1. Diabetes:
Step care approach to management
Dr. B. K. Iyer

2. Diabetes:
classification, diagnosis, management
 Classification
 Diagnosis
 Treatment

3. Diabetes classification – a relook
 Classification
 Diagnosis
 Treatment

4. Classification
 Type 1 diabetes
 Type 2 diabetes
 Other
1. Genetic defects of beta cell function
2. Genetic defects in insulin action
3. Diseases of the exocrine pancreas
4. Endocrinopathies
5. Drug/ chemical - induced
6. Infections
7. Uncommon forms of immune-mediated diabetes
8. Genetic syndromes sometimes associated with diabetes
 Gestational diabetes mellitus

5. Type 1 diabetes
 Type 1 diabetes is characterized by β-cell
destruction, usually leading to absolute
insulin deficiency.
A. Immune-mediated
B. Idiopathic
* Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

6. * Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.
Type 1 diabetes - progression

7. Type 1 diabetes – immune mediated
 Absolute insulin deficiency
 Usually due to autoimmune destruction of the
pancreatic beta cells
 Islet-cell antibodies (ICA) or
 other autoantibodies
 antibodies to glutamic acid decarboxylase [anti-GAD] and
 anti-insulin)

8. Type 2 diabetes
 Hyperglycemia
 Insulin resistance
 Relative insulin secretion/ response impairment

9. Type 2 diabetes - causes
Hyperglycemia in type 2 diabetes can be due to 2 causes:
Pancreas
Insulin Resistance
Liver
Hyperglycemia
Islet Cell Degranulation;
Reduced Insulin Content
Muscle Adipose Tissue
Decreased Glucose
Transport & Activity
(expression)
of GLUT4
Increased
Lipolysis
↑Glucose
Production
↓Glucose
Uptake
Reduced
Plasma Insulin
Increased Glucose Output
Cell Dysfunction
Elevated
Plasma FFA

10. Type 2 diabetes & declining β–cell function :
UKPDS
Dashed line = extrapolation from UKPDS data
Lebovitz HE, Diabetes reviews, 1999;7: 139-153

11.  Maturity–onset diabetes of the young (MODY)
 6 subtypes:
 MODY 1 - Mutation in HNF-4-alpha (transcription factor),
chromosome 20
 MODY 2 - Mutation in glucokinase gene, chromosome 7
 MODY 3 - Mutation in HNF-1-alpha (transcription factor),
chromosome 12 (most common form)
 MODY 4 - Mutation in insulin promoter factor-1 (IPF-1),
chromosome 13
 MODY 5 - Mutation in HNF-1-beta, chromosome 17
 MODY 6 - Mutation in Neurogenic Differentiation Factor-
1 (NEUROD1) , chromosome 2
Other specific types of diabetes:
Genetic defects in β-cell function

12. Other specific types of diabetes:
Genetic defects in insulin action
 Type A insulin resistance
 Leprechaunism
 Rabson- Mendenhall syndrome
 Lipoatrophic diabetes
 Others

13. *A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman
PG. Diabetes Care. 2006 May;29(5):970-5
Latent Autoimmune Diabetes in Adults
(LADA)
 Adult-onset diabetes with circulating islet
antibodies but not requiring insulin therapy
initially
 Adults who should be considered for antibody
testing*:
 age of onset <50 years
 acute symptoms
 BMI <25 kg/m2
 personal or family history of autoimmune disease

14. Gestational DM
 Any degree of impaired glucose tolerance with
onset or first recognition during pregnancy
 Gestational diabetes (GDM) occurs when
pancreatic function is not sufficient to overcome
the insulin resistance created by changes in
diabetogenic hormones during pregnancy.
 Most have impaired glucose tolerance that begins
in pregnancy
 Some have previous undiagnosed type 2 diabetes.
 10% have circulating islet cell antibodies

15. Diabetes diagnosis
 Classification
 Diagnosis
 Treatment

16. Diagnosis
 Diabetes mellitus
 Impaired fasting glucose (IFG)
 Impaired glucose tolerance (IGT)
 Gestational diabetes mellitus (GDM)

