they consume Casava.
of insulin. C. That leads to pancreatic calcification and pain
B. Hyperglycemia in the fetus causes release of insulin. abdomen.
(i) Insulin increases fat stored in adipose tissue. 10. Mitochondrial Gene defects:
(ii) Insulin increases muscle mass by increasing A. Point mutations in mitochondrial DNA are sometimes
amino acid uptake in muscle (growth hormone
associated with DM and deafness.
effect of insulin).
B. A form of type 1 DM, associated with mitochondrial
C. Congenital malformations of the baby is a complication mutations, is the wolfram syndrome.
of pregestational diabetes mellitus.(not seen with the
gestational diabetes mellitus) C. Wolfram syndrome is characterized by diabetes
insipidus, DM, optic atrophy, and deafness – thus, the
2. Drug induced Diabetes Mellitus. Various drugs can cause acronym DIDMOAD.
Hyperglycemia
D. MIDD (Maternally inherited diabetes and deafness
A. Steroids B. Thiazides
11. Genetic defects of insulin action: It is seen in
C. Nicotinic Acid D. Phenytoin
A. Leprechaunism
E. Alpha Interferon F. Protease Inhibitor
G. Beta Agonist H. Clozapine B. Rabson Mendenhall syndrome

3. Pancreatic diabetes: C. Cystic fibrosis

A. Surgery (where >90% pancreas is removed); trauma: 12. Autoimmune disease having associated diabetes
B. Pancreatic destruction (hemochromatosis, cystic A. Chronic lymphocytic thyroiditis (Hashimoto)
fibrosis) B. Celiac disease (Hence celiac disease is also known as
C. Pancreatic cancer. diabetic diarrhea)
D. Fibrocalculous pancreatopathy/ Tropical calcific C. Multiple endocrine deficiency syndrome
pancreatitis
 9

13. Type 3 diabetes LMRP

A. It is a term used when Alzheimer’s disease is triggered 3. Endocrine:
by insulin resistance in the brain. A. Cushing’s disease B. Acromegaly
B. This condition is most often used to describe people

SECTION 1
C. Pheochromocytoma D. Glucagonoma
who have type 2 diabetes and are also diagnosed with
Alzheimer›s or dementia. E. Somatostatinoma
4. Potential Diabetes
Golden line to remember : 5. Latent Diabetes
GH is antiinsulin so it causes increase blood sugar. It is 6. Acute Fulminant diabetes mellitus
proinsulin for amino uptake by muscle
7. Malnourished diabetes
8. Brittle Diabetes
LMRP
9. Tropical diabetes
1. Drug induced Diabetes Mellitus

ENDOCRINOLOGY
10. Mitochondrial Gene defects
A. Steroids B. Thiazides
11. Genetic defects of insulin action
C. Nicotinic Acid D. Phenytoin
12. Tropical diabetes
2. Pancreatic:
13. Autoimmune disease having associated diabetes
A. Surgery B. Pancreatic destruction 14. Type 3 diabetes
C. Pancreatic cancer. D. Malnutrition related DM

Pathophysiology of Diabetic Symptoms

Insulin deficiency

Tissue
Glucose Gluco- Gluco- Proteolysis Lipolysis
Uptake genolysis neogenesis

Hyperglycemia,
Protein,weight Plasma free
Glycosuria
loss fatty acids

Plasma Osmotic
losmolality Diuresis
Vomiting Ketogenesis,
Ketonemia,
Ketonuria
Loss of Water
Thirst
Na and K

Hypovofemia
Hyper- Anion gap
ventilation metabolic
acidosis
Cerculation failure
Tissue perfusion

Serum
lactate
Coma/Death

Recent Advances 2. Several adipokines, secreted by fat cells, can affect insulin
Action.
1. Genes for type II diabetics that cause the insulin
resistance and the beta cell failure- a gene on 3. Example of adipokines
chromosome 2 encoding a cysteine protease, A. Leptin B. Adiponectin
calpain –10, has been reported in some patient. C. TNFα D. Resistin
 10 

Basic concept about Glycemic Index (GI)

1. The glycemic index is a number associated with a particular
type of food that indicates the food’s effect on a person’s
blood glucose level.
SECTION 1

2. A value of 100 represents the standard, an equivalent

amount of pure glucose.
3. The GI represents the total rise in a person’s blood sugar
level following consumption of the food.
Glycemic index of various foods.
100% Glucose
80–90% Corn Flakes, carrots, potatoes (mashed), maltose, honey
ENDOCRINOLOGY

Lady of 500 kg due to congenitel defeiency of leptin 70-79% Bread (whole meal), millets, rice (white), broad beans,
potato (new),
Endocrine condition associated with obesity
60 –69% Bread (white), Wheat, rice (brown, unhusked), shredded
1. Hypothyroidism
wheat, beetroot, banana, raisins, sprouted green gram,
2. Cushing syndrome sucrose.
3. Insulimous 50-59% Wheat, noodles (white), peas (frozen), sweet corn, and
potato chips.
4. Hypogonadism
40-49% Noodles (whole mal), porridge oats, beans, potato (sweet),
5. Pseudo hypoparathyroidism oranges (juice), peas (dried), black gram.
6. PCOS
Managment 30-39% Black-eyed peas, apple, skimmed milk, curd/ yogurt,
tomato soup, ice cream
Essential elements in comprehensive care of type 2 diabetes.
20-29% Kidney beans, lentils , fructose
1. Best Initial management is Patient Education: (Life style 10-19% Soya beans groundnut
management)
Food of very high glycemic index = value>70
A. For any obese type II diabetic patient initial therapy is
diet therapy and exercise. Daily Caloric Requirement
(per kilogram of ideal body weight per day)
B. Weight loss can control as much as 25% cases of Type
Body Build Activity Level
2 DM without need of any drug by decreasing insulin
Sedentary Moderately Very active
resistance due to decrease adipose tissues.
active
C. Exercising muscle do not need insulin Obese 20 – 25 30 35
D. He should be advised to stop smoking, Normal 30 35 40
E. Reduce weight to maintain normal BMI <25 Underweight 35 40 45 - 50
BMI: body weight (kg) / height in Mt2
Golden lines to remember :
BMI: > 25 (Overweight)
> 30 (Obese) Yo-yo dieting (weight cycling).
> 35 (Morbid Obesity) 1. In this process, the dieter is initially successful in weight
loss but is unsuccessful in maintaining the loss long-
South Asian Criteria for using BMI as a Measure of Obesity in term and begins to over eat again to gain the weight
Adults back.
2. The dieter then again seeks to lose the regained weight
Category BMI ( Kg/m2) and the cycle begins again. !!!
Under weight < 18.5
Normal Weight 18.5-22.9 Treatment of Type 2 DM (continued) general health Maintenance

overweight 23 – 24.9 I. Cardiovascular risk modification

Obesity grade 1 25 – 29.9 1. The presence of diabetes is equivalent to the highest risk for
cardiovascular disease regardless of all other risk factors.
Obesity grade 2 30 – 34.9
2. All diabetic patients should be placed on a statin regardless
Obesity grade 3 >35
of lipid levels (provided they are > 40 years old and have at
F. Avoid food of high glycemic index (i.e. any food least 1 other cardiovascular risk factor).

like sugar, glucose powder etc. which are absorbed 3. Use the AHA risk calculator to determine whether moderate
or high-intensity statin is recommended
immediately in GIT and raised blood sugar very fast).
  11

Treatment of Type 2 DM (continued) general health Maintenance III. Thiazolidinediones

1. Example: Pioglitazone
II. BP management
2. Mechanism of action
Strict BP control to < 140/80 mm Hg; ACEIs/ARBs are first -line A. ↑insulin sensitivity in peripheral tissue.

