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Diabetes:Definition
PathophysiologyTreatment Goals
By
Scott Magee, MD, FACE
Disclosures
No disclosures to report
Definition of Diabetes Mellitus
Diabetes Mellitus comprises a group of disorders characterized by high blood
glucose levels.
Four major types:
• Type 1
• Type 2
• Gestational
• Diabetes secondary to other conditions
Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency
Insulin effects: inhibits breakdown of triglycerides (lipolysis) in adipose tissue
• Consequences of insulin deficiency: elevated FFA levels
Insulin effects: Inhibits ketogenesis
• Consequences of insulin deficiency: ketoacidosis, production of ketone bodies
Insulin effects in muscle: stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription
• Consequences of insulin deficiency: muscle wasting
A1C
Measures your average blood sugar over last 3 months
Hemoglobin A1C Correlation between HbA1C level and mean plasma glucose levels
5% 97 mg/dl 6% 126mg/dl 7% 154mg/dl 8% 183mg/dl 9% 212mg/dl 10% 240mg/dl 11% 269mg/dl 12% 298mg/dl
A1C to eAG Conversion Chart
A calculator for converting A1c results is available at:http://professional.diabetes.org/eAG
Diagnosis of Diabetes
• A1c > 6.5%OR
• FPG > 126 mg/dlOR
• Two-hour PG > 200 mg/dl during a 75 g OGTTOR
• In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose of > 200 mg/dl
ADA Standards of Medical Care in Diabetes-2015
Type 1 Diabetes Mellitus
• Characterized by absolute insulin deficiency
• Pathophysiology and etiology
– Result of pancreatic beta cell destruction
• Prone to ketosis
– Total deficit of circulating insulin
– Autoimmune
– Idiopathic
Normal Pancreatic Islet
Islet staining for Glucagon (R) and Insulin (L)
Autoimmune Isletitis
Models for Pathogenesis of T1DM
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
TYPE 1 DIABETES PRESENTATION
• * USUALLY MORE RAPID ONSET OF HYPERGLYCEMIC SYMPTOMS OVER WEEKS ESPECAILLY IN <20 YO
• * MARKEDLY ELEVATED GLUCOSE
• * OFTEN LEAN
• * OFTEN NEGATIVE FH
• * DKA AT PRESENTATION IS COMMON
• * MEASUREMENT OF AT LEAST 2 AUTOANTIBODIES AT DIAGNOSIS IS STANDARD OF CARE AND ARE PRESENT IN 80 TO 90 % OF ALL PTS AT DIAGNOSIS
Basal (background) insulin needs
Normal Insulin Secretion
0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
Seru
m in
sulin
(µU
/mL)
Time
Meal Meal Meal
Bolus (meal)
insulin needs60
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Glargine or detemir
Pla
sma
insu
linBasal/Bolus Treatment Program With Rapid-
Acting and Long-Acting Analogs
Bed
Rapid
(lispro,
aspart,
glulisine)
Rapid
(lispro,
aspart,
glulisine)
Rapid
(lispro,
aspart,
glulisine)
A1C levels and the risk of complications in type 1 diabetes
Adapted from DCCT. Diabetes 1995;44:968-43.
Diabetes Control and Complications Trial
Survival in Scotland: People with T1DM vs. general population
SJ Livingstone et al, JAMA 2015: 3013 (1) 37-44
DCCT/EDIC: Long-Term Benefits of Early Intensive Glycemic Control
Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.
Intensive glycemic control over a mean of 6.5 years reduced CVD complications by 57% after a mean of 17 years of follow-up
Prevalence of DM and Pre-DM in USA, 2012
T.M. Dall et al, Diabetes Care 2014; #37: 3172-3179.
Impaired Glucose
Tolerance
Impaired Fasting Glucose
Diabetes
Progression to Type 2 Diabetes
Or both
Prediabetes
Natural History of Type 2 Diabetes
30
Figure courtesy of CADRE.Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258
Fasting glucose
Type 2 diabetes
Years from diagnosis
0 5–10 –5 10 15
Prediabetes
Onset Diagnosis
Postprandial glucose
Macrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
-Cell functionIncretin effect
FFA = free fatty acids; TG = triglycerides.
Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-4058.
Ludwig DS. JAMA. 2002;287:2414-2423.
Factors that May Drive the Progressive Decline of -Cell Function
InsulinResistance
Glucose Toxicity(hyperglycemia)
-CellDysfunction
“Lipotoxicity”(elevated FFA, TG)
Acute Insulin Response Is Reduced in Type 2 Diabetes
33IRI=immunoreactive insulin.Pfeifer MA, et al. Am J Med. 1981;70:579-588.
