Diabetes Basics

1. DIABETES
BASICS
Dr. K. Jeganathan
Consultant Physician.

2. WHAT GOES WRONG IN
DIABETES ?
 Metabolic disorder characterized by chronic hyperglycaemia with
disturbance of carbohydrate protein and fat metabolism.
 Disease in which the body doesn’t produce or properly use insulin,
leading to hyperglycemia.

3. DM- PREVALENCE IN SL
 1990 study on rural community-2.5%
 2005 study- men 14.2%
women 13.5%
Latest cross sectional study by Diabetic research unit of the University of Colombo
Urban population- 16.4%
Rural population- 8.7%
T1DM- 4.4%
Men-9.8%
Women- 10.9%
Previously undiagnosed- 36%

4. HOW DO YOU DIAGNOSE DM
 Diagnosis of DM can be established in 4 ways,
 Symptoms of DM plus casual plasma glucose level >200mg/dL
(casual defined as any time of day)
 FPG >126 mg/dL (fasting at least 8 hrs)
 Oral Glucose Tolerance Test (OGTT)
 HbA1C > 6.5

5. OGTT
 75 grams of glucose dissolved in water, which patient drinks (consumed
over a period of 5 min)
 2 hours later, blood glucose level of 200 mg/dL or greater is a positive
test
 Done in the morning after 8 hrs of over night fasting following atleast 3
days of unrestricted diet

6. POINTS TO REMEMBER
 If asymptomatic - Need more than one value
 Capillary blood glucose - 18mg higher than plasma
 FPG may be normal due to suppression of hepatic glucose output
but PPBS may be high

7. CLASSIFICATION AND
DIAGNOSIS
1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute
insulin deficiency)
2. Type 2 diabetes (due to a progressive insulin secretory defect on the
background of insulin resistance)
3. Other specific types of diabetes due to other causes, e.g., genetic defects
in b-cell function, genetic defects in insulin action, diseases of the
exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced
(such as in the treatment of HIV/AIDS or after organ transplantation)
4. Gestational diabetes mellitus (GDM) (diabetes diagnosed during
pregnancy that is not clearly overt diabetes

8. PHYSIOLOGY OF INSULIN
SECRETION
 Insulin secretion in 24 hrs is 30-40 units
 50% is secreted in basal condition and the remainder in response meal

9. 0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Hours)
Meal Meal Meal
Basal Insulin Needs
Bolus insulin needs
Seruminsulin(mU/L)

10. PHYSIOLOGY OF INSULIN
SECRETION
 Ultrdian pulses occur every 90-120 min
 Exaggerated after each meal
 Besides this rapid oscillation of insulin level occurs every 8-16min
 Oscillatory insulin inhibit hepatic glucose output

11. Insulin affects many organs:
• It stimulates skeletal muscle
fibers.
• It stimulates liver cells.
• It acts on fat cells
• It inhibits production of
certain enzyme.
In each case, insulin triggers
these effects by binding to
the insulin receptor.
protein
synthesis
amino acids
uptake
enzyme
production
glycogen
breaking
glucose
uptake
glycogen
synthesis
fat
synthesis

12. •Insulin decrease blood glucose by facilitating glucose uptake in muscles and
adipose tissue
•Insulin increase glycogen synthesis (glycogenesis)in liver&
decrease glycogen breakdown (glycogenolysis)
•Insulin is an anabolic hormone & promotes the rate of protein
synthesis by:
- stimulating amino acid uptake in the liver and skeletal muscle
- inhibiting protein breakdown
- inhibiting conversion of amino acids to glucose
(gluconeogenesis)

13. • Insulin inhibit the breakdown of stored lipid (by hormone-sensitive
lipase) and decrease free fatty acid levels in circulation
• stimulate fatty acid synthesis from glucose in the liver
• promoting glycerol synthesis in lipid cells
• Insulin promotes storage of fat and decreases its utilization by:
• promoting carbohydrate utilization so that fat is spared

14. HOW THE FPG IS
CONTROLLED
Hepatic glucose production is the primary factor determining
FPG

15. HOW PPBS IS REGULATED
 Clearance of ingested glucose
 Peripheral clearance of glucose
 Inhibition of hepatic glucose production

17. PHASES OF INSULIN
RELEASE
• First phase
– Release starts as soon as food comes to the stomach
– Preformed stored insulin is released
– 10-fold increase in levels within 3-5 minutes
– Speeds up the use of glucose
– Within 5-10 minutes, insulin secretion decreases by half