SECTION 1
agents.
B. Binds to PPAR-γ nuclear transcription regulator.
III. Screening exams C. Genes activated by PPAR-γ regulate fatty acid
Annual physical examination to screen for cardiovascular storage and glucose metabolism.
disease (BP and lipid monitoring), nephropathy (test for D. Activation of PPAR-γ ↑insulin sensitivity and levels
microalbuminuria), retinopathy (dilated-eye exams), and of adiponectin.
neuropathy (foot care evaluations).
E. Used as monotherapy in type 2 DM or combined
IV. Other with above agents.
All diabetic patients > 19 years should receive the pneumonia F. Safe to use in renal impairment.
vaccine.
G. Can cause ovulation in PCOS

ENDOCRINOLOGY
Pharmacology of Antidiabetic Drugs H. Also used in NAFLD
I. They do not cause hypoglycemia
I. Metformin (Biguanide)
Side effects
1. It is the Best Initial drug in type II obese diabetic
2. It has got anorexic effect so it causes loss of body 1. Na + H2O retention (Can precipitate heart failure)
weight. 2. Hepatotoxicity 3. Bone fracture
3. It causes increase utilization of glucose in peripheral 4. Bladder cancer. 5. Weight Gain
tissues
4. Increases insulin sensitivity 6. Macular edema
5. It also blocks gluconeogenesis, Increases glycolysis Contraindication:
6. It does not cause hypoglycemia. 1. CHF 2. CAD
7. S/E –
3. Hypertension 4. History of bladder cancer
A. Nausea, Diarrhea,
B. Lactic acidosis 5. Serious hepatic impairment
C. Prolong use can cause Vit B12 deficiency. IV. Alpha-glucosidase inhibitor
8. Contraindication 1. Mechanism of actions
A. Severe renal impairment – eGFR < 30ml/ min/1.73
m2 A. Inhibit intestinal brush-border α-glucosidases.
B. Liver failure iii. Alcoholics (due to risk of lactic B. Delayed carbohydrate hydrolysis and glucose
acidosis) absorption
C. Any serious medical disease like septicemia 2. This reduces postprandial hyperglycemia
9. Metformin therapy does not need plasma level 3. They are very good drug for postprandial hyperglycemia
monitoring.
4. Do not cause hypoglycemia
II. Sulfonylurea.
5. Examples
1. These are insulin secretogogue
A. Acarbose B. Miglitol
2. Act on ATP sensitive K+ channel
C. Voglibose
3. They Close K+ channel in β-cell membrane
6. They decrease about 0.5 to 1% HBAIC
4. This leads to cell depolarization
7. Contraindications: They should not be used in
5. Hence insulin is released via Ca2+ influx A. Gastroparesis
6. They act by release of pre formed insulin from pancreas. B. Inflammatory Bowel Disease
7. Stimulate release of endogenous insulin in type 2 DM. 8. Side Effects
8. Require some islet function, so useless in type 1 DM. A. Flatulence
9. They can cause hypoglycemia and weight gain. B. Abdominal distension/Pain
Examples C. Diarrhea.
A. Short acting: Tolbutamide V. Meglitinide (Nateglinide, Repaglinide).
1. Mechanism of actions
B. Medium acting: Gliclazide
A. Stimulate postprandial insulin release by binding
C. Long acting: to K+ channels on β-cell membranes.
(i) Glibenclamide B. Increases beta-cell insulin release (insulin
secretogogue).
(ii) Chlorpropamide
C. So action mimics like sulphonylurea but they don’t
(iii) Glimepiride contain sulpha molecule
(iv) Glyburide (has highest affinity for beta cell )
 12 

2. They target post-parandial hyperglycemia because II. Anti diabetic drugs which raise GLP -1 and GIP
their half life (t1/2) is short. 1. Exenatide (Given S/C)
3. They may have a role in those with irregular mealtimes 2. Liraglutide (Approved as a drug for weight loss also)
if glycemic control is poor. (Given S/C)
SECTION 1

LMRP GLP-1 agonist (given once a week)

1. Metformin. 1. Injection Dulaglutide
A. Best Initial drug in type II obese diabetic 2. Injection Albiglutide
B. Has anorexic effect 3. Semaglutide It is available as oral and injection
C. Causes weight loss 4. Oral Semaglutide is given daily
D. Causes Vit. B12 deficiency. Advantage of GIP & GLP-1 agonist
2. Sulfonylurea. 1. Weight loss
A. Insulin secretogogue. 2. No hypoglycemia
ENDOCRINOLOGY

B. Causes weight gain 3. Decrease CVS mortality

3. Thiazolidinediones: 4. Decrease nephropathy
A. Act on PPAR gamma nuclear receptor. Side effects of GIP & GLP-1 agonist
B. Also used in NAFLD, PCOS 1. Nausea & vomiting
C. Can precipitate heart failure 2. Acute pancreatitis
4. Alpha-glucosidase inhibitor 3. Medullary thyroid carcinoma (so Black Box Warning is
A. Decreases breakdown of starch to simple sugar in GIT. given)
5. Meglitinide (Nateglinide, Repaglinide).
A. They are Insulin secretogogue
B. Have short half life

Incretin effect
I. Physiology WARNING
1. Normally when anybody eats food it causes increased
insulin secretion.
What is black box warning ?
2. Normal people who take oral glucose tend to have
A Black Box Warning
higher serum insulin level as compared to those normal
people to whom glucose was given I/V although blood 1. Is the strictest warning
sugar was same in both the groups of people. 2. Put in the labeling of prescription drugs or drug
3. It is because oral glucose causes release of some products by the Food and Drug Administration (FDA)
polypeptide from L cells of the intestine especially 3. When there is reasonable evidence of an association of
from duodenum which raise serum insulin level a serious hazard with the drug.
(insulinotropic polypeptide). III. Drugs which raised GLP-1 and GIP level by inhibiting DPP –
4. These polypeptide include IV (DPP – IV inhibitors)
(i) Glucagon like Peptide (It is a misnomer because Golden Lines To Remember
GLP actually inhibits glucagon!!! ii. GIP (Glucose 1. Sitagliptin Gliptin which can be given in CKD is
Insulinotropic peptide) 2. Vildagliptin LINAGLIPTIN
5. Mechanism of action: (Insulin secretogogue) 3. Saxagliptin
A. These two peptide increase glucose dependent 4. Ritagliaptin
release of insulin 5. Alogliaptin
B. They decrease release of glucagon from pancreases. 6. Tenegliptin
7. Linagliptin
C. Slow gastric emptying
D. They decrease Beta cell apoptosis Mechanism of action
1. Inhibits DPP-4 enzyme
E. Hence they preserve ß cells
2. This enzyme deactivates GLP-1 and GLP
F. They also act on CNS satiety center so they cause
3. They increase glucose-dependent insulin release
anorexia and weight loss
4. They decrease glucagon release
6. These two polypeptide have 5. They decrease gastric emptying
A. A short half-life of only 1 to 2 minutes 6. They Increase satiety (Early satiety is feeling of stomach
B. They are degraded by enzyme DPP – IV fullness after eating less than usual)
  13

Side effects:- Recent Advances: Newer Drugs

1. Nasopharyngitis
2. Inflammatory Bowel Disease (IBD) is precipitated I. Colesevelam
1. It is a bile acid sequestrant

SECTION 1
3. Increase pancreatitis
2. It bind bile acids but mechanism of glucose lowering
4. Increase neuroendocrine tumor not known.
5. Myositis (CPK levels need monitoring) 3. Side Effects:
6. Skin vesicles formation A. Constipation E. Increase
Advantages of DPP –IV inhibitors B. Dyspepsia triglycerides
1. Are given orally. C. Abdominal pain F. Intestinal
obstruction
2. These drugs reduce body weight or weight neutral D. Nausea
3. Hypoglycemia is not a feature II. Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors
(Renal glucose transporter inhibitors)