Pla
sma
IRI
(µU
/ml)
Time (minutes)
20 g glucose infusion
2nd phase1st
-300
20
40
60
80
100
0 30 60 90 120
120Normal (n=85)
Type 2 diabetes (n=160)
Defective Insulin Action in T2DM
34
Leg
Glu
cose
Up
take
(mg/
kg le
g w
t p
er m
in)
Time (minutes)
0
P<0.01
12
1801401006020
8
4
0
Tota
l Bo
dy
Glu
cose
Up
take
(mg/
kg •
min
)
T2DMNormal0
7
6
5
4
3
2
1
DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.
Natural History of Type 2 Diabetes
35
Figure courtesy of CADRE.Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258
Fasting glucose
Type 2 diabetes
Years from diagnosis
0 5–10 –5 10 15
Prediabetes
Onset Diagnosis
Postprandial glucose
Macrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
-Cell functionIncretin effect
Mechanisms of hyperglycemia in T2DM
United Kingdom Prospective Diabetes Study (UKPDS)
*Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical
practice. If FPG exceeded 270 mg/dL, then patients were re-randomized to receive non-intensive metformin, chlorpropamide,
glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, then those on SU would have metformin added. If FPG exceeded
270 mg/dL after this, then insulin was substituted.
Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.
Traditional Monotherapies Do Not Maintain
A1C Control Over Time
Conventional*
Insulin
Glibenclamide (glyburide)
Metformin
Med
ian
A1C
(%
)
0
6
7
8
10
Time From Randomization (Years)
0 3 6
9
9 12 15
ADA Goal
Gestational Diabetes
Gestational Diabetes Mellitus (GDM) is diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes.
ASA Standards of Medical in Diabetes 2015.
Diagnosis of GDM
“One Step” “Two Step”
75 G OGTT 100 G OGTT
Fasting: > 92 mg/dl Fasting: > 95 mg/dl
1h: > 180 mg/dl 1h: > 180 mg/dl
2h: > 153 mg/dl 2h: > 155 mg/dl
3h: > 140 mg/dl
One abnormal Two abnormal
Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study
• 6 yr international study• Approximately 25,000 pregnant women• Studied association of various levels of glucose intolerance
during the 3rd trimester on risk of adverse outcomes of the baby
• Macrosomia—strong association (4-6 times)• Hyperinsulinemia-strong association (10 times)
from low to high in range• C-section-weak association• Hypoglycemia-weak association
New Findings in Gestational Diabetes-the HAPO Study, Metzger, et alDiabetes Voice, May 2009. Volume 54. Special Issue
Target Blood Glucose in Pregnancy
Fasting 1 hour 2 hour
ACOG <95 130-140 <120
ADA <105 <155 <130
ACE 60-90 <120
GDM ComplicationsMacrosomia
Effects of treatment of GDM on outcomes.
Jovanovic, Endocrine Practice; Vol. 14, No. 2, March 2008
Why test blood glucose?
• Adjunct to and verification of A1c
• Allows patient and provider to evaluate response to therapy and assess if glycemictargets are being met
• Results can be useful in preventing hypoglycemia and adjusting
diet, exercise and medications
When to test ?
Intensive Insulin Therapy
Pre meals
Occasionally post prandial
Bedtime
Pre/post exercise
Suspected hypoglycemia
During treatment for hypoglycemia
Before critical tasks (driving)
Date Breakfast Lunch Dinner Bedtime
3/12 112
3/13
3/14 136
3/15
3/16 89
3/17
3/18 114
Grid analysis of SMBG
Date Breakfast Lunch Dinner Bedtime
3/12 102 90 189
3/13 115 103
3/14 105 130
3/15 96 119
3/16 89 127
3/17 120 95
3/18 112 164
3/19 104 122
3/20 117 145
Grid analysis of SMBG
Date Breakfast Lunch Dinner Bedtime
3/10 120
105
112
99
72
133
92
86
104
Date Breakfast Lunch Dinner Bedtime
3/9 120 107 63 174
3/10 105 86 88 120
3/11 112 139 72 158
3/12 99 122 94 105
3/13 72 124 55 180
3/14 133 99 109 112
3/15 92 103 116 96
3/16 86 88 59 200
3/17 104 128 100 99
3/18 131 115 72 127
Grid analysis of SMBG
Questions