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Course no 1

DIABETES MELLITUS
• Diabetul zaharat
Curs 1

2019
Agenda

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
HISTORIC LANDMARKS OF DIABETES
Aretaeus from
Cappadocia
81-138 AC Paul Langerhans
(1847 – 1888)

Nicolae C. Paulescu
(1869-1931)

Introduced the term


“diabetes”
Frederick Charles
Described the Banting Best
“Langerhans islets”

1911 - Extracted from the pancreas


the antidiabetic hormone, which he
named pancreatin
1923 - Received Nobel prize for discovering
the insulin. Administered for the first time
CI Targoviste. Tratat de Diabet Paulescu. 2004 purified insulin to one children
Agenda

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition of and classification diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
POSTPRANDIAL GLUCOSE HOMEOSTASIS
Protein synthesis
Formation of protein from amino Glycolysis
acids in liver and muscle Breakdown of glucose to
release energy

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

The pancreas is comprised of two major functional compartments:


– exocrine pancreas (99%) produces enzymes for digestion
(amylase, lipase, proteases)
– endocrine pancreas (1%) contains the islets of Langerhans,
which have five hormone-producing cell types:
o alpha (α) cells (20-30%) – that produces glucagon
o beta (β) cells (60-70%) – that produces insulin, proinsulin, C Glucose
homeostasis
peptide, amylin
o delta (δ) cells (10%) – that produces somatostatin
o PP cells (<5%) – that produces pancreatic polypeptide
Regulation of
o epsilon (ε) cells (1%) - that produces ghrelin. appetite
Structure of the pancreas
BIOSYNTHESIS of INSULIN
• Insulin is initially synthesized as PREPROINSULIN.
• Cleavage of the signal peptide generates the PROINSULIN.
• Cleavage of PROINSULIN generates the:
• C PEPTIDE (31 aa)
• INSULIN composed by A (21 aa) and B (30 aa) chains which are connected by disulfide
bonds.
• Insulin and C peptide are cosecreted from secretory granules in the beta cells.
INSULIN SECRETION
• GLUCOSE is the main trigger of insulin secretion
• GLUCOSE enters the beta-cell via the GLUT-2 transporter protein.
• Metabolism of glucose via glycolytic enzyme glucokinase which generates ATP.
• ATP closes potassium channels in the cell membrane (A)
• Closure of potassium channels predisposes to cell membrane depolarization
• Membrane depolarisation allow calcium ions to enter the cell via calcium channels (B).
• The rise in intracellular calcium leads to fusion of the insulin-containing granules with the cell
membrane and exocytosis of the insulin-rich granule contents.
INSULIN SIGNALING PATHWAYS
Insulin secretion by pancreatic
beta-cells is 24 h/day
Insulin is a hypoglycemic and
anabolic hormone

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)

Unger RH. N Eng J Med. 1971;285:443-449.


Copyright © 1971 Massachusetts Medical Society. All rights reserved. Translated with permission 2006.
Agenda

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
Definition of diabetes mellitus (DM)

• DM is characterized by:

– defects of insulin secretion, insulin action or both


– chronic hyperglycemia
– disturbances of carbohydrate, fat and protein
metabolism
Definition of prediabetes (PreDM)

• PreDM (Categories of Increased Risk for Diabetes)


is defined as glucose levels which did not meet the
criteria for diabetes, but were too high to be considered
normal
• PreDM is represented by:
– Impaired fasting glucose (IFG) and/or
– Impaired glucose tolerance (IGT) and/or
– Increased HbA1c
Classification
I. Type 1 diabetes (β -cell destruction, usually leading to
absolute insulin deficiency)
- Autoimmune (90% of cases)
- Idiopathic (10% of cases)

II. Type 2 diabetes (progressive insulin secretory defect and


insulin resistance)
III. Gestational diabetes mellitus (GDM) (diabetes
diagnosed at 24-28 weeks of pregnancy).
Classification
IV. Specific types of diabetes - due to other causes.
• Genetic defects of β-cell function (MODY - Maturity Onset Diabetes of
Young, etc)
• Genetic defects of insulin action (Type A insulin resistance, etc)
• Diseases of exocrine pancreas (acute/chronic pancreatitis, trauma,
pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, etc)
• Endocrinopathies (Cushing syndrome, Acromegaly, pheochromocytoma,
glucagonoma, etc)
• Drug/chemical induced (glucocorticoids, thiazides, etc)
• Infections (congenital rubella, cytomegalovirus, etc)
• Uncommon forms of immune-mediates disease (insulin autoimmune
syndrome, anti insulin receptor antibody, “Stiff man” syndrome), etc
• Other genetic syndromes (Down syndrome, Huntington chorea,
Klineffelter syndrome, Prader Willy syndrome, Turner syndrome, etc ).
Agenda

