امك مايصلا مكيلع بتك اونمأ نيذلا اهيأاي “ نوقتت مكلعل مكلبق نم نيذلا ىلع بتك ” “ O you who believe! Fasting has been prescribed to you as it was prescribed to those before you so that you attain Taqwa ”

  Fasting is not meant to create excessive hardship on the Muslim individuals. The Quran specifically exempts the sick from the duty of fasting. The Prophet Mohammad said, “God likes his permission to be fulfilled, as he likes his will to be executed.”

Things Happened During Ramadan

     During Ramadan, Muslims must fast from dawn to sunset. This will involve a sudden change in the daily meals.

Two meals named Iftar and Sahur .

Ramadan is a lunar-based month. Its timing changes with respect to seasons. Depending on the geographical location and season, the duration of the daily fast may range from a few to more than 20 h.

Uniqueness of Ramadan Fasting

    It is a voluntary undertaking rather than being ordered by a physician There is no selective food intake i.e. protein only, juice only, fruit only , water only etc There is no total calorie malnutrition An exercise in self discipline i.e. from constant nibbling , drinking, smoking etc

Physiological Effects of Fasting:

   On Calorie intake On fluid /water intake Effects on – Digestive System - Kidneys - Endocrine glands - Lipid Metabolism - Respiratory system - Neurological System

Some Facts :

    

The most important metabolic fuels are glucose and fatty acids.

In normal circumstances, glucose is the only fuel the brain uses.

To ensure the continuous provision of glucose to the brain and other tissues, metabolic fuels are stored.

Carbohydrates are stored as glycogen - the amount of available glycogen stored is not large - about 75g in the liver and little amounts in the muscles. Liver glycogen can supply glucose for no longer than 16h.

To provide glucose over longer periods, the body transforms non-carbohydrate compounds into glucose (Gluconeogenesis).

Insulin and Glucagon

Main determinants of glucose metabolism

Proinsulin Insulin& C-peptide Proglucagon Glucagon

Both cell types release their hormones simultaneously at a basal level.

This is augmented in response to alterations in blood glucose levels .

Blood glucose<70mg/dl Proinsulin -- +++ Insulin& C-peptide Proglucagon +++ -- Glucagon Blood glucose >90mg/dl

Paracrine Actions of Insulin and Glucagon

Glucagon + Insulin Insulin - glucagon

glycogenolysis glycogenesis

Insulin

Protein synthesis gluconeogenesis from aa

Glucagon

lipogenesis lipolysis

So, insulin favors anabolic reactions and storing energy glucagon , catabolic reactions and release of stored energy

1- 6 hours: blood glucose < 60 mg/dl 2- Lowered blood glucose ++ secretion of glucagon& -- insulin

+++

3-Glycogenolysis maintain blood glucose for 12-16 hours 4- Then stimulates gluconeogenesis 5- Ketone bodies Alanin &lactate glycerol FFA Fuel reserves are: Triacylglycerols & tissue proteins

So, Effects of Fasting on Carbohydrate Metabolism

1 . Slight fall in serum glucose from 9 to 11 am, but not from 11 am to 6 pm .

Serum Insulin Serum glucagon Growth hormone Catecholamine 2-Slight decrease blood glucose in the first week then normalization by day 20 ± rise in the last week

Fasting and Lipid Metabolism

  Decrease in : Total Cholesterol ,LDL and Triglycerides in first few days then rise to pre fasting levels (quality and quantity of food consumed at Iftaar and Sahur) Increase in HDL-C

Endocrine functions in Fasting

   Fall in free T3 but rise in rT3 Slight fall in total T4 (due to fall in TBG) but normal freeT4 and TSH Serum Testosterone, LH, FSH may be normal or slightly low with change of circadian pattern

-- Sexual desire during fasting hours

Altered circadian patterns of cortisol and testosterone , with sharper decreases of these hormones in the morning and later rises at night

Decrease in appetite due to ketosis and increase in Beta endorphins

Decreased and delayed melatonin peak

Decreased Nocturnal sleep Daytime alertness Psychomotor performance

Renal Function in Fasting

    

Urinary volume Osmolality Shift of fluids intracellularly Dehydration Slight increase in BUN (insignificant) Increase in Uric acid (less in Ramadan fasting than in prolonged fasting)

Other Effects of Fasting

 

Weight loss of 1.7 - 3.8 Kg (obese lose more weight than non obese) Fewer suicide in Ramadan than in other months (reported in Jordan)

Benefits of fasting:

Muslims do not fast because of medical benefits but because they are ordered to.

