diabetes pathophysiology, natural history and treatment

International Diabetes CenterGlucose Metabolism and the Natural History of Diabetes • Normal Glucose Metabolism • Type 1 Diabetes IDDM-- Autoimmune • Type 2 Diabetes NIDDM-- Insulin Res

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International Diabetes Center

Diabetes:

Pathophysiology, Natural

History and Treatment

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Glucose Metabolism and the

Natural History of Diabetes

• Normal Glucose Metabolism

• Type 1 Diabetes (IDDM) Autoimmune

• Type 2 Diabetes (NIDDM) Insulin Resistant and

Insulin Deficient

• Gestational Diabetes Mellitus (GDM) Diabetes in

Pregnancy

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Normal Glucose Metabolism

Peripheral Tissues (Muscle and Fat)

Glucose Liver

Insulin and glucagon

Glucose (glycogen) storage and metabolism

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Abnormal Glucose Metabolism

Peripheral Tissues (Muscle and Fat)

Glucose Liver

Relative Insulin deficiency (type 2, GDM) or no insulin

Insulin resistance (type 2, GDM)

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Diabetes Pathophysiology:

Defects Associated with

Type 1, Type 2 and GDM

Diabetes Pathophysiology:

Defects Associated with

Type 1, Type 2 and GDM

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Natural History of Type 1 Diabetes

Genetic background

At risk for Type 1 diabetes

Islet cell antibodies appear

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Genetic background

At risk for Type 1 diabetes

Islet cell antibodies appear

DM ONSET

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0 50

At risk for Diabetes

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0 50

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Nucleus

Insulin Glucose

Insulin Receptor

Glucose Transporter (GLUT 4)

G

G G G

G

G G G G

G G

G

Adipose and muscle tissues require insulin for 90-95% of glucose uptake

Liver, pancreas and brain do not require insulin for glucose uptake

G G

G

G G G G

G G

G

Insulin Signaling Pathway in

Insulin Sensitive Cells

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Nucleus

Insulin Sensitive Cell (Muscle or Fat)

Insulin Glucose

Insulin Receptor

Glucose Transporter (GLUT 4)

G

G G

G

G G G G

G G

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Relative Insulin Deficiency

Post Meal Glucose

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Normal Beta Cell Function

Beta cells produce insulin and

store it in secretory vesicles

ATPADP

Glucose Transporter(Glut 2)

G

G G G

G

G G

Potassium Channel

K +

X

K+ Channel Blocked- membrane becomes depolarized

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Deficiency in Beta Cell Function

ATPADP

Pyruvate

Voltage-gated Calcium Channel*

Ca++

G

G G

Glucose Transporter(Glut 2)

G

G G G

G

G G

K +

Initially, loss of glucose induced (first phase) insulin secretion Eventually, reduction in beta cell mass

Note: Glucose toxicity

occurs when there is

chronic exposure to high

glucose levels

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Natural History of Gestational Diabetes

0 50

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Common to all Forms of Diabetes

• Hyperglycemia

• Hyperglycemia is related to microvascular

1 and Type 2; and to excess fetal growth

• Treatment of hyperglycemia results in

improved outcomes

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– Thiazolidinediones - Rosiglitazone and Pioglitazone

 -Glucosidase Inhibitors - Acarbose, Miglitol

Insulin

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Treatment: Type 1 Diabetes

Genetic background

At risk for Type 1 diabetes

Islet cell antibodies appear

Insulin + Medical Nutrition Therapy

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Type 1 Clinical Pathway

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Medical Nutrition Therapy

(Food Plan and Exercise)

– Kidney Disease : low protein

diet for macroalbuminuria

– Liver Disease : none

– Heart Disease : assess fitness

before initiating activity

program

• Pregnancy

– Alter diet and activity to promote normal fetal development and avoid fetal stress

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• Normally recommend 3-5 carbohydrate choices/meal

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Personal Food Plan

TO LOSE WEIGHT

TO CONTROL WEIGHT

FOR THE VERY ACTIVE

Snacks: 0-2 choices/meal (if needed)

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• 30 minutes of exercise per day, cumulative

• Age and lifestyle appropriate e.g walking, bicycling,

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0 50 100

Beta cell dysfunction

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA Diabetes 37:667, 1988

Tokuyama Y Diabetes 44:1447, 1995 Polonsky KS N Engl J Med 1996;334:777.

