1. Introductions and complications of Diabetes Mellitus
Dr. Nakwagala Fred
Senior Consultant Physician
Mulago National referral hospital
17 Oct 2018

2. What is diabetes?
Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.
The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. b

3. What is diabetes?
Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.
The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. b

4. DM and Survival

5. Types of Diabetes Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus
Gestational Diabetes
Other types:
LADA (Latent Autoimmune Diabetes of Adults}
MODY (maturity-onset diabetes of youth)
Secondary Diabetes Mellitus

6. Criteria for Screening for T2D and Prediabetes in Asymptomatic Adults
Q1. How is diabetes screened and diagnosed?
Criteria for Screening for T2D and Prediabetes in Asymptomatic Adults
Age ≥45 years without other risk factors
Family history of T2D
CVD
Overweight
BMI ≥30 kg/m2
BMI kg/m2 plus other risk factors*
Sedentary lifestyle
Member of an at-risk racial or ethnic group: Asian, African American, Hispanic, Native American, and Pacific bIslander
Dyslipidemia
HDL-C <35 mg/dL
Triglycerides >250 mg/dL
IGT, IFG, and/or metabolic syndrome
PCOS, acanthosis nigricans, NAFLD
Hypertension (BP >140/90 mm Hg or therapy for hypertension)
History of gestational diabetes or delivery of a baby weighing more than 4 kg (9 lb)
Antipsychotic therapy for schizophrenia and/or severe bipolar disease
Chronic glucocorticoid exposure
Sleep disorders† in the presence of glucose intolerance
Screen at-risk individuals with glucose values in the normal range every 3 years
Consider annual screening for patients with 2 or more risk factors
*At-risk BMI may be lower in some ethnic groups; consider using waist circumference.
†Obstructive sleep apnea, chronic sleep deprivation, and night shift occupations.
BMI = body mass index; BP = blood pressure; CVD=cardiovascular disease; HDL-C = high density lipoprotein cholesterol; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovary syndrome; T2D, type 2 diabetes.

7. Diagnostic Criteria for Prediabetes and Diabetes in Nonpregnant Adults
Q1. How is diabetes screened and diagnosed?
Diagnostic Criteria for Prediabetes and Diabetes in Nonpregnant Adults
Normal
High Risk for Diabetes
Diabetes
FPG <100 mg/dL
IFG
FPG ≥ mg/dL
FPG ≥126 mg/dL
2-h PG <140 mg/dL
IGT
2-h PG ≥ mg/dL
2-h PG ≥200 mg/dL
Random PG ≥200 mg/dL + symptoms*
A1C <5.5%
5.5 to 6.4%
For screening of prediabetes†
≥6.5%
Secondary‡
*Polydipsia (frequent thirst), polyuria (frequent urination), polyphagia (extreme hunger), blurred vision, weakness, unexplained weight loss.
†A1C should be used only for screening prediabetes. The diagnosis of prediabetes, which may manifest as either IFG or IGT, should be confirmed with glucose testing.
‡Glucose criteria are preferred for the diagnosis of DM. In all cases, the diagnosis should be confirmed on a separate day by repeating the glucose or A1C testing. When A1C is used for diagnosis, follow-up glucose testing should be done when possible to help manage DM.
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; PG, plasma glucose.

8. Acute and chronic complications
- diabetic ketoacidosis
(DKA)
- hyperglycemic
Hyperosmolar
Syndrome (HHS)
- hypoglycemia
- Metformin associated
lactic acidosis, MALT
Microvascular
Opthalmopathy
Nephropathy
Neuropathy
Macrovascular diseases
Cardiovascular
Peripheral vascular disease
Cerebral Vascular Disease

9. Effect of Hyperglycemia
• Acute, reversible intracellular metabolic changes • Cumulative, irreversible effects on stable macromolecules

10. Good glycemic control decreases the diabetic complications
In the DCCT trial by reducing HBA1c from 9 % to 7% the following reductions occurred.
Retinopathy 76%
Nephropathy 54 %
Neuropathy 60 %
Macro vascular 41 %

11. Acute, reversible intracellular metabolic changes
• Increased activity of polyol pathway • Modified protein kinase C activity • Early glycation products • Increased production of free radicals

12. Consequences of increased protein kinase C (PKC) activity

13. Biochemistry pathways

14. Effects of advanced glycation end products (AGE)
• Crosslinking of extracellular proteins • Interactions with specific AGE receptors • Crosslinking with intracellular DNA

15. Hemodynamic disturbances in diabetes
• Increased blood flow • Increased permeability • Hemorrheological and coagulation abnormalities - increased plasma viscosity - decreased red-cell deformability - increased platelet aggregability

16. Structural abnormalities in diabetes
• Leakage of glycated plasma proteins • Extracellular matrix is increased - BM is thickened - mesangial matrix is expanded - collagen is increased • Hypertrophy and hyperplasia of endothelial, mesangial and arterial smooth muscle cells

17. Diabetes and infections
• Infections are more frequent: pneumonia, urinary tract, skin and mucosal infections x ↑ • Infections are more severe, mortality rate is increased 2-3x ↑. • Provokes hyperglycemic crisis. • Rare, life threatening infections. • Immunization: annually influenza vaccine, pneumococcal polysaccharid vaccine > 2 years (repeat > 64 years of age, renal disease, transplantation)

