DIABETICS

WHAT IS DIABETICS MELLITUS?
A metabolic disorder characterized by chronic hyperglycaemia.
It is now recognized that DM affects the metabolism of all body fuels (carbohydrate, fats and protein) and encompasses a group of genetically and clinically heterogeneous disorders, in which glucose intolerance or hyperglycaemia is the common denominator.

THE STATUS OF DM GLOBALLY
GLOBAL ESTIMATES OF DIABETES MELLITUS

GLOBAL ESTIMATES OF DIABETES AND IMPAIRED     
GLUCOSE TOLERANCE

Recent estimates compiled by the World Health Organization (WHO) indicate that DM has reached epidemic proportions in many parts of the world.
Presently, more than half of the cases of DM are from only three countries –China, India and the United States of America.
It is projected that the prevalence of DM will rise to an all time high figure of 300 million in 2025. Most of these future cases are expected to occur in the developing world. This expected increase in the global incidence of DM is attributed to factors such as ageing urbanization increased prevalence of obesity and inactivity.

THE STATUS OF DM IN AFRICA-1

Africa is experiencing a rapid epidemiological transition with the burden of non-communicable diseases esp. diabetes that will overwhelm the health care systems which is already overburdened by HIV/AIDS, TB and Malaria.
This is due to:

1. Rapid urbanization and westernization of lifestyle
2. Rapidly decreasing physical activity
3. Changes in dietary habits
4. Ageing of the population

THE STATUS OF DM NATIONWIDE

1. The Health system in Nigeria
2. Poor linkages between primary, secondary and tertiary health care.
3. Manpower is lacking and distribution is skewed towards the cities.
4. Lagos state has the largest concentration of centres (6) offering DM care
5. Prevalence of  DM as at 1997  in Nigeria is 2.2%-No updated version of this report
6. Hospital based incidence rates for Type 2 DM -10-15%
7. Hospital based prevalence rates of Type 1 DM -0.2-0.3%
8. Type 2 DM make up 98% of all cases of DM 1
9. 6.5% of the subjects with Type 2 DM are on insulin therapy either singly or in combination with OHA 1.

1. Ogbera et al. Audit of diabetes mellitus (In Press)
The burden of DM in Nigeria

1. DM related admissions made up 15% of all the medical admissions.
2. 1 in 6 cases of DM admissions result in death.
3. The commonest causes of deaths are hyperglycaemic emergencies (46%) and DM foot ulcers (DFU) (30%).
4. The highly predictive factors of DM mortality are DFU and CVD or Stroke.
5.  DFU with an Length of hospital stay (LOS) ranging from 15-122 days had the longest LOS.

Ogbera et al. Prognostic Indices of DM mortality. Ethn and Disease 2007; 7; 17:721-725.
Ogbera et al. The disease burden of diabetes mellitus. Tropical Doctor 2007
Disease burden of DM 

1. Prevalence of Foot ulcers (FUs): 8-9.5%.
2. FUs - second leading cause of DM deaths
3. FUs account for half of all lower limb amputations.
4. DM and the kidneys: DM nephropathy accounts for a sixth of all people with end-stage renal disease undergoing dialysis. Prevalence of hypertension in DM-29-40%

Ogbera et al. High costs, low awareness and a lack of care-the diabetic foot in Nigeria. Diabetes Voice 2006:51;30-32
Ogbera et al. An assessment of the disease burden of foot ulcers in Nigerians with Diabetes Mellitus. International journal of lower Extremity Wounds 2006; (5)4:244-249

The economic costs of diabetes mellitus in Cameroun
In Cameroon in the year 2001:

1. Average direct medical cost of treating a patient with diabetes was USD 489.
2. 56% -hospital admission
3. 33.5% - anti-diabetic drugs
4. 5.5% -laboratory tests
5. 4.5% on consultation fee.

 (Nkegoum, 2002)
The economic costs of DM in Nigeria (Ogbera et al: In Press)

1. The total yearly cost of DM per patient which is made up of direct and indirect costs of treatment was found to be NGN 88,656 ($751).
2. The number of days lost per year to illness per person is 16days.

THE VERDICT

1. The magnitude of the burden of DM in Nigeria is unacceptably high.
2. DM results in reduced quantity and quality of life
3. The most hard hit age group is the productive age group
4. Diagnosis of DM (WHO 1999 criteria)
5. Symptoms of DM plus casual blood glucose ≥ 200mg% (≥ 11.1mmol/L) The classic symptoms of DM include polyuria, polydipsia and unexplained weight loss.

