Dr. Sarbast Fakhradin
MBChB, MSc Diabetes Care & Management
Diabetes mellitus
It is a clinical syndrome characterised by hyperglycaemia caused by absolute
or relative deficiency of insulin and this affects the metabolism of
carbohydrate, protein and fat, and can cause significant disturbance of water
and electrolyte homeostasis.
Complications:
1. Acute metabolic decompensation.
2. Chronic complications affecting the eye, the kidney and the nervous
system.
Epidemiology
Worldwide prevalence is 366 million patients & its rising, mainly type 2.
UK is around 4%, but is much higher in the Middle and Far East (11-30%).
• 350 A.D. : "water tasters" diagnosed diabetes by tasting the urine.
• 1675 : the word "mellitus," meaning honey, was added to the name "diabetes,"
meaning siphon.
• 1800s: chemical tests to detect the presence of sugar in the urine.
• The first diabetes treatment involved prescribed exercise (horseback riding)
• 1700s and 1800s: dietary changes could help manage diabetes
• In 1889 researchers in France, showed that the removal of a dog's
pancreas could induce diabetes.
• In 1900s a German scientist, found that injecting pancreatic extract
into patients could help control diabetes.
• In 1920 Frederick Banting, a physician from Canada, first had the idea
to use insulin to treat diabetes in lab, 1922 in human, then awarded the Nobel prize.
Classification of DM:
Primary: Type 1 (A or B) & Type 2
Other specific types:
•Genetic defects of β-cell function/insulin action
• Pancreatic disease (pancreatitis, pancreatectomy, neoplastic disease, cystic
fibrosis, haemochromatosis)
• Excess endogenous production of hormonal antagonists to insulin (growth
hormone; glucocorticoids; glucagon; catecholamines; thyroid hormones)
• Drug-induced (corticosteroids, thiazide, phenytoin)
• Viral infections (congenital rubella, mumps, Coxsackie virus B)
• Associated with genetic syndromes (Down's syndrome; Klinefelter's
syndrome; Turner's syndrome; DIDMOAD (Wolfram's syndrome)-diabetes
insipidus, diabetes mellitus, optic atrophy, nerve deafness; Friedreich's
ataxia; myotonic dystrophy)
Gestational diabetes
LADA & MODY
Metabolic actions of insulin
Increase (anabolic effects)
Decrease (anticatabolic effects)
Carbohydrate metabolism
Carbohydrate metabolism
Glucose transport (muscle, adipose tissue)
Gluconeogenesis
Glycogenolysis
Glucose phosphorylation
Glycogenesis
Glycolysis
Pyruvate dehydrogenase activity
Pentose phosphate shunt
Lipid metabolism
Lipid metabolism
Triglyceride synthesis
Lipolysis
Fatty acid synthesis (liver)
Lipoprotein lipase (muscle)
Lipoprotein lipase activity (adipose tissue)
Ketogenesis
Fatty acid oxidation (liver)
Protein metabolism
Protein metabolism
Amino acid transport
Protein degradation
Protein synthesis
Pancreatic structure and endocrine function:
Cont.
Aetiology & pathogenesis of diabetes
Type 1 DM:
Pathology:
•T cell-mediated autoimmune destruction of the β cells in pancreas.
• Insulitis: recurrent infiltration of islets with mononuclear cells
Patchiness of the lesion.
• β-cell specificity of the destructive process, with the glucagon and other
hormone-secreting cells in the islet remaining intact.
• Islet cell antibodies (glutamic acid decarboxylase (GAD)) can be
detected.
• Associated with other autoimmune disorders , including thyroid
disease, coeliac disease, Addison's disease , pernicious anaemia, & vitiligo.
Honeymoon period: its occur after initial clinical
presentation of type 1 DM during which time glycemic
control is achieved with modest doses of insulin or rarely
insulin isnt needed
Genetic Predisposition:
It is account for about one-third of the susceptibility to type
1 diabetes.
Short arm of chromosome 6 (Polygenetic inheritance).
HLA haplotypes DR3 and/or DR4.
Concordance rate between monozygotic twins is less than
40%.
Environmental Factors:
1. Infection:
A. Hygiene hypothesis : reduced exposure to microorganisms in early childhoods
limits maturation of immune system and increases susceptibility to autoimmune
disease.
