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Diabet si boli de nutritie
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DIABETES_ LECTUREDIABETES_ LECTURE
PROF. DR. DOINA CATRINOIUPROF. DR. DOINA CATRINOIU
Diabetes MellitusDiabetes Mellitus One of the most common non-One of the most common non-
communicable diseasescommunicable diseases
Fourth leading cause of death in most Fourth leading cause of death in most developed countriesdeveloped countries
More than 194 million people with More than 194 million people with diabetes worldwidediabetes worldwide
Incidence of diabetes is increasing – Incidence of diabetes is increasing – estimated to rise to 333 million by 2025estimated to rise to 333 million by 2025
• To more than double in Africa, the Eastern To more than double in Africa, the Eastern Mediterranean and Middle East, and South-East AsiaMediterranean and Middle East, and South-East Asia
• To rise by 50% in North America, To rise by 50% in North America, 20% in Europe, 20% in Europe, 85% in South and Central Americas and 75% in the 85% in South and Central Americas and 75% in the Western PacificWestern Pacific
: International Diabetes Federation website
Types of Diabetes MellitusTypes of Diabetes Mellitus Type 1 diabetes (insulin-dependent Type 1 diabetes (insulin-dependent
diabetes)diabetes)• mainly in childhood/early adult lifemainly in childhood/early adult life• 10-20% of cases10-20% of cases
Type 2 diabetes (non-insulin-dependent Type 2 diabetes (non-insulin-dependent diabetes)diabetes)• usually develops in the middle-age/elderlyusually develops in the middle-age/elderly• incidence increasing at a younger ageincidence increasing at a younger age• 80-90% of cases80-90% of cases
At least 50% of all people with diabetes At least 50% of all people with diabetes are unaware of their conditionare unaware of their condition
: International Diabetes Federation website
CLASSIFICATION OF DIABETESCLASSIFICATION OF DIABETESImpaired glucose tolerance without Impaired glucose tolerance without
diabetes (IGT)diabetes (IGT)
Primary diabetes mellitusPrimary diabetes mellitus• Insulin dependent (IDDM or Type 1)Insulin dependent (IDDM or Type 1)• Noninsulin dependent (NIDDM or Type 2)Noninsulin dependent (NIDDM or Type 2)
Malnutrition-related diabetes mellitus Malnutrition-related diabetes mellitus (MRDM)(MRDM)
Secondary diabetes mellitusSecondary diabetes mellitus• Pancreatic diseasePancreatic disease• Endocrine disordersEndocrine disorders• Drug therapyDrug therapy• Inherited disordersInherited disorders
Secretia de insulinaSecretia de insulinaSynthesis of insulin
ESR10-08
S
S
S
S
HOOC
SS
NH2
Proinsulin (86aa)
Synthesis of insulin
ESR10-09
S
S
S
S
HOOC
SS
NH2
Insulin (21 + 30aa)HOOC
NH2
- chain
- chain
C - peptide (35aa)
Glucose
Basal-bolus therapy attempts to re-Basal-bolus therapy attempts to re-create physiological insulin secretioncreate physiological insulin secretion
Pre
dic
ted p
lasm
a insu
lin c
once
ntr
ati
on
pro
file
(m
U/l)
Time of day
Rapid-acting insulin
Basal insulin
Total
Diabetes is defined biochemically Diabetes is defined biochemically by the following criteriaby the following criteria
A fastingA fasting venous plasma glucose venous plasma glucose level greater than level greater than 7.8 mmol/litre 7.8 mmol/litre (126 mg/dl)(126 mg/dl) on more than one on more than one occasion; occasion;
oror A 2-hour A 2-hour (plus one other) venous (plus one other) venous plasma glucose level in excess of plasma glucose level in excess of 11.1 mmol/litre (200 mg/dl)11.1 mmol/litre (200 mg/dl) in a in a formal formal 75 g oral 75 g oral glucose tolerance glucose tolerance test test (GTT).(GTT).