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
HYPERGLYCEMIA
The defining feature of diabetes

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

Impaired Insulin Secretion

Increased HGP Decreased Glucose Uptake

HGP=hepatic glucose production. DeFronzo RA. Diabetes. 2009;58:773-795


Classic concept
Hyperglycemia triad
Islet b-cell

Impaired Insulin Secretion

Decreased Glucose Uptake


Increased HGP
DeFronzo RA. Diabetes. 2009;58:773-795
The Disharmonious Quartet

Islet b-cell

↑ FFA

Impaired Insulin Secretion Increased Lipolysis

Increased HGP

FFA=free fatty acids. Decreased Glucose Uptake


DeFronzo RA. Diabetes. 2009;58:773-795
The Disharmonious Quartet
Increased lipolysis

 Lipolysis
Muscle Liver
 FFA and Glycerol

β-cells

Glucose uptake  Gluconeogenesis


and utilisation β-cell dysfunction

Boden G. Proc Assoc Am Physicians. 1999;111:241-248.


The Quintessential Quintet

Islet b-cell

Decreased
Incretin Effect

Impaired Insulin Secretion


Increased Lipolysis

Increased HGP Decreased Glucose Uptake


DeFronzo RA. Diabetes. 2009;58:773-795
The Quintessential Quintet
↓ Incretin effect
Incretin effect Consequences of decreased incretin effect

↓ Appetite • Weight gain

• Postprandial hyperglycemia
Delays gastric emptying

↑ Glucose-mediated insulin • Postprandial hyperglycemia


secretion

↑ Supression of glucose- • Postprandial hyperglycemia


mediated glucagon secretion

↑β cells neogenesis • β cell dysfunction


↓ β cells apoptosis
The Setaceous Sextet
Islet b-cell

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 Increased Glucose


Glucagon Secretion Reabsorption

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

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
Diabetes worldwide …

Diabetes in Romania - PREDATORR 2013 …


DIABETES WORLDWIDE PREVALENCE

Diabetes is a huge and growing problem!


ROMANIA Studiul PREDATORR 2013/ 2014

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

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
DIAGNOSIS OF DM - SYMPTOMS
- Thirst (intracellular dehydration caused by hyperosmolarity,
stimulation of the hypothalamic thirst center by hyperosmolarity)
- Polyuria (osmotic diuresis induced by glycosuria)
- Weight loss (insulin defficiency which led to decreased glucose
utilisation, glycosuria – caloric loss, lipolysis)
- Feeling very hungry
- Blurring of vision
- Extreme fatigue
- Recurent infections
- Precoma/coma in more severe cases
- 30-50% of type 2 diabetic patients may be totally asymptomatic
or they already have the signs of chronic complications – the
necessity of screening
DIAGNOSIS OF DM - SYMPTOMS
CRITERIA FOR THE DIAGNOSIS OF DM AND PREDM
CRITERIA FOR THE
DIAGNOSIS OF DM

A! In the absence of unequivocal


hyperglycemia, results should be
confirmed by repeat testing on a
separate day.
CRITERIA FOR THE DIAGNOSIS OF INCREASED RISK
FOR DIABETES (PREDIABETES)
SCREENING OF DM OR PREDM IN ASYMPTOMATIC ADULTS
DETECTION AND DIAGNOSIS OF GDM

• Screen for GDM at 24–28 weeks of gestation in pregnant women


not previously known to have diabetes
• Screen women with GDM for persistent diabetes at 6–12 weeks
postpartum, using OGTT, nonpregnancy diagnostic criteria
• Women with a history of GDM should have lifelong screening for
the development of diabetes or prediabetes at least every 3 years
• Screen for undiagnosed type 2 diabetes at the first prenatal visit
in those with risk factors, using nonpregnancy diagnostic criteria
DIAGNOSIS OF GDM

Diabetes diagnosed before 24th week or after 28th week


is not gestational!!
Trends Better Than Points

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?

• How do you explain the lack of concordance


between HbA1c and glycemia?