Medical Nutrition

(11.1 mmol/L) (7.0 mmol/L)

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HbA1c <8% Medical Nutrition Stage ~1%

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Insulin Secretagogues: Sulfonylureas (Glimepiride, Glibenclamide, Gliclazide) Repaglinide,

– Liver Disease: Use caution, not well studied with liver disease

– Known hypersensitivity to the drug

• Pregnancy

– Contraindicated, initiate insulin therapy

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ATPADP

Pyruvate

Voltage-gated Calcium Channel

Glucose Transporter

G G

G

G G

K +

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Insulin Sensitizer:

Metformin

– Overcomes liver insulin

resistance resulting in lower

– Liver Disease : if present or if

excessive alcohol intake, metabolic acidosis

– Heart Disease : Active cardiac

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Glucose Production in the Liver

Glycogenolysis(glycogen stores)

Gluconeogenesis(lactate, glycerol,amino acids)

Glucose

Insulin Resistance and Glucose

Regulation in the Liver

Glucose

Insulin insensitivity reduces insulin’s ability to suppress endogenous

glucose production

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Insulin Sensitizer: Thiazolidindione

Pioglitazone and Rosiglitazone

• Action

– Overcomes insulin resistance

insulin sensitive tissue

– Kidney Disease : none

– Liver Disease : don’t initiate

therapy if ALT>2.5X upper

limit of normal, more monitoring for mildly elevated ALTs

– Heart Disease : Evidence of

ischemic heart disease or CHF

• Pregnancy

– passes placental barrier, initiate insulin therapy

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Overcoming Insulin Resistance

Nucleus

Insulin Glucose

Insulin Receptor

Glucose Transporter (GLUT4)

G

G G G

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Effect of Thiazolidinediones

TZD

Liver

• Improve insulin sensitivity

• Gluconeogenesis

PPAR 

Activate Gene ExpressionCell Signaling

Nucleus Inside Cell

Pancreas

• Improve Beta-cell function

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– Heart Disease : none

– Inflammatory bowel disease

• Pregnancy

– passes placental barrier, initiate insulin therapy

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0 50

Medical Nutrition

Metformin Thiazolidinediones

Secretagogue

(11.1 mmol/L) (7.0 mmol/L)

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Secretagogue + Sensitizer

Oral Agent + Insulin

Oral Agent Stage

~1%

Insulin Deficiency Secretagogues ~2%

Combination Oral Agent Stage Combination Oral Agent/Insulin Stage

Combination Oral Agent Stage Combination Oral Agent/Insulin Stage ~2-4%

Note: Each stage requires a

pre-set BG target: and a timeline to

reach that goal

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Insulin

• Action

– Compensates for diminished

beta cell secretion of insulin

– Overcomes insulin resistance in

• Precautions and

Contraindications

– Kidney Disease : none

– Liver Disease : none

– Heart Disease : none

• Pregnancy

– Therapy of choice in GDM when FPG >95 mg/dL (5.3 mmol/L) or CPG >120 mg/dL (6.6 mmol/L)

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Overcoming Insulin Resistance

Nucleus

Insulin Glucose

Insulin Receptor

Glucose Transporter (GLUT4)

G G

G

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Basal Insulin Needs

Bolus insulin needs

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0 50

Medical Nutrition Insulin

Metformin Thiazolidinediones

Secretagogue

(11.1 mmol/L) (7.0 mmol/L)

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Oral Agent Stage

~1%

Insulin Deficiency Secretagogues ~2%

Combination Oral Agent Stage Combination Oral Agent/Insulin Stage

Note: Each stage requires a

pre-set BG target: and a timeline to

reach that goal

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Treatment: Gestational Diabetes

Nutrition Alone/with pharmacological agent

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Oral Agent Stage-Glyburide

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Diabetes: Pathophysiology,

Natural History and Treatment

• Insulin Resistance and Insulin

Deficiency

• Common to all disorders

• More than glucose

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2004 Priorities of Care for Adults with Diabetes

Prevention - Diagnosis

Preventions Prediabetes (IFG -IGT) & Metabolic Syndrome

Diagnosis Fasting glucose > 126 mg/dL (7 mmol/L) or

Casual glucose > 200 mg/mL (11.1 mmol/L) + Symptoms

History and Physical Exam

Prevention - Diagnosis

Casual glucose > 200 mg/mL (11.1 mmol/L) + Symptoms

History and Physical Exam

Lipid Targets

LDL < 100 mg/dL (2.6 mmol/L)

Triglyceride < 150 mg/dL (1.7 mmol/L)

HDL > 40 mg/dL (1.0 mmol/L)

Statin therapy Fibrate therapy Combination therapy

Blood Pressure Targets

Mean BP <130/80 mmHg

ACEI or Thiazide therapy Combination therapy

Blood Pressure Targets

ACEI or Thiazide therapy Combination therapy

Annual Screening Nephropathy

Care of the Hospitalized Patient with Diabetes Care of Gestational DM

Foot Care Oral & Dental Care Immunizations

Flu Shot + Pneumovax

Care of the Hospitalized Patient with Diabetes Care of Gestational DM

Foot Care Oral & Dental Care Immunizations

Flu Shot + Pneumovax

Patient Education Emotional assessment

BG Monitoring distress, depression, complications Medical Nutrition Support needs Physical Activity family, peers, medical

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