Facts about Type II Diabetes Mellitus

“Diabetes was long thought to be a kidney disease” (Greek & Arabic Methodology).

“Thomas Willis (1621 - 1679), discovered the sweetness of urine, hence, the name Diabetes Mellitus arised”

“Mathew Dobson (1776), identified glycosuria.”

“Claude Bernard and Von Mering (1889), discovered in the same year that pancreatectomy causes diabetes”

“Fredrick Banting (1921), successfully, extracted insulin, gaining the Nobel prize for this great discovery.”

“Leonard Thompson (14 year old boy) & Elizabeth Hughes (aged 14 years), were the first patients to be treated with insulin in 1922.

Dear Mom,

.. I look entirely different gaining every hour strength & weight..

..it is truly miraculous..

..I wish you could see the expression on there faces, they are so astounded in my unheard of progress..Leonard,April, 1922

It includes all the biochemical reactions that start in the cell after the absorption of food stuff.

Metabolism may be:

t Anabolism: building up, needs energy.

u Catabolism: breaking down, gives energy.

METABOLISM

Important Terminology In Carbohydrate Metabolism

Glycolysis:

Glucose breakdown & utilization that occurs in cells.

The breakdown of glycogen to glucose.

Glycogenolysis:

Formation of glucose from fatty acids & amino acids (new glucose formation).

Glycogenesis:

Glycogen formation that occurs in liver & muscles for storage of carbohydrates (as glycogen).

Gluconeogenesis:

Organic substance composed of

carbon, hydrogen & oxygen.

CHO are the first source of energy

for the organism.

CARBOHYDRATES

Simple sugar Complex sugar

Rapidly-absorbed CHO

Monosaccharides directly

absorbed.

Glucose - Fructose -

Galactose.

Slowly-absorbed CHO.

Disaccharides to polysaccharides need to be broken down to be absorbed as simple sugar.

Starch - Maltose.

CLASSIFICATION OF CHO

Fate of Absorbed Glucose

GGlycogenesis

Glycolysis Muscle Cells 50 %

GGlycolysis

Lipogenesis

GGlycogenesis

Glycolysis

Liver Cells 30 %

Fat Cells 5 %

Regulation of Blood Glucose

Hormonal Regulation

Organic Regulation

Hormonal Regulation

Blood Glucose Level

< 110 mg/L

Insulin

GlucagonGrowth Hormone

AdrenalineCortisol

Hypoglycemic Hormone Counterregulatory Hormones

Insulin

The only Hypoglycemic Hormone

It is secreted by ß- cells of the islets of Langerhans of

the pancreas.

Daily 20 - 50 units are secreted.

Insulin Synthesis

PrePro Insulin

Pro Insulin

C peptideInsulin

Split at position61/62

INSULIN SECRETION

GLUCOSE GKG-6-P

PK

PYRUVATES

ATP

Ca2+DEPOLARIZATION

++ +

__

_

K +

INSULIN

Glu t2

Blood Glucose

Insulin Secretion CurveBiphasic insulin response to a constant glucose stimulation

(IVGTT - hyperglycemic Clamp)

Insulin rate

Time (min)

Basal

4 60

Early Peak

Late Phase

Insulin secretion pattern

Insulin Secretion Pattern

Early peak :

rapid.. Prestored insulin to prevent the marked increase

of the blood glucose level.

Late phase:

slow.. Newly fabricated insulin to normalise the blood glucose

level .

Uptake

Utilization

Insulin Controls Blood Glucose metabolism by:

Insulin: Uptake of glucose

Stimulates glucose

transporters to move to the cell

surface.

The process is passive in the

kidney, liver and brain.

Active in the other tissues.

Insulin: Glucose utilisation

Oxidation

Storage

Liver & Muscles

glycogen

Adipocytes lipids

Glucose Oxidation (Glycolysis)

InsulinGlucose

T+Glucose GKG - 6 - P PKPyruvates Lactic Acid +2ATP PDH

-02

Kreb’sCycle

36ATP+

CO2+

H2O

GK: GlucokinasePK: Pyruvate KinasePDH: Pyruvate DehydrogenaseT: Insulin-dependent Transporter

How is Glucose Used in the Liver?

InsulinGlucose

T-

Glucose GK

G - 6 - PGS PK

Glycogen Pyruvates

ATP

GS: Glycogen SynthaseT-: Non-insulin Dependent Transporter

How is Glucose Used in the Muscle Cells?

InsulinGlucose

T-Glucose HKG - 6 - P

GS PKGlycogen Pyruvates

ATP

HK = Hexokinase

How is Glucose Used in the Adipocytes?

