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)
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
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
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
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
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
Notas del editor
-Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Dual Impairment Impaired insulin action (Insulin Resistance) Impaired insulin secretion (Impaired -cell function) In adipose tissue resistant to the effects of insulin, there is increased lipolysis resulting in elevated level of plasma free fatty acids (FFA). Elevated FFA lead to an increase in hepatic glucose production and decrease in glucose uptake in the muscle. Impaired -cell function and -cell degranulation lead to a reduction in circulating insulin. This reduction in circulating insulin leads to hyperglycemia. Impaired insulin action or insulin resistance results in a decreased response to insulin in insulin sensitive tissues. In the liver, insulin resistance results in an increase in hepatic glucose production. Whether the impairment is to insulin secretion or action, the resulting hyperglycemia has a negative effect on muscle and adipose tissue by decreasing expression of GLUT4 which, in turn, limits glucose transport into insulin-sensitive tissues. Key words: Type 2 Defects Beta cell Insulin resistance
had anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, current status as a smoker, or obesity).
Mean duration of DM – 8 yrs
½ w/o and ½ with clinical retinopathy
Glycosylated hemoglobin values were measured quarterly and fasting lipid levels, serum creatinine values, and other risk factors for cardiovascular disease were measured annually in a central laboratory. Microalbuminuria and albuminuria were defined by urinary albumin excretion of at least 40 mg in a 24-hour period and of at least 300 mg in a 24-hour period, respectively. Renal disease was defined by the development of a serum creatinine level of at least 2 mg per deciliter (177 µmol per liter) or the need for dialysis or kidney transplantation. Electrocardiograms were obtained and examined annually by readers who were unaware of patients' treatment assignments. During the EDIC follow-up study, the methods used in the DCCT were continued, but glycosylated hemoglobin was measured annually and fasting lipid levels and renal function were measured in alternate years.