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DIABETES MELLITUS
• Diabetul zaharat
Curs 1
2019
Agenda
Nicolae C. Paulescu
(1869-1931)
Lipogenesis
Glycogenesis Formation of triglycerides for storage
Formation of glycogen for storage from from fatty acids and glycerol in adipose
unused glucose in liver and muscle tissue and liver
FASTED-STATE GLUCOSE HOMEOSTASIS
Glycogenolysis Lipolysis
Gluconeogenesis
Proteolysis
GLUCOSE HOMEOSTASIS
Pancreas: structure and function
Glycolysis
Glycogenesis
Lipogenesis
Protein synthesis
Glycogenolysis
Gluconeogenesis
Lipolysis
Proteolysis
Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.
Echilibrul secretor între insulină şi glucagon
menţine controlul normal postprandial al glicemiei
140 Masa Glicemie
Insulină
mg%
120 Glucagon
După masă
100
160
120 Insulină Glucagon
mU/ml
80
40
Acest echilibru controlează
strict creşterile glicemice care
130
120
apar după ingestia de alimente
110
pg/ml
100
90 În condiţii normale, controlul
0 glicemic se auto-reglează
-60 0 60 120 180 240
Timp (min)
• DM is characterized by:
Excessive Impaired
glucose HYPERGLYCEMIA glucose
production clearance
Tissue
injury
American Diabetes Association Standards of Medical Care in Diabetes 2016. Diabetes Care 39(1):S52–S59, 2016
HYPERGLYCEMIA
PATHOGENIC MECHANISMS
• Type1 DM – absolute insulin secretion deficiency secondary to β –
cells distruction throught autoimmune mechanism
• Type 2 DM – there are 2 pathogenic concepts :
– Classic concept - Hyperglycemia triad: hepatic insulin
resistance (↑ heptaic glucose production) and muscle insulin
resistance (↓ glucose uptake and utilisation) associated with
impaired β-cell function
– Modern concept – the egregious eleven of hyperglycemia
PATHOPHYSIOLOGICAL ABNORMALITIES IN T1DM
• Genetic predisposition (HLA DR3-DQ2/DR4-DQ8 genotype)
• Environmental factors that are suspected to trigger beta-cell autoimmunity
include:
– dietary factors (short duration of breast-feeding, the intake of cow’s milk
proteins during the first months of life, the early introduction of cereals)
– viral infections (congenital rubella infection, acute enterovirus infections)
• The relevant islet autoantibodies identified so far are:
– autoantibodies to insulin,
– autoantibodies to GAD,
– autoantibody to Zn transporter 8 (ZnT8)
– autoantibody to tyrosine phosphatases IA-2 and IA-2beta
• Inflammatory cells heavily infiltrate pancreatic islets leading to insulitis and
selective killing of beta cells
NATURAL HISTORY OF TYPE 1 DIABETES
NATURAL HISTORY OF TYPE 2 DIABETES
Classic concept
Hyperglycemia triad
Islet b-cell
Islet b-cell
↑ FFA
Increased HGP
Lipolysis
Muscle Liver
FFA and Glycerol
β-cells
Islet b-cell
Decreased
Incretin Effect
• Postprandial hyperglycemia
Delays gastric emptying
Decreased
Incretin Effect
Impaired
Insulin Secretion
Islet a-cell
Increased
Lipolysis
Increased
Glucagon Secretion
Increased
HGP Decreased Glucose
Uptake
The Septicidal Septet
Islet b-cell
Decreased
Impaired Incretin Effect
Insulin Secretion Increased
Lipolysis
Islet a-cell
Increased
Increased Glucose
Glucagon Secretion
Reabsorption
Increased
HGP Decreased Glucose
Uptake
The Septicidal Septet
↑ Glucose reabsorbtion
Glucose
SGLT2 S1
S3
SGLT1
↑Glucose reabsorption
↑Glycemia ↓Glycosuria
The Ominous Octet
Islet b-cell
Decreased
Incretin Effect
Increased
Impaired Lipolysis
Insulin Secretion
Islet a-cell
Increased
Decreased Glucose
HGP
Uptake
Neurotransmitter Dysfunction
The Ominous Octet
Neurotransmitter Dysfunction
Kalra S. Recent advances in pathophysiology of diabetes: beyond the dirty dozen. J Pak Med Assoc. 2013;63(2):277-80
The egregious eleven
NATURAL HISTORY OF TYPE 2 DIABETES
Adaptat după: Mazze R, et al. Part two: The treatment of diabetes. In: Mazze R, Strock ES, Simonson G, Bergenstal RM, eds. Staged Diabetes
Management: A Systematic Approach. 2nd ed. rev. 2006:78-154. Int J Clin Pract. Dec 2012; 66(12): 1147–1157
TYPE 1 DM vs. TYPE 2 DM
Agenda
Mota M, Popa SG, Mota E, Mitrea A, Catrinoiu D. et al. Prevalence of Diabetes Mellitus and Prediabetes in the Adult
Romanian Population: PREDATORR Study. J Diabetes. 2015. doi: 10.1111/1753-0407.12297. [Epub ahead of print]
Agenda
Insight No
clue
what
to do
Sensor-augmented insulin pump
CSII + CGMS
• CSII in conjunction with a CGMS give
the patient more information about their
blood glucose levels and allow them to
make better informed decisions about
insulin dosing.