1- Self -regulation and self-training 2- Concentration of all fluids within the tissues and plasma. 3-Lower of blood sugar 4-Lowering of LDL and elevation of HDL 5-Lowering of the systolic blood pressure.

6-Lowering of body weight 7-Psychological :sense of inner peace and tranquility (Fasting Muslims realize that anger may take away the blessings of fasting) (stress elevate blood sugar via catecolamines)

Ramadan fasting would be an ideal recommendation for treatment of mild to moderate stable NIDDM, obesity and essential hypertension.

What will happen in diabetic patient ?????????

In patients with diabetes

Insulin replacement Glucagon secretion may fail to increase Epinephrine secretion is also defective due to a autonomic neuropathy .

Hypoglycemia Insulin replacement Gluconeogenesis Hyperglycemia & Ketosis Ketogenesis

EPIDIAR STUDY-T2DM: 78.2% fasted >15days

Salti et al: Diabetes Care Vol 27; 10 Oct 2

Risks associated with fasting in diabetic patient???

Risks associated with fasting in patients with diabetes

*

Hypoglycemia

: Severe hypoglycemia Type 1 diabetes Type 2 diabetes 3 to14 events/100 people/ m 0.4 to3 events/100 people/ m. Finch GM et al, Appetite 31:2, 1998 Ghaznawi H I. et al. "The Effect of Ramadan Fasting on Body Weight." Joumalfo the IMA, 1993 Al-Hurani HM etal, Singapore Med J. 2007 Oct;48(10):906-10 Faye J et al, Dakar Med. 2005;50(3):146-51

* Hyperglycemia

: severe hyperglycemia (requiring hospitalization) Type 1 diabetes 3 fold increase 5 fold increase ± Ketoacidosis

Type 2 diabetes

due to excessive reduction in dosages of medications to prevent hypoglycemia

*

Dehydration and thrombosis :     if prolonged fasting In hot and humid climates Among individuals who perform hard physical labor Hyperglycemia Might lead hypovolemia and orthostatic hypotension , however, hospitalizations due to coronary events or stroke were not increased

Taking the decision



The decision to fast is usually taken by three people: the patient , the physician and a religious advisor. Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Thank You

Insulin Glargine during Ramadan

Eman Rushdy

Epidemiology of Diabetes and Ramadan 1422/2001 : (EPIDIAR) study 12,243 people with diabetes from 13 Islamic countries about 43% of patients with type 1 diabetes and 78% of patients with type 2 diabetes fast during Ramadan

.

Diabetes Care2004 : 27:2306–2311

32

   During Ramadan about 60% of patients change their antidiabetic drug intake. 35% stop treatment 8% change the dosage  Importantly, this is done at the patients’ own initiative without medical supervision. Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries. Diabetes Care 2004; 27: 2306–11.

Aslam M, Healey MA. Compliance and drug therapy in Moslem patients. J Clin Hosp Pharm 1986; 11: 321–5.

Aslam M, Assad A. Drug regimens and fasting during Ramadan: a survey in Kuwait. Public Health 1986; 100: 49–53.

Results in



Sequelae of hypoglycaemia Mild ”: Adrenergic (BG<70)

– No direct serious clinical effects – With a rapid decline in blood glucose :

tachycardia, tachypnea, vomiting, and diaphoresis

– May impair subsequent hypoglycaemia

awareness



Severe Neuroglycopenic (BG<50)



Usually associated with slower or prolonged hypoglycemia,

– Stroke and transient ischaemic attacks – Memory loss/cognitive impairment – Myocardial infarction

Recent Clinical Trial Findings:

Intensive glucose control in type 2 diabetes:

 

Was associated with increased mortality in patients with longstanding DM and known CVD (ACCORD) Increases risk of severe hypoglycemia (ADVANCE, ACCORD and VADT)

ACCORD:

N Engl J Med

2008; 358(24):2545-59. ADVANCE:

N Engl J Med

2008; 358 (24): 2560-72.