• Do you need other laboratory tests to


establish the diagnosis?
• There is no concordance between HbA1c and blood glucose.

• Case no 1: The high glycemic value is explained by the presence of an acute


infection (suggested by the fever, cough with purulent expectoration). The lack
of concordance between high glycemia and normal HbA1c is due to the short
duration of hyperglycemia, which did not have enough time to glicate the
hemoglobin.

• Case no 2: A high glycemia associated with normal HbA1c, in the absence of


signs or symptoms of hyperglycemia may be a laboratory error!!

FPG should be repeated in order to confirm/infirm the diagnosis of diabetes


(the patient does not have the signs or symptoms of hyperglycemia)
Case no 3 Case no 4
Personal history of diabetes Type 1 DM Type 1 DM
Duration of diabetes 10 years 10 months
Student, Call Center Operator
Basketball player Constant work schedule
Variable work schedule
HbA1c 6.8% 6.8%
Glycemia at the time of the last 315 mg/dl 115 mg/dl
visit at the diabetologist
Case 3 (HbA1c 6.8%)
SEVEN PLUS (Dex Com)

MiniMed Paradigm
System (Medtronic)

Case 4 (HbA1c 6.8%)

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

• Historic landmarks of diabetes


• Glucose homeostasis. Insulin biosynthesis, secretion and role
• Definition and classification of diabetes and prediabetes
• Pathogeny of diabetes
• Epidemiology of diabetes
• Diagnosis of diabetes and prediabetes
• Management of diabetes and prediabetes
MANAGEMENT OF PATIENT WITH DIABETES
• Management of Hyperglycemia
• Management of associated CVD risk factors such as:
– Smoking,
– Dyslipidemia,
– Obesity
– Hypertension
• Prevent, diagnose and treat acute complications of diabetes
(next course)
• Screening and treatment of chronic complication of
diabetes (next course)
• Good control is important. Therapy targets should be individually
determined for each case
Weight loss goal
Overweight and Obesity
If BMI ≥ 25kg/m²
or WC ≥ 94/80 cm for man/women

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

Management (Nutrition, physical activity, cognitive


behavioral therapy, pharmacotherapy, metabolic Weight loss goal
surgery, prevention and treatment of co morbidity) achieved
Hypertension and diabetes
Systolic targets/ Diastolic targets

• People with DM and HTN should be treated to a


systolic/ diastolic BP goal of <140/ 90 mmHg.
• Lower systolic/ diastolic targets (<130/ 80 mmHg),
may be appropriate for:
- younger patients,
- those with albuminuria,
- HTN and one or more additional ASCVD risk factors.
Lipid Targets for Pacients with Type 2 DM
GLYCEMIC TARGETS FOR NONPREGNANT
ADULTS WITH DIABETES
A1C <7.0%*
(<53 mmol/mol)
Preprandial capillary 80–130 mg/dL*
plasma glucose (4.4–7.2 mmol/L)
Peak postprandial capillary <180 mg/dL*
plasma glucose† (<10.0 mmol/L)

* Goals should be individualized.


† Postprandial glucose measurements should be
made 1–2 hours after the beginning of the meal.
INDIVIDUALIZATION OF GLYCEMIC
Approach to the managementTARGETS
of hyperglycemia
more HbA1c less
stringent 7% stringent
PATIENT / DISEASE FEATURES
Risks potentially associated
with hypoglycemia and low high
other drug adverse effects

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

Patient attitude and


expected treatment efforts highly motivated, adherent, less motivated, non-adherent, Potentially
excellent self-care capacities poor self-care capacities modifiable

Resources and support


Readily available limited
system
MANAGEMENT OF HYPERGLYCEMIA

• 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

INCREASED ACTIVITY LEVEL


THERAPEUTIC LIFESTYLE CHANGES
Parameter Treatment Goal
Weight loss • Reduce by 5% to 10% (for overweight and obese patients)
Physical • Least 150 min/week of moderate-intensity aerobic physical activity,
activity spread over at least 3 days/week with no more than 2 consecutive days
without exercise.
• Attention to hypoglycemia risk and chronic complications of DM –
diabetic neuropathy, diabetic foot ulcers, proliferative diabetic
retinopathy, ischemic heart disease!!!
Diet • Medical nutrition therapy is recommended for all people with diabetes
as treatment
• Eat regular meals and snacks; avoid fasting to lose weight
• Understand Nutrition Facts Label information
• Incorporate beliefs and culture into discussions
• Use mild cooking techniques instead of high-heat cooking
Alcohol • No more than one drink per day for adult women and no more than two
drinks per day for adult men
• Alcohol consumption may increase the risk for hypoglycemia, especially if
taking insulin or insulin secretagogues