Clinical features of diabetes at Clinical features of diabetes at diagnosisdiagnosis
Type 1 Type 2 Type 1 Type 2
Polyuria and thirst ++ +Polyuria and thirst ++ +
Weakness or fatigue ++ +Weakness or fatigue ++ +
Polyphagia with weight loss++ –Polyphagia with weight loss++ –
Recurrent blurred vision + ++Recurrent blurred vision + ++
Vulvovaginitis or pruritus + ++Vulvovaginitis or pruritus + ++
Peripheral neuropathy + ++Peripheral neuropathy + ++
Nocturnal enuresis ++ –Nocturnal enuresis ++ –
Often asymptomatic – ++Often asymptomatic – ++
DIABETES
Fasting plasma glucose 109-125 mg/dl
postprandial plasma glucose > 200mg/dl
Classical Symptoms* +
Blood glucose > 200 mg/dl
Fasting plasma glucose> 126 mg/dl
2-h Plasma glucose after "OGTT" > 200 mg/dl
and/orFasting plasma glucose >
126 mg/dl
Blood glucose 100 -200 mg/dl
A diagnostic algorithm for diabetes mellitus
Blood glucose > 200 mg/dl "occasionally"
ASYMPTOMATIC
INVESTIGATIONSINVESTIGATIONS
Blood glucoseBlood glucose is the key to diagnosis in is the key to diagnosis in diabetes.diabetes.
Glycosylated haemoglobinGlycosylated haemoglobin and other and other proteins: measurement of these proteins proteins: measurement of these proteins reflects the degree of diabetic control in reflects the degree of diabetic control in the previous 4-6 weeks and is of value in the previous 4-6 weeks and is of value in long-term management and control .long-term management and control .
INVESTIGATIONSINVESTIGATIONS
Urine testing for glucose-Urine testing for glucose-glucose will glucose will be found in the urine only when it rises be found in the urine only when it rises above the renal threshold (usually about above the renal threshold (usually about 10 mmol/l10 mmol/l
Urine testing for ketone bodiesUrine testing for ketone bodies the the presence of ketones suggests loss of presence of ketones suggests loss of control.control.
ProteinuriaProteinuria is a reflection of the is a reflection of the development of renal complications and development of renal complications and is an early indicator of diabetic renal is an early indicator of diabetic renal disease Multiple test strips allow rapid disease Multiple test strips allow rapid testing for all these substancesin urine.testing for all these substancesin urine.
INVESTIGATIONSINVESTIGATIONS
ProteinuriaProteinuria is a reflection of the is a reflection of the development of renal complications and development of renal complications and is an early indicator of diabetic renal is an early indicator of diabetic renal disease Multiple test strips allow rapid disease Multiple test strips allow rapid testing for all these substancesin urine.testing for all these substancesin urine.
MicroalbuminuriaMicroalbuminuria is a very sensitive is a very sensitive marker of early and potentially reversible marker of early and potentially reversible renal impairment; it is the term given to renal impairment; it is the term given to the presence of protein below the level of the presence of protein below the level of detection with the stick methods, that is detection with the stick methods, that is 200 mg/litre.200 mg/litre.
INVESTIGATIONSINVESTIGATIONS
Serum electrolytes, blood gases, Serum electrolytes, blood gases, osmolality and anion gaposmolality and anion gap are all are all of value in metabolic crises if there is of value in metabolic crises if there is loss of water, sodium and potassium loss of water, sodium and potassium and acidosis is developing, or if there and acidosis is developing, or if there is a hyperosmolar state.is a hyperosmolar state.
Lipid profileLipid profile: elevations in serum : elevations in serum cholesterol are common, and cholesterol are common, and elevation of serum triglycerides is a elevation of serum triglycerides is a reflection of poor glycaemic control, reflection of poor glycaemic control, which usually reverts to normal when which usually reverts to normal when euglycaemia is achieved. euglycaemia is achieved.
PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES
AcuteAcute: the typical presentation of the young : the typical presentation of the young patient with IDDM; features include polyuria, patient with IDDM; features include polyuria, polydipsia and weight loss of short duration, polydipsia and weight loss of short duration, often associated with, or apparently often associated with, or apparently precipitated by, a viral infection;visual precipitated by, a viral infection;visual disturbance or impairment of the conscious disturbance or impairment of the conscious level associated with severe ketoacidosis level associated with severe ketoacidosis
ChronicChronic: the typical presentation of a patient : the typical presentation of a patient with NIDDM; the symptoms have usually been with NIDDM; the symptoms have usually been present for some months and often include present for some months and often include weight loss, thirst, excess urine volume, genital weight loss, thirst, excess urine volume, genital and skin infectionsand skin infections
PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES
Coincidental discoveryCoincidental discovery: routine : routine screening for urine or blood glucose as screening for urine or blood glucose as part of a pre-employment medical, during part of a pre-employment medical, during pregnancy or in local campaignspregnancy or in local campaigns
ComplicationsComplications: visual disturbance or : visual disturbance or overt retinopathy, neuropathy, overt retinopathy, neuropathy, nephropathy or after major thrombotic nephropathy or after major thrombotic events such as premature stroke or events such as premature stroke or myocardial infarction myocardial infarction
PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES
Drug-relatedDrug-related diabetes may develop in diabetes may develop in patients on long-term steroids or thiazide patients on long-term steroids or thiazide diureticsdiuretics
Disease-related Disease-related as in acromegaly, as in acromegaly, Cushing's syndrome, Cushing's syndrome, phaeochromocytoma, thyrotoxicosis, phaeochromocytoma, thyrotoxicosis, pancreatitis, haemochromatosis, cystic pancreatitis, haemochromatosis, cystic fibrosis, carcinoma or surgical removal of fibrosis, carcinoma or surgical removal of the pancreasthe pancreas
GestationalGestational: pregnancy may unmask : pregnancy may unmask diabetes in a woman who is predisposed. A diabetes in a woman who is predisposed. A full history and clinical examination are full history and clinical examination are essential to detect any of the causative essential to detect any of the causative diseases and document the consequences.diseases and document the consequences.
PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES
Patients with type 2 diabetes may Patients with type 2 diabetes may or may not have characteristic or may not have characteristic features. The presence of features. The presence of obesity or a strongly positive obesity or a strongly positive family history for mild diabetes family history for mild diabetes suggests a high risk for the suggests a high risk for the development of type 2 diabetes.development of type 2 diabetes.
DM Kendall et al. Eur J Intern Med 20, ( 2009) S329–S339 Prin amabilitatea Prof. Dr. N. Hâncu
Adapted from IDC, MinneapolisDiabetes duration (years)
-20 -10 0 10 20 30
Obesitate IGT Diabet [necontrolat]
Postprandial
Fasting
insulinorezistenta
Insulin Level
Treatmentul DZ tip 2: „inlocuirea deficitului“Treatmentul DZ tip 2: „inlocuirea deficitului“
Glicemia(mg/dl)
Functia ß-celulara
(%)
126
100
The Progression from CV Risk Factors to The Progression from CV Risk Factors to Endothelial Injury and Clinical EventsEndothelial Injury and Clinical Events
The Progression from CV Risk Factors to The Progression from CV Risk Factors to Endothelial Injury and Clinical EventsEndothelial Injury and Clinical Events
Risk factors
Oxidative stress
Endothelial dysfunction
NO Local mediators Tissue ACE-Ang II
PAI-1 VCAM
ICAM cytokines
Endothelium Growth factors matrix
Proteolysis
LDL-C BP Heart failureSmokingDiabetes
Vasoconstriction Vascular lesion and remodelling
Plaque ruptureInflammationThrombosis
Clinical endpoints
NO Nitric oxideGibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.
The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors
Insulin Resistance
AtherosclerosisAtherosclerosis
Endothelial Dysfunction
Hypertension
Abdominal obesity
Hyperinsulinaemia
Dyslipidaemia• high TGs
• small dense LDL• low HDL-C
Diabetes
Hypercoagulability
Deedwania PC. Am J Med 1998;105(1A);1S-3S.
NCEP ATP III: The Metabolic NCEP ATP III: The Metabolic SyndromeSyndrome
<40 mg/dL (1.0 mmol/L)<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)<50 mg/dL (1.3 mmol/L)
MenMenWomenWomen
>102 cm (>40 in)>102 cm (>40 in)>88 cm (>35 in)>88 cm (>35 in)
MenMenWomenWomen
110 mg/dL (6.0 mmol/L)110 mg/dL (6.0 mmol/L)Fasting glucoseFasting glucose130/130/85 mm Hg85 mm HgBlood pressureBlood pressure
HDL-CHDL-C150 mg/dL (1.7 mmol/L)150 mg/dL (1.7 mmol/L)TGTG
Abdominal obesity Abdominal obesity (Waist circumference)(Waist circumference)
Defining LevelDefining LevelRisk FactorRisk Factor
Recommends a diagnosis when 3 of these risk factors are present
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.
WHO: The Metabolic SyndromeWHO: The Metabolic Syndrome
A working definition is glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the following:
• Raised arterial pressure 160/90 mmHg
• Raised plasma triglycerides (1.7 mmol/L, 150 mg/dL) and/or low HDL-C (men <0.9 mmol/L, 35 mg/dL; women <1.0 mmol/L, 39 mg/dL)
• Central obesity
• Microalbuminuria (UAER 20 g/min or albumin: creatinine ratio 20 mg/g)
Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.