17. Diagnosis: Diabetes mellitus
 Symptoms of diabetes (polydipsia, polyuria,
unexplained weight loss) PLUS a random plasma
glucose >200 mg/dL (11.1 mmol/L)
or
 Fasting plasma glucose > 126 mg/dL (7.0 mmol /
L) after overnight (at least 8 hours) fast
or
 Two-hour plasma glucose> 200mg/dL (11.1
mmol / L) during a standard 75g oral glucose
tolerance test
Any of these criteria establishes the diagnosis but needs to be confirmed on a later day

18. Diagnosis: Impaired fasting glucose (IFG)
 Fasting plasma glucose (FPG) < 100 mg/dl
(5.6 mmol/l) = normal
 FPG 100-125 mg/dl (5.6-6.9 mmol/l) =
impaired fasting glucose (IFG)

19.  Oral glucose tolerance test (OGTT) – glucose
load containing the equivalent of 75 g anhydrous
glucose dissolved in water
 2-h post-load glucose < 140 mg/dl (7.8 mmol/l) =
normal
 2-h post-load glucose 140 - 199 mg/dl (7.8 – 11.1
mmol/l) = impaired glucose tolerance (IGT)
Diagnosis: Impaired glucose tolerance (IGT)

20. Diagnosis:
Gestational Diabetes Mellitus (GDM)
1. Unequivocal hyperglycemia
(confirmed on a subsequent day)
Fasting plasma glucose > 126 mg/dL
(7.0 mmol/L)
Random plasma glucose >200 mg/dL
(11.1 mmol/L)
OR
2. Diagnostic OGTT
100-g glucose load
7.81403-h
8.61552-h
10.01801-h
5.395Fasting
mmol/lmg/dl

21. Diabetes:
management
 Classification
 Diagnosis
 Treatment – drugs in brief

22. Treatment
Treatment
Lifestyle intervention Hypoglycaemic drugs
•Weight loss
•Increased exercise
Oral
hypoglycemic
drugs
Insulin &
insulin
analogs
Others
[incretins,
pramlintide]
1.Biguanides
2.Sulfonylureas
3.Meglitinide analogs
4.Thiazolidinediones
5.α-Glucosidase Inhibitors
6.DPP-4 Inhibitors

23. Treatment:
Oral Antihyperglycemic Drugs

24. Oral antihyperglycemic drugs:
Biguanides
 Metformin & Extended-
release metformin now
available
 decrease hepatic glucose
output
 lower fasting glycemia
 reduce HbA1c by 1.5%
 adverse effects: lactic
acidosis, gastro-
intestinal disturbances
AMPK - adenosine
monophosphate-activated protein
kinase, ACC - acteyl-CoA
carboxylase, SREPB-1 - sterol-
regulatory-element-binding-
protein-1
Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal
172(2),2005 pp213-226

25. Oral antihyperglycemic drugs:
Metformin titration
1. Begin with low-dose metformin (500 mg) taken once or twice
per day with meals (breakfast and/or dinner).
2. After 5–7 days, if GI side effects have not occurred, advance
dose to 850 or 1,000 mg before breakfast and dinner.
3. If GI side effects appear as doses advanced, can decrease to
previous lower dose and try to advance dose at a later time.
4. The maximum effective dose is usually 850 mg twice per day,
with modestly greater effectiveness with doses up to 3 g per
day. GI side effects may limit the dose that can be used.
5. Based on cost considerations, generic metformin is the first
choice of therapy. A longer-acting formulation is available in
some countries and can be given once per day.

