1. Diabetes Mellitus Diabetes Mellitus is a group of
multifactorial, polygenic syndromes characterized by an elevation
of blood glucose caused by a relative or absolute deficiency in
insulin.
2. Insulin Insulin is the most important hormone coordinating
the use of fuels by tissues. Its metabolic effects are anabolic,
favoring, for example, synthesis of glycogen, triacylglycerols, and
protein.
3. Insulin Structure Insulin is composed of 51 amino acids
arranged in two polypeptide chains, designated A and B. Linked
together by two disulfide bridges and an intramolecular disulfide
bridge between amino acid residues of the A chain.
4. Insulin Synthesis Insulin is produced by the cells of the
islets of Langerhans, in pancreas. The islets of Langerhans make up
only about 1 2% of the total cells of the pancreas
5. Steps of Insulin Synthesis Preproinsulin synthesized in RER
cleavage of presignal proinsulin stored in secretory granules
cleavage of proinsulin Exocytosis of insulin and C-peptide in
equimolar amounts by beta cells upon stimulation
6. Regulation of Insulin Secretion Stimulation of insulin
secretion: 1. Glucose 2. Amino acids 3. Beta adrenergic stimulation
4. GI hormones: e.g. GIP (Gastric Inhibitory Peptide) CCK
(cholecystokinin)
7. Regulation of Insulin Secretion Inhibition of insulin
secretion: By far, the most important inhibitor of insulin
secretion is Epinephrine. In conditions of stress, such as
exercise, infection surgery, this action of epinephrine is
necessary to maintain adequate blood glucose levels.
8. Metabolic Effects of Insulin Increased glucose transport in
liver, skeletal muscle and adipose tissue Most cells of the body
take up glucose by an Insulin- independent mechanism. Increased
glycogen synthesis and storage Decreased glycogenolysis and
gluconeogenesis
9. Metabolic Effects of Insulin Increased triglyceride
synthesis Decreased triglyceride degradation Increased Na+
retention (kidneys) Increased protein synthesis (muscles, proteins)
Increased cellular uptake of K+ and amino acids Decreased glucagon
release
10. In the absence of Insulin there is Decreased GLUCOSE
UPTAKE, Decreased GLYOGENESIS and Increased GLYCOGENOLYSIS and
Increased GLUCONEOGENSIS This results in HYPERGLYCEMIA.
11. In the absence of Insulin there is Decreased LIPOGENESIS,
Decreased PROTEOGENESIS and Increased LIPOLYSIS, Increased
PROTEOLYSIS This results in decreased muscle mass and increased
levels of fatty acids in the body.
12. Diabetes Mellitus Diabetes Mellitus is a group of
multifactorial, polygenic syndromes characterized by an elevation
of blood glucose caused by a relative or absolute deficiency in
insulin.
13. OVERVIEW OF DIABETES MELLITUS Most cases of diabetes
mellitus can be separated into two Groups, type 1 (formerly called
insulin-dependent diabetes mellitus) type 2 (formerly called
noninsulin-dependent diabetes).
14. Type 1 Diabetes Type 2 Diabetes Age of Onset Usually during
childhood or puberty; symptoms develop rapidly Frequently after age
35; symptoms develop gradually NUTRITIONAL STATUS AT TIME OF
DISEASE ONSET Frequently undernourished Obesity usually present
PREVALENCE 10 % of diagnosed diabetics 90 % of diagnosed diabetics
Genetic Predisposition Moderate Very strong DEFECT OR DEFICIENCY
Cells are destroyed, eliminating production of insulin Insulin
resistance combined with inability of cells to produce appropriate
quantities
15. Type 1 Diabetes Type 2 Diabetes FREQUENCY OF KETOSIS Common
Rare PLASMA INSULIN Low to absent High early in disease; low in
disease of long duration ACUTE COMPLICATIONS Ketoacidosis
Hyperosmolar Coma RESPONSE TO ORAL HYPOGLYCEMIC DRUGS Unresponsive
Usually responsive TREATMENT Insulin is always necessary Diet,
exercise, oral hypoglycemic drugs; insulin may or may not be
necessary.
16. Type 1 DM Formerly called Insulin- Dependent DM
Characterized by an absolute deficiency of insulin Caused by
destruction of cells of the pancreas (most commonly an auto-immune
attack) Over a period of years, this autoimmune attack on the cells
leads to gradual depletion of the -cell population.
17. However, symptoms appear abruptly when 80 90% of the cells
have been destroyed At this point, the pancreas fails to respond
adequately to ingestion of glucose, and insulin therapy is required
to restore metabolic control and prevent life-threatening
ketoacidosis.
18. Clinical Symptoms: The onset of type 1 diabetes is
typically during childhood or puberty, and symptoms develop
suddenly: polyuria (frequent urination), polydipsia (excessive
thirst), and polyphagia (excessive hunger), often triggered by
stress or an illness. These symptoms are usually accompanied by
fatigue, weight loss, and weakness
19. Metabolic changes in type 1 diabetes The metabolic
abnormalities of type 1 diabetes mellitus result from a deficiency
of insulin which profoundly affects metabolism in three tissues:
liver, muscle, adipose tissue.
