Glucose homeostasis, Glucose homeostasis, pathophysiology of pathophysiology of

diabetes & ADA diabetes & ADA GuidelinesGuidelines

JC LynchJC Lynch

PHPT 726PHPT 726

20072007

Glucose homeostasisGlucose homeostasis

Glycogenolysis & Glycogenolysis & GlucoeogenesisGlucoeogenesis

Hepatic Glucose OutputHepatic Glucose Output

GlycogenolysisGlycogenolysis– Catabolism of Catabolism of

glycogen.glycogen.

GluconeogenesisGluconeogenesis– Production of Production of

glucose from glucose from carbohydrates or carbohydrates or proteins.proteins.

(this is the simple slide: know this first)

Comparison of normal glucose patterns to patient with diabetes (probably type 1).

Direct Effects of InsulinDirect Effects of Insulin

Glucose metabolismGlucose metabolism Lipoprotein metabolismLipoprotein metabolism Ketone metabolismKetone metabolism Protein metabolismProtein metabolism

Insulin Action: DefinitionsInsulin Action: Definitions

Insulin SensitivityInsulin SensitivityAbility of insulin to lower Ability of insulin to lower

circulating glucose circulating glucose concentrationsconcentrations

Insulin ResistanceCondition of low insulin sensitivity

Glucose MetabolismGlucose Metabolism

Major Metabolic Major Metabolic Effects of InsulinEffects of Insulin

Consequences of Consequences of Insulin Insulin

DeficiencyDeficiencyStimulates Stimulates glucose uptake glucose uptake into muscle and into muscle and adipose cellsadipose cells

Inhibits hepatic Inhibits hepatic glucose glucose production production

HyperglycemiaHyperglycemia osmotic diuresis osmotic diuresis and dehydrationand dehydration

Lipoprotein MetabolismLipoprotein Metabolism

Major Metabolic Major Metabolic Effects of InsulinEffects of Insulin

Consequences of Consequences of Insulin Insulin DeficiencyDeficiency

Inhibits Inhibits breakdown of breakdown of triglycerides triglycerides (lipolysis) in (lipolysis) in adipose tissueadipose tissue

Elevated FFA Elevated FFA levelslevels

Ketone MetabolismKetone Metabolism

Major Metabolic Major Metabolic Effects of InsulinEffects of Insulin

Consequences of Consequences of Insulin Insulin

DeficiencyDeficiencyInhibits Inhibits ketogenesis ketogenesis

Ketogenesis: is the Ketogenesis: is the process by which process by which ketone bodies are ketone bodies are produced as a result produced as a result of fatty acid of fatty acid breakdown. breakdown.

KetoacidosisKetoacidosis

Protein MetabolismProtein Metabolism

Major Metabolic Major Metabolic Effects of InsulinEffects of Insulin

Consequences Consequences of Insulin of Insulin DeficiencyDeficiency

Stimulates amino Stimulates amino acid uptake and acid uptake and protein synthesisprotein synthesis

Inhibits protein Inhibits protein degradation degradation

Regulates gene Regulates gene transcription transcription

Muscle wastingMuscle wastingOthersOthers

Insulin and Amylin Co-Insulin and Amylin Co-secretedsecreted

Amylin

Insulin

Without Diabetesn = 6

Pla

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lin

(p

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Pla

sma

am

ylin

(p

M)

30

25

20

15

10

5

7 am Midnight5 pm12 noon

Time

600

400

200

0

Meal Meal Meal

Koda et al, Diabetes. 1995; 44 (s1): 23BA.Data on file. (Fineman)

AmylinAmylin

Secreted by pancreatic beta-cellsSecreted by pancreatic beta-cells An anorectic hormoneAn anorectic hormone Works on the brain to stimulate the Works on the brain to stimulate the

feeling of satiety.feeling of satiety. This results in decreased G.I. This results in decreased G.I.

motility, slowed carbohydrate motility, slowed carbohydrate absorption, and decreased appetite.absorption, and decreased appetite.

GLP-1GLP-1 ““Incretin” hormone secreted by jejunal Incretin” hormone secreted by jejunal

and ileal L cells in response to a mealand ileal L cells in response to a meal Stimulates insulin secretionStimulates insulin secretion Decreases glucagon secretionDecreases glucagon secretion Slows gastric emptyingSlows gastric emptying Reduces fuel intake (increases satiety)Reduces fuel intake (increases satiety) Improves insulin sensitivityImproves insulin sensitivity Increases Increases -cell mass and improves -cell mass and improves --

cell function (animal studies)cell function (animal studies)

GLP-1 release following meal:GLP-1 release following meal:comparison of control, T2DM & IGTcomparison of control, T2DM & IGT