OR

1. FPG ≥ 126mg% (≥7mmol/L)  OR
2. 2 Hour plasma glucose (≥ 11.1mmol/L) during an OGTT
3. The intermediate states (IGT and IFG)
4. IGT is plasma glucose following a 75-g OGTT (140-199mg%  or 7.8-11.0mml/dl)
5. IFG is plasma glucose (110-125mg% or 6.1-6.9 mol/dl)
6. IFG is plasma glucose (100-125mg% or 5.6-6.9 mol/dl)

Classification of DM (WHO 1999 classification)

1. Type 1 DM. Beta cell destruction and insulin is required for survival.
2. Type 2 DM: Characterized by disorders of insulin action or secretion either of which may be prominent.  Usually both are present at the time of presentation
3. Gestational DM- Any degree of glucose intolerance occurring in pregnancy
4. Others

Type 1 DM (Type 1A)

1. Type 1A-autoimmune basis for the destruction of beta cells. Associated with auto antibodies (anti-Glutamic acid decarboxylase (anti- GAD), Insulin autoantibodies (IAA) and antibodies to tyrosine phosphatase –like insulinoma antigen (IA2)).
2. Shows strong association with certain haplotypes or alleles at the DQ-A and DQ-B loci of the human leucocyte antigen (HLA complex).

Type 1 DM (Type 1B)

1. Shows strong association with certain haplotypes or alleles at the DQ-A and DQ-B loci of the human leucocyte antigen (HLA complex).
2. Type 1 B-basis of B cell destruction, not known
3. May likely be the type that is the common variant of type 1 in  our setting.

OVERVIEW OF TYPE 1 DM

1. Approx. 10-15% of cases
2. Tends to occur in the young, but can occur at any age
3. Onset of symptoms is often rapid
4. There may be a genetic susceptibility to the disease
5. Environmental factors and viral infections have also been implicated

Type 2 DM

1. Most common form of DM. The specific etiology is unknown.
2. They usually have insulin resistance (impairment of the ability of muscle and fat to respond to insulin with increased glucose uptake and of the liver to respond with decreased glucose output) and relative insulin deficiency
3. May go undiagnosed for long because DM develops gradually
4. Genetic factors and Type 2 DM
5. Genes and environment contribute to the development of Type 2 DM.

Evidence for genetic contribution

1. Familial clustering
2. Higher concordance rate in monozygotic twins compared to dizygotic twins
3. High prevalence in certain ethnic groups (Pima Indians)
4. Environmental factors and Type 2 DM
5.  Diet: Excess caloric intake
6. Sedentary  lifestyle or inactivity
7. Type 2 DM secondary to other conditions
8. Risk factors of Type 2 DM
9. Age: 45 years or more
10. Family history of type 2 diabetes
11. Excess weight/obesity
12. Physical inactivity
13. Alcohol and tobacco consumption
14. Diet
15. Socio-economic status.
16. Overview of Type 2 DM
17. Data: increasing but still limited
18. Prevalence
1. Low in rural areas
2. Moderate in rural and urban areas with development
3. High in urban areas
4. Urban > Rural
5. Increasing in same population
19. Ethnicity
20. Modifiable risk factors

GDM

1. Glucose intolerance of variable severity with onset or first recognition in pregnancy.
2. In early pregnancy, fasting and postprandial glucose levels are normally lower than in non-pregnant women.
3. High risk women should be screened at first trimester
4. Other specific Types
5. Infections-Congenital rubella, CMV
6. Drugs-Phenytoin, thiazides, steroids, thyroid hormones, alpha and beta agonists
7. Endocrinopathes-Cushings acromegaly, glucagonoma, phaechromocytoma, hyperthyroidism
8. Disease of the endocrine pancreas-Trauma, pancreatitis, cystic fibrosis, haemochromatosis, neoplasia
9. Other specific types
10. Genetic syndromes-Downs, Klinefelter’s, Turner’s, Porphyria, Wolfram,Myotonic dystrophy
11. Genetic defects in insulin action- Lipoatrophic DM, Leprechaunism
12. Genetic defects in Beta cell function: MODY

ACKNOWLEDGEMENT:              Dr. Anthonia Ogbera, Consultant Endocrinologist/Diabetologist
Lagos State University Teaching Hospital,
Ikeja, Lagos

MANAGEMENT OF DIABETES- THE ORAL HYPOGLYCAEMIC AGENTS
MANAGEMENT OF DM

1. Non pharmacologic- Life style modification
2. Pharmacologic management

GLYCAEMIC TARGETS
Management goals should be individualized.