TREATMENTTREATMENT
Type 1 diabetes ONLY INSULIN – is a Type 1 diabetes ONLY INSULIN – is a replacement therapyreplacement therapy
Type 2 diabetes ORAL DRUGS+/- Type 2 diabetes ORAL DRUGS+/- INSULIN THERAPYINSULIN THERAPY
Human insulins do not closely match the endogenous insulin response
Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8
Insulin analogues address the limitations of human insulin
Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8
Defining glucose variability• Hypoglycaemic events
• Postprandial glucose excursions
• Minor fluctuations in blood glucose levels
Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S150–4
Nonglycemic effects of oral therapyCardiovascular Cardiovascular risk factorrisk factor
SulfonilSulfonilureaurea
Rapid-Rapid-acting acting insulin insulin secretagosecretagoguesgues
MetforMetforminmin
ThiazolidindiThiazolidindionesones
--glucosidaglucosidase se inhibitorsinhibitors
Insulin resistanceInsulin resistance
HyperinsulinemiaHyperinsulinemia
LDL chol levelsLDL chol levels
LDL particle patternLDL particle pattern
HDL chol levelsHDL chol levels
TriglyceridesTriglycerides
LP (a)LP (a)
PAI-1PAI-1
Endothelial functionEndothelial function
Body weightBody weight
Visceral adiposityVisceral adiposity
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00
00
00
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00
00
00
00
00
00
??
??
00
or 0or 0
Large buoyantLarge buoyant0 or 0 or
00
00
00
00
00
00
00
00
00
00
Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933
Potential down-sides of pharmacological treatment modalities in patients with
T2DMPotential problemPotential problem Avoid or reconsiderAvoid or reconsider
Unwanted weight gainUnwanted weight gain
Gastrointestinal symptomsGastrointestinal symptoms
Hypoglycemia Hypoglycemia
Impaired kidney functionImpaired kidney function
Impaired liver functionImpaired liver function
Impaired cardio-pulmonary Impaired cardio-pulmonary functionfunction
Sulphonylureas, glinides, Sulphonylureas, glinides, glitazones, insulinglitazones, insulin
Biguanides, alpha-glucosidase Biguanides, alpha-glucosidase inhibitorsinhibitors
Sulphonylureas, glinides, Sulphonylureas, glinides, insulininsulin
Biguanides, sulphonylureasBiguanides, sulphonylureas
Glinides, glitazones, Glinides, glitazones, biguanides, alpha-glucosidase biguanides, alpha-glucosidase
Biguanides, glitazonesBiguanides, glitazones
ESC, EASD Guidelines, 2007
Suggested policy for the selection of glucose-lowering therapy according to the glucometabolic
situation
Post-prandial Post-prandial hyperglycemiahyperglycemia
Fasting hyperglycemiaFasting hyperglycemia
Insulin resistanceInsulin resistance
Insulin deficiencyInsulin deficiency
alpha-glucosidase inhibitors, short-alpha-glucosidase inhibitors, short-acting SU, glinides, short-acting acting SU, glinides, short-acting regular insulin or insulin analogsregular insulin or insulin analogs
Biguanides, long-acting SU, glitazones, Biguanides, long-acting SU, glitazones, long-acting insulin or insulin analogslong-acting insulin or insulin analogs
Biguanides, glitazones, alpha-Biguanides, glitazones, alpha-glucosidase inhibitorsglucosidase inhibitors
SU, glinides, insulinSU, glinides, insulin
ESC, EASD Guidelines, 2007
Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York: Medical Information Press; 2004:145―68.
Persistent HbA1c
>7%
Revisit T2DM treatment strategies: the evolving HbA1c position
Achieving and maintaining HbA1c at target may require
incremental and combination therapies
Treat-to-target concept
Realistic target: lowest HbA1c possible without
unacceptable hypoglycaemia
Healthy individual HbA1c 4–6%
ACTION
Summary of antidiabetic interventions as monotherapy
InterventionsInterventions Expected Expected decrease decrease
in A1c in A1c (%)(%)
AdvantagesAdvantages DisadvantagesDisadvantages
Step 1: initialStep 1: initial Lifestyle to decrease weight Lifestyle to decrease weight and increase activityand increase activity MetforminMetformin
Step 2: additional therapyStep 2: additional therapy InsulinInsulin
SulphonylureasSulphonylureas TZDsTZDs
Other drugsOther drugs -glucosidase inhibitors-glucosidase inhibitors
ExenatideExenatide
GlinidesGlinides PramlintidePramlintide
1-21-2
1.51.5
1.5-2.51.5-2.5
1.51.50.5-1.40.5-1.4
0.5-0.80.5-0.8
0.5-1.00.5-1.0
1-1.51-1.50.5-1.00.5-1.0
Low cost, many Low cost, many benefitsbenefitsWeight neutral, Weight neutral, inexpensiveinexpensive
No dose limit, No dose limit, inexpensive, inexpensive, improved lipid profileimproved lipid profileInexpensiveInexpensiveImproved lipid Improved lipid profileprofile