72
Riscuri ale consumului de alcool

• Crește riscul de hipoglicemie


• Crește riscul ca hipoglicemia să nu fie diagnosticată
• Indiferența pacienților legată de tratament/dietă
• Crește apetitul
• Agravarea hiperTG
• Agravarea neuropatiei, bolilor pancreatice si hepatice.
HEALTHFUL EATING RECOMMENDATIONS
Carbohydrate • Specify healthful carbohydrates (fresh fruits and vegetables, legumes,
whole grains); target 7-10 servings per day
• For people with T1DM or T2DM on a flexible insulin program, education
on carb counting and can improve glycemic control.
• For people whose daily insulin dosing is fixed, a consistent pattern of
carb intake can result in improved glycemic control and a reduced risk of
hypoglycemia
Fat • Specify healthful fats (low mercury/contaminant-containing nuts,
avocado, certain plant oils, fish)
• Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods)
and trans fat; choose low-fat dairy products
Protein • Consume protein in foods with low saturated fats (fish, egg whites,
beans)
• There is no need to avoid animal protein
• Avoid or limit processed meats
Micronutrients • Routine supplementation is not necessary; a healthful eating meal plan
can generally provide sufficient micronutrients
• Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are
not recommended for glycemic control
• Vitamin supplements should be recommended to patients at risk of
insufficiency or deficiency 74
PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES

All people with Type 1 DM need insulin treatment for survival!!


ANTI-HYPERGLYCEMIC THERAPY FOR TYPE 2 DIABETES

Oral agents Insulin injectables


• Metformin Human Insulins
• Sulfonylureas • Neutral protamine Hagedorn (NPH)
• Thiazolidinediones • Regular human insulin
• DPP-4 inhibitors • Pre-mixed formulations
• SGLT-2 inhibitors Insulin Analogues
• Meglitinides • Basal analogues (glargine, detemir,
• a-glucosidase inhibitors degludec)
• Bile acid sequestrant • Rapid analogues (lispro, aspart,
• Dopamine-2 agonists glulisine)
• Pre-mixed formulations.
Non insulin injectables
• GLP-1 receptor agonists
• Amylin mimetics.
PHARMACOLOGICAL THERAPY FOR TYPE 2 DIABETES
Metformin

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)

Generaţia I: hipoglicemiante slabe


Tolbutamida, Clorpropamida, Tolazamida

Generaţia a II-a: hipoglicemiante puternice


- Glibenclamid (MANINIL): cp 5 mg, 1,75 mg, 3,5 mg
- Gliclazid (DIAPREL): cp 80 mg, 30 mg , 60mg
- Glipizid (GLUCOTROL XL): cp 5 mg, 10 mg
- Gliquidon (GLURENORM): cp 30 mg

Generaţia a III-a: hipoglicemiant puternic


- Glimepirid (AMARYL): cp 1, 2, 3, 4, 6 mg.
Derivaţii de sulfoniluree (SU)
Mecanism de acţiune
● Stimulează secreţia de insulină din celulele beta
pancreatice (faza I a secreţiei insulinice) prin acţiune
asupra canalelor de K+
Reactii adverse
• Hipoglicemie:
– favorizată de: alcool, nealimentaţie, vârstă peste 70 de ani,
efort, afecţiuni hepatice, insuficienţă renală
– durată lungă (câteva ore, chiar zile) - necesită supraveghere
• Digestive: greţuri, vărsături, anorexie, alterarea probelor
hepatice
• Hematologice (rare dar foarte severe): pancitopenie, anemie
hemolitică, trombocitopenie
Meglitinidele
Mecanism de acţiune:
- Stimulează secreţia de insulină
Durată de acţiune scurtă:
- Controlează glicemia imediat după masă
Reprezentanţi:
– Repaglinida (Novonorm): cp 0,5, 1, 2 mg
• doza: 1,5-16 mg/zi
“o masă, o doză, nici o masă, nici o doză”
– Nateglinida (Starlix)
Reacţii adverse:
- Hipoglicemia.
Inhibitorii de alfa-glucozidază
• Mecanism de acţiune: inhibă alfa-glucozidaza
intestinală => scade digestia glucidelor, care vor fi
eliminate în scaun
• Reprezentanţi:
– Acarboza (GLUCOBAY) de 50mg şi 100mg
– Miglitol
• Reacţii adverse:
– meteorism, flatulenţă
– insuficienţă hepatică.
Rolul Incretinelor în homeostazia glicemică

 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

*Incretinele sunt totuşi eliberate în tot cursul zilei, la nivel bazal.


Agoniști de receptori de GLP
Exenatide (Byetta) / injectabil, sc
- 2 injecţii/zi de 5 microgr
Sau
- 2 injecţii/zi de 10 microgr
• Se adm înainte de masă, cu maxim 60 min
• Durata între prize va fi mai mare de 6 ore
Bydureon 2mg – formă cu acțiune prelugită: durata 7 zile.
Administrare injectabil, sc.
Inhibitorii de DPP4

• 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

*Incretinele sunt totuşi eliberate în tot cursul zilei, la nivel bazal.


Inhibitori ai SGLT 2 (transportori de Na-
glucoza)

• Actioneaza la nivel renal, inhiband reabsorbtia de


glucoza si de Na
• Se pierd aprox 70g de glucoza prin urina
• Actiune:
- Scade glicemia
- Scade greutatea
- Scad valorile tensionale
Contraindicatii: RFG-e sub 60 ml/min/1,73m²
Inhibitori ai SGLT 2 (transportori de Na-glucoza)

Glucose

SGLT2 S1

S3
SGLT1

↑Glucose reabsorption

↑Glycemia ↓Glycosuria
Indicaţiile insulinoterapiei în DZ tip 2

• Eşecul terapiei cu ADO: doze maxime tolerate


• Contraindicaţii ADO: boli hepatice, renale
• Reacţii adverse ale ADO
• Stres metabolic acut: infecţii, abdomen acut, IMA,
AVC, interventii chirurgicale
• Complicaţii acute: cetoacidoza diabetică, starea
hiperglicemică hiperosmolară
• Sarcina şi lactaţie.
ANTIHYPERGLYCEMIC THERAPY IN T2DM – ADA 2018

ADA Standards of Medical Care in Diabetes. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
Combination
Injectable
Therapy in T2DM

American Diabetes Association Standards of Medical Care in Diabetes.


Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
PHARMACOKINETICS OF INSULIN
INSULIN REGIMENS
INTENSIVE

CONVENTIONAL
Insulin pumps components
Continuous Subcutaneous Insulin Pump

• Basal insulin is supplied in the form of a


continuous infusion (40 to 60 percent of the total
daily dose) with pre-meal bolus doses given to
minimize postprandial glucose excursions.
• Only short acting insulin are used.
• Types:
– Conventional Insulin pump (CSII)
– Sensor-augmented insulin pump (CSII with CGMS)
Asigurarea insulinemiei bazale prin
pompă:
- Insulina se eliberează continuu, în anumite cantităţi ce se
programează pe oră, constituind rata bazală, adaptată
necesarului fiecărei persoane şi ţinând seama de perioadele
de insulinorezistenţă.
Physiologic insulin secretion
Insulin pump therapy
Prandial boluses which covers
the mealtime carbs intake

Basal rate which covers


fasting and interprandial
hepatic glucose
production

Basal rate increased to help Basal rate reduced to help prevent


prevent nocturnal hypoglycemia
Expectations regarding insulin pump

Unrealistic Realistic

The pump will cure my diabetes. I will feel better.


I won’t have to test as much. I must test at least 4 times a day.
I can eat anything I want. I will have more freedom with my
food choices if I bolus for my carb
intake.
My blood sugar will be perfect. I will have better control with fewer
lows.
It will be very easy to start a It will take time to learn and adjust
pump. to the pump.
Main ADVANTAGES
• Simulates normal physiologic insulin delivery
• Improved lifestyle flexibility
• One needle stick every 3 days

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

Bariatric surgery may be considered for adults with BMI


≥35 kg/mp and type 2 diabetes, especially if diabetes or
associated comorbidities are difficult to control with
lifestyle and pharmacological therapy.
↑ Lipolysis

β cell
dysfunction
Take Home Message

All of the Knowledge we have


does no good if…….….
……the patient does NOT take
their medication or does NOT take
it correctly

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