ENDOCRINOLOGY
4. Linagliptin can be given in patient of Renal failure Also
1. These agents lower the blood glucose by selectively
Amylin effect inhibiting sodium glucose co-transporter, these are
present the PCT in the kidney.
I. Physiology: 2. This inhibits glucose reabsorption, lowers the renal threshold
for glucose, and leads to increased urinary glucose excretion.
1. Amylin is a peptide hormone that is cosecreted with
insulin from the pancreatic β-cell 3. Hence, Renal glycosuria occur.
2. It is also deficient in diabetic people 4. Only extra sugar is filtered
3. Normal physiology 5. Shows better outcome in cardiac patient

A. It inhibits glucagon secretions 6. The glucose-lowering effect of SLGT-2 inhibitors

A. It is insulin independent
B. Delays gastric emptying
B. It is not related to changes in insulin sensitivity or
C. Acts as a satiety agent. secretion.
II. Anti-diabetic drugs which increases Amylin secretion Side Effect
(Amylin agonist)
1. Glucosuria -not a side effect
1. Pramlintide (Injection) 2. UTI - Genitourinary infection
2. It can be given in both type 1 and type 2 DM 3. Dehydration (due to osmotic diuresis by glucosuria)
4. Orthostatic hypotention (due to Dehydration)
LMRP 5. Fractures - only in 1 trial with canagliflozin
6. Acute kidney injury
1. GLP- 1, and GIP 7. Euglycemic diabetic ketoacidosis
A. Increase release of insulin Example : (All are given Orally)
B. Slow gastric emptying 1. Canagliflozin 2. Dapagliflozin
C. Exenatide 3. Empagliflozin
D. Liraglutide Glucose

E. Semaglutide this can be given as oral and injection

Proximal
F. Dulaglutid tubule -90%
2. DPP – IV inhibitors reabsorption
SGLT2
A. Sitagliptin
B. Vildagliptin
C. Linagliptin
3. Amylin agonist S1 segment

A. Pramlintide (Injection) SGLT1

Collecting
Distal S2/S3
-10% duct
Diabetic drugs & weight change -90% reabsorption segment
reabsorption
Weight gain Weight neutral Weight loss -10% reabsorption
1. Sulfonylureas 1. Metformin 1. GLP 1- Receptor
2. Thiazolidinediones ( Potential for Modest agonists
3. Insulin loss) 2. SGLT 2 inhibitor No glucose
2. DPF -4 inhibitor
 14 

Glucose filtration and reabsorption by the nephron (Phisiology) LMRP

1. Some 90% of filtered glucose is reabsorbed by sodium and D. Lorcaserin - Withdrawn
glucose transporter 2 (SGLT2) and 10% by SGLT1. i. It is an Anorexic drug, 5HT2C agonist.
2. SGLT2 inhibitors reduce net reabsorbed glucose by 25%.
SECTION 1

6. Drugs which do not cause hypoglycemia

3. For a mean plasma glucose of 8 mmol/L (144 mg/dL), this A. Metformin B. Alpha glucosidase inhibitor
results in a glucose loss of approximately 80 g per day in
the urine, which in turn reduces plasma glucose. C. Pioglitazone D. DPP- IV inhibitor
E. Renal glucose transport inhibitor
4. This equates to 320 kcal per day and subsequent weight
loss.
III. Bromocriptin
Insulin Therapy
1. It is thought to act on the circadian neuronal activities Non Diabetic uses of insulin.
in the hypothalamus
2. To reset an abnormally elevated hypothalamic drive 1. Treatment of Hyperkalemia
ENDOCRINOLOGY

for increased plasma glucose, free fatty acids, and 2. To assess anterior pituitary function to look for GLT or ACTH
triglycerides in insulin-resistant patients. deficiency called insulin tolerance test.
IV. Hydroxychloroquine 3. To assess completeness of truncal vagotomy
1. It has been approved as anti diabetic drug. Indications of use of insulin in diabetes
V. Anti-obesity Drugs: 1. Type I diabetes
2. Diabetes in pregnancy
1. Phentermine/Topiramate combination
3. Acute complications of DM (DKA, HHI)
2. Naltreoxone/Bupropion combination
4. Acute medical illness (MI, sepsis)
3. Resveratrol
5. Major surgery
A. A natural compound found in grape skin
6. Primary and secondary Failure of oral hypoglycemic drugs (OHA)
B. It mimics some of the effects of dietary restriction
Mechanism of actions
C. It is a anorexic drug
1. Binds insulin receptor (tyrosine kinase activity).
4. Lorcaserin - withdrawn from Market
2. Liver: Increase glucose stored as glycogen.
A. It is an Anorexic drug
3. Muscle: Increase glycogen and protein synthesis;
B. 5HT2C receptor agonist
4. Increase K+ uptake by the cells.
C. It causes weight loss. 5. K+ and PO4 go inside cell by cotransport with glucose.
D. It does not lead to Valvular lesion in heart 6. Fat: Increase Triglyceride storage
5. Orlistat

Golden lines to remember :

Antidiabetic drugs which do not cause hypoglycemia
1. Metformin
2. Alpha glucosidase inhibitor
3. Pioglitazone
4. DPP- IV inhibitor
5. SGLT2 Inhibitor Insulin Pump
Pharmacology of Insulin
LMRP
Preparation Onset Peak Duration
1. Colesevelam
1. Ultra Short-acting: 5-15 mts 30-90mts 3-4 hr
A. A bile acid sequestrant
A. Aspart
2. Renal glucose transport inhibitors B. Glulisine
A. Canagliflozin B. Dapagliflozin C. Lispro
C. Empagliflozin 2. Short acting: 30-45 2-3hrs 4-6 hrs
A. Regular
3. Bromocriptin
3. Intermediate acting: 2 -4 hr 6-7 hr 10-16 hr
4. Hydroxychloroquine A. NPH
5. Newer anti-obesity Drugs: B. Lente
A. Phentermine/Topiramate combination 4. Long acting:
B. Naltreoxone/Bupropion combination A. Detemir 1-4 hr Peakless 20- 24 hr
C. Resveratrol B. Glargine 1-4 hr Peakless 20- 24 hr
i. It is a anorexic drug C. Degludee 1-9 hr Peakless 42 hr
  15

Golden Lines to Remember : Insulin regimens.

1. Glargine & Detemir give a steady state of insulin level for 1. Profiles of soluble insulins are shown as: dashed lines;
entire 24 hours. intermediate- or long-acting insulin as solid lines (purple);
2. They are peakless insulin!!! and rapid-acting insulin as dotted lines (blue).