DESIRABLE GLYCAEMIC GOALS

1. Fasting blood glucose: <120MG%
2. Post-prandial glucose:<180MG%
3. Glycosylated haemoglobin (Hba1c):7%

ORAL HYPOGLYCAEMIC AGENTS
These are essentially divided into three
1. Secretagogues
2. Insulin sensitizers
3. Alpha glucosidase inhibitors

Secretagogues

1. Sulfonylureas
2. Meglitinides

Historical Timeline of the Sulfonylureas (1)

1. 1955- The SUs were first assessed clinically
2. 1950s-1960s-Ist generation SU (tolbutamide and chlorpropamide were introduced into clinical practice.
3. Late 1960s-90s- 2nd generation SUs (glimepiride, glipizide, gliclazide and glimepiride were introduced.

Historical Timeline of the Sulfonylureas (2)

1. 1970-University Group Diabetes Program-first major outcome of sulfonylurea treatment
2. 1998- The United Kingdom Prospective Diabetes Study (UKPDS)- second  major outcome trial of sulfonyl urea treatment

SULFONYL UREAS

1. SU act on the pancreatic beta cells to stimulate insulin secretion provided there is adequate beta cell function
2. Stimulate the secretion of insulin by causing the closure of the adenosine triphosphate (ATP) dependent potassium channel (KATP) in the plasma membrane of the beta cell.

SU Pharmacokinetics

1. Low binding affinity is a feature of 1st generation sulphonlyurea- therefore given in large milligram doses
2. Greater binding properties from additional chemical moieties of the 2nd generation Sulfonylureas allow usage of lower doses
3. Almost all of an oral dose of all sulphonlyurea is absorbed
4. Peak plasma concentration in 2-4 hours
5. All highly protein bound-potential for interaction with other highly protein bound drugs.

Pharmacokinetics of Glimepiride

1. Insulin release is more rapid and of shorter duration than with other SUs.
2. Glimepiride increases  second phase insulin secretion
3. Extra pancreatic effect: Increases in whole body glucose uptake and increases in insulin sensitivity.
4. Duration of action is 12->24 hours
5. Time to peak plasma concentration  is 2-3 hours
6. >99% is protein bound
7. 60% of glimepiride is eliminated in urine

THE SECRETAGOGUES

1. SULFONYLUREA: Chlorpropamide, Glyburide (Glibenclamide), Glipizide, Glimepiride
2. Chlorpropamide-First generation sulfonylurea.
3. Long half life and it is given once daily;
4. Maximal dosage -500mg

Glyburide/Glibenclamide:

1. Maximal dosage is 20 mg. Once to twice daily

Glimepiride (Azulix)

1. Dose 1-6mg once daily.
2. Maximal dose 6-8mg

Glipizide:

1. Dose 5-20mg

THE NON-SULFONYLUREA SECRETAGOGUES

1. Meglitinides (repaglinide, nateglinide)

It is the first of a new class of oral hypoglycaemic agents that enhance insulin secretion but by a mechanism different from that of the Sulfonylureas.
It acts rapidly to enhance insulin secretion, so it is designed to be used immediately before meals. It addressed meal time needs for insulin secretion.

Side effects of the Sulfonylureas (SE)

1. Major SE is hypoglycaemia (occurs rarely) more especially in the elderly. Age associated impairments in hepatic and renal function often alter metabolism and excretion.
2. Impairment of hepatic oxidative pathways associated with ageing may increase the half lives of SUs which are metabolized extensively by the liver
3. Renal function declines with ageing hence reduced insulin clearance
4. Weight gain (due to anabolic effects  of insulin and reduced glucose loss in urine)
5. flushing with alcohol, protracted and severe hypoglycaemia and water retention/hyponatraemia because it potentiates ADH actions (Side effects specific to chlorpropamide)

Sulfonylureas- Advantages for the management of hyperglycaemia

1. They are efficacious, with proven ability to decrease HbA1c levels by up to 3-5%.
2.  They have a good safety profile.
3. Easy dosing schedule
4. Much less expensive than newer oral agents
5. The Secretagogues especially the newer ones  like Glimepiride (AZULIX) target the two defects in type 2 DM –namely insulin resistance and insulin secretory defects
6. May be used as monotherapy or in combination with the other glucose lowering agents
7. They remain first line agents for treatment

