Pathophysiology behind symptoms and complications of diabetes

 Polydipsia or increased thirst is due to high blood glucose that raises the osmolarity of blood
and makes it more concentrated.

 Polyuria or increased frequency of urination is due to excess fluid intake and glucose-
induced urination.

 Weight loss occurs due to loss of calories in urine.

 Polyphagia or increased hunger due to loss or excess glucose in urine that leads the body to
crave for more glucose.

 Poor wound healing, gum and other infections due to increased blood glucose providing a
good source of nutrition to microbes and due to a diminished immunity.

 Heart disease – this occurs due to changes in the large blood vessels leading to coronary,
cerebral, and peripheral artery diseases, atherosclerosis, dyslipidemia etc.

 Eye damage – this is termed diabetic retinopathy and occurs due to damage of the fine
blood vessels of the retina in the eye due to long term exposure to high blood sugar.

 Kidney damage – similar damage to small and large blood vessels of the kidneys. Initially
there is proteinuria or increased outflow of protein and may lead to end stage renal disease
(ESRD).

 Nerve damage – this can affect the arms and legs and is called stocking-glove
numbness/tingling. It can also affect autonomic functions leading to impotence, erectile
dysfunction, difficulty in digestion or gastroparesis etc.

 Diabetic foot – this occurs due to peripheral nerve damage as well as blood vessel affliction
due to long term diabetes. Little trauma, sores and blisters go unnoticed due to lack of
sensation and peripheral vascular disease impairs healing and allows infection.

 Diabetic Ketoacidosis is caused in type 1 diabetes where there is complete lack of insulin and
reliance on fatty acids for energy. This uncontrolled lipid breakdown leads to formation of
ketones and causes acidosis and ketonemia. This is a medical emergency.

 Non-Ketotic Hyperosmolarity – this is caused due to extreme rise of blood sugar. This is seen
in type 2 diabetics. There is just enough insulin to suppress ketone synthesis. The high blood
sugar leads to excessive concentration or osmolarity of blood which in turn leads to dieresis
and collapse of the blood vessels and cardiovascular shock. This is a medical emergency.

The causes of type 1 diabetes are unknown, although several risk factors have been identified. The
risk of developing type 1 diabetes is increased by certain variants of the HLA-DQA1, HLA-DQB1,
andHLA-DRB1 genes. These genes provide instructions for making proteins that play a critical role in
the immune system. The HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes belong to a family of genes
called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system
distinguish the body's own proteins from proteins made by foreign invaders such as viruses and
bacteria.

Type 1 diabetes is generally considered to be an autoimmune disorder. Autoimmune disorders occur

when the immune system attacks the body's own tissues and organs. For unknown reasons, in
people with type 1 diabetes the immune system damages the insulin-producing beta cells in the
pancreas. Damage to these cells impairs insulin production and leads to the signs and symptoms of
type 1 diabetes.

HLA genes, including HLA-DQA1, HLA-DQB1, and HLA-DRB1, have many variations, and individuals
have a certain combination of these variations, called a haplotype. Certain HLA haplotypes are
associated with a higher risk of developing type 1 diabetes, with particular combinations of HLA-
DQA1, HLA-DQB1, and HLA-DRB1 gene variations resulting in the highest risk. These haplotypes
seem to increase the risk of an inappropriate immune response to beta cells. However, these
variants are also found in the general population, and only about 5 percent of individuals with the
gene variants develop type 1 diabetes. HLA variations account for approximately 40 percent of the
genetic risk for the condition. Other HLA variations appear to be protective against the disease.
Additional contributors, such as environmental factors and variations in other genes, are also
thought to influence the development of this complex disorder.

Changes in these genes are associated with type 1 diabetes.

 CCR5
Cytogenetic Location: 3p21.31
Molecular Location on chromosome 3: base pairs 46,370,142 to 46,376,206
Diabetes mellitus, insulin-dependent, 22 (IDDM22): A multifactorial disorder of glucose
homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin
therapy.

 CTLA4
Cytogenetic Location: 2q33
Molecular Location on chromosome 2: base pairs 203,867,788 to 203,873,960
Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune
disorder associated with overactivity of the thyroid gland and hyperthyroidism, Addison
disease, breast cancer, hashimoto thyroiditis, rheumatoid arthritis, DM type 1.
Diabetes mellitus, insulin-dependent, 12 (IDDM12): A multifactorial disorder of glucose
homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin
therapy.

 FOXP3
Cytogenetic Location: Xp11.23
Molecular Location on the X chromosome: base pairs 49,250,436 to 49,269,727
At least 21 mutations in the FOXP3 gene have been found to cause immune dysregulation,
polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Most mutations change one
protein building block (amino acid) in the region of the FOXP3 protein that binds to DNA or
lead to the production of an abnormally short, nonfunctional protein. Mutations in
the FOXP3gene result in reduced numbers or a complete absence of regulatory T cells.
 Without the proper number of regulatory T cells, the body cannot control immune
responses. Normal body tissues and organs are attacked, causing the multiple autoimmune
disorders present in people with IPEX syndrome.

 HLA-DQA1
Cytogenetic Location: 6p21.3
Molecular Location on chromosome 6: base pairs 32,637,396 to 32,654,774

 HLA-DQB1
Cytogenetic Location: 6p21.3
Molecular Location on chromosome 6: base pairs 32,659,464 to 32,666,689

 HLA-DRB1
Cytogenetic Location: 6p21.3
Molecular Location on chromosome 6: base pairs 32,578,769 to 32,589,836
Combinations of variations in the HLA-DRB1/HLA above gene and other HLA genes affect the
risk of type 1 diabetes. Type 1 diabetes is characterized by high blood sugar levels resulting
from a shortage of the hormone insulin and is caused by autoimmune damage to insulin-
producing cells in the pancreas.