SECTION 1
3. Insulin glargine and detemir cannot be mixed with other 2. The arrows indicate when the injections are given.
insulin's B, breakfast; L, lunch; S, supper; Sn, snack (bedtime).
4. Insulin degludec can be mixed with rapid acting insulin
co-formulation of insulin degludec with aspart is Inhaled insulin
available. 1. Afrezza (insulin human) Inhalation Powder
As part, lis pro, glulisine 2. A rapid-acting inhaled insulin to improve glycemic control
in adults with diabetes mellitus.
Regular
3. Afrezza is a rapid-acting inhaled insulin
NPH Onset 30 min

ENDOCRINOLOGY
Determir Peak 2-3 hrs
Duration 3-4 hrs
Glargine
Injection Degludec (Pharmacology)
Mechanism of action
1. Insulin degludec is an ultra-long acting insulin that, unlike
0 5 10 15 20 25
insulin glargine, is active at a physiologic pH.
Time (hours)
2. The addition of hexadecanedioic acid to lysine at the B29
Basal insulin analogues position allows for the formation of multi-hexamers in
subcutaneous tissues.
1st Generation 2nd generation
3. This allows for the formation of a subcutaneous depot that
1. Insulin glargine 100u/ml Insulin glargine 300u/ml results in slow insulin release into the systemic circulation.
2. Insulin determir insulin degludec
Site of injecting Any kind of insulin
Insulin therapy 1. Abdomen
a. Twice-daily mixed soluble and intermediate insulins 2. Anterior & lateral aspect of thigh
3. Upper ARM (lateral side)
Insulin effect

Insulin is never injected in following places

1. Around umbilicus 2. Dorsum of hands
Newer anti-obesity medications
B L S SN B 1. GLP1 Receptor agonists
Morning Afternoon Night A. Semaglutide – subcutaneous injection – weekly
B. Livaglutide – “subcutaneous injection“ - daily
b. Three-times-daily soluble with intermediate- or long-acting
nsulin given before bedtime 2. Dual GLP 1 & GIP receptor agonists
A. Tirzepatide
Drugs which can be used in both type I and type II diabetes
Insulin effect

1. Injection pramlintide 2. Injection insulin

3. Tablet alpha glucosidase inhibitor
Newer Emerging Trend
I. Whole pancreas transplantation
B L S SN B
Morning Afternoon Night A. Performed concomitantly with a renal transplant
B. It may normalize glucose tolerance
c. Three-times-daily rapid-acting analogue with long-acting II. Pancreatic islet transplantation
analogue insulin given before bedtime
A. It has been plagued by limitations in pancreatic islet
supply and graft survival.
B. In islet transplantation, Islet cells from the donor is
Insulin effect

injected into the portal vein of recipient.

After Successful pancreatic transplantation
1. Complication that may be reversed / healed
B L S B A. Early diabetic nephropathy (microalbuminuria stage)
Morning Afternoon Night B. Diabetic neuropathy
 16 

2. Complications that do not appear to be reversed / healed. 9. Goals of treatment in a diabetic

A. Diabetic retinopathy A. HbA1C < 7
B. Peripheral vascular disease B. Pre parandial BS 70 – 130 mg% PP BS < 180 mg%
III. Closed-loop pumps that infuse the appropriate amount of C. BP < 140 / <90 mmHg. In Younger patients <130/<80)
SECTION 1

insulin in response to changing glucose levels.

IV. Bariatric surgery Complications of DM
1. It is done for markedly obese individuals with type 2
diabetes. Acute Complications
2. Bariatric surgery should be considered in individuals I. Diabetes Ketoacidosis (Medical Emergency)
with DM and a BMI >35 kg/m2.
3. BMI cut off for bariatric surgery in south Asian Biochemistry of diabetes ketosis (DKA)
A. if no comorbidities – 37.5kg.m2
B. If associated with high risk comorbid condition like
Protein degradation. Muscle wasting
diabetes, sleep apnea or degenerative joint disease
ENDOCRINOLOGY

(muscle)
– 32.5kg/m2 .
Goals of treatment in a diabetic patient: To achieve
1. HbA1C < 7
Gluconeogenosis
2. LDL <100 mg% (Liver)
3. Pre prandial blood sugar 70 – 130 mg% PP blood sugar < Glucose release
180 mg% from liver
4. PP blood sugar < 180 mg%
Glucogenolysis
5. BP < 140 / <90 mmHg. In Younger patient <130/<80) (Liver) Hyperglycmia
6. HDL >40mg% in male, >50mg% in female
7. Tg <150 mg%
Insulin
Insulin Resistance Glucagont Glucose uptake by
Epinepherine muscle and adipose tissue
When a patient needs more than 200 units of the insulin per day,
he is said to have insulin resistance.
Causes of insulin resistance
Lipolysis
1. Obesity. 6. Lipodystrophy syndrome, (adipose tissue)
2. Polycystic ovarian 7. Type A insulin resistance,
syndrome, β-Oxidation
8. Werner syndrome,
3. Renal failure. 9. Ataxia telangiectasia
4. Pregnancy. Acetyl CoA Hepatic ketone
(liver) body production Ketoacidosis
5. Leprechaunism,
LMRP
1. Non Diabetic use of insulin. Lipoprotein lipase Chylomcrons Hypertri-
A. Hyperkalemia activity and VLDL glyceridemia
(peripheral blood)
B. Pituitary function Assessments – to look for GH or
ACTH deficiency
C. Truncal vagotomy. Gycogen Glucose
2. Ultra Short-acting (Limited store)
A. Aspart B. Glulisine C. Lispro
Vit B1
3. Short acting: Oxalo acetate Pyruvate Lactate
A. Regular
4. Intermediate acting:
A. NPH B. Lente Acetyl CoA FFA Tg/VLDL
5. Long acting: Cholesterol
A. Detemir B. Glargine
C. Injection degludec duration of action is 40-42 hrs Citrate
HMG COA
6. Injection Dulaglutide: Once a week.- It is a GLP 1 receptor
agonist
7. Drugs which can be used in both type I and type II Acetoacetate*
(TCA)cycle
A. Pramlintide B. Insulin
8. Newer Emerging Trend Tricaroxylic acid cycle
A. Whole pancreas transplantation Acteone* 3 times faster
B. Pancreatic islet transplantation β (OH)butyrate
C. Closed-loop pumps
Nitroprusside test detects*
D. Bariatric surgery: BMI >35 kg/m2.
  17

Features Causes of pseudohyponatremia:

1. More common in Children with type-1 DM
1. Severe hyperglycemia (DKA, NKHOC)
2. It is usually of sudden onset
2. Hyperlipidemia
3. In some cases it may be the initial manifestation.

SECTION 1
3. Hyperproteinemia (Multiple myeloma)
4. Important precipitating factors are
A. Sudden withdrawal of insulin Management of DKA in intensive care unit :
B. Infection
1. IV fluids:
C. Medications (eg, glucocorticoids)
A. Replace fluids: 2–3 L of 0.9% saline over first 1–3 h
D. Trauma or acute illness
(10–20 mL/kg per hour);
Clinical features B. Subsequently, 0.45% saline at 250–500 mL/h;
1. Symptoms C. Change to 5% glucose and 0.45% saline at 150–250 mL/h
A. Nausea D. Altered mental function. when plasma glucose reaches 250 mg/dL (13.9 mmol/L).
B. Vomiting E. Shortness of breath