26. Oral antihyperglycemic drugs:
Sulfonylureas
 1st generation no longer used: Chlorpropamide Tolbutamide
 2nd generation : Glyburide, Glipizide, Glimepiride
 enhance insulin secretion
 lower HbA1c by 1.5 %
 side effects: hypoglycemia, weight gain

27. Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr
18;(2):CD004654.
Oral antihyperglycemic drugs:
Meglitinide analogs
 Repaglinide
 Nateglinide
 enhance insulin secretion (early-phase insulin release)
 lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.2- 0.6%
(nateglinide)
 side effects: weight gain, hypoglycemia

28. Oral antihyperglycemic drugs:
Thiazolidinediones (TZDs)
 Rosiglitazone & Pioglitazone
 peroxisome proliferator-activated receptor γ
modulators (PPAR γ)
 insulin sensitizers (increase the sensitivity of muscle,
fat and liver to endogenous and exogenous insulin)
 lower HbA1c by 0.5 - 1.4 %
 adverse effects: weight gain, fluid retention

29. Oral antihyperglycemic drugs:
-Glucosidase Inhibitors
 Acarbose
 Miglitol
 reduce the rate of digestion of polysaccharides in
the proximal small intestine, primarily lowering
post-prandial glucose levels
 lower HbA1c by 0.5 – 0.8 %
 side effects: increased gas production and
gastro-intestinal symptoms

30. Oral antihyperglycemic drugs:
DPP-IV inibitors
 Sitagliptin : DPP-IV inhibitor
 Dipeptidyl peptidase IV (DPP-
IV) is a ubiquitous enzyme
that deactivates a variety of
bioactive peptides, including
GIP and GLP-1
 Used alone or in combination
with metformin or TZDs
 Reduces HbA1c by 0.5 – 0.7 %
 Side effects: increased rate of
respiratory infections,
headaches

31. Other antihyperglycemic drugs:
Incretins
 Glucagon-like peptide 1 (GLP-1) agonist
 Exenatide - active ingredient in Exenatide
(Byetta) is a synthetic version of a protein
present in the saliva of the Gila monster

32. Glucagon-like Peptide - 1
 The majority of GLP-1 producing cells are in the
terminal ileum and proximal colon.
 GLP-1 levels in the blood increase rapidly after a meal.
 Half-life is very short, approximately one minute.
 GLP-1 binding to its G-protein coupled receptor on ß-
cells increases glucose stimulated insulin secretion
 GLP-1 infused into healthy subjects decreases gastric
emptying, causes a sensation of satiety, and decreases
appetite.
 Effects:
 enhances insulin secretion
 limits postprandial hyperglycemia.

33. Other antihyperglycemic drugs:
Incretins [Exenatide]
 Added to
metformin or
sulfonylureas will
reduce HbA1c by
0.4-0.6 %
 Side effects:
 nausea (dose-
depended, declines
with time)
 acute pancreatitis
(some necrotizing
or hemorrhagic
pancreatitis cases
reported as well)

34. Figure 1. Insulin levels following oral vs IV glucose
administration in healthy individuals. Despite
identical glucose concentrations, plasma insulin
levels peaked much earlier and were greater in
response to an oral vs IV dose of glucose.
Figure 2. Insulin levels following oral vs IV glucose
administration in patients with type 2 diabetes. The
markedly reduced early peak of insulin after oral
glucose, along with the smaller differences in insulin
levels in response to oral and IV glucose doses,
illustrate the diminished incretin effect.
Data extrapolated from Perley, et al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp
Incretin Effect

35. Antihyperglycemic drugs: Others
 Pramlintide (Symlin)
 synthetic analog of amylin
 Delays gastric emptying,
suppresses glucagon
secretion, decreases
appetite
 Associated with weight loss
(1 - 1.5 kg over 6 months)
 Used only in conjunction
with insulin treatment
 ↓ HbA1c by 0.5- 0.7 %
 Side effects: nausea, gastro-
intestinal symptoms

36. Amylin
 Stored in insulin secretory granules in the ß-
cells
 Co-secreted with insulin
 Decreases glucagon
 Satiety signal?
 Decreases GI motility

37. * Onset and duration are rough estimates. They can vary greatly within
the range listed and from person to person
** Human insulin is made by recombinant DNA technology
Available insulin preparations