20. Hyperglycemia Elevated levels of blood glucose and ketones
are the hallmarks of untreated type 1 diabetes mellitus.
Hyperglycemia is caused by increased hepatic production of glucose,
combined with diminished peripheral utilization muscle and adipose
have the insulin-sensitive Glucose transporters.
21. Ketoacidosis Ketosis results from increased mobilization of
fatty acids from adipose tissue, combined with accelerated hepatic
fatty acid -oxidation and synthesis of 3-hydroxybutyrate and aceto
- acetate. Diabetic ketoacidosis (DKA, a type of metabolic
acidosis) occurs in 2540% of those newly diagnosed with type 1
diabetes, and may recur if the patient becomes ill (most commonly
with an infection) or does not comply with therapy.
22. Ketoacidosis DKA is treated by replacing fluid and
electrolytes, and administering short-acting insulin to gradually
correct hyperglycemia without precipitating hypoglycemia.
24. LAB Findings in DKA Hyperglycemia, Increased [H+],
Decreased [HCO3] ( metabolic acidosis), Increased blood ketone
levels, Hyperkalemia, but depleted intracellular K+. Glucosuria and
Ketonuria
25. Type 2 DM Type 2 diabetes is the most common form of the
disease. Typically, type 2 diabetes develops gradually without
obvious symptoms Often detected during routine screening tests. The
classical signs and symptoms of polyuria, polydipsia and polyphagia
may also be present.
26. Type 2 DM Patients with type 2 diabetes have a combination
of insulin resistance and dysfunctional cells The metabolic
alterations observed in type 2 diabetes are milder than those
described for type 1, This is because insulin secretion in type 2
diabetesalthough not adequatedoes restrain ketogenesis and blunts
the development of DKA.
27. Insulin Resistance Insulin resistance is the decreased
ability of target tissues, such as liver, adipose, and muscle, to
respond properly to normal (or elevated) circulating concentrations
of insulin. For example, insulin resistance is characterized by
uncontrolled hepatic glucose production, and decreased glucose
uptake by muscle and adipose tissue.
28. Dysfunctional cells In type 2 diabetes, the pancreas
initially retains - cell capacity, resulting in insulin levels that
vary from above normal to below normal. However, with time, the
cell becomes increasingly dysfunctional and fails to secrete enough
insulin to correct the prevailing hyperglycemia
29. Metabolic changes in type 2 diabetes The metabolic
abnormalities of type 2 diabetes mellitus are the result of insulin
resistance expressed primarily in liver, muscle, and adipose
tissue
30. Hyperglycemia Hyperglycemia is caused by increased hepatic
production of glucose, combined with diminished peripheral use.
Ketosis is usually minimal or absent in type 2 patients because the
presence of insulineven in the presence of insulin
resistancediminishes hepatic ketogenesis
31. Dyslipidemia VLDL and Chylomicrons are responsible for
transporting hepatic and dietary lipids to the peripheral tissues
by the help of Lipoprotein Lipase in adipose and muscle tissues.
Lipoprotein lipase is low in diabetics, the plasma chylomicron and
VLDL levels are elevated, resulting in hypertriacylglycerolemia Low
HDL levels are also associated with type 2 diabetes.
32. Hyperglycemic Hyperosmolar non- ketotic coma (HONK) HONK
usually presents in older patients with type 2 DM and carries a
higher mortality than DKA In a preexisting lack of or resistance to
insulin, a physiologic stress such as an acute illness can cause
further net reduction in circulating insulin and increase in
glucagon, epinephrine and other stress hormones. This can lead to
severe hyperglycemia.
33. HONK HONK is characterized by hyperglycemia and
hyperosmolarity, and osmotic diuresis without significant
ketoacidosis. Most patients present with severe dehydration most
notably cerebral dehydration and can lead to focal or global
neurologic deficits, such as Drowsiness and lethargy Delirium Coma
Focal or generalized seizures Visual changes or disturbances
34. Laboratory Findings in HONK These include: Plasma glucose
level of 600 mg/dL or greater Effective serum osmolality of 320
mOsm/kg or greater Profound dehydration, up to an average of 9 L
Serum pH greater than 7.30 Normal Range =285 - 295 mOsm/kg
35. DKA and HONK at a glance
36. CHRONIC EFFECTS OF DIABETES Available therapies moderate
the hyperglycemia of diabetes, but fail to completely normalize
metabolism. The long-standing elevation of blood glucose is
associated with the chronic complications of diabetes.
37. HbA1C HbA1C is a measure of Haemoglobin Glycosylation. It
occurs non-enzymatically Proportional to blood glucose
concentration As average lifespan of RBCs is 3 months, HbA1C can be
used as a measure of blood glucose conc. control over three
months.