VADT:

J Diabetes Complications

2003; 17 (6): 314-22

Hypoglycaemia and CV Disease

Desouza C

et al Diabetes Care

26: 1485-1489, 2003

Hypoglycaemia and CV Disease Haematologic Responses To Hypoglycaemia

• Increased RBCs Leading To Increased Blood Viscosity • Enhanced Platelet Aggregation • Increased Platelet Factor 4 • Increased Thromboglobulin • Increased Coagulation Factor VIII • Increased Von Willebrand Factor • Increased Thrombin Generation

Wright R et al Diabetes/ Metabolism Research and Reviews , 2008

Hypoglycaemia and CV Disease Inflammatory Responses To Hypoglycaemia

CRP (mg/L) Baseline 4 Hours 24 Hours Diabetes 0.77 0.84 2.31* Control 0.32 ND 0.96*

*p < 0.04 vs. Baseline

Galloway P et al Diabetes Care 23: 861-862, 2000

Hypoglycaemia and CV Disease

Hemodynamic Hypoglycaemia Thrombotic Inflammatory Ischaemia Wright R et al Diabetes/ Metabolism Research and Reviews , 2008

Hypoglycemia Unawareness

Type 1 DM DURATION Autonomic neuropathy Recurrent hypoglycemia

MIMICKING NATURE WITH INSULIN THERAPY

All persons need both basal and mealtime insulin to control glucose

6 19

•The normal human pancreas has a basal insulin secretory rate of 1-2 U per hr, with post prandial rates increasing to 4-6 U / hr.

in two phases (early & Late phase).

•Insulin secreted into portal circulation where 50% of it extracted by liver without reaching systemic circulation.

•Insulin catabolized by insulinase in Liver, Kidney, & placenta .

Regulation of Basal insulin secretion

Pacemaker ß cells GLUT2 Na + K + Signal Na + K + KIR K + V m K + Ca 2+ Voltage-gated Ca 2+ channel Pancreatic ß cell Ca 2+ Ca 2+ Ca 2+ Mature insulin granules contracts by exposure to high intracellular Ca.

Insulin granules

Glucose

Post prandial insulin secretion

Glucokinase K Ca

Physiologic Insulin Secretion: Basal/Prandial Concept

Nutritional (Prandial) Insulin 50 25 0 Basal Insulin Breakfast Lunch Supper 150 100 Nutritional Glucose 50 Basal Glucose 0 7 8 9 1011 12 1 2 3 4 5 6 7 8 9 A.M.

P.M.

Time of Day Basal Insulin *Suppresses Glucose Production Between Meals & Overnight *Nearly constant levels 40- 50% of daily needs Prandial Insulin *Limits hyperglycemia after meals *Immediate rise and sharp peak * 10% to 20% of total daily insulin requirement at each meal

Good

  70/30 premixed insulin twice daily, ….Use the usual morning dose at the sunset meal (Iftar) and half the usual evening dose at predawn (Suhur), e.g., 30 units in morning and 20 units in evening…e.g., 70/30 premixed insulin, 30 units in Iftar and 10 units in Suhur .

The best:



Consider changing premixed insulin preparations to Glargine or Dtemir Aspart .

plus Lispro, Glulisine or

Diabetes Care September 2005 , pages 2305-11 48

Types of basal insulin

Onset Peak Duration Intermediate Long-Acting Acting (e.g. NPH, lente) (glargine, detemir) 1-3 hr(s) 1.5-3 hrs 5-8 hrs Up to 18 hrs No peak with glargine, dose dependent peak with detemir 9-24 hrs (detemir); 20-24 hrs (glargine) Rossetti P,

et al. Arch Physiol Biochem

2008;114(1): 3 – 10.

49

Ideal Basal Insulin:

   Safe Effective Less glucose excurtions

Why Glargine

Insulin Glargine Peakless with 24hour Release 6 5 4 3 2 1 0 0 8 NPH Insulin Glargine 16 24 Time

Insulin Glargine has less intra-patient variation & has a relatively constant, longer action profile with no pronounced peak in contrast to the peak and intermediate activity of NPH insulin 52

LAPTOP: lower incidence of hypoglycaemia with Insulin Glargine versus premix

Janka HU,

et al

.

Diabetes Care

2005;28(2):254 –259

Meta-Regression Analysis Less hypoglycemia with glargine vs NPH

11 randomized controlled trials; n=3,083 200

p

=0.021

150

NPH insulin

100 50 0 6 7 8 HbA 1c (%)

Insulin glargine

9 10

54

Adapted from Mullins P,

et al. Clin Ther

2007;29:1607-1619.