18. PHASES OF INSULIN
RELEASE
• Second phase
– Rising glucose levels send signals to the beta cell nucleus  DNA
produces mRNA  mRNA produces more insulin
– Causes a less acute rise in insulin levels
– Reaches a plateau in 2-3 hours

19. NATURAL HISTORY OF TYPE 2
DIABETES

20. NATURAL HISTORY OF TYPE 2
DIABETES

21. NATURAL HISTORY OF TYPE 2
DIABETES

22. NATURAL HISTORY OF TYPE 2
DIABETES

23. DID YOU KNOW HOW MUCH PANCREAS IS LEFT
WHEN YOUR FPG IS 110MG
 Almost 50% beta cell function is lost
 FPG >140 mg- 75% is lost
 FPG > 180 mg-acute insulin response is totally lost

24. BETA CELL MASS
 May vary by 3-5 million in adults
 Beta cell mass expands in the first decade of life and is
mostly established by late adolescence
 Adult beta cells live for many years and have little
proliferative or regenerative capacity
 Young beta cells have considerable proliferative capacity

25. WHAT WOULD BE THE PHYSIOLOGICAL
THERAPEUTIC APPROACH
 Drugs to stimulate insulin secretion
Surviving 25% of beta cells has to compensate for the lost 75%
• Cause beta cell apoptosis
• Co secretion of amylin lead to amyloid deposits between islet cells
 Restore the defective early phase insulin secretion by insulin
 Drugs to stimulate regeneration of beta cells [GLP analogues]

26. Consider
insulin when
FPG is more
than 140mg
How early to
use insulin

27. MANAGEMENT OF DM
• The major components of the treatment of diabetes are:
• Diet and ExerciseA
• Oral hypoglycaemic
therapyB
• Insulin TherapyC

28. EXERCISE
 Increase the supply of fuel and oxygen to working muscles while
maintaining the supply to brain and other vital organs
 In the resting phase muscles derive 90% of energy by oxidation of
free fatty acids
 Increased demand is met by breakdown of muscles and liver
glycogen and from neoglucogenesis

29.  Exercise
• Short burst
• Muscle glycogen breaks down first
 Moderate intensity exercise
• Fall in insulin level
• Rise in glucagon -
 High intensity exercise
• Exercise prolonged beyond 30 minutes
• Free fatty acids generated by adipocyte lipolysis account for major
portion muscle fuel
• Exercise induced rise in glucagon stimulate hepatic fat oxidation
Hepatic Glycogenolysis & Hepatic
Neoglucogenesis

30. American College of Sports Medicine recommendation
• 3-5 exercise session per week
• Each session should be between 20-30 min
• Maximal heart rate – 70% of age adjusted target heart rate(220
minus age)
Continued exercise program
• Improve insulin sensitivity
• Reduce TG level
• Reduce blood pressure

31. RECOMMEND EXERCISES
 Brisk walking
 Aerobic dancing
 Slow running
 Swimming
 Cycling
 Skipping
 Physical activity and moderate weight loss have been shown
lower T2DM risk by 58% in high risk population

32. ORAL ANTI-DIABETIC AGENTS
 There are currently five classes of oral anti-diabetic agents:
• Biguanides
• Insulin Secretagogues – Sulphonylureas
Non-sulphonylureas
Glinides
• α-glucosidase inhibitors
• Thiazolidinediones (TZDs)
• Incretin

33. BIGUANIDES (Insulin Sensitizers)
Work by improving insulin target cell response
 It increases glucose uptake and utilization by target tissues
 Metformin reduces plasma glucose levels by inhibiting hepatic
gluconeogenesis.
 It also slows the intestinal absorption of sugars. It also reduces
hyperlipidemia (↓LDL & VLDL cholesterol and ↑ HDL).
 It is the only oral hypoglycemic shown to reduce
cardiovascular mortality.

34. These agents promote the release of insulin from β-cells (secretogogues);
 Mechanism:
 These agents require functioning β-cells, they stimulate release by
blocking ATP-sensitive K+ channels resulting in depolarization
with Ca+2 influx which promotes insulin secretion.
 They also reduce glucagon secretion and increase the binding of
insulin to target tissues.
SULFONYLUREAS

35. SULFONYLUREAS
 First generation sulfonylureas
• Tolbutamide
• Chlorpropamide
 Second generation
• Glibenclamide
• Glipizide
• Gliclazide
 Third generation
• Glimeperide

36. MEGLITINIDE ANALOGUES
 Mechanism:
 These agents bind to ATP sensitive K+channels like sulfonylureas
acting in a similar fashion to promote insulin secretion however
their onset and duration of action are much shorter.
 They are particularly effective at mimicking the prandial & post-
prandial release of insulin.