ENDOCRINOLOGY
2. Insulin:
C. Pain abdomen F. Polyuria A. Administer short-acting regular insulin: IV ,
2. Signs B. Then 0.1 units/kg per hour by continuous IV infusion
A. Tachycardia it does not indicate C. Switch to SC insulin D. Overlap SC & IV insulin by 1-2 hours
B. Tachypnea infection)
3. Potassium:
C. Kussmaul respiration F. Dehydration
D. Hypotension G. Dry mucous membrane A. In DKA, Initially hyperkalemia occur due to metabolic acidosis
E. Fever may be there H. Fruity odour of the B. Nearly all patients are K+ depleted, even with
(it is a feature of dka breath hyperkalemia
I. Abdominal tenderness C. Later on, hypokalemia can occur due to
3. Investigations i. Lost in the urine by osmotic diuresis.
A. Best initial Test is Serum HCO3/ABG ii. Potassium entered the cell with glucose due to insulin
B. Blood sugar – 250 – 600 mg% D. Add IV potassium (20-30 mEq/L of infused fluid, if serum K+
C. TLC – Leucocytosis.(It is a feature of DKA it does not ≤5.2 mEq/L E. Hold insulin for serum K+ ÷ <3.3 mEq/L
indicate infection) 4. Phosphate:
D. Na+ - Pseudohyponatremia A. Hypophosphatemia can occurs
E. Serum K+ - increase B. Phosphate goes along with glucose into the cell as a
F. Blood urea – increases (due to intravascular fluid co-transport (k also goes)
depletion) C. Consider for PO4 replacement if serum phosphate <1.0
G. S. Osmolality 300 – 320mosm/Kg mg/dL, cardiac dysfunction, or respiratory depression
H. Plasma ketones – Positive D. Monitor serum calcium frequently
I. Metabolic acidosis - Low HCO3 with increase anion gap. 5. Antibiotics
I. Hypertriglyceridemia A. If Infection is the precipitating factor, Fever is there
J. Hyperamylasemia B. Leucocytosis is a feature of DKA. It does not indicate
K. Serum PO4: May be reduced, infection
6. Bicarbonate:
Improtant Points
A. Consider for patients with pH <6.9
1. Beta Hydroxybutyrate are checked as a marker of ketone
production. 7. Measure capillary glucose every 1–2 h; measure electrolytes
(especially K+, bicarbonate, phosphate) and anion gap every
2. Anion Gap increases because Ketones are negatively charged. 4 h for first 24 h.
3. It lowers HCO3 level Criteria for Resolution of DKA
4. Blood pH is the single best test to know the prognosis of 1. Blood Glucose < 200mg /dl
a case of DKA
2. Serum bicarbonate > 18meq/L
5. In diabetes pseudohyponatremia occurs i.e. the measured
serum sodium is reduced as a consequence of the 3. Venous PH > 7.3
hyperglycemia. Complications of DKA–
A. There is a reduction of (1.6 meq) of serum sodium for 1. Cerebral edema (most dangerous complication, seen
each 100 mg/dL rise in the serum glucose. mostly in children) this is the most common cause of
B. A normal serum sodium in the setting of DKA indicates death due to DKA in children
a more profound water deficit.
2. Venous thrombosis
C. So when we treat a case of DKA, as the blood glucose
level falls then measured serum sodium rises. 3. ARDS
4. MI
 18 

LMRP Common precipitating factors include.

1. Abdominal pain 1. Infection (most common)
2. Medications (e.g., glucocorticoids, thiazide diuretics,
2. Dehydration pentamidine, atypical antipsychotics)
SECTION 1

3. Kussmaul respiration 3. Interruption of anti diabetic therapy

4. Best initial Test is Serum Bicarbonate/ABG 4. Trauma or acute illness (e.g., stroke myocardial infarction)
Investigations
5. ↑ Blood Sugar+ ↓HCO3 = DKA
1. Blood sugar 700 – 1100 mg/dl
6. Treatment
2. Serum osmolality > 320 mosm/kg
A. Fluids – 0.9% saline 3. Prerenal azotemia (occurs due to marked dehydration)
B. Short-acting regular insulin: IV 4. Pseudo hyponatremia
5. Do ABG
C. Potassium
A. pH normal i.e. no acidosis.
D. Bicarbonate B. Most patients have pH >7.30 and serum bicarbonate
ENDOCRINOLOGY

E. Phosphate >20 mEq/L.

6. Ketonuria is absent. i.e. no ketosis
F. Antibiotics 7. Check Ca, Mg, PO4
7. Complication Q. How to calculate plasma Osmolality of a patient. Who has
A. Cerebral edema RBS= 90 mg %, Na = 135, K = 5, BUN= 14 mg %
Ans. Serum osmolality is calculated as follows:
Golden Lines to Remember
[2 × (serum Na + serum K) + plasma glucose (mg%)/18 +
1. DKA is characterized by the triad of BUN (mg%) / 2.8)]
A. Hyperglycemia [2 × (135 + 5) + (90 / 18) + (14 / 2.8)]
= (2 × 140) + (5 + 5)
B. Ketonemia
= 290
C. Metabolic acidosis with increase Anion gap (Normal serum osmolality is 280 to 300 mosm/lit.)
2. ↑Blood Sugar+ ↓HCO3 = DKA Calculation of plasma osmolality in a patient of NKHOC who has
RBS = 1080 mg/dL, Na= 135, K+ = 5, BUN = 14 mg/dL
Non Ketotic Hyperosmolar Coma (NKHOC) 2 × (135 + 5) + (1080/18) + 14 /2.8
= 280 + 60 + 5
Also known as hyperglycemic hyperosmolar state (HHS) = 345 mosml/L
1. It is a medical emergency characterized by
A. Severe hyperglycemia and high serum osmolality
Golden Line to Remember
B. Due to relative insulin deficiency and/or elevated Plasma osmolality is very high in NKHOC
counterregulatory hormones (glucagon catecholamines, Treatment of NKHOC:
cortisol, growth hormone)
I. IV fluids
Symptoms –Classically patient is 1. Fluid → Total fluid deficit (9 – 10L) should be reversed
1. Elderly, type-2 DM over 1 –2 day
2. Initially give normal saline because it is hypotonic to
2. H/O polyuria of several weeks with weight loss and decrease patient existing osmolality and it also stabilize the
oral intake.
patients hemodynamically (if systolic BP is <90 mmHg)
3. Mentally confused due to later on give 0.45% saline.
A. Severe hyperglycemia II. Insulin
B. Elevated serum osmolality 1. Initial continuous IV insulin infusion
4. Frequently develop neurologic symptoms 2. Switch to Subcutaneous (SC) (basal bolus) insulin for
the following:
A. Focal signs A. When patient is able to eat
B. Lethargy blurry vision B. Glucose <200 mg/dL.
C. Obtundation 3. Overlap SC & IV insulin by 1-2 hours
Signs III. Potassium
1. Add IV potassium if serum K+ ≤5.2 mEq/L
1. Tachycardia 3. Dehydration
2. Hold insulin for serum K+ <3.3 mEq/L
2. Hypotension 4. Altered sensorium, coma 3. Nearly all patients K+ depleted, even with hyperkalemia
IV. Phosphate
Important Point:
1. Consider for serum phosphate <1.0 mg/dL, cardiac
Nausea, Vomiting, Abdominal Pain, Kussmaul respiration &
Ketosis, acidosis are not the features of NKHOC dysfunction, or respiratory depression
2. Monitor serum calcium frequently
  19

Treatment:
V. Subcutaneous heparin
1. It is typically associated with tissue hypoperfusion.
1. To prevent deep vein thrombosis (DVT) in legs
2. Appropriate measures include
VI. Prognosis

SECTION 1
A. Treatment of shock,
Mortality rates in HHS is as high as 20%, which is about 10
times higher than the mortality in DKA B. Increasing oxygen to the tissues and giving IV fluids are
often used to reduce lactic acid levels.
LMRP C. Sodium bicarbonate
1. Elderly (i) It is given I/V.
2. H/O polyuria (ii) It is the main treatment
3. Dehydration
3. Mortality is very high
4. Altered sensorium, coma
Thiamine:
5. Blood sugar 700 – 1100 mg/dl

ENDOCRINOLOGY
6. Serum osmolality > 320mosm/kg 1. Thiamine deficiency may be associated with cardiovascular
7. Give normal saline compromise and lactic acidosis.
8. Regular Insulin intravenous 2. The response to thiamine repletion may be dramatic and
Difference in laboratory characteristics of DKA & HHS potentially lifesaving