Contraindications to the use of SUs

1.  Known hypersensitivity
2. Type 1 DM
3. Pregnancy and breast feeding
4. Beta cell failure in type 2 DM

INSULIN SENSITIZERS

1. Biguanides
2. Thiazolidinediones

The Role of Biguanides in the management of Type 2 DM

Metformin: This is an old drug (has been in usage since the 1960s) but with new applications. This agent belongs to the biguanide class of drugs. It is an insulin sensitizer and enhances the effectiveness of insulin.
The target tissue of Metformin is the liver where it acts to inhibit glucose production by the liver or gluconeogenesis. (It does not inhibit the ability of the liver to respond to hypoglycaemia)
Metformin may also improve the response of muscles to insulin

1. Treatment with Metformin reduces HbA1c by  1-2%.
2. Metformin results in a slight decline of weight
3. Lipid profile and blood pressure may improve minimally

Side effects of Metformin

1. Main side effects are in the GIT notably anorexia, metallic taste, nausea, abdominal cramps

(In many patients, these side effects are transient and can be minimized by dose titration)

1. The main risk is lactic acidosis (LA) which is rare. Conditions predisposing to LA include renal disease, cardiac and liver failure.
2. Reduced absorption of Vitamin B12

Dosing

1. Metformin is rapidly cleared from the plasma by the kidney, hence it is usually taken twice or thrice a day.
2.  Extended release formulations are taken once or twice daily.
3. Maximum dosages range from 2,500-3000 mg.

Benefits of Metformin

1. Targets insulin resistance defect in type 2 DM
2. Decreases  obesity particularly central obesity
3. Decreases serum triglycerides
4. Decreases LDL cholesterol levels
5. Decreases macrovasular complications since it targets aspects of the metabolic syndrome

Contraindications or Metformin treatment

1. Decreased renal function (Cr clearance <60ml/min)
2. Patients with congestive heart failure
3. Liver disease
4. Chronic alcohol abuse
5. Sepsis or other acute illness

THIAZOLIDINEDIONES

1. Thiazolidinediones (pioglitazone, rosiglitazone)
2. Peroxisome-proliferator activator gamma.
3. Promote insulin mediated glucose uptake in muscle.
4. It promotes adipogenesis and paradoxically reduces the release of FFA , tumour necrosis factor, resistin and leptin that are released from adipose tissues and cause insulin resistance
5. Well absorbed orally.
6. Metabolized in the liver and excreted in the kidneys and bile.
7. Rosiglitazone: Dose 4-8 mg daily
8. Pioglitazone-15-45mg once daily

Side effects:

1. Fluid retention, weight gain (due to fluid retention and adipogenesis),
2. Worsening of CCF.
3. Idiosyncratic hepatotoxicity.

ALPHA-GLUCOSIDASE INHIBITORS

1. Controls postprandial hyperglycaemia.
2. Delays carbohydrate digestion
3. Side effects: abdominal discomfort, diarrhoea and flatus

WHICH CATEGORY OF PEOPLE WITH TYPE 2 DM SHOULD HAVE INSULIN THERAPY?

1. People whose blood glucose cannot be adequately controlled by oral hypoglyceamic agents (OHAs) and lifestyle modification. (OHA combination in this case should have been used for a period of about 6-months. This notwithstanding, there should be flexibility in this duration).

WHICH CATEGORY OF PEOPLE WITH TYPE 2 DM SHOULD HAVE INSULIN THERAPY (C0NTD.)

1. Persistent poor glycaemic control despite the absence of ongoing stress factors such as chronic infections, myocardial infarction or usage of steroidal drugs.
2. **maximal doses of OHA- Glibenclamide-20mg, glimepiride (AZULIX) – 6-8mg, gliclazide -240mg, glipizide- 30mg.
3. People with type 2 DM who are receiving multiple medications.
4. People who cannot tolerate the   side effects of OHAs.
5. People with hepatic/renal diseases
6. *transient insulin therapy is important during intercurrent illness, pregnancy, mi and transient steroid usage.

INSULIN THERAPY

1. Normal pancreas produces about 30 units of insulin a day.
2. Types of insulin preparations- porcine? No longer in use?
3. Human insulin- recombinant DNA technology/enzymatic modification

TYPES OF INSULIN

1. Rapidly acting insulin – analogs
2. Short acting insulin- soluble insulin.
3. Intermediate acting insulins-lente, NPH
4. Insulin mixtures
5. Long acting insulin