38. Summary of antidiabetic interventions as
monotherapy
Interventions
Expected
decrease in
A1C (%)
Advantages Disadvantages
Step 1: initial
Lifestyle to decrease weight
and increase activity
1–2 Low cost, many benefits Fails for most in 1st year
Metformin 1.5
Weight neutral,
inexpensive
GI side effects, rare lactic acidosis
Step 2: additional therapy
Insulin 1.5–2.5
No dose limit,
inexpensive, improved
lipid profile
Injections, monitoring, hypoglycemia, weight
gain
Sulfonylureas 1.5 Inexpensive Weight gain, hypoglycemia*
TZDs 0.5–1.4 Improved lipid profile Fluid retention, weight gain, expensive
Other drugs
α-Glucosidase inhibitors 0.5–0.8 Weight neutral
Frequent GI side effects, three times/day dosing,
expensive
Exenatide 0.5–1.0 Weight loss
Injections, frequent GI side effects, expensive,
little experience
Glinides 1–1.5† Short duration Three times/day dosing, expensive
Pramlintide 0.5–1.0 Weight loss
Injections, three times/day dosing, frequent GI
side effects, expensive, little experience

39. Diabetes:
management
 Classification
 Diagnosis
 Treatment – goals

40. * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes.
Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care;32:S13-S61.
Glycemic goals: non-pregnant adults with
diabetes
 Key concepts in setting glycemic goals
 HbA1c is the primary target for glycemic
control
 HbA1c < 7.0%
 Preprandial capillary plasma glucose 70-130
mg/dl (3.9-7.2 mmol/l)
 Peak postprandial capillary plasma glucose <
180 mg/dl (< 10.0 mmol/l)*

41. * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes.
Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care;32:S13-S61.
Glycemic goals: non-pregnant adults with
diabetes
 Goals should be individualized based on:
 duration of diabetes
 age/life expectancy
 comorbid conditions
 known CVD or advanced microvascular complications
 hypoglycemia unawareness
 individual patient considerations
 More or less stringent glycemic goals may be
appropriate for individual patients
 Postprandial glucose may be targeted if HbA1c goals
are not met despite reaching preprandial glucose
goals

42. Glycemic goals - pregnant adults with
diabetes
 Women with GDM
 Maternal capillary
glucose concentrations:
 preprandial:≤95 mg/dl
(5.3 mmol/l) and either
 1-h postmeal: ≤140
mg/dl (7.8 mmol/l)
 Women with
preexisting diabetes
who become pregnant
 Maternal capillary
glucose concentrations:
 premeal, bedtime, and
overnight: 60-99mg/dl
 Peak postprandial: 100-
129 mg/dl
 HbA1c <6.0%

43. Road map to achieve glycaemic goals:
Naive to type 2 therapy

44. Diabetes:
management
 Classification
 Diagnosis
 Treatment – step care approach

45. Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months
until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. a)Sulfonylureas other than
glybenclamide (glyburide) or chlorpropamide. b)Insufficient clinical use to be confident regarding safety.
ADA Treatment Algorithm

46. Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. *Check A1C every 3 months until
<7% and then at least every 6 months. +Although three oral agents can be used, initiation and intensification of insulin therapy is preferred
based on effectiveness and expense.
ADA Treatment Algorithm

47. Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm
can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixed insulins not
recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid-
and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
ADA Treatment Algorithm

48. Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The
algorithm can only provide basic guidelines for initiation and adjustment of insulin. See ref. 71 for more detailed instructions. +Premixed
insulins are not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner if
proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
ADA Treatment Algorithm

49. Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The
algorithm can only provide basic guidelines for initiation and adjustment of insulin. See ref. 71 for more detailed instructions. +Premixed
insulins are not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner if
proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
ADA Treatment Algorithm

50. Clarifications on the watch list
 Insulin therapy in outpatient and inpatient settings
 Glycemic control and inpatient outcomes
 Does a perfect eating plan exist?
 Medical Nutrition Therapy for Diabetes
 Review goals and outcomes of Medical Nutrition
Therapy [MNT]
 Discuss basic recommendations for MNT
 Review specific recommendations for patient
population groups

51. Road Maps to Achieve
Glycemic Control in Type 2
Diabetes Mellitus
ACE/AACE Diabetes Road Map
Task Force