diabetes mellitus · diabetes mellitus 46 glp-1 & gip •entero-insular axis •“incretins”...

Diabetes mellitus

Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH

petercelec@gmail.com

www.imbm.sk

2Diabetes Mellitus

Level 0

Cell interior

Glucose

InsulinCell

membrane

3Diabetes Mellitus

Level 0

• Definition and classification of DM

– !!!Group of diseases associated with

hyperglycemia!!!

– !!!Disorders of secretion and/or effect of insulin!!!

– Type 1 (ID DM)

– Type 2 (NID DM)

– Gestational DM

– Other secondary types

– IFG, IGT, MODY, LADA

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Level 0

Diabetes Mellitus

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• Pathogenesis of DM symptoms

– Hyperglycemia glycosuria polyuria

dehydration polydipsia

– Tissue starvation loss of muscle and lipid tissue +

loss of minerals and water weight loss despite

increased food intake cachexia

– Mobilization of lipids hyperlipidemia oxidation

of FFA acetylCoA hyperketonemia

ketonuria

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• Etiopathogenesis DM Type I

– ID DM

– Decreased production of insulin

– Genetic and epigenetic factors (50% concordance)

– Autoimmune destruction of beta cells in the pancreas

– Antibodies GAD, ICA, INS

– HLA associations

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Pathogenesis of DM Type 1

Diabetes Mellitus

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Pathogenesis of DM Type 1

Environment

Viruses?

Genetics

HLA-DR3/DR4

Insulin deficiency

Destruction of ß cells

DM type 1

Autoimmune insulitis

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Level 0

• Etiopathogenesis DM Type 2

– Not NID DM!!!

– Disorders of insulin sensitivity AND! beta cells

– Genetic and epigenetic factors (90% concordance)

– Various hypotheses

– Obesity insulin resistance hyperinsulinemia

down-regulation of receptors glucose toxicity

beta cells disorders

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DM type 2 and obesity

Diabetes Mellitus

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DM type 2 and obesity

Diabetes Mellitus

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Pathogenesis of DM type 2

Environment

Obesity

Genetics

Defect of ß cells

Exhaustion

of ß cellsDM Type 2

Insulin resistance

Relative insulin deficiency

IDDM

Altered secretion

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Pathogenesis of DM type 2

Diabetes Mellitus

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• Specific types of DM

– Maturity Onset Diabetes of the Young

• MODY 1-10 – mutations of HNF, glucokinase, insulin

– Latent Autoimmune Diabetes of the Adults

• LADA (cca. 5-10% DM 2), type 1,5

– Maternally inherited diabetes and deafness

• MIDD – mtDNA

– Gestational DM

• Placental hormones

– Secondary and iatrogenic DM

• Hormones, immunosuppressives, streptozotocin, aloxan

– Impaired/Increased Fasting Glucose (IFG)

– Impaired Glucose Tolerance (IGT)

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• Insulin resistance

– Obesity, DM, „systemic diseases“

– Prereceptor

• Immunity, metabolism, genetics

– Receptor

• Gene, expression, transport, degradation

– Postreceptor

• Downstream pathways, glucose transport, enzymes of

glycolysis

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Level 0

• Insulin resistance syndrome

– Reaven’s metabolic syndrome X

– Central obesity

– DM type 2

– Hyperlipidemia

– Hypertension

– Hyperurikemia

– Hyperfibrinogenemia

– Hyperandrogenism

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Level 0

• Diabetic nephropathy

– Hyperfunction of glomeruli

– Hyperfiltration

– Mesangioproliferative changes

– Microalbuminuria

– Proteinuria

– Hypertension

– „Nephrectomy“

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Blood Urine

Microangiopathy

Nephropathy

Health Microalbuminuria Proteinuria

Blood Urine Blood Urine

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Level 0

• Acute and chronic complications of DM

– Acute – diabetic coma

• 1. Hyperglycemia – diabetic ketoacidosis (DM1)

• 2. Hyperosmolar hyperglycemic state (DM2)

• 3. Severe hypoglycemia (coma)

– Chronic

• 1. Microangiopathy

• 2. Macroangiopathy

• 3. Neuropathy

• (nephropathy, infections, gingivitis, cataract...)

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Level 0

Dizziness

Sweating Irritability

Tremor

•Hypoglycemia

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Level 0

Hypoglycemic coma Hyperglycemic coma

with ketoacidosis

Hyperglycemic coma

without ketoacidosis

DM 1 or 2 DM 1 DM 2

Glucagon, glucose Insulin, rehydration, K+ Rehydration, insulin, K+

1-3 mmol/l 15-30 mmol/l 30-60 mmol/l

Glycosuria negative Glycosuria positive Glycosuria positive

Sweating, tachycardia Kussmaul, ketone smell Without ketoacidosis

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Level 1

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Level 1

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Level 1

• In the liver insulin

– Increases glucose uptake

– Stimulates glycogen and

fatty acid synthesis

– Inhibitis synthesis of

ketone bodies from fats

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Level 1

• In muscles insulin

– Increases glucose and

amino acid uptake

– Increases glycogen

synthesis

– Stimulates protein

synthesis and inhibits

proteolysis

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Level 1

• In fat tissue insulin

– Increases glucose uptake

– Stimulates fatty acid

synthesis

– Inhibits lipolysis

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Level 1

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Level 1

• Contraregulation

– Glucagon

– Cortisol

– Adrenalin

– Somatotropin

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Level 1

• DM

– Endocrine or metabolic diseases???