 HNF1A
Cytogenetic Location: 12q24.2
Molecular Location on chromosome 12: base pairs 120,977,787 to 121,002,512
Maturity-onset diabetes of the young 3 (MODY3): A form of diabetes that is characterized by
an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually
before 25 years of age), a primary defect in insulin secretion and frequent insulin-
independence at the beginning of the disease. The disease is caused by mutations affecting
the gene represented in this entry.
Diabetes mellitus, insulin-dependent, 20 (IDDM20): A multifactorial disorder of glucose
homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin
therapy.

 IL2RA
Cytogenetic Location: 10p15-p14
Molecular Location on chromosome 10: base pairs 6,010,694 to 6,062,370
Diabetes mellitus, insulin-dependent, 10 (IDDM10): A multifactorial disorder of glucose
homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin
therapy.

 IL6
Cytogenetic Location: 7p21
Molecular Location on chromosome 7: base pairs 22,725,442 to 22,732,002

 INS
Cytogenetic Location: 11p15.5
Molecular Location on chromosome 11: base pairs 2,159,779 to 2,161,209
At least 10 mutations in the INS gene have been identified in people with permanent
 neonatal diabetes mellitus. Individuals with this condition often have a low birth weight and
develop increased blood sugar (hyperglycemia) within the first 6 months of life.
INS gene mutations that cause permanent neonatal diabetes mellitus change single protein
building blocks (amino acids) in the protein sequence. These mutations are believed to
disrupt the cleavage of the proinsulin chain or the binding of the A and B chains to form
insulin, leading to impaired blood sugar control.
Mutations in the INS gene can also cause other disorders involving insulin production and
blood sugar control. Some individuals with INS gene mutations have increased levels of
proinsulin in their blood (hyperproinsulinemia) and may also have impaired blood sugar
control. INS gene mutations are also associated with a disorder called maturity-onset
diabetes of the young (MODY). This term refers to hereditary forms of relatively mild
diabetes mellitus caused by changes in single genes.

 ITPR3
Cytogenetic Location: 6p21
Molecular Location on chromosome 6: base pairs 33,621,379 to 33,696,574

 OAS1
Cytogenetic Location: 12q24.2
Molecular Location on chromosome 12: base pairs 112,906,934 to 112,932,049

 PTPN22
Cytogenetic Location: 1p13.2
Molecular Location on chromosome 1: base pairs 113,813,811 to 113,871,757
Studies have associated a variation in the PTPN22 gene with an increased risk of several
autoimmune disorders. Autoimmune disorders occur when the immune system
malfunctions and attacks the body's tissues and organs. These disorders include type 1
diabetes, rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus
erythematosus.

 SUMO4
Cytogenetic Location: 6q25
Molecular Location on chromosome 6: base pairs 149,400,359 to 149,401,046
Diabetes mellitus, insulin-dependent, 5
A widely accepted sequence of events involved in glucose-induced insulin secretion is as follows:

1. Glucose is transported into beta cells through facilitated diffusion of GLUT2 glucose transporters.

2. Intracellular glucose is metabolized to ATP.

3. Elevation in the ATP/ADP ratio induces closure of cell-surface ATP-sensitive K+ (KATP) channels,
leading to cell membrane depolarization.

4. Cell-surface voltage-dependent Ca2+ channels (VDCC) are opened, facilitating extracellular Ca2+
influx into the beta cell.

5. A rise in free cytosolic Ca2+ triggers the exocytosis of insulin.

Parasympathetic input to the pancreatic beta cells stimulates insulin secretion. Parasympathetic
stimulation of insulin secretion is part of what is known as cephalic phase stimulation of insulin
secretion. Cephalic phase refers to sensory stimuli and neural inputs that are activated when food is
first eaten ("cephalic" means pertaining to the head). There is activation of parasympathetic
preganglionic neurons whose axons travel in the vagus nerve. These activate postganglionic
neurons that stimulate insulin secretion even before there is an increase in blood glucose. This is an
example offeedforward regulation: insulin secretion is stimulated in anticipation of the rise in blood
glucose.

Sympathetic input to the pancreatic beta cells inhibits insulin secretion. Sympathetic inhibition of
insulin secretion is important during exercise. Muscle cells are utilizing glucose at much higher rates,
and so the body needs to activate fuel-producing mechanisms, just as it does during fasting. At the
same time, the body needs to prevent glucose uptake by non-muscle cells (which insulin stimulates),
so insulin secretion is inhibited.

Although one chemical component accounts for 92% of hemoglobin A, approximately 8% of

hemoglobin A is made up of minor components that are chemically slightly different. These minor
components include hemoglobin A1c, A1b, A1a1, and A1a2. Hemoglobin A1c (HbA1c) is a minor
component of hemoglobin to which glucose is bound. HbA1c also is sometimes referred to as
glycated, glycosylated hemoglobin, or glycohemoglobin.

Usual Adult Dose for Diabetes Type 2

Immediate-release:
Initial dose: 500 mg orally twice a day or 850 mg orally once a day
Dose titration: Increase in 500 mg weekly increments or 850 mg every 2 weeks as tolerated
Maintenance dose: 2000 mg daily
Maximum dose: 2550 mg daily

Comments: Take in divided doses 2 to 3 times a day with meals. Titrate slowly to minimize
gastrointestinal side effects. In general, significant responses are not observed with doses less than
1500 mg/day.

Extended-release:
Initial dose: 500 to 1000 mg orally once a day
Dose titration: Increase in 500 mg weekly increments as tolerated
Maintenance dose: 2000 mg daily
Maximum dose: 2500 mg daily

Comments: If glycemic control is not achieved with once a day administration of an extended-
release product, consider dividing doses. If higher doses are required, may switch to immediate-
release product.