HHS DKA LMRP

Plasma glucose (mg/dl ) >250 >600 1. Serum lactate levels >5 mmol/L and blood pH <7.35
PH < 7.3 7.3 2. Metabolic acidosis with increased anion gap
ABG Bicarbonate <18 18
3. Metformin therapy
Anion gap >10 Variable
4. Kussmaul breathing
Ketones Positive Negative
Serum osmolality Variable >320 5. Cohen-Woods classification
6. Thiamine deficiency
Lactic Acidosis
7. Sodium bicarbonate is given I/V
1. Lactic acidosis is characterized by low pH in body tissues
and blood. Recommendation for screening of microvascular
complication ( Neuropathy, Nephropathy, retinopathy)
2. Elevated lactate is indicative of
In Diabetes
A. Tissue hypoxia C. State of acute
Screening should be done at the time of diagnosis
B. Hypoperfusion circulatory failure. type 2 diabetes and 5year after diagnosis of type 1 diabetes
3. Lactic acidosis is characterized by
M i c r o v a s c u l a r How to screen
A. Serum lactate levels >5 mmol/L complication
B. Blood pH <7.35
1. Retinopathy Dilated eye examination
4. Metabolic acidosis with increased anion gap
2. Nephropathy Spot urine albumin to creatinine ratio (UACR)
5. It is seen in patient of type 2 diabetes who are on metformin
therapy. estimated GFR ( eGFR )
3. Neuropathy History examination (see table below )
6. Signs and Symptoms:
A. Occur due to metabolic acidosis
B. Vomiting Chronic Complications
C. Abdominal pain
Cardiovascular Complication
D. Deep and rapid breathing (Kussmaul breathing)
1. Cardiovascular disease is increased in individuals with
7. The Cohen-Woods classification categorizes causes of type 1 or type 2 DM.
lactic acidosis as follows: 2. There is a marked increase in
A. Type A: Decreased perfusion or oxygenation (i.e. in A. PAD
shock)
B. CHF
B. Type B: C. CAD
(i) B1: Underlying diseases (Sometimes causing type A) D. Sudden death
(ii) B2: Medication or intoxication 3. Diabetes is a major risk factor for CAD.
(iii) B3: Inborn error of metabolism
 20 

4. MI is 3-5 times commoner in DM Important Points:

5. MI is more likely to be ‘silent’ (Painless) 4. Two studies (DCCT and UKPDS) were done.
6. CAD is the commonest cause of death in diabetic. A. In both the DCCT (type 1 diabetes) and the UKPDS
(type 2 diabetes),
SECTION 1

7. Earliest dyslipidemia to occur is diabetes is raised Tg B. Cardiovascular events were not reduced immediately
8. Later on increased, LDL and decreased HDL by intensive treatment during the trial
9. PAD (Peripheral Arterial Disease) C. They were reduced at follow-up 10–17 years later
D. This effect has been termed legacy effect or metabolic
A. Diabetes is the most common cause of non memory
traumatic amputation
B. Wet gangrene occurs in diabetes Eye Involvement in DM
C. It spreads very fast 1. DM is the leading cause of blindness
D. Hence urgent surgery is indicated 2. Individuals with DM are 25 times more likely to become blind
ENDOCRINOLOGY

than individuals without DM material within the nerve fiber layer.

3. Do annual fundoscopy for all diabetic patients
Diabetic Retinopathy (DRP)
I. Non proliferative
1. Pathophysiology of non proliferative RP is Retinal
ischemia.
2. It constitute 90 to 95% cases
II. Background retinopathy:
1. Microaneurysms (dots)
2. Hemorrhages (blots)
PAD (wet gangrene)

Golden Lines to Remember

Diabetic dyslipidemia
1. ↓HDL
2. ↑TG
3. ↑LDL, Predominance of small dense LDL
Major risk factors for CAD
1. Smoking 3. Hyperlipidemia
Dot and Blot intraretinal hemorrhages
2. Hypertension 4. Diabetes
III. Pre-proliferative retinopathy:
BP. Target is
1. Hard exudates
1. <140/< 90 mmHg A. Yellow flecks
2. In younger patients the target is <130/< 80 mmHg B. They are made up of lipid residues of serous
leakage from damaged capillaries;
ACEI are the drug of choice in diabetic with hypertension.
1. Strict blood pressure control significantly reduced macro-
and microvascular complications.
2. The beneficial effects of BP control are greater than the
beneficial effects of glycemic control!!!
3. Lowering BP to moderate goals reduced the risk of DMrelated
death, stroke, microvascular end points, retinopathy, and
heart failure (risk reductions between 32 and 56%).

Important Points:
1. Telmisartan is the only ARB which acts on PPAR gamma
receptor also. Hard exudates in DRP
2. So it is the ARB of choice that should be used in diabetes
3. Seroglitazaar 2. Cotton wool spots
A. Acts on PPAR alpha & gamma receptor A. They are caused by damage to nerve fibers
B. It reduces both blood sugar & lipid B. They are a result of accumulations of axoplasmic
C. Reduces Insulin resistance material within the nerve fiber layer.
D. Reduces LDL and Triglyceride. C. Indicates areas of retinal ischemia or infarction
  21

Cotton wool in DRP

SECTION 1
Hard exudates are lipoprotein deposits

ENDOCRINOLOGY
Soft exudates are deposits in Nerve
fibre layer due to retinal hypoxia
Features of diabetic eye disease
(a) The normal macula (centre) and optic disc (to left).
(b) Microaneurysms (small circles) and blot haemorrhage (larger
circle) – early background retinopathy.
(c) Hard exudates (circled) and single cotton wool spot (arrowed) in
addition to multiple blot haemorrhages in background retinopathy.
(d) Intraretinal microvascular abnormalities (IRMA) – pre-
proliferative retinopathy (circled).
(e) Venous loop (circled) also indicates pre-proliferative change.
(f) Fronds of new vessels on the disc and elsewhere (proliferative).
(g) Pre-retinal haemorrhage in proliferative disease.
(h) Hard exudates within a disc-width of the macula (maculopathy).
(i) Cortical and
(j) Central cataracts can be seen against the red reflex with the
ophthalmoscope.
The pathophysiologic mechanisms invoked in non proliferative
retinopathy: (NPRP)
1. Loss of retinal pericytes
2. Increased retinal vascular permeability
3. Alterations in retinal blood flow (venous dilatation)
4. Abnormal retinal microvasculature (vascular occlusion)
5. All of above lead to retinal ischemia.
Important Points:
1. The best predictors of the development of retinopathy.
A. Duration of DM and degree of glycemic control
B. Hypertension is also a risk factor.
2. Only management NPRP is tight control of blood sugar
3. Fluorescein angiography
A. It is useful to detect macular edema
B. It is associated with a 25% chance of moderate visual
loss over the next 3 years.
 22 

Therapy of nonproliferative DRP

1. Background retinopathy is less likely to progress if diabetic
control is good.
2. Annual screening for retinopathy is recommended, because
SECTION 1

blindness may be prevented by early treatment.

IV. Proliferative retinopathy:
1. New vessels form
2. They can lead to
Snowflake Cataract
A. Retinal detachment B. Vitreous hemorrhage.
3. Both can lead to sudden blindness.
4. Proliferative retinopathy may be treated with
A. Glucose and blood pressure control are very important.
ENDOCRINOLOGY

B. Laser-beam photocoagulation, which is effective in

obliterating new vessels.
C. Vitrectomy is beneficial in selected cases.