37.  These agents are insulin sensitizers, they do not promote insulin
secretion from β-cells but insulin is necessary for them to be effective
Mechanism of Action:
 These agents act through the activation of peroxisome proliferator-
activated receptor-γ (PPAR-γ).
 Agents binding to PPAR-γ result in increased insulin sensitivity is
adipocytes, hepatocytes and skeletal muscle.
 Accumulation of subcutaneous fat occurs with these agents.
THIAZOLIDINEDIONES
(GLITAZONES)

38. Α-GLUCOSIDASE INHIBITORS
 Acarbose and miglitol are two agents of this class used for type 2
diabetes.
 Mechanism of action:
• These agents are oligosaccharide derivatives taken at the beginning of
a meal.
• They delay carbohydrate digestion by competitively inhibiting α-
glucosidase, a membrane bound enzyme of the intestinal brush
border.
 Pharmacokinetics: Acarbose is poorly absorbed remaining in the
intestinal lumen.
 Exert their effect in the intestinal lumen.

39. INCRETIN THERAPY
 Incretins are naturally occurring hormones that the gut releases
throughout the day; the level of active incretins increases
significantly when food is ingested.
 Endogenous incretins
GLP-1 (glucagon-like peptide 1)
GIP (glucose-dependent insulinotropic peptide)

40.  These incretins are released from the gut in response to
ingestion of food
• Stimulate glucose-dependent insulin release from pancreatic beta
cells (GLP-1 and GIP):
• Decrease glucagon production from pancreatic alpha cells (GLP-1)
when glucose levels are elevated.
 The combination of increased insulin production and
decreased glucagon secretion reduces hepatic glucose
production when plasma glucose is elevated.
INCRETIN THERAPY

41.  The Incretin Effect Is Diminished in Type 2 Diabetes
• Levels of GLP-1 are decreased.
• The insulinotropic response to GIP is diminished.
 Defective GLP-1 release and diminished response to GIP may be
important factors in glycemic dysregulation in type 2 diabetes.
T2DM and INCRETIN

42. INCRETIN BASED THERAPY
The physiologic activity of incretins is limited by the enzyme dipeptidyl
peptidase-4 (DPP-4), which rapidly degrades active incretins after their
release
1. GLP1 receptor agonist
• Short acting (exenatid , liraglutide(victoza)
• Long acting
2. Dipeptidyl peptidase 4(DPP-4)inhibitors
• Sitagliptin
• Saxagliptin
• Vildalagliptin

43. INSULIN
 Discovered by Banting and Best
 Consist of A & B chains linked by
2 disulfide bonds (plus additional
disulfide in A)~~~~
 A = 21amino acids B = 30 amino acids

44. Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin by removing the one amino
acid that distinguishes them and replacing it with the human version.
INSULIN DRUG EVOLUTION

45.  Stage 3 Insert the human insulin
gene into E. coli and culture the
recombinant E.coli to produce
insulin (trade name = Humulin®).
Yeast is also used to produce
insulin (trade name =Novolin®)
(1987).
 Recombinant DNA technology has also made it possible to manufacture
slightly-modified forms of human insulin that work faster (Humalog®
and NovoLog®) or slower (Lantus®) than regular human insulin.

46. INSULIN THERAPY
Short-term use:
 Acute illness, surgery, stress and emergencies
 Pregnancy
 Breast-feeding
 Insulin may be used as initial therapy in type 2 diabetes in marked
hyperglycaemia
 Severe metabolic decompensation (diabetic ketoacidosis, hyperosmolar
nonketotic coma, lactic acidosis, severe hypertriglyceridaemia)
Long-term use:
 If targets have not been reached with combination therapy

47. TYPES OF INSULIN
 Bolus insulin
1. Rapid acting (Actrapid, Humalin R)
2. Short acting (Lispro-humalog , Aspart-novorapid)
3. Ultra rapid acting
 Basal insulin
1. Intermediate acting ( isophane. Humalin N, Insultard)
2. Long acting (Glargine-lantus, Detemir-levimir)
 Premixed insulin

48. INSULIN

49. BOLOUS INSULINS (MEALTIME
OR PRANDIAL)
Insulin Type Onset of
action
Peak of
action
Duration
of action
Human
regular
Short acting 30-60
minutes
2-4 hours 8-10 hours
Insulin
analogs
(Lispro,Aspart
,Glulisin)
Rapid
acting
5-15 minutes 1-2 hours 4-5 hours
The time course of action of any insulin may vary in different individuals, or at
different times in the same individual. Because of this variation, time periods
indicated here should be considered general guidelines only.