• Advantages:
CSII in conjnction with CGMS may
effectively improve glycemia while
limiting the rise in hypoglycemia that
often accompanies improved glycemic
control
Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA, STAR 3 Study
Group. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363(4):311
Case no 1 Case no 2
Personal history of diabetes No No
Signs and symptoms Polyuria, polydipsia, Dizziness (without
fever, polyuria, polydipsia,
cough with purulent expectoration weight loss)
The duration of signs and 3 days 3 hours
symptoms
HbA1c 5.2% 5.2%
Fasting plasma glucose 485 mg/dl 485 mg/dl
Seric ketone level 7 mmol/l 0.2 mmol/l
(normal <0.6 mmol/l)
Blood pressure 120/70 mmHg 190/100 mmHg
• Is there a concordance between HbA1c and
blood glucose?
MiniMed Paradigm
System (Medtronic)
iPro2 (Medtronic)
• How do you explain the lack of concordance
between HbA1c and glycemia?
Case 3
• The lack of concordance between glycemia at the time of the
last visit at the diabetologist and HbA1c is explained by the
glycemic variability: glycemic values ranging between 50
mg/dl and 300 mg/dl (according to CGMS registration) which
led to a mean glycemia of 175 mg/dl corresponding to a
HbA1c of 6.8%
Agenda
Assess
Underlying causes, Co-morbidities, Assess effects on co-
Weight loss history morbidities, weight,
maintenance and weight
Set goals and propose realistic, individualized and regain.
sustainable lifestyle changes at the log term
Weight loss goal
5-15% of body weight or 0,5-1.0 kg/week
Disease duration
newly diagnosed long-standing
Usually not
Life expectancy modifiable
long short
Important comorbidities
absent few / mild severe
Established vascular
complications absent few / mild severe
• Lifestyle optimization
• Medical nutrition therapy,
• Physical activity,
• Smoking cessation
• Antidiabetic drugs
• Oral agents
• Non insulin injectables
• Insulin injectables
• Therapeutic patient-centered education regarding
• Glycemic targets
• Therapeutic options
LIFESTYLE OPTIMISATION
WEIGHT OPTIMIZATION
HEALTHY DIET
72
Riscuri ale consumului de alcool
Mecanism de actiune
• Metformin controlează insulinorezistenta (acţiunea antidiabetică
necesită insulină în circulaţie):
- Suprimă producţia hepatică de glucoză
- Crește captarea musculară a glucozei mediată de insulină
Metformin scade în principal hiperglicemia a jeun in DZ tip 2
Nu stimulează insulinosecreţia
• Monoterapia cu metformin nu cauzează hipoglicemie
• Metforminul nu cauzează creştere ponderală
Indicații ale Metformin
Indicaţii - Ca monoterapie, sau în combinaţie cu alte
antidiabetice orale sau insulină în DZ tip 2
Utilizare - Se va lua după masă
- Se va creşte doza progresiv, maxim 3 g/zi
Contraindicaţii - Boli renale şi hepatice
şi atenţionări - Insuficienţă cardiacă şi respiratorie
- Infecţii severe, abuz de alcool, istorie de
acidoză lactică, sarcină
- În explorările cu substanţe de contrast iv
Efecte - Simptome gastrointestinale, gust metalic
secundare - Poate altera absorbţia vitaminei B 12 şi a
acidului folic
- Risc de acidoză lactică, dar scăzut.
Derivaţii de sulfoniluree (SU)
Captarea
Pancreas Insulina Glucozei de
Ingestia de (GLP-1 şi GIP) ţesuturile
hrană Glucozo periferice
dependent
β cells
Tract
GI
Eliberare de
Incretine α cells
active GLP-1 şi GIP Glucoza
Glucozo sanguină a jeun
dependent
DPP-4 şi pp
enzyme
Glucagon
(GLP-1)
GLP-1 GIP
Inactiv Inactiv Producţia
Hepatică de
glucoză
• Januvia (Sitagliptin)
• Saxagliptin - recent
• 1tb de 100 mg se adm înainte de masă
• Creşte GLP 1 prin scăderea catabolismului,
inhibând DPP 4.
JANUVIA (sitagliptin) ™†
Mecanism de acţiune
Captarea
Pancreas Insulina Glucozei de
Ingestia de (GLP-1 şi GIP) ţesuturile
hrană Glucozo periferice
dependent
β cells
Tract
GI
Eliberare de
Incretine α cells
active GLP-1 şi GIP Glucoza
Glucozo sanguină a jeun
dependent
şi pp
JANUVIA
(DPP-4 X DPP-4
enzyme Glucagon
(GLP-1)
inhibitor)
GLP-1 GIP
Inactiv Inactiv Producţia
Hepatică de
glucoză
Glucose
SGLT2 S1
S3
SGLT1
↑Glucose reabsorption
↑Glycemia ↓Glycosuria
Indicaţiile insulinoterapiei în DZ tip 2
ADA Standards of Medical Care in Diabetes. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
Combination
Injectable
Therapy in T2DM
CONVENTIONAL
Insulin pumps components
Continuous Subcutaneous Insulin Pump
Unrealistic Realistic
Main DISADVANTAGES
•Pumps on occasion can become occluded
which may lead to diabetic ketoacidosis
•The continuous in-situ catheter is a daily
reminder of the disease and also others may
recognize that the patient has diabetes
CGM Benefits
– Increased security
– Immediate feedback – look and
learn
– BG trend provides more
info than static readings
– Control + safety
Efecte secundare ale insulinoterapiei
Hipoglicemia
Cresterea ponderala
Abcese locale
Alergia la insulina
Lipodistrofia atrofică sau hipertrofică
Dureri la locul injectării
Tulburări de vedere
Edeme insulinice
Insulinorezistenţa
Declansarea unui episod de neuropatie hiperalgica
BARIATRIC SURGERY
β cell
dysfunction
Take Home Message