Golden Lines to Remember

1. Anti VEGF Senile Cataract
Agents approved by US – FDA for treatment of
A. Ranibizumab
B. Aflibercept
} proliferative diabetic retinopathy (PDR)
Diabetic mascular edema ( DME)
Recent advances
In The Management of PDR
C. Bevacizumab Used off label for treatment of PDR & DME 1. Bevacizumab or Ranibizumab
2. Faricimab A. They are monoclonal antibodies
B. They are used for treatment of Proliferative RP
A. Bispecific antibody which inhibits VEGF-A and angiopoi- C. They are vascular endothelial growth factor antagonist.
etin 2 pathways (VGEF Inhibitor)
B. Approved by FDA for treatment of DME D. They are used as intraocular injection into the vitreous
cavity
V. Maculopathy 2. Aflibercept
1. This is often not visible at an early stage. A. It is used to treat certain serious eye conditions
2. It leads to profound ↓ in visual acuity. (i) Wet age-related macular degeneration
(ii) Diabetic retinopathy
Other eye manifestation (iii) Diabetic macular edema
I. Rubeosis iridis: (iv) Macular edema following retinal vein occlusion
1. New vessels are formed on iris
2. It occurs late in diabetes LMRP
3. It can may lead to glaucoma 1. DM is the leading cause of blindness
2. Proliferative retinopathy
3. Non proliferative
4. Fluorescein angiography
5. Maculopathy
6. Rubeosis iridis
7. Snowflake Cataract
8. Senile Cataract
9. Bevacizumab or Ranibizumab

Diabetic Foot
1. Foot ulceration
Rubeosis Iridis
A. Usually painless, punched-out ulcer in an area of thick
II. Cataracts: callus + superadded infection.
1. May be juvenile ‘snowflake’ form B. Can lead to cellulitis, abscess and osteomyelitis.
2. ‘Senile’-which occur much earlier in diabetic subjects C. Great toe & MTP areas are most common site
as compared to non diabetic persons
  23

Pathology:
1. Capillary BM thickening
2. Diffuse glomerulosclerosis (Most common).

SECTION 1
A. In this there is increase in mesangial matrix.
B. It is PAS positive
3. Nodular glomerulosclerosis.
A. It is the most characteristic feature).
B. It is accompanied by accumulation of hyalin material.
Neuropathic ulcers
C. If it is within capillary loop (Fibrin cap) or it is attached
Risk factor for foot ulcers or amputation to Bowman capsule (Capsular drop)
1. Male sex 4. Armani Ebstein Reaction: Collection of glycogen clumps
2. Diabetes >10 years’ duration

ENDOCRINOLOGY
within the renal tubules found in diabetic nephropathy
3. Peripheral neuropathy 5. Dietary advice- Protein intake = 0.8 gm/kg/day in micro
4. Abnormal structure of foot (bony abnormalities, callus, Albuminuria, < 0.8 gm/ kg /day = in macro albuminuria
thickened nails
5. Peripheral arterial disease
6. Smoking
7. Poor glycemic control
8. Poor wound healing
9. Autonomic neuropathy anhidrosis and altered superficial
blood flow in foot

Diabetes Nephropathy
1. ↑GFR is the 1st manifestation of diabetic nephropathy.
2. Microalbuminuria – new term – moderately increased albuminuria
A. Next stage is the stage of Microalbuminuria (30 to 300
mg/ day of albumin in urine).
B. It is the most reliable marker of diabetic nephropathy.
C. Micro albuminuria is one of the early marker of diabetic
Natural history of diabetic nephropathy.
nephropathy. In the first few years of type 1 diabetes mellitus, there is
D. It is associated with increased long term cardiovascular hyperfiltration, which declines fairly steadily to return to a
morbidity. normal value at approximately 10 years (blue line). In susceptible
E. Strict glycemic control may prevent or revert micro patients (about 30%), after about 10 years, there is sustained
albuminuria. proteinuria, and by approximately 14 years it has reached the
F. ACEI reduces microalbuminuria nephrotic range (red line). Renal function continues to decline,
with the end stage being reached at approximately 16 years.
3. Macro albuminuria (new term - severely increased
albuminuria) (> 300 mg/day of albumin in urine)
4. ESRD
A. DM is M/C cause
B. Enlarge kidney size
Golden Lines to Remember
I. Albuminuria can be screened by measuring urinary
albumin to creatinine ratio in a random spot urine
collection
II. Table
Urine albumin / creatinine
ratio
Normal <30 mg/g
Nodular diabetic glomerulosclerosis. There is thickening
Moderately elevated albuminuria > 30-300 mg/g
of basement membranes, mesangial expansion and
(previously known as microalbuminuria) a Kimmelstiel– Wilson nodule (arrow), which is
Severely elevated albuminuria ( Previously > 300 mg/g pathognomonic of diabetic kidney disease.
known as macroalbuminuria)
 24 

Glomerular capillary subendothelial hyaline (hyaline caps) Diabetic Neuropathy

1. Diabetes mellitus is the most common cause of peripheral
neuropathy (PNP)
SECTION 1

2. The risk is related to the

A. Duration of disease
B. Glycemic control status.
3. Features of diabetic PNP
Symptom Signs

Green arrow Glomerular hyalinosis is formed by Large 1. Numbness 1. vibration

myelinated 2. Tingling 2. Proprioception
plasma components that are accumulated in peripheral
nerve fiber
segments of the tuft, (hyaline cap or fibrin cap). 3. Ataxia ( reduce absent )
ENDOCRINOLOGY

Small nerve 1. pain burning 1. Hot/ cold

fiber 2. Hyperalgesia discrimination

A. Allodynia 2. Pinprick sensation

( Reduce / absent)
4. Diabetic neuropathy is the most common chronic
complication of diabetes prevalence – 50% in people with
diabetes
Types of DM Neuropathy
I. Somatic
1. Polyneuropathy
A. Symmetrical, mainly sensory, distal: Most common
form of diabetic neuropathy – Distal symmetric
poly neuropathy
B. Asymmetrical, proximal mainly motor (including.
Amyotrophy wasting of quadriceps and other
pelvifemoral muscles.)
2. Mononeuropathy
3. Mononeuritis multiplex
4. Painful neuropathy: Patient has severe pain in the legs
especially at night.
Treatment of painful neuropathy:
1. Anticonvulsants
A. Pregabalin B. Gabapentin
2. SNRI
A. Duloxetine B. Venlafaxine
Fibrin cap & capsular drop in diabetic retinopathy 3. Tricyclic Antideprenant
Important Points: A. Amitriptyline
1. In diabetes, patient may develop hyperkalemia without 4. Topical Treatment
renal failure because of RTA type IV. A. Capsaicin 8% patch B. Lidocaine 5% Patch
2. Radiographic contrast media can precipitate nephropathy
in a diabetic patient. 5. Centrally acting opiod analgesics – last line therapy
A. Tapentadol B. Tramadol
LMRP
1. Sequence of changes in diabetic nephropathy: Golden Lines to Remember
A. Increase GFR (earliest)
B. Microalbuminuria US-FDA approved medications for diabetic neuropathy
C. Macroalbuminuria 1. Pregabalin
D. End stage renal disease 2. Duloxetine
2. Role of BP Control and ACEI
3. Hyperkalemia 3. capsaicin patch ( 8%)
4. RTA type IV
4. Tapentadol ( last line therapy )
  25

II. Autonomic neuropathy (ANP)

Features:
1. Postural Hypotension

SECTION 1
A. Drug used in treatment of Postural hypotension:
(i) Fludrocortisone (iv) Octreotide
(ii) Midodrine (v) Yohimbine
(iii) Clonidine
2. Tachycardia
3. Urine retention (Due to bladder distetion) Malignant otitis externa
4. Retrograde ejaculation (Urine contains sperms in males) Treatment
1. Aminoglycoside,
5. Diarrhea or Constipation.
2. IIIrd generation cephalosporin.
6. Hypoglycemic unawareness
II. Rhino cerebral mucormycosis