18. Rare, life threatening infections. in diabetes
• Rhinocerebral Mucormycosis • Malign otitis externa (Ps. aeruginosa) • Psoas abscessus (St. aureus) • Emphysematosus cholecystitis (E. coli, Cl. Perfringens) • Emphysematosus urocystitis, pyelonephritis (E. coli, K. pneumoniae) • Necrotising Fasciitis (polymicrobe)

19. DM Autonomic Neuropathy

20. Classification of diabetic neuropathy
• Diffuse neuropathy -somatic np.: sensorimotor - autonomic np.: cardiovascular, gastrointestinal, genitourinary, pupil • Focal syndromes - focal np.: mononeuritis, entrapment syndr. - multifocal np.: proximal neuropathies • Subclinical neuropathy - abnormal electrodiagnostic tests - abnormal quantitative sensory tests - abnormal autonomic function tests

21. Cardiovascular risk in diabetes
• Peripheral arterial disease 2-4x ↑ (risk of amputation 16x ↑) • CHD: risk of AMI 2-3x ↑, heart failure 5x ↑ • Stroke 2-4 x ↑ • Protection of female gender is disappeared • The macrovascular risk is 10 x ↑ in the presence of microvascular complication

22. Comprehensive Management of CV Risk
Q12. How is CVD managed in patients with diabetes?
Comprehensive Management of CV Risk
Manage CV risk factors
Weight loss
Smoking cessation
Optimal glucose, blood pressure, and lipid control
Use low-dose aspirin for secondary prevention of CV events in patients with existing CVD
May consider low-dose aspirin for primary prevention of CV events in patients with 10-year CV risk >10%
Measure coronary artery calcification or use coronary imaging to determine whether glucose, lipid, or blood pressure control efforts should be intensified
CV = cardiovascular; CVD = cardiovascular disease.

23. Statin Use Q12. How is CVD managed in patients with diabetes?
Majority of patients with T2D have a high cardiovascular risk
People with T1D are at elevated cardiovascular risk
LDL-C target: <70 mg/dL—for the majority of patients with diabetes who are determined to have a high risk
Use a statin regardless of LDL-C level in patients with diabetes who meet the following criteria:
>40 years of age
≥1 major ASCVD risk factor
Hypertension
Family history of CVD
Low HDL-C
Smoking
ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; HDL-C = high density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

24. DM Nephropathy

25. Assessment of Diabetic Nephropathy
Q9. How is nephropathy managed in patients with diabetes?
Assessment of Diabetic Nephropathy
Annual assessments
Serum creatinine to determine eGFR
Urine AER
Begin annual screening
5 years after diagnosis of T1D if diagnosed before age 30 years
At diagnosis of T2D or T1D in patients diagnosed after age 30 years
AER = albumin excretion rate; eGFR = estimated glomerular filtration rate; T1D = type 1 diabetes; T2D = type 2 diabetes.

26. Diagnosis and treatment of Microalbuminuria
• Screening once a year in T1DM (at least), at diagnosis in T2DM • Urinary albumin excretion (299) mg / 24 h • 2 positive out of 3 samples (collected urine) (fever, urinary tract infection, heart failure etc.) • ACE-inhibitors (ARB), good metabolic control • DM + albuminuria increases the CVD mortality with 20 x

27. Staging of Chronic Kidney Disease
Q9. How is nephropathy managed in patients with diabetes?
Staging of Chronic Kidney Disease
Persistent albuminuria categories
Description and range
Previous NKF CKD stage
Guide to frequency of monitoring (number of times per year) by GFR and albuminuria category A1 A2 A3
Normal to mildly increased
Moderately increased
Severely increased
<30 mg/g <3 mg/mmol
mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
GFR categories (mL/min/1.73 m2) 1 G1
Normal or high
≥90
1 if CKD 2 G2
Mildly decreased
60-89 3
G3a
Mild to moderately decreased
45-59
G3b
Moderately to severely decreased
30-44 4 G4
Severely decreased
15-29 4+ 5 G5
Kidney failure
<15
CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Levey AS, et al. Kidney Int. 2011;80:17-28.

28. Assessment of Diabetic Retinopathy
Q10. How is retinopathy managed in patients with diabetes?
Assessment of Diabetic Retinopathy
Annual dilated eye examination by experienced ophthalmologist or optometrist
Begin assessment
5 years after diagnosis of T1D
At diagnosis of T2D
More frequent examinations for:
Pregnant women with DM during pregnancy and 1 year postpartum
Patients with diagnosed retinopathy
Patients with macular edema receiving active therapy
DM = diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes.

29. Management of Diabetic Retinopathy
Q10. How is retinopathy managed in patients with diabetes?
Management of Diabetic Retinopathy
Slow retinopathy progression by maintaining optimal control of
Blood glucose
Blood pressure
Lipids
For active retinopathy, refer to ophthalmologist as needed
For laser therapy
For vascular endothelial growth factor therapy
DM = diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes.

30. Management of Diabetic Retinopathy
Q10. How is retinopathy managed in patients with diabetes?
Management of Diabetic Retinopathy
Slow retinopathy progression by maintaining optimal control of
Blood glucose
Blood pressure
Lipids
For active retinopathy, refer to ophthalmologist as needed
For laser therapy
For vascular endothelial growth factor therapy
DM = diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes.