Diabetes Mellitus
Dr. CAI MengyinDepartment of Endocrinology
3rd Affiliated HospitalSun Yat-sen University
•Populous country with westernized lifestyle
•Limited resources for healthcare expenditure
•Increasing prevalence of obesity
The official mascots of the Beijing 2008 Olympic Games
Populous country with obesity pandemic
Asia countries are facing challenge from Diabetes
Economy taking-off like a rocket with dramatic lifestyle change
State “on Bicycle”
Traffic jam in Beijing
Coupon for food in Guangzhou
One week’s food for a family in Beijing
Exercise less Eat More
Prevalence rate of Diabetes
Throughout the world: 150 millions
? 2%
USA: 15 millions
China: 9.7% -- N Engl J Med 2010;362:1090-101.
Canton: 1980
0.411% in 42788
China: 1980
0.609% in 304537
What is Diabetes Mellitus?
Definition:
Syndrome
Metabolic disorder of multiple etiology (causes) characterized by hyperglycemia with carbohydrates, fat, and protein metabolic alterations, which result in defects in the secretion or action of insulin, or both.
HyperglycemiaX or Metabolic Syndrome
Metabolic abnormalities and by long-term complications involving eyes, kidneys, nerves, and blood vessels
Acute complications: diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma.
homogenous Heterogeneous
Genetic factorsGenetic factors Environmental factorsEnvironmental factors
Chinese population9%
MonogenicMonogenic
PolygenicPolygenic
AgingAging
LifestyleLifestyle
InfectionsInfections
Diabetes
Type IType I<10%<10%
Type IIType II>90%>90%
Etiology and Development
Defect of β Cell in Insulin Secretion & Action
Non-diabetes Pre-diabetes
Diabetes
IGT/IF
G
Fasting plasma glucose
Insulin requirement
Insulin production
<6.1mmol/L
>7.0 mmol/L
Derangements are due to relative or absolute
insulin deficiency and glucagon excessiveness.
Normally, it is a rise in the molar ratio of glucagon to
insulin which leads to diabetic decompensation.
Why does metabolic derangement happen?
Spectrum of Diabetes Mellitus
Insulin receptor gene mutations Insulin receptor gene mutations (<1%)(<1%) Insulin gene mutations (<1%)Insulin gene mutations (<1%)
Mitochondrial gene mutations (2%)Mitochondrial gene mutations (2%)
Type 2 (70%)Type 2 (70%)
Type 1 (10%)Type 1 (10%)
LADA (10-12% ?)LADA (10-12% ?)
MODY (2-4% ?)MODY (2-4% ?)
1 yr 10 yr 21 yr 32 yr 45 yr 60 yr Age at diagnosis
TYPE1TYPE2
MODY LADAMIDDDIDMOAD?
Variable Faces of Diabetes Mellitus
Type 1 diabetes mellitus
Usually onset before age of 40.
In USA, peak incidence is around 14 years old.
Onset of symptoms may be abrupt, with thirst, excessive urination, increased appetite and weight loss developing over a several-day period.
In some cases, the disease is heralded by the appearance of DKA during and intercurrent illness or following surgery.
Type 2 Diabetes Mellitus
Usually starts in middle age or older.
Symptoms begin more gradually than in type 1 diabetes, and diagnosis is frequently made when an asymptomatic person is found to have an elevated plasma glucose on routine lab. Exam..
Type 1 vs. Type 2
Type 1 Type 2
Age of onsetChildhood, young
adultAdulthood, elder
people
Body cells Responsive to insulin Resistant to insulin
Autoantibodies Positive Negative
Body fatness Low to average High
Endogenous insulin Little or none Normal or too much
Pancreatic functionBeta cells not
functionalBeta cell normal
Severity of symptoms Severe; liable to DKAMild; few or none, not liable to DKA
Insulin shots? Yes, indispensableNot during early and
middle stage
Drugs? Not solely Yes
Maturity-onset diabetes of the young (MODY)
45
33 22
1216 17
10
INS
OHA
OHA DIET
DIET
DIET
INS
Classical MODY-criteria:1. Two patients diagnosed
with diabetes before the
age 25 years.
2. Autosomal dominant
inheritance of diabetes
( 3 generations)
Note: Yellow figures indicating ages at on-set.
History of MODY genesHistory of MODY genes
MODY2MODY2GCKGCK
MODY1MODY1LinkageLinkageto chr20to chr20
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
MODY2MODY2LinkageLinkageto chr7to chr7
MODY3MODY3LinkageLinkageto chr12to chr12
MODY3MODY3HNF-1HNF-1
MODY1MODY1HNF-4HNF-4
MODY5MODY5HNF-1HNF-1
MODY4MODY4IPF1IPF1
Severe insulin resistance syndrome
Insulin signaling associated mutation
Lypodystrophy syndrome linked
mutation
Other gene
IR gene
AKT2 gene
BSCL FPLD MAD CaR gene
AGPAT2 gene
Seipin gene
LMNA PPARγ gene
LMNA ZMPSTE24 gene
Type A insulin resistance syndrome
• Autosomal recessive inheritance
• Autosomal dominant inheritance
• Penetrance is not constant
Sequencing of IR exon20
Black Arrow ：P1174W
Green Arrow ：P1178P
Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.
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Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.
HGPS, RDthe “most” complicated and lethal type of laminopathies
HGPSRD
Hum Mol Genet, 2004, 13: 2493-2503.N Engl Med, 2008,358: 552-555.
In some other secondary identifiable condition, a diabetic syndrome can develop
• Pancreatic diseases, pancreatitis • Hormonal causes: pheochromocytoma, acromegaly,
Cushing syndrome and therapeutic administration
• Stress hyperglycemia: severe burns, acute myocardial
infarctions and other life-threatening illnesses
Mechanism of Stress of Hyperglycemia
• Endogenous release of glucagon and catecholamines
• Combinations of impairment of insulin release and induction
of insulin resistance
Gestational Diabetes Mellitus
◆ ◆ Definition:Definition:
Carbohydrates intolerance of variable severity with Carbohydrates intolerance of variable severity with onset or first recognition during pregnancyonset or first recognition during pregnancy
◆◆ Screening:
American Diabetic Association(ADA) Recommend screening all pregnant women at 24-26 wks using 50g oral glucose test with 1 hour blood glucose value of 140mg or more as an indication for standard oral glucose tolerance test. No stipulations as to the time of last meal.
Clinical manifestation
The manifestations of symptomatic diabetes
mellitus vary from patient to patient.
Most often medical help is sought because of
symptoms related to hyperglycemia: polyuria,
polydipsia, polyphagia.
But, the first event may be an acute
metabolic decompensation resulting in
diabetic coma. More occasionally, the
initial expression can be a degenerative
complication such as neuropathy in the
absence of symptomatic hyperglycemia.
Classifications of Diabetic Vascular Disease
A. Macrovascular disease: an accelerated form of athersclerosis,
accounts for the increased incidence of myocardial infarction,
stroke and peripheral gangrene .
B. Microvascular disease: basement membrane thickening of the
small blood vessles, the capillary and the precapillary arteriols,
involving the retina leads to diabetic retinopathy, the kindney
causes diabetic nephropathy, also the heart, resulting in the
cardiomegaly with heart failure in diabetic patients.
Increased coagulability
Platelet hypersensitivity
Increased blood viscosity
Impaired microvascular flow
Increased microvascular pressure and flow
Microvascular sclerosis
Limitation of maximum perfusion
Failure of autoregulation
Raised capillary pressure
Tissue damage
Hypothesis for Diabetic Microangiopathy
Microaneurysms
Scattered exudates
Haemorrhages
•Flame-shaped
•Dot and blot
Cotton-wool spots(<5)
Venous dilatation
Background
•Rapid increase in microaneurysm count
•Multiple haemorrhages
•Cotton-wool spots(>5)
•Venous beading, looping and duplication
Preproliferative
New vessels• On disc (NVD)•Elsewhere (NVE)Fibrous proliferation• On disc (FPD)• Elsewhere (FPE)Haemorrhages• Preretinal•Vitreous
Proliferative
•Retinal
detachment
•Rubeosis
iridis
•Neovascular
glaucoma
Advanced diabetic eye
disease
Macular oedema
• Focal
• Diffuse
Ischaemic maculopathy
Maculopathy
Stages of Diabetic Retinopathy
Background Proliferative
Diabetic Retinopathy
Diabetic Nephropathy
※Mechanism: thickening of capillary basement membranes and of the mesangium of renal glomeruli, produces varying degrees of glomerulosclerosis and renal insufficiency. Proteinurea is the initial manifestation.
※Natural history:
• Initial stage of normoalbuminuria: enlargement of the kidney with increased filtration rate, but the urinary albumin excretion rate (AER) is within the normal range (<15 ug/min).
• Microalbuminuria: 20 ug/min <AER<200 ug/min.
• Clinical proteinuria: AER>200 ug/min (or 300 mg/24hr), dip-stick-positive proteinuria.
• End-stage renal disease: renal dysfunction with increased serum creatine level, edema, hypertension, etc.
Diabetic NeuropathyPeripheral neuropathy
Distal, symmetric sensory loss
Motor neuropathy
Foot drop, wrist drop
Mononeuropathy multiplex (diabetic amyotrophy)
Cranial nerves III, IV, VI, VII
Autonomic neuropathy
Postural hypotension
Resting tachycardia
Loss of sweating
Gastrointestinal neuropathy
Gastroparesis
Diabetic diarrhea
Urinary bladder atony
Erectile dysfunction
Limited joint mobility
Motor damage Sensory damage Autonomic damageMicrocirculatory
diseaseMacrovascular
disease
Diabetic neuropathy
Diabetes• Smoking•Hypertension• Dyslipidaemia
Abnormal foot posture
Reduced pain and proprioception A-V shunting
• Orthopaedic problems• Charcot arthropathy
Increased foot pressures
Reduced tissue nutrition
Callus formation
Ischaemia
Ulceration
Infection
Pathways to Diabetic Foot
Foot ulceration Charcot arthropathy
Diabetic Foot
Laboratory Findings
◇ Analysis of urine glucose :
Factors affecting the result:
• kidney threshold for glucose excretion
• glomerulosclerosis
◇ Other substances in the urine :
• ketonuria
• proteinuria
• microaluminuria
urine albumin excretion rate (AER)
－ ± + ++ +++ ++++
◇ Blood glucose testing:
• venous blood sample for diagnosis
• capillary blood sample for self monitoring
◇ Glycosylated hemoglobin assay:
• GHbA1C comprised major form of GHb.
• reflects the state of glycemia over the past 2~3 months.
◇ Glucose tolerance test :
• OGTT:
• IVGTT
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control
PATIENT
0.693K (glucose)= × 100
t 1/2
Insu
lin (m
U/L
)
30 60 90 120 150 180 210 min
T2DMNormal
T1DM
◇ Serum insulin concentration:
• fasting.
• challenged with glucose.
Reflection of insulin storage and sensitivity
C peptide
A chain
B chain
◇ Serum C peptide concentration:
• in equimolar amounts with insulin
during cleavage from proinsulin
• reflection of insulin secretion
• fasting and post-load indicating basal and storage of insulin
◇ Lipid profile:
• dependent on normal level and action of insulin
• dyslipidemia characteristic of a high level of serum triglyceride,
with low HDL-C but increased LDL-C concentration
• sufficient insulin supplement in T1DM, or improvement in
insulin sensitivity in T2DM may rectify the disorder
Diagnosis of Diabetes Mellitus
1) Symptoms of diabetes plus a random plasma
glucose concetration >11.1 mmol/L.
2) Fasting plasma glucose >7.0 mmol/L after an
overnight (at least 8-hour) fast.
3) Two-hour plasma glucose > 11.1 mmol/L during a
standard 75 g oral glucose tolerance test.
4) Impaired fasting glucose (IFG): plasma glucose
after an overnight fast that is >6.1 mmol/L but less
than 7.0 mmol/L.
Treatment of Diabetes Mellitus
Management Goals
– Obtain optimal glycemic control– Prevent and retard microvascular complications– Reduce macrovascular complications– Avoid acute diabetic complications– Better quality and lengthen span of life
Strategies
• Earlier diagnosis and treatment
• Acting on results of SMBG and GHbA1c
• Combination therapy• Education for healthy life style and self management
Good Moderate PoorFPG mmol/L 4.4-6.1 ≤ 7.0 >7.0PBS mmol/L 4.4-8.0 ≤ 10.0 >10.0 HbA1c ★ % <6.2 6.2-8.0 >8.0BMI Kg/m2 M<25
F<24M<27F<26
M ≥ 27F ≥ 26
Tch mmol/L <4.5 ≥ 4.5 6.0HDL-c mmol/L >1.1 1.1-0.9 <0.9TG mmol/L <1.5 <2.2 ≥ 2.2LDL-c mmol/L <2.5 2.5-4.4 >4.5
★According to UKPDS data.