Diabetes Diabetes PathophysiologyPathophysiology

Diabetes is a Diabetes is a Multi-Hormonal DiseaseMulti-Hormonal Disease

Pancreatic hormonesPancreatic hormones– Insulin (Insulin (-cell)-cell)– Glucagon (Glucagon (-cell)-cell)– Amylin (Amylin (-cell)-cell)

Intestinal Hormones (Incretins) Intestinal Hormones (Incretins) – GLP-1 (L-cells)GLP-1 (L-cells)– GIP (K-cells)GIP (K-cells)

Type 1 Diabetes: Type 1 Diabetes: PathophysiologyPathophysiology

Impaired insulin secretionImpaired insulin secretion– Absolute insulin deficiencyAbsolute insulin deficiency

T1DMT1DM

Typically autoimmune (~90%)Typically autoimmune (~90%) Beta-cells destroyed by multiple Beta-cells destroyed by multiple

antibodies.antibodies. Can occur at any age (but more in kids)Can occur at any age (but more in kids) Fast progression (the older the slower)Fast progression (the older the slower) Related to ketones @ Related to ketones @

– Urine ketonesUrine ketones– KetoacidosisKetoacidosis

Weight loss, N&V, lethargyWeight loss, N&V, lethargy

KetogenesisKetogenesis

Normal physiological responses to Normal physiological responses to carbohydrate shortages cause the carbohydrate shortages cause the liver to increase the production of liver to increase the production of ketone bodies from the acetyl-CoA ketone bodies from the acetyl-CoA generated from fatty acid oxidation. generated from fatty acid oxidation.

Allows the heart and skeletal Allows the heart and skeletal muscles primarily to use ketone muscles primarily to use ketone bodies for energy, thereby bodies for energy, thereby preserving the limited glucose for preserving the limited glucose for use by the brain use by the brain

HoneymooningHoneymooning

The ability of the failing b-cells to The ability of the failing b-cells to become hyper-productive and become hyper-productive and compensate for failing insulin compensate for failing insulin

response.response.

T2DMT2DMDiagnosis characteristicsDiagnosis characteristics

InsidiousInsidious Obesity (almost always), or weight gainObesity (almost always), or weight gain Related to other IRS signsRelated to other IRS signs

– Hyperlipidemia, acanthosis nigricansHyperlipidemia, acanthosis nigricans Older (Older (↑Obesity = ↓Age; fatter = ↑Obesity = ↓Age; fatter =

youngeryounger)) Ethnic linksEthnic links Family history of T2DMFamily history of T2DM No ketonesNo ketones

Acanthosis NigricansAcanthosis Nigricans

Hyperpigmented, velvety patches of skin in axillary regions and neck (typically).

Type 2 Diabetes: Type 2 Diabetes: PathophysiologyPathophysiology

Impaired insulin secretionImpaired insulin secretion– Absolute or Absolute or relativerelative insulin insulin

deficiencydeficiency

Impaired insulin action Impaired insulin action (sensitivity)(sensitivity)– Insulin resistanceInsulin resistance

Dual Metabolic Abnormalities in Dual Metabolic Abnormalities in

Type 2 DiabetesType 2 Diabetes

Excessive HepaticGlucose Output

Decreased Glucose Uptake

Insulin DeficiencyInsulin Resistance

Decreased Insulin Secretion

Unrestrained Lipolysis

Natural History of T2DMNatural History of T2DM

*IGT = impaired glucose toleranceYears of Years of DiabetesDiabetes

SymptomaticSymptomatic Obesity Obesity IGT* Diabetes IGT* Diabetes HyperglycemiaHyperglycemia

Relative Relative -Cell -Cell FunctionFunction

100 (%)100 (%)

-20-20 -10-10 00 1010 2020 3030

PlasmaPlasmaGlucoseGlucose

Insulin ResistanceInsulin Resistance

DiabetesDiabetes

120 (mg/dL)120 (mg/dL) Fasting Fasting GlucoseGlucose

Post-Post-meal meal

GlucoseGlucose

InsulinResistance

Glucose Intolerance

Obesity

Dyslipidemia (High TG, Low HDL)

Cardiovascular Disease

Hypertension

PCOS

Insulin Resistance Syndrome Insulin Resistance Syndrome (Metabolic Syndrome)(Metabolic Syndrome)

Response to Insulin Resistance:The Pancreatic Cell (early T2DM)

EnvironmentGenes

INSULIN RESISTANCE

Hyperglycemia(relative insulin deficiency)

Hyperinsulinemia(normal glucose)

Normal cells

Abnormal cells

C

Hepatic Insulin ResistanceHepatic Insulin Resistance(T2DM)(T2DM)

Adapted from Consoli A. Diabetes 1989;38:550–557.

