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Highlights Dr Mick Kumwenda MSc FRCP (London)

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1 Highlights Dr Mick Kumwenda MSc FRCP (London)
Consultant Nephrologist and Clinical Director (Medicine) Glan Clwyd Hospital Rhyl Denbighshire UK

2 PACD We are delighted to present you with the highlights this year from yet again a very successful congress attended by 2003 multidisciplinary delegates from around the globe. We wish to thank all those who attended and hope you left the congress full of knowledge that made a difference when you returned back to your home base. We also thank all the speakers that contributed, the quality of all the papers was exceptional and we have selected a few slides with the kind permission of the presenters to summarise key messages from the congress.

3 PACD The PACD continues to serve the diabetes health care providers in the Middle East as an academic forum for the exchange of knowledge, training and experience. Conference chair : Sherif Hafez Vice chairs: Mohamed Fahmy Abdel-Aziz Megahed Abou El-Magd Assistant Secretary General: Gamela Nasr Hyam Refaat Tantawi

4 Message from molecular metabolism workshops

5 Type 2 diabetes Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Existing genetic markers explain only a modest (15%) part of the heritability of T2D.

6 Epigenetics Epigenetics has been defined as heritable changes in gene function that occur without a change in the nucleotide sequence. i e Non -sequence dependent inheritance

7 Key Enzymes in epigenetics
It has recently been suggested that glucose availability can affect histone acetylation in an ATP-citrate lyase-dependent manner, further linking energy metabolism to epigenetic regulation

8 Mitochondrial disease and diabetes

9 Immune cells and Modulation of Energy Balance
The effectors of innate and adaptive immune cells implicated in maintaining energy balance include: - Macrophages(MQ) - T cells - Neutrophils - Dendritic cells(DCs) - Mast cells (MCs) - Eosinophil's - Natural Killer (NK ) cells - Natural killer T(NKT) cells

10 Cooperation between brain and islet in glucose homeostasis and diabetes
The BCGS is proposed to regulate tissue glucose metabolism and plasma glucose levels via mechanisms that are both insulin dependent (for example, by regulating tissue insulin sensitivity) and insulin independent. Because of extensive redundancy between islet- and brain-centred pathways, dysfunction of both may be required for T2D to develop, and diabetes remission may be possible with therapies that target both pathways. If insulin-independent glucose disposal is subject to rapid and potent regulation by the brain, it is not clear why neural control of GE has not been detected previously. One explanation may be that previous studies have relied on methods that are not optimized to detect GE. Chief among these is the euglyaemic–hyperinsulinaemic clamp method, considered by many to be the gold standard for quantitative, in vivo assessment of glucose metabolism. With this method, insulin sensitivity is measured as the amount of exogenous glucose that must be infused to maintain stable (or ‘clamped’) blood glucose concentrations when insulin levels are raised. Consequently, experimental interventions that change the amount of glucose required during the clamp are interpreted as having changed insulin sensitivity, despite the fact that some of the infused glucose could have been disposed of by insulin-independent mechanisms. Thus, one cannot know with certainty the extent to which observations based on the clamp method are due to changes in insulin-independent glucose disposal instead of, or in addition to, changes of insulin sensitivity. This limitation can be addressed using a complementary approach based on minimal model analysis of glucose and insulin kinetics during an intravenous glucose tolerance test. This method has seen broad use in clinical research39, 42, 44 and was recently used to reveal the potent stimulatory effect of centrally infused FGF19 on GE in ob/ob mice5. (Schwartz, M.W. et al., 2013)

11 Message from obesity workshop

12 Obesity and life expectancy
January 2003 Life Table analysis of Framingham Data Obese at 40 live 6 to 7 years less than normal Overweight at 40 live 3 years less than normal Obese smoker live 14 years less than normal