– Viruses and their role in the pathogenesis of DM

• Enteroviruses (Coxsackie B), rotaviruses, rubella

– Molecular mimicry

• Cow milk antigens (casein)

• Gliadin

• Infections

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Symptoms of DM

1. POLYDIPSIA

BLOOD CELLS

BLOOD CELLS

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Level 1

2. POLYURIA

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Level 1

3. POLYPHAGIA

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Level 1

4. LOSS OF WEIGTH

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Level 1

5. FATIQUE

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Glucose uptake in tissues

Control DM 2

Brain

Muscle

Adipose

7

6

5

4

3

2

1

0

Splachnic

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-30

-10

10

30

50

70

90

0 15 30 45 60 75 90

TIME (min)

0

50

100

150

200

0 15 30 45 60 75 90

TIME (min)

DG

lycem

ia(m

g/1

00m

l)

DIn

su

lin

em

ia(m

U/L

)

oral

intravenous

Insulin secretion

after oral and intravenous glucose application

Inkretins

46Diabetes Mellitus

GLP-1 & GIP

• Entero-insular axis

• “Incretins” are secreted by jejunum and ileum as a response to food intake

• Stimulate the secretion of insulin

• Decrease the secresion of glucagon

• Slow-down gastric emptying

• Increase satiety

• Improve insulin sensitivity

• Increase the number of beta cells and improve their functions

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Absorbed nutrition

Neural signals

Endocrine signals

GUT PANCREAS

Enteroinsular axis

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Inkretin drugs

• Analogues of GLP-1

– Exenatide

– Liraglutide

• Inhibitors of dipeptidyl peptidase 4 (DPP4)

– Vildagliptin

– Sitagliptin

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Metabolic surgery

Diabetes Mellitus

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Metabolic surgery

Diabetes Mellitus

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Metabolic surgery

Diabetes Mellitus

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Combinatory drugs

Diabetes Mellitus

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Inositol-3-phosphate

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SGLT2 inhibitors

Diabetes Mellitus

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Heterogenity of DM

Diabetes Mellitus

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Resistin

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Klotho

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Level 1

• Pathogenesis of DM complications

– Ketones

– Sorbitol

– Advanced glycation end products (AGEs)

– Reactive oxygen species (ROS)

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Level 1

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Level 1

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Level 1

• Advanced glycation end products (AGEs)

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Level 1

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Level 1

Diabetes Mellitus

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Level 1

Diabetes Mellitus

Mean plasma glucose

A1C (%) mg/dL mmol/L

6 126 7.0

7 154 8.6

8 183 10.2

9 212 11.8

10 240 13.4

11 269 14.9

12 298 16.5

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Level 1

Diabetes Mellitus

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Level 1

• Epidemiology

– 3-5% of the whole population are diagnosed diabetics

– cca. 10%

– 50% in the population > 70y

– Incidence and prevalence rapidly increases

– 10% DM 1

– 90% DM 2

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Level 1

• Diagnostics

– Criteria

• Fasting glucose >7,0 mmol/l

• Random glucose >11,1 mmol/l + symptoms of DM

• HbA1C>6,5%

• oGTT 2h >11,1 mmol/l

– Further diagnostic parameters

• Glycosuria

• Ketonuria

• C-peptide

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Level 1

• Impaired/Increased fasting glucose (IFG)

– Fasting Glycemia 5,6-6,9 mmol/l

– Insulin resistance in the liver – early phase

• Impaired glucose tolerance (IGT)

– oGTT 2h 7,8-11,1 mmol/l

– 8x higher risk for DM

– Insulin resistance in the muscles – late phase

• Pre-diabetes

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Level 1

• Diagnostics

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• Diagnostics

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Take home message 1

• Insulin is an anabolicum

• Oxidative and carbonyl stress are involved in the

pathogenesis of DM and its complications

• Oral glucose tolerance test (oGTT)

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Genetic

predisposition

Preclinical

state

Normal IGT

Disability

Death

Clinical

disease

NIDDM Disability

Death

Complications

Complications

DM type 2

Primary Secondary Tertiary

prevention prevention prevention

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Secondary prevention

Diabetes Mellitus

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Primary prevention?

Diabetes Mellitus

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Level 3

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Level 3

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Level 3

• Pharmacotherapy

– Insulin

• Bovine, porcine

• Human – recombinant

– Peroral antidiabetics

• Sulfonylurea – Glibenclamid, tolbutamid

• Repaglinid - dtto

• Biguanidy – Metformin

• Thiazolidendiony (Insulinsensitizer)

• Acarbose

– Antihypertensives (ACE inhibitors, beta blockers)

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Level 3

• DCCT

– 1993 Diabetes Control and Complications Trial

– Intensive insulin therapy

• 60% neuropathy

• 76% retinopathy

• 39% nefropathy

• 53% renal and eye disorders

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Level 3

• UKPDS

– 1998 UK Prospective Diabetes Study

• Antihypertensive therapy

• Blood pressure

• Intensive monitoring of glycemia

• 1% HbA1C 25% mortality

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Level 3

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Level 3

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Level 3

• Gene therapy

– Ex vivo

• Transformation of stem cells

• Cultivation of beta cells

– In vivo

• Naked DNA

• Viral vectors

• Transformed bacteria

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Level 3

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Level 3

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