B. viral infection: mumps, Coxsackie B4, retroviruses, rubella (in utero),
cytomegalovirus and Epstein-Barr virus.
2. Stress
3. Dietary factors: Various nitrosamines (found in smoked and cured meats),
coffee, & cow’s milk have been proposed as potentially diabetogenic .
4. Immunological factors: Hyperglycaemia accompanied by the classical
symptoms of diabetes occurs only when 70-90% of β cells have been destroyed.
Type 2 DM:
Pathology:
Insulin resistance & β-cell failure
•It is a complex condition there is a combination of insulin resistance in liver
and muscle together with impaired pancreatic β-cell function leading to
'relative' insulin deficiency.
•Intra-abdominal 'central' adipose tissue is metabolically active, and releases
large quantities of FFAs, cytokines, & adipokines which act on specific
receptors to influence sensitivity to insulin.
•Sedentary lifestyle leads to obesity & more insulin-resistant.
•There might be fatty infiltration of the liver (non-alcoholic fatty liver disease
(NAFLD) or non-alcoholic steatohepatitis (NASH).
•At the time of diagnosis, around 50% of β-cell function has been lost.
•Some pathological changes are typical such as is deposition of amyloid.
Heavy deposition of islets with amyloid is rare without diabetes, but small
quantities are very common in elderly non diabetic patients.
•Hyperglycemia & elevated FFA are toxic to β-cell
•However, while β-cell numbers are reduced, α-cell mass is unchanged and
glucagon secretion is increased, which may contribute to the
hyperglycaemia.
Genetic predisposition:
Its not HLA linked & autoimmunity or viral infections are less significant
Concordance rates for type 2 diabetes might reach 100%
A mutation of the glucokinase gene is associated with some cases of the
uncommon syndrome of maturity onset diabetes in the young (MODY),
constitute less than 5% of all cases of type 2 diabetes
Environmental factors:
Diet & obesity:
Type 2 diabetes is associated with overeating, especially when combined
with obesity and underactivity.
The risk of developing type 2 diabetes increases tenfold in people with a
body mass index (BMI) > 30 kg/m2. Obesity probably acts as a diabetogenic
factor (through increasing resistance to the action of insulin) only in those
who are genetically predisposed both to insulin resistance and to β-cell
failure. Sweet foods rich in refined carbohydrate consumed frequently may
increase the demand for insulin secretion, while high-fat foods may
increase FFAs and exacerbate insulin resistance.
Environmental factors: Cont.
Age: Type 2 diabetes is more common in the middle-aged and elderly.
Pregnancy:
During normal pregnancy, insulin sensitivity is reduced through the action
of placental hormones and this affects glucose tolerance. The insulinsecreting cells of the pancreatic islets may be unable to meet this increased
demand in women genetically predisposed to develop diabetes. The term
'gestational diabetes' refers to hyperglycaemia occurring for the first time
during pregnancy. Repeated pregnancy increases the likelihood of
developing irreversible diabetes, particularly in obese women; 80% of
women with gestational diabetes ultimately develop permanent diabetes.
Changes in Pancreatic Islet Morphology
Represent Underlying Functional Defects
Normal
T2DM
β-Cells
(insulin)
α-Cells
(glucagon)
Amyloid
plaque
• Disorganised and misshapen
• Marked reduction in β-cell number
• Amyloid plaques
Therefore the main etiologies of type 2 DM are:
1. Relative insulin deficiency
2. Increase hepatic production of glucose.
3. Insulin resistance which usually accompanies obesity this includes:
•Abnormal insulin molecule
•An excessive amount of circulating antagonists.
•Target tissue defect(common cause)
Natural History of type 2 DM:
1.
2-6 fold increased risk of heart disease, stroke and
peripheral vascular disease.
2.
60% will die of cardiovascular problems.
3. 60-80% are hypertensive.
4. 60-70% have some kind of peripheral neuropathy.
5. Up to 50% of all amputations occur in diabetic
patients.
6. Is the single commonest (13.8%) cause of blindness
in those of working age.
7. Nephropathy occurs in about 25%
8. Accounts for 8-10% of healthcare budget.
Xanthelasma
Arcus Senilis
Diabetic Retinopathy
Acanthosis nigricans
Thank you
Questions?