15 Understanding natural history of type 2 diabetes and targeted therapies

16 Dual defect of type 2 diabetes: treating a moving target
Insulin Resistance Type 2 Diabetes b-cell Dysfunction Hyperglycaemia Insulin Action b-cell Failure Insulin Concentration Insulin Resistance Dual defect of type 2 diabetes: treating a moving target The pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction. Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic. As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further. Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15: Euglycaemia Normal IGT ± Obesity Diagnosis of type 2 diabetes Progression of type 2 diabetes DeFronzo et al. Diabetes Care 1992;15:318-68

17 Guiding principles for nutrition education
Patients are responsible Patients are therefore the final decision-makers Knowing what is best for diabetes, is not the same as knowing what is best for that patient These principles have re-defined how we provide education Both structured education and one to one approach benefits patients.

18 Trials to Prevent / Delay Progression From IGT to Type 2 Diabetes
Lifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention Study Diabetes Prevention Program Medications Diabetes Prevention Program: metformin TRIPOD: troglitazone PIPOD: pioglitazone STOP-NIDDM: acarbose NAVIGATOR: nateglinide and valsartan DREAM: rosiglitazone and ramipril XENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone Several trials in the prevention of diabetes with life style modification or drug treatment have either reported results or are ongoing. TRIPOD=Troglitazone in Prevention of Diabetes Study; PIPOD= Pioglitazone in Prevention of Diabetes Study; STOP-NIDDM=Study to Prevent Non–Insulin-Dependent Diabetes Mellitus; NAVIGATOR=Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM=Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN=Outcomes Reduction with Initial Glargine Introduction.

19 ADA/EASD position statement 2012
Towards personalized glycaemic targets

20 ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27
ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27. Figure 2; adapted with permission from Inzucchi SE, et al. Diabetes Care 2012;35:1364–1369

21 The A1C and ABCDE of glycaemia management in type 2 diabetes: a physician's personalized approach.
AGE (years) 15-40 40-70 >70 COMPLICATIONS DURATION>10yrs - + - + - + HbA1c (%) <6 <6.5 <6.5 6.5-7 <7 7-8 HbA1c≥ 9% Insulin treatment HbA1c< 9% METFORMIN Pozzilli P, Leslie RD, Chan J, De Fronzo R, Monnier L, Raz I, Del Prato S. The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach. Diabetes Metab Res Rev May;26(4): 21 21

22 Diabetes duration (years)
Insulin initiation is often delayed in type 2 diabetes despite high HbA1c INITIATEplus4 0.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 Baseline HbA1c (%) INITIATE1 EuroMix2 9.2% IMPROVETM 3 9.7% 9.9% 17075 9.5% 10.3 7.4 7.7 - - 9.1% Note: Results shown from insulin-naïve subjects INITIATE: Raskin et al. Diabetes Care 2005 EuroMix: Kann et al. Exp Clin Endo Diab 2006 IMPROVE: Valensi et al. Int J Clin Pract 2009;63(3):522–31 INITIATEplus: Oyer et al. Am J Med 2009 1707: Yang et al. (2008) – Baseline HbA1c reflects BIAsp 30 BID A1chieve Egypt sub-group 8.6 Diabetes duration (years) Raskin et al. Diabetes Care 2005;28:260–5 Kann et al. Exp Clin Endo Diab 2006; 114:527–32 Valensi et al. Int J Clin Pract 2009;63:522–31 Oyer et al. Am J Med 2009;122:1043–9 Yang et al. Diabetes Care 2008;31:852–6

23 Improvement of glycaemic control in combination therapy
Glycated Hb reduction vs insulin alone - 0.4% - 1.3% Regime Insulin and SU – 7 studies Insulin and metformin – 4 studies Insulin and TZD – 2 studies Yki Jarvinen H Diabetes Care :