ENDOCRINOLOGY
7. Erectile dysfunction Drug used for ED:
1. It is caused by fungus.
A. Sildenafil (a 5 phosphodiesterase inhibitor-PDE5)
2. It is potentially fatal.
B. Apomorphine
3. Treatment is amphotericin-B.
C. Yohimbine
D. PgE1
8. Gastroparesis:
A. Occurs due to decrease ability of GUT to sense the
stretching of bowel wall.
B. Usually stretch is the main stimulus for GIT motility.
C. It may respond to erythromycin, (erythromycin acts on
the motilin receptor)
D. Metoclopromide can be used
III. Cranial Neuropathy
1. III, IV, VI & VII cranial nerves are commonly involved.
2. In DM IIIrd nerve is involved most commonly but
pupillary reaction remains normal
LMRP
1. Polyneuropathy Rhinocerebral Mucormycosis
A. Distal, symmetrical sensory
B. Proximal asymmetrical motor Golden Line to Remember
C. Mononeuropathy M/C oral infection in DM is candidiasis
D. Mononeuritis multiplex
E. Painful neuropathy III. Emphysematous pyelonephritis
2. Autonomic neuropathy (ANP) 1. Caused by E. coli patient presents with fever and flank pain.
A. Postural Hypotension 2. It is potentially fatal. (Gas is seen in perinephric area, on
B. Tachycardia X-ray abdomen)
C. Urine retention
D. Retrograde ejaculation
E. Diarrhea or Constipation.
F. Hypoglycemic unawareness
G. Erectile dysfunction
3. Cranial Neuropathy

Other Complications
I. Malignant otitis externa
1. It is cause by pseudomonas infection
2. It leads to pain Image shows striated intrarenal gas (within medullary rays) and
3. Discharge from external ear. perinephric gas.
4. It is potentially fatal
 26 

IV. Emphysematous cholecystitis

1. It is more common in males
2. Gas is seen in gall bladder on X-ray abdomen
SECTION 1

Scleredema
Woody induration and thickening of the skin, most often involving
the upper back, neck, and shoulders
ENDOCRINOLOGY

Emphysematous Cholecystitis. Supine view of the

abdomen shows air in the wall (blue arrows) of the
gallbladder (GB).
There is also a lucency within the lumen of the gallbladder
(GB) suggesting air inside the lumen.
V. Diabetes Mellitus increases risk of Alzheimer’s
disease
Dupuytren contracture
1. Diabetes with Alzheimer disease is also known as type
III diabetes
VI. Skin Involvement in DM
1. Pigmented pretibial papules (also known as diabetic
dermopathy)
2. Necrobiosis lipoidica most common in shin (pre tibial)
part of legs
3. Acanthosis nigricans Lipodystrophy
4. Granuloma annulare
5. Lipoatrophy and lipohypertrophy
6. Scleredema
7. Dupuytren’s contracture.

Bullous diabeticorum Necrobiosis lipoidica

Acanthosis nigricans is a disorder that may begin at any age. It

causes velvety, light-brown-to-black, markings usually on
the neck, under the arms
Prayer sign-Limited joint mobility with flexion contracture
affecting the proximal interphalangeal joints.

Granuloma annulare

Golden Line to Remember

Most common dermatological manifestation of DM –
Prayer Sign Xerosis & Pruritis

Golden Line to Remember
Protease inhibitor can cause lipodystrophy
Theories of Pathophysiology of Diabetic
Complication
I. First theory
1. Nonenzymatic glycosylation (NEG)
A. Glucose combines with amino groups in proteins.
B. Advanced glycosylation products are synthesized.
(i) Increase vessel permeability to protein ii.
Increase atherogenesis
C. Role in diabetes mellitus
(i) Production of glycosylated HbA1c
(ii) Hyaline arteriolosclerosis
(iii) Diabetic glomerulopathy
(iv) Ischemic heart disease, strokes (lacunar
strokes), peripheral vascular disease
II. Second Theory
1. Hyperglycemia increases the formation of diacylglycerol
leading to activation of protein kinase C (PKC).
2. PKC alters the transcription of genes for fibronectin,
type IV collagen, contractile proteins, and extracellular
matrix proteins in endothelial cells and neurons.
3. Diabetic microangiopathy
A. Increased synthesis of type IV collagen in basement
membranes and mesangium
B. Important in diabetic glomerulopathy
III. Third theory
1. Hyperglycemia increases the flux through the
hexosamine pathway, which generates fructose-6-
phosphate, a substrate for O-linked glycosylation and
proteoglycan production.
IV. Fourth theory
1. Hyperglycemia results in increased intracellular glucose
concentrations in these tissues. Glucose undergoes
conversion into sorbitol by aldose reductase, and
sorbitol, in turn, is converted into fructose.
2. Sorbitol and fructose increase the osmotic pressure
in tissues and stimulate the influx of water leading to
osmotic cellular injury. Increased water in lens fiber
cells leads to rupture of these cells with resultant
Opacification of the lens and cataract formation.
3. Osmotic injury of Schwann cells contributes to
peripheral neuropathy in diabetes.
4. Polyol pathway impairment occurs in tissues that
do not depend on insulin for glucose transport (lens,
peripheral nerves, blood vessels and kidneys).
5. Recently a new drug Epalrestat has been launched
which is a aldose reductase inhibitor. Which is supposed
to reduce the complication of diabetes.
 27
Important Points:
International research studies which prove that intensive
diabetes control Significantly reduced microvascular end
points.
SECTION 1
1. Kumamoto Study- Type 2 DM
2. The United Kingdom Prospective Diabetes Study
(UKPDS) -Type 2 DM
3. The steno-2 study
4. DCCT (Diabetes Control and Complication Trial)-Type 1
DM
Golden Lines to Remember
1. The DCCT demonstrated that improvement of glycemic
ENDOCRINOLOGY
control reduced
A. Non proliferative and proliferative retinopathy (47%
reduction),
B. Microalbuminuria (39% reduction)
C. Clinical nephropathy (54% reduction)
D. Neuropathy (60% reduction).
E. Improved glycemic control also slowed the progression
of early diabetic micro vascular complications.
2. There was a nonsignificant trend in reduction of
macrovascular events during the trial
3. The UKPDS demonstrated that each percentage point
reduction in A1C was associated with a 35% reduction
in microvascular complications.
4. One of the major findings of the UKPDS was that strict
blood pressure control significantly reduced both
macro- and microvascular complications.
5. The findings of the DCCT, UKPDS, and Kumamoto study
strongly support the idea that chronic hyperglycemia
plays a causative role in the pathogenesis of diabetic
microvascular complications.
Metabolic Syndrome (also known as syndrome X or
Reaven’s Syndrome)
1. Central obesity: waist circumference > 102 cm in male, >
88 cm in Female (In south Asian population – cut offs are
different ( male - ≥ 90cm, female ≥ 80 cm ))
2. Hypertriglyceridemia: > 150 mg%,
3. Low HDL cholesterol: <40 mg% (male), < 50 mg% (Female)
4. Hypertension: > 130 mm systolic or > 85% diastole
5. Fasting plasma glucose > 100 mg% or previously diagnosed
type 2 diabetes
6. If ≥3of 5 criteria is required to make a diagnosis of metabolic
syndrome according to NCEP ATP3 2005 criteria.
A. NCEP – national cholesterol education program
B. ATP – Adult Treatment panel
Golden Line to Remember
Syndrome Z = Syndrome X + Obstructive sleep apnea