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