Targets for Diabetic Control
Major Therapeutic Trials 1Major Therapeutic Trials 1DCCT (Diabetes Control & Complications Trial) 1983-1993
1441 Type 1 patients (726 no retinopathy or microalbuminuria; 715 non-prolif. retinopathy and microalbuminuria)
•Randomised to INTENSE or CONVENTIONAL Rx *
•Average follow-up 6.5 years
•INTENSE Rx reduced by approx. 60% the risk of retinopathy, nephropathy and neuropathy.
•3-fold increase in risk of hypoglycemia in INTENSE group.
* INTENSE = tid INS or pump frequently adjusted by at least qds BG
CONVENTIONAL = qd/bid INS and single daily BG or urine check
Major Therapeutic Trials 2Major Therapeutic Trials 2UKPDS (UK Prospective Diabetes Study) 1977-1997
•5102 newly diagnosed Type 2 patients from 23 centres
•Median follow up of 11 years
•Randomised to diet or Rx (INS, SU or Meformin)
•All Rx showed similar efficacy over diet
•Good glycaemic reduced risk of microvasculopathy
•Approx. 35% reduction for each 1% fall in HbA1c
•Macrovascular disease risk not affected *
function deteriorated steadily during the study regardless of Rx
* Only reduced by anti-hypertensive Rx in a sub study where the impact of aggressive BP control mirrored HOT trial.
◆◆ Set total calorie IntakeSet total calorie Intake
according to ideal body weight (IBW) and working strengthaccording to ideal body weight (IBW) and working strength
◆◆ Sample calorie distribution
◆◆ Set total calorie IntakeSet total calorie Intake
according to ideal body weight (IBW) and working strengthaccording to ideal body weight (IBW) and working strength
◆◆ Sample calorie distribution
• 50-60 % CHO• 15-20 % Protein• 20-30 % Fat
◆ ◆ About sweetenersAbout sweetenersFDA approves 4 sugar substitutes which have no CHO:FDA approves 4 sugar substitutes which have no CHO:
aspartame, saccharin, acesulfame-K, sucraloseaspartame, saccharin, acesulfame-K, sucralose
◆ ◆ Limitative drinkingLimitative drinking
◆ ◆ Reduce Sodium Intake
Diet
Food PyramidFood Pyramid
• Food Group/Servings• starch 6 -
11 • vegetable 3 -
5 • fruit 3 - 4 • milk 2 - 3• meat/protein 2 -
3– use fats, sweets,
and alcohol sparingly
Physical Activities
◇Benefits:
※Lowers glucose levels in blood
※Improves blood circulation in the entire body
※Contributes to weight loss
※Improves physical and mental wellbeing
※Helps the body to utilize insulin more efficiently
Exercise Guidelines
※※ Monitor BG before and after exercise.Monitor BG before and after exercise.
※※Avoid exercise if BG >250 mg/dl, ketones present.Avoid exercise if BG >250 mg/dl, ketones present.
※※ Use caution with exercise if BG>300 mg/dl, without ketones.Use caution with exercise if BG>300 mg/dl, without ketones.
※※ Eat CHO if BG < 100 mg/dlEat CHO if BG < 100 mg/dl
※※ If exercise is planned for just after a meal, consider reducingIf exercise is planned for just after a meal, consider reducing
the short acting insulin that covers that meal.the short acting insulin that covers that meal.
※※ If exercise is planned for 3-4 hours after a meal, consider reducingIf exercise is planned for 3-4 hours after a meal, consider reducing
the long-acting insulin.the long-acting insulin.
※※ For unplanned exercise, consider adding carbohydrate.For unplanned exercise, consider adding carbohydrate.
※※ Consume CHO before, during, or after exercise to prevent Consume CHO before, during, or after exercise to prevent
hypoglycemia.hypoglycemia.
※※ Always keep CHO foods readily available during exercise.Always keep CHO foods readily available during exercise.
Oral Hypoglycemic Agents
Sulphonylureas
Mode of action:
• Increase pancreatic insulin secretion
• May improve insulin sensitivity in peripheral tissue and decrease hepatic glucose output
Sulfonylurea Activates Insulin Secretion
Small figure shows the site of action.