Hep

atic

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cose

out

put

(µm

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g/m

in)

CON

25

20

15

10

5

0

T2DM

Glycogenolysis

Gluconeogenesis

Relative Organ Contribution to Decreased Glucose Uptake

Control T2DM

Adapted from DeFronzo RA. Diabetes 1988;37:667–687.

Brain

Muscle

Adipose

7

6

5

4

3

2

1

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Insulin Resistance:Inherited and Acquired Influences

Rare Mutations

Insulin receptorGlucose transporterSignalling proteins

Common Forms

Largely unidentified

Inactivity

Obesity

Stress

Medications

Glucose toxicity

Lipotoxicity

INSULIN RESISTANCE

AcquiredInherited

C

AgentAgent TargetTarget Site(s) of actionSite(s) of action

Insulins/AnaloguesInsulins/Analogues Insulin receptorInsulin receptor Liver, muscle, fatLiver, muscle, fat

SulfonylureasSulfonylureas

Phenylalanine Der.Phenylalanine Der.

MeglitinidesMeglitinides

SFU receptorSFU receptor

K-ATP ChannelK-ATP ChannelPancreatic Pancreatic cell cell

MetorminMetormin UnknownUnknown Liver (muscle)Liver (muscle)

Glucosidase Glucosidase inhibitorsinhibitors

-glucosidase-glucosidase IntestineIntestine

ThiazolidinedionesThiazolidinediones PPAR-PPAR- Muscle (liver, fat)Muscle (liver, fat)

ExenatideExenatide GLP-1 receptorsGLP-1 receptors PancreasPancreas

VildagliptinVildagliptin DPP 4 (inhibition)DPP 4 (inhibition) EnzymaticEnzymatic

Atypical diabetesAtypical diabetes

Idiopathic type 1 diabetesIdiopathic type 1 diabetes

Also known as “Flatbush diabetes”Also known as “Flatbush diabetes” African American and Asian men (18-African American and Asian men (18-

25)25) Fluctuating insulin secretionFluctuating insulin secretion No antibodiesNo antibodies Many honeymoonsMany honeymoons

LADALADA Latent autoimmune diabetes of Latent autoimmune diabetes of

adulthoodadulthood Like type 1 but diagnosed after age 25.Like type 1 but diagnosed after age 25. ~20% of those with diagnosis of T2 may ~20% of those with diagnosis of T2 may

actually have LADA.actually have LADA. Slower onset than type 1 dm.Slower onset than type 1 dm. Positive antibodies.Positive antibodies. Low or no c-peptideLow or no c-peptide No family historyNo family history

MODYMODY

Maturity Onset Diabetes of the YoungMaturity Onset Diabetes of the Young A collection of many (at least 6) A collection of many (at least 6)

inherited diseases affecting insulin inherited diseases affecting insulin secretion.secretion.

Dominant inheritance characteristicsDominant inheritance characteristics Normal insulin sensitivityNormal insulin sensitivity Impaired insulin secretion (but still Impaired insulin secretion (but still

some).some). Diagnosis confirmed by genetic testing.Diagnosis confirmed by genetic testing.

Pancreatic DiabetesPancreatic Diabetes

Results from a failure of the pancreas Results from a failure of the pancreas as a whole.as a whole.

May be secondary to ETOH abuse, May be secondary to ETOH abuse, trauma, repeat pancreatitis.trauma, repeat pancreatitis.

Exocrine pancreas generally fails Exocrine pancreas generally fails before endocrine pancreas.before endocrine pancreas.

Will need pancreatic enzyme Will need pancreatic enzyme replacement as well as insulin.replacement as well as insulin.

Gestational diabetesGestational diabetes

Any glucose intolerance first Any glucose intolerance first diagnosed during pregnancydiagnosed during pregnancy– Some definitions require return to Some definitions require return to

normal following end of pregnancy.normal following end of pregnancy.

Closely related to T2DMClosely related to T2DM Treat only with insulinTreat only with insulin

– Some data support the use of SUs & Some data support the use of SUs & metformin.metformin.

mg/dl mmol/l

Fasting 95 5.3

1-h 180 10.0

2-h 155 8.6

3-h 140 7.8

Diagnosis of GDM with a 100-g oral glucose load

A1C monitoringA1C monitoring

For every 1% point of increase in A1c

add 35mg/dl of glucose.

A1c (%) Mean Plasma glucose mg/dl

6 135

7 170

8 205

9 240

10 275

11 310

12 345

False A1C ReadingsFalse A1C Readings

ElevatedElevated– Iron deficiency Iron deficiency

anemiaanemia– SplenectomySplenectomy

DecreasedDecreased– Hemolytic anemiaHemolytic anemia– Sickle cell anemiaSickle cell anemia– TransfusionTransfusion

ADA GuidelinesADA Guidelines

http://www.diabetes.org/http://www.diabetes.org/

Case #1Case #1