Weight neutralWeight neutral
Weight lossWeight loss
Short durationShort durationWeight lossWeight loss
Fails for most in first yearFails for most in first yearGI side effects, rare lactic GI side effects, rare lactic acidosisacidosis
Injections, monitoring, Injections, monitoring, hypoglycemia, weight gainhypoglycemia, weight gain
Weight gain, hypoglycemiaWeight gain, hypoglycemiaFluid retention, weight Fluid retention, weight gain, expensivegain, expensive
Frequent GI side effects, Frequent GI side effects, expensiveexpensiveInjections, frequent GI side Injections, frequent GI side effects, expensive, little effects, expensive, little experienceexperience3x/ day dosing, expensive3x/ day dosing, expensiveInjections, frequent GI side Injections, frequent GI side effects, expensive, little effects, expensive, little experienceexperience
A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21
Diagnosis
Lifestyle intervention + metformin
Add basal insulin
-most efective
Add sulfonylurea-least expensive
Add glitazone-no hypoglycamia
HbA1C≥7%HbA1C≥7%HbA1C≥7%
HbA1C≥7%
Intensify insulin Add glitazone Add basal insulin Add sulfonylurea
HbA1C≥7% HbA1C≥7%
Add basal or intensify insulin
Intensive insulin + metformin +/- glitazone
A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21
Algorithm for the metabolic management of T2DMStrategii si algoritmuri
Management of hyperglycemia in type 2 diabetesHow do I establish and sustain glycemic control?
Lifestyle change: an option?
Is metformin still the first line drug?
Which drugs after metformin?
Sulphonylureas, TZDs or insulin?
And then? Three oral agents, insulin as add-on or insulin alone?
What is the evidence for the proposed algorithm?
Will new drugs be able to halt the decline of beta-cell function?
Q & A
RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204
Contraindications can damage your health—is metformin a case in point?
Standard contraindications to the use of metformin should be relaxed, and that the benefits of reducing the number of patients excluded from using it would by far outweigh the potential risks
propose removal of the following contraindications from the list:
1. old age
2. chronic renal insufficiency (as long as GFR>40 ml/min)
3. chronic heart failure (NYHA stages I and II)
4. discontinuation of metformin therapy 2 days before surgery and i.v. contrast medium administration
A clear re-definition of metformin contraindications will enable more physicians to prescribe within the guidelines
The main effect of revising these contraindications and precautions will be to bring the official guidelines into harmony with day-to-day clinical practice
A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59
Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160
Insulin
Oral agents
SIOFOR 1000
Management ofType 2 Diabetes
Glycemic controlDiet / LifestyleExerciseMedication
Treat associatedconditions
DyslipidemiaHypertensionObesityCoronary heartdisease
Screen for/managecomplications of
diabetesRetinopathyCardiovasculardiseaseNephropathyNeuropathyOther complications
Dyslipidemia in Diabetes
Triglycerides HDL
HMG CoAreductase inhibitor
Triglycerides HDL LDL
LDL
Medical nutritional therapy, increased physical activity
Improve glycemiccontrolHMG CoAreductase inhibitor
Improve glycemiccontrol
GLP-1GLP-1
Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier© 2007.
Ţesut
adipos
SNC
Ficat
Pancreas
Muşchi
Stomac
Preluarea şi stocarea glucozei
Sensibilitate la insulină Secreţia de insulină
Secreţia de glucagon
Sinteza de insulină
Proliferarea beta-celulară
Apoptoza celulelor beta
Evacuarea conţinutului gastric
ApetitulNeuroprotecţie
Cardioprotecţie
Funcţia cardiacă
Producţia de glucoză
Cord
GLP-1
Intestinul
Efects ofGLP-1 in healthy Efects ofGLP-1 in healthy subjectssubjects
50
Eliberare de insulină
Insulină
Exenatid is not Exenatid is not iinactivatednactivated by by DPP-4DPP-4
51Insulină
Eliberare de insulină
Basal insulinBasal insulin• Suppresses glucose production between Suppresses glucose production between
meals and overnightmeals and overnight
• 40% to 50% of daily needs40% to 50% of daily needs
Bolus insulin (mealtime)Bolus insulin (mealtime)• Limits hyperglycaemia after mealsLimits hyperglycaemia after meals
• Immediate rise and sharp peak at 1 hour Immediate rise and sharp peak at 1 hour
• 10% to 20% of total daily insulin10% to 20% of total daily insulin requirement requirement at each meal at each meal
The basal/bolus insulin conceptThe basal/bolus insulin concept