◇Contra-indications :
pregnancy, surgery, severe renal failure, type 1diabetes, hypersensitivity
◇Side effects:
hypoglycaemia weight gain
◇Administer: before meal
Secondary Failure
• Secondary failure rate 5% to 10% a year(UKPDS 7% a year)
– Decreasing β-cell function– Obesity– Non-adherence to treatment– Lack of exercise– Intercurrent illness
Biguanides (Metformin)
Mode of action:
◇reduces hepatic glucose production
◇decreased intestinal absorption of glucose
◇increases peripheral utalisation of glucose in muscle &
fat tissue
◇decreased insulin requirements for glucose disposal
Precautions: ●chronic renal or cardiac failure
●hepatic impairment ●elderly ●excessive alcohol intake
Side effects: ◆gastrointestinal disturbances ◆metallic taste◆malabsorption of B12
Administer: with or after meals
Alpha Glucosidase Inhibitor (Acarbose)
Mode of action:Delays breakdown of CHO such as starch & sucrose
Contra-indications:Pregnancy, renal impairment, gastrointestinal disorders
Side effects:Gastrointestinal, rash, erythema
Administer:With the first few spoons of the meal
Thiazolidinedione
Mode of action:• Peroxisome proliferator-activated receptor gamma agonist (PPAR-Peroxisome proliferator-activated receptor gamma agonist (PPAR-))• Improves sensitivity to insulin in skeletal muscle and adipose tissue• Enhances peripheral glucose uptake, reduces hepatic glucose Enhances peripheral glucose uptake, reduces hepatic glucose
productionproduction• Preserves pancreatic functionPreserves pancreatic function• Optimum effect seen in 12 weeksOptimum effect seen in 12 weeks
Contra-indications: Heart failure, moderate to severe hepatic impairment.
Insulin Indications:
1) Type 1 diabetes
2) Type 2 diabetes whose hyperglycemia does not respond to diet therapy and oral hypoglycemic drugs
3) Pregnancy and delivery
4) Acute diabetic complications
5) Severe chronic complications
6) Severe infections, major surgery, stress etc
7) Secondary insulin insufficiency: pancreaectomy
Insulin preparations and time of reaching peak and duration
Lipoatrophy due to long term injection of ‘impure’ insulin preparations.
Novopen
Inhaled insulin
Insulin pump
Oral Agents + Insulin in Type 2 Diabetes
• Simplifies insulin regimen
• Improves glycemic control
• Better patient acceptance
• Compliance
• Convenience
• Lower doses of exogenous insulin
• Less weight gain
Rationale:
Diabetic Ketoacidosis
Presentation
Physical examination Laboratory results
Polyuria, polydipsia
Nausea, vomiting
Diarrhea, abd. Pain
Evolution for a few days
Stupor or coma in Loss of skin turgor
Kussmaul breathing
Acetone odor
Cerebral edema
PH <7.3, HCO3 <15 Eq/L
Glucose > 250 mg/dl
Elevated anion gap
High serum ketones
High uric acid
Normal osmolality
Precipitating Factors of DKA
• Noncompliance with medication
• Infection • myocardial infarction • Cerebrovascular accident • Trauma• Pancreatitis
• Emotional stress• Insulin pump dysfunction• Pregnancy
Treatment of DKA – IV fluid
Normal saline 1 liter/hr until not orthostatic hypotensive, then NS at 500 ml/hr
Electrolytes every 2 hrs initially, then every 4 hours
Glucose <250 mg/dl, change to Dextrose with 1:4 regular insulin at 250-500 ml/hr
When anion gap normal, bicarbonate >15 mEq/L, taking PO fluid, give meal and SC insulin
Treatment of DKA – Insulin
IV insulin at 5-10 u/hr in adult, 0.1 u/kg/hr in child
Check glucose hourly, if no change in 2 hrs double the insulin infusion
Glucose <250 mg/dl, slow insulin to 2-4 u/hr
Discontinue IV insulin 2-3 hrs after SC insulin dose
Treatment of DKA – Potassium
Potassium repletion if initial K is normal or low at 10-40 mEq/hr
Check potassium every 2- 4 hrs
Replete total body potassium stores over 2- 3 days
Treatment of DKA – Bicarbonate, Phosphorus
Bicarbonate replacement if pH less than 6.90
Check phosphorus 12 hrs into treatment. Replace if < 1 mEq/L