InsulinGlucose

T+

Glucose GKG - 6 - P

PKPyruvates

ATP

PDH

GPDHGlycerol 3P

+3 Fatty Acids

Triglycerides

What Happens Between Meals?

glycogenolysis

Glucose

Gluconeogenesis

I

glycogenolysis

Glucose

Gluconeogenesis

energy

I

I

Lipolysis

Fatty Acids+

Glycerol

Organic regulation of the blood glucose

I- Liver:

Blood glucose Blood glucose

glycogenolysis

gluconeogenesis

HGP

glycogenesis

glycolysis

glucose

Organic regulation of the blood glucose

II. Kidney

Normally no glucosuria

Above renal thresholdglucosuria( 1.8g / L)

Definition

Diabetes Mellitus is a group of Metabolic Diseases

characterized by Hyperglycemia resulting from

defects in insulin secretion, insulin action, or both.

American Diabetes Association

Diabetes Estimates and Projection

1994 2000 2010

Type 1 11.5 million 18.1million 23.7 million

Type 2 98.9 miilion 157.3 million

215.6 million

Total 110.4 million

175.4 million

239.3 million

Classification of Diabetes Mellitus

Primary Diabetes

Type 1insulin dependent

diabetes

Type 2non insulin

dependent diabetes

Secondary DiabetesGestational diabetes Malnutrition related

diabetesDiabetes resulting from:

Pancreaticdisease

Hormonaldiseases

Drug/chemicalinduced

Geneticsyndromes

Secondary DiabetesGestational diabetesMalnutrition related

diabetesDiabetes resulting from:

Pancreatic disease

Hormonal diseases

Drug/chemical induced

Genetic syndromes

Classification of Diabetes Mellitus

Stage/Test Fasting Plasma Glucose (FPG)

(Preferred)

Casual Plasma Glucose

Oral Glucose Tolerance Test

(OGTT)

Diabetes FPG > 126 mg/dL

(7.0 mmol/L)

Casual Plasma Glucose > 200

mg/dL (11.1 mmol/L) plus symptoms.

Two-hour Plasma (2hPG) >200 mg/dl

Impaired Glucose Homeostasis

Impaired Fasting Glucose

(IFG) = FPG > 110 and <126

mg/dl

Impaired glucose Tolerance (IGT) =

2hPG>140mg/dl and <200 mg/dL

Normal FPG< 110 mg/dL 2hPG<140 md/dl

New Criteria: Diagnosis of D. Mellitus

American Diabetes Association

Diabetes: Clinical Features

Symptoms:PolyuriaPolydypsia=thritPolyphagia=appetiteAsthenia & Loss of weight

Signs:

No specific signs may besigns of complications

Signs:

No specific signs may be signs of complications

Key Organs of Diabetes

Muscle

Pancreas

Liver

Hyperglycemia

in glucose storage in hepatic glucose production

insulin secretion disorder

Peripheral Abnormalities

GlycogenogenosisGlycolysis

Gluconeogenesis Lipogenesis

LipolysisGlycogenogenesis

Glycolysis

Gluconeogenesis

Liver Fat tissues Muscles

FFA

Hyperglycaemia

Glucose StorageGlucose production

Pathogenesis of diabetes: metabolic features

Genetic predisposition

Genetic predisposition

Insulinresistance

Insulinresistance

Defectiveinsulin secretion

Hyperglycemia

Impaired Insulin Secretion

Causes of Impaired Insulin Secretion

Decrease in number of Beta

cells by 40-50%

{In Insulin resistance states ,

the number is either normal or

increased}

Amyloid depositsAmylin : amyloid material

secreted by B cells Interferes with the

recognition of

the glucose signal

Causes of Impaired Insulin Secretion

Reduced activity of the glucokinase

ATP production reduced inside B

cells

Closure of K channel decreases

Entry of Calcium reduced

release of Insulin reduced

Causes of Impaired Insulin Secretion

Insulin Resistance

Types of Insulin Resistance

Receptor defect

Post Receptor defect

Types of Insulin Resistance

Receptor defect

Decrease in the affinity

Decrease in number (rare)

Post receptor defect

Glucose Transporter

Intra cellular

utilization

Enzymatic activity

Types of Insulin Resistance

Chronic hyperglycemia

Insulin secretion disorder

Insulin resistance

Gluco-toxicity

Vascular complications

Microvascular complications

Macrovascular complications

Microvascular complications

Retinopathy

Nephropathy

Neuropathy

Macrovascular complications

CHD

CVD

PAD

10 years accelerated

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