24 Be aware of hypoglycemia
<3.5-4 mmol/L (<63-72 mg/dL) Whipple’s triad: Symptoms Low blood glucose Relief of symptoms when blood glucose raised Hypoglycaemia, which literally means ‘low blood sugar’, can arise from many causes, and can occur at any age. The most common forms of moderate and severe hypoglycaemia occur as a complication of treatment of diabetes with insulin or oral medications. Endocrinologists typically consider the following criteria (known as Whipple's triad) as indicating that a person’s symptoms can be attributed to hypoglycaemia: The presence of symptoms known to be caused by hypoglycaemia Low glucose at the time the symptoms occur Reversal or improvement of symptoms when glucose levels are restored to normal. The definition is a level of 3.5 mmol/L (63 mg/dL). However, for practical purposes and for teaching, we usually talk about a cut-off point of below 4 mmol/L (72 mg/dL).

Normal mech Type 1 Type 2 As blood glucose levels drop, a counter-regulatory response is provoked in all of us. In people without diabetes, the normal counter-regulatory responses are as follows: When the blood glucose level is about 4.5 mmol/L (81 mg/dl) the secretion of endogenous insulin is suppressed. This does not happen in type 1 diabetes because injected insulin (exogenous) cannot be suppressed. At about 65–70 mg/dl (3.6 –3.9 mmol/l) the secretion of glucagon and epinephrine is increased – releasing stored glucose. This is followed by increases in cortisol and growth hormone. All these hormones are in effect trying to raise blood glucose. At about 3.1 mmol/L (55.8 mg/dl) autonomic (adrenergic) symptoms appear: Tremors in 32%-78% of people Palpitations in 8%-62% Sweating in 47%-84% Anxiety in 10%-44% Ravenous hunger in 39%-49% Nausea in 5%-20% Tingling especially around lips in 10%-39%.

26 Hypoglycemia unawareness
Glucagon response often lost after five years with type 1 diabetes Epinephrine response may be blunted and delayed Adrenergic symptoms blunted Reliance on recognizing neuroglycopenic symptoms Why does this phenomenon occur? The glucagon response to hypoglycaemia in people with type 1 diabetes is lost after about five years of diabetes. If a person has repeated hypoglycaemic episodes, the action of epinephrine may be blunted or delayed. The adrenergic symptoms of hypoglycaemia are thus also blunted or delayed. It therefore becomes increasingly important for people to recognize neuroglycopenic symptoms.

27 Metformin: multiple mechanisms for vascular protection
Improved Reduced All refs Diabetes Metab (2003): 1Gianarelli R vol. 29:6S28-35; 2Després JP 29:6S53-61; 3Grant PJ ;29:6S44-52; 4Wiernsperger N 29:6S77-8; 5Schäfers RF 29:6S62-70; 6Beisswenger 29:6S95-103; 7Leverve XM 29:6S88-94; 8Mamputu JC 29:6S71-6;

28 The proposed pathways by which GLP-1 may exert its cardiovascular Effects .

29 Cardio protective potentials of DPP-4 inhibitors beyond their glucose-lowering action
Balakumar P, et al. Cell Signal Sep;25(9):

30 197 studies identified Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia. Formal estimates of combined effects from the five trials which reported appropriate data indicated a significant reduction in insulin dose (6.6 U/day, p<0.001) but no significant reduction in HbA1c (absolute reduction 0.11%, p=0.42). No reported trials included cardiovascular outcomes 12

31 Alpha Glucosidase Inhibitors in Type 1 DM
Prevention of nocturnal hypoglycemia? Reduce postprandial hyperglycemia Raju B, et al. J Clin Endocrinol Metab Jun;91(6): Riccardi G, et al. Diabet Med Mar;16(3): 13

32 Thiazolidinediones in Type 1 DM
Potential insulin sparing role in overweight patients with type 1 diabetes. Mixed effects on progression of diabetes reported Strowig SM, Raskin P. Diabetes Care Jul;28(7): Shimada A, et al. Diabetes Metab Res Rev. 2011 Nov;27(8):951 Yang Z, et al. Diabetes Res Clin Pract Jan;83(1):54-60. 14