Insulin glargine consistently achieves HbA 1C ≤ 7%

Baseline Study end 9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

8.6

7.0

(

n

T-T-T 1 = 367 ) 8.6

7.0

INSIGHT 2 (

n

= 206) 8.7

7.0

8.8

6.8

8.7

7.0

APOLLO 3 (

n

= 174) INITIATE 4 (

n

= 58) Schreiber 5 (

n

= 12,216) 1. Riddle M,

et al. Diabetes Care

2003;26:3080 –6. 2. Gerstein HC,

et al. Diabetes Med

2008;371:1073 –84. 4. Yki-Järvinen H,

et al. Diabetes Care

2007;30:1364 2006;23:736 –42. 3. Bretzel RG, –9. 5. Schreiber SA,

et al. Lancet et al. Diabetes Obes Metab

2007;9:31 –8.

LAPTOP: once-daily Insulin Glargine + oral antidiabetic drug therapy is better than two premixes when initiating insulin in Type 2 diabetes

Randomized study in 371 insulin-naïve subjects with T2DM, who received Insulin Glargine or premix (70% NPH/30% regular) insulin for 24 weeks Insulin Glargine + OADs is more efficient in lowering HbA1c, with less hypoglycaemia 56 Janka HU, et al. Diabetes Care 2005;28(2):254–259

PK/PD: Insulin Glargine has a longer duration of action than detemir

Randomized study comparing the pharmacokinetics and pharmacodynamics of Insulin Glargine with that of detemir in 24 subjects with T1DM who were naïve to Insulin Glargine and detemir Porcellati F, et al. Diabetes Care 2007;30(10):2447–2452 57

The need for prandial insulin despite optimal titration of basal insulin is indicated by:

– FBG at or close to target (90–130 mg/dl) but HbA1c ≥7%1 – FBG controlled but PPBG consistently high – Basal insulin dose > 0.5U/Kg 58

Fasting and Insulin Glargine in Individuals With Type 1 Diabetes

Fasting during Ramadan in T2DM patients with insulin Glargine

Breaking the fast

  

Diabetic patients must end their fast immediately in the following cases:

if blood glucose levels drop dramatically to 60 mg/dl if blood glucose levels rise excessively to 300 mg/dl.

or lower if blood glucose reaches of the fast, especially if insulin, sulfonylureas, or meglitinides are taken at the pre-dawn meal 70 mg/dl in the first few hours after the start

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

THANK YOU

Management:

People with type 1 diabetes

 In general, people with type 1 diabetes are at very high risk of developing severe complications, and should be strongly advised to not fast during Ramadan.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Management:

 To be Discussed later in the following sessions

 Two daily injections of NPH intermediate-acting insulin in combination with a short-acting insulin administered the usual dose before Iftar and half the dose before Sahour, However, there is an increased risk of hypoglycaemia around midday  Another option : use one daily injection of the long-acting insulin analogue, glargine; or detemir along with pre-meal rapid-acting insulin analogues.

Management

People with type 2 diabetes Lifestyle and nutrition

    In people who manage their diabetes with diet and physical activity, the risks associated with fasting are quite low. However, if people eat excessively, a potential risk of post-meal hyperglycaemia . Distributing energy intake over two to three smaller meals during the non fasting interval may help. A person’s regular daily exercise programme should be modified in its intensity and timing to avoid episodes of hypoglycaemia .

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Major Targeted Sites of Oral Drug Classes Pancreas The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.

Beta-cell dysfunction Sulfonylureas Liver Meglitinides Muscle and fat DPP-4 inhibitors GLP-1 ↓ Glucose level Hepatic glucose overproduction Insulin resistance Biguanides Gut TZDs TZDs Biguanides DPP-4 inhibitors Glucose absorption Alpha glucosidase inhibitors Biguanides

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.

DeFronzo RA.

Ann Intern Med

. 1999;131:281 –303. Buse JB et al. In:

Williams Textbook of Endocrinology

. 10th ed. Philadelphia: WB Saunders; 2003:1427 –1483.



Source of hyperglycemia during fasting hours:

1- Dietary 2- Insulin deficiency 3- Hepatic glucose output 4- Non of the above.

An Ideal Oral Agent Should You Select during fasting..?

 Achieve A1c Target  Has lower hypoglycemic events  Promotes weight loss In general, medications that act by increasing insulin sensitivity are associated with a significantly lower risk of hypoglycaemia than insulin secretagogues

Major Targeted Sites of Oral Drug Classes Pancreas The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.