38. HbA1C The better the control, lesser is the HbA1C It is
expressed as a percentage, not mmol/l Normal HbA1C is <
5.7%
39. Hyperglycemia Can Cause Serious Long-Term Problems
40. How hyperglycemia causes the chronic complications of
diabetes? Two main mechanisms: 1. In cells where entry of glucose
is not dependent on insulin, elevated blood glucose leads to
increased intracellular glucose and its metabolites. For example,
increased intracellular sorbitol contributes to the formation of
cataracts. 2. Hyperglycemia promotes the non-enzymic condensation
of glucose with cellular proteins and proteins of the basement
membrane in a manner analogus to that of formation of HbA1C
41. Vascular Complications of Type 2 Diabetes Vascular
complications are the major cause of morbidity and mortality in
Type 2 diabetes Microvascular nephropathy retinopathy neuropathy
Macrovascular cardiovascular disease peripheral vascular disease
cerebrovascular disease
42. Microvascular Complications-- Retinopathy Diabetic
retinopathy-leading cause of blindness in those 20-75 and above.
Blood vessel changesworst case scenario, proliferative retinopathy.
Also an increased incidence of cataracts and glaucoma in diabetics.
Need regular eye exams Control BP, control BS and cessation of
smoking can help
43. Microvascular complications- Nephropathy Accounts for 50%
of patients with ESRD Earliest clinical sign of nephropathy is
microalbuminuria. Warrants frequent periodic monitoring for
microalbuminuriaif exceeds 30mg/24h on two consecutive random
urines, need 24h urine sample
44. Nephropathy Diabetes causes hypertension in renal vessels
which cause leaking glomeruli, deposits in narrow vessels, scarring
and vascular damage
45. Microvascular disease-Nephropathy Medical management:
control BP (ACE or ARB) Tx of UTIs Avoid nephrotoxic agents,
contrast dyes Low sodium diet Low protein diet Tight glycemic
control
46. Nephropathy May require dialysis May have co-existent
retinopathy Kidney transplantationsuccess now 75-80% for 5 years
Pancreas transplantation may also be performed at time of kidney
transplantation
47. Neuropathies Group of diseases that affect all types of
nerves. Includes peripheral, autonomic and spinal nerves.
Prevalence increases with duration of the disease and degree of
glycemic control
48. Capillary basement membrane thickening and capillary
closure may be present. May be demyelination of the nerves, nerve
conduction is disrupted. Two most common types of neuropathies are:
sensorimotor polyneuropathy and autonomic neuropathy.
Neuropathies
50. Macrovascular Complications Macrovascular complications are
due to atherosclerosis, if it is in Coronary blood vessels: angina
and MI Cerebral blood vessels: Stroke Peripheral blood vessels:
gangrene.
51. Criteria for the Diagnosis of Diabetes A1C 6.5% OR Fasting
plasma glucose (FPG) 126 mg/dL (7.0 mmol/L) OR 2-h plasma glucose
200 mg/dL (11.1 mmol/L) during an OGTT OR A random plasma glucose
200 mg/dL (11.1 mmol/L) ADA. I. Classification and Diagnosis.
Diabetes Care 2014;37(suppl 1):S15; Table 2
52. EXTRA SLIDES
53. Websites http://www.cdc.gov/diabetes/consumer/index.ht m
http://www.emedicinehealth.com/diabetes/articl
e_em.htm#Diabetes%20Overview http://www.diabetes.org/
54. Criteria for the Diagnosis of Diabetes A1C 6.5% The test
should be performed in a laboratory using a method that is NGSP
certified and standardized to the DCCT assay* Diabetes Control and
Complications Trial (DCCT) National Glycohemoglobin Standardization
Program(NGSP) *In the absence of unequivocal hyperglycemia, result
should be confirmed by repeat testing. ADA. I. Classification and
Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
55. Criteria for the Diagnosis of Diabetes Fasting plasma
glucose (FPG) 126 mg/dL (7.0 mmol/L) Fasting is defined as no
caloric intake for at least 8 h* *In the absence of unequivocal
hyperglycemia, result should be confirmed by repeat testing. ADA.
I. Classification and Diagnosis. Diabetes Care 2014;37(suppl
1):S15; Table 2
56. Criteria for the Diagnosis of Diabetes 2-h plasma glucose
200 mg/dL (11.1 mmol/L) during an OGTT The test should be performed
as described by the WHO, using a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in water* *In the
absence of unequivocal hyperglycemia, result should be confirmed by
repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care
2014;37(suppl 1):S15; Table 2
57. Criteria for the Diagnosis of Diabetes In a patient with
classic symptoms of hyperglycemia or hyperglycemic crisis, a random
plasma glucose 200 mg/dL (11.1 mmol/L) ADA. I. Classification and
Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
58. 70 Diagnostic Criteria Any one test should be confirmed
with a second test, most often fasting plasma glucose (FPG). This
criteria for diagnosis should be confirmed by repeating the test on
a different day.