51. Blood Sugar
Time hrs
0 1 2
30 min
Soluble insulin
Human insulin

54. PHYSIOLOGIC INSULIN SECRETION:
BASAL/BOLUS CONCEPT
Nutritional (Prandial) Insulin
Insulin
(µU/mL)
Glucose
(mg/dL)
Breakfast Lunch Supper
Basal Glucose
150
100
50
0
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
A.M. P.M.
Time of Day
Basal Insulin
50
25
0
Nutritional Glucose
Suppresses Glucose
Production Between
Meals & Overnight

55. THE BASAL/BOLUS INSULIN CONCEPT
 Basal Insulin
1. Suppress glucose production between meals and overnight
2. Nearly constant levels
3. 50% of daily needs
 Bolus insulin(Mealtime and prandial)
1. Limits hyperglycaemia after meals
2. Immediate rise and sharp peak at 1 hour
3. 10% to 20% of daily insulin requirement at each meal

56. THE GOAL OF INSULIN THERAPY
Administration of insulins are arranged to mimic the normal basal, prandial and
post-prandial secretion of insulin. Short acting forms are usually combined with
longer acting preparations to achieve this effect.

57. WHAT IS THE RATIONAL E FOR BE D TIME
INSUL IN AND DAY TIME SUL FONY LURE A
 Bed time insulin lower FBG by suppressing the hepatic glucose output
 Day time sulfonylurea augment the insulin release and also promotes
the glucose uptake in peripheral tissues and control PPBS

58. IS THE RE A PL ACE FOR IN TE N SIVE IN SUL IN
THE RAPY IN N E W LY D IAG N OSE D T2D M ?
 Transient intensive insulin treatment
 Re-establish responsiveness for several years

59. PREDIABETES & DIABETES
diabetesprediabetesnormoglycemic
100mg/dl 125 mg/dl
140 mg/dl 199 mg/dl
Fasting glucose
2hr Plasma glucose
Prediabetes is a condition in which the blood sugar level is higher than normal,
but not high enough to be classified as diabetes. HbA1c 5.7- 6.4
Risk of developing DM in 5 years is 25%-50%

60. TESTING FOR DIABETES IN
ASYMPTOMATIC PATIENTS
 Testing to detect type 2 diabetes and pre diabetes in asymptomatic people
should be considered in adults of any age who are
• Overweight or obese (BMI -25 kg/m2)
• DM in a first degree relative
• Sedentary lifestyle
• History of delivering a baby weighing>4.1kg

61. TESTING FOR DIABETES IN
ASYMPTOMATIC PATIENTS
 Hypertension
 Dyslipidemia (HDL<35,TG>250)
 Polycystic ovary syndrome
 History of vascular disease
 In those without these risk factors, testing should begin at age 45 years
If tests are normal, repeat testing at least at 3-year intervals is reasonable

62. TAKE HOME MESSAGE
 Normal FBS does not exclude diabetes
 Diet and exercise are important as OHD
 Metformin should be the first drug
 Pancreas exhaustion rapidly occures at rate of 2-4 % year, and in 10 years
majority of patient needs insulin
 Insulin should be introduced early ,do not wait until all OHDs fail
 Consider drugs which stimulate beta cell mass proliferation(GLP analog)

63. Thank You

64. GESTATIONAL DIABETES
 Screen for undiagnosed type 2 diabetes at the first prenatal visit
 In those with risk factors, using standard diagnostic criteria
 Screen for GDM at 24–28 weeks of gestation in pregnant women not
previously known to have diabetes.
 Screen women with GDM for persistent diabetes at 6–12 weeks postpartum,
using the OGTT and non pregnancy diagnostic criteria
 Women with a history of GDM should have lifelong screening for the
development of diabetes or pre diabetes at least every 3 years
 Women with a history of GDM found to have pre diabetes should receive
lifestyle interventions

65. GLYCEMIC GOALS IN PREGNANT
WOMEN
 Recommendations from the Fifth International Workshop-
Conference on Gestational Diabetes Mellitus
 Capillary glucose concentrations:
• Preprandial: #95 mg/dL (5.3 mmol/L)
• 1-h postmeal: #140 mg/dL (7.8 mmol/L)
• 2-h postmeal: #120 mg/dL (6.7 mmol/L)