Beta-cell dysfunction Sulfonylureas Liver Meglitinides Muscle and fat DPP-4 inhibitors GLP-1 ↓ Glucose level Hepatic glucose overproduction Insulin resistance Biguanides Gut TZDs TZDs Biguanides DPP-4 inhibitors Glucose absorption Alpha glucosidase inhibitors Biguanides

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.

DeFronzo RA.

Ann Intern Med

. 1999;131:281 –303. Buse JB et al. In:

Williams Textbook of Endocrinology

. 10th ed. Philadelphia: WB Saunders; 2003:1427 –1483.

Management

Oral medications

 Metformine : two thirds of the total daily dose to be taken after the sunset meal, with the other third taken after the pre-dawn meal.

 Rosiglitazone and Pioglitazone : have a low risk of hypoglycemia. Usually no change in dose is required.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

   Sulfonylureas are believed to be unsuitable for use during fasting because of the inherent risk of hypoglycemia; they should be used with caution and select the safest SU (glimipride). Meglitinides are superior to SU as long as they could control hyperglycemia.

Chlorpropamide is absolutely contraindicated during Ramadan because of the high possibility of prolonged and unpredictable hypoglycemia.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Insulin

  The aim should be to maintain necessary levels of basal insulin to suppress output of glucose from the liver to near-normal levels during fasting. Careful use of intermediate or long-acting insulins plus a short acting insulin administered before meals would be an effective strategy.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Recommended changes to treatment regimen in patients with type 2 diabetes who fast during Ramad an (MONIRA AL-AROUJ, MD. RADHIA BOUGUERRA, MD. JOHN BUSE, MD, PHD. SHERIF HAFEZ, MD, FACP. MOHAMED HASSANEIN, FRCP. MAHMOUD ASHRAF IBRAHIM, MD. FARAMARZ ISMAIL-BEIGI, MD, PHD. IMAD EL-KEBBI, MD. OUSSAMA KHATIB, MD, PHD. SUHAIL KISHAWI, MD. ABDULRAZZAQ AL-MADANI, MD. ALY A. MISHAL, MD, FACP. MASOUD AL-MASKARI, MD, PHD. ABDALLA BEN NAKHI, MD. KHALED AL-RUBEAN, MD) Recommendations for Management of Diabetes During Ramadan; Reviews / Commentaries / ADA Statements ADA WORK GROUP REPORT;

DIABETES CARE, VOLUME 28, NUMBER 9: 2305-2311, SEPTEMBER 2005

Case #1

 47 years old male , accountant  Sedentary lifestyle  BMI 32  Diabetic 5 years on Glimipride 4 mg /day and metformin 500 mg 3 times daily Glimipride adjusted dose (2 or 3 mg) before Iftar and metformin 1000 mg after Iftar and 500mg after Sahour

Case #2

   51 year old male Type 2 diabetes currently treated with Metformin 1500 mg Serum creatinin 1.9 mg/dl Not to fast Shift to Insulin Sensitizers

Case #1

 48 years old male  BMI 28  Diabetic 11 years controlled on mixed Insulin 60 U breakfast &40 U dinner and metformin 850mg after lunch 60 U Iftar and 20 U Sahour Basal Insulin 40 U & Short acing (better ultra short analogues) 30 U Iftar & 10 U Sahour

Patient Care and Management !!!

Frequent monitoring

 This is especially critical in people who require insulin

Medical assessment

  This should take place one to two months before Ramadan. Specific attention should be paid to people’s overall well-being and to the control of their blood glucose levels, blood pressure, and lipids.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Nutrition

 People should maintain a healthy and balanced diet during Ramadan.  The common practice of ingesting large amounts of foods that are high in fat and carbohydrates, should be avoided

x

 It is recommended that non-caloric fluid intake be increased during the non-fasting hours.  The Sahour meal should be taken as late as possible before the start of the daily fast.

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Physical activity

   Normal levels of physical activity can be maintained.

However, excessive physical activity may lead to higher risk of hypoglycaemia and should be avoided.

x

If Tarawih prayers (multiple prayers after the sunset meal) are performed, they should be considered a part of a person’s daily physical activity programme .

Ibrahim M. A. ; Managing diabetes during Ramadan; Diabetes Voice;

June 2007 | Volume 52 | Issue 2

Diabetics should not fast if :

       Uncontrolled (no defined figure) Recurrent hypoglycemic attacks Hypoglycemia unawareness.

A history of Diabetic Ketoacidosis · Recent infections Kidney disease Unstable ischemic heart disease.