33 Incretin-based Therapies in Early Type 1 DM
Hari Kumar KV, Shaikh A, Prusty P. Diabetes Res Clin Pract May;100(2):e55-8 2

34 Ramadan and glycaemic control
Oral hypoglycemic agents SUs Unsuitable for use during fasting because of the inherent risk of Hypoglycemia, use with caution. Consider dose adjustment. TZDs No treatment adjustment required 2–4 weeks to exert substantial antihyperglycemic effects Metformin Modify timing of doses: Two thirds of dose at Iftar • One third at suhur. DPP4 inhibitors The best tolerated drugs, Consider DPP4i as an alternative to SUs if the risk of hypoglycemia is high Short acting insulin SUs Take twice daily at suhur and iftar E Hui et al , BMJ, 26 june 2010 , Volume 340; Al-Arouj M. et al, Recommendations for management of diabetes during Ramadan. Diabetes Care. 2010;33:

35 Don’t miss MODY! Genetic Testing for MODY
Who should be tested? MODY misdiagnosed as type 2 diabetes and sometimes type 1 diabetes. Mutations can be inherited (commonly) or de novo (rarely). What genes should be tested? Most common causes of MODY are mutations in GCK, HNF1A and HNF4A. Is genetic testing good healthcare policy? Change from expensive therapy to cheaper therapy – saves money. If you have a GCK mutation, you DO NOT have type 2 diabetes and you do not need any drugs or a diabetes doctor!

36 MODY – Treatment Decisions
HNF1A Low-dose sulfonylurea (pills) GCK No therapy except during pregnancy HNF4A HNF1B Insulin?


38 OASIS Study Mortality by Diabetes and CVD Status
Diabetes/CVD (n=1,148) RR=2.88 ( ) No Diabetes/CVD (n=3,503) Diabetes/No CVD (n=569) No Diabetes/No CVD (n=2,796) RR=1.99 ( ) Event rate RR=1.71 ( ) RR=1.00 3 6 9 12 15 18 21 24 Months OASIS=Organization to Assess Strategies for Ischemic Syndromes Malmberg K, et al. Circulation. 2000;102:

39 State of the art lecture in memory of Prof Zakarya El BAZ Diabetic Nephropathy by Prof Sherif Hafez Dr Mick Kumwenda

40 Definitions – based on quantification
Micro albuminuria - dipstick negative > 2.5 mg/mmol males > 3.5 mg/mmol females mg/day Macrolbuminuria – dipstick positive > 25 mg/mmol both males and females > 300mg/day – diabetic nephropathy (low serum albumin = nephrotic syndrome Can be proteinuria negative in type 2 +/- e GFR < 60ml/min

41 Diabetic Nephropathy: pathological classification
Class 1 – EM proven GBM thickening Class 2a – Mild mesangial expansion Class 2b – Severe mesangial expansion Class 3 - Nodular sclerosis ( KW lesions) Class 4 - Advanced sclerosis ( > 50% glomeruli) Tervaert TC et al J Am Soc Nephrol 2010 online

CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA). Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Persistent albuminuria categories Description and range A1 A2 A3 Normal to mildly increased Moderately Severely <30 mg/g <3 mg/mmol mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol Previously micro-albuminuria Previously macro-albuminuria GFR categories (ml/min/ 1.73 m²) Description and range G1 Normal or high ≥90 G2 Mildly decreased 60-89 G3a Mildly to moderately decreased 45-59 G3b Moderately to severely decreased 30-44 G4 Severely decreased 15-29 G5 Kidney failure <15 Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3: Accessed February 26, 2013

43 Although we understand the natural history of diabetic kidney disease some patients with type 2 diabetes progress to end stage kidney disease without developing proteinuria

44 Nonalbuminuric Renal Insufficiency in Type 2 Diabetes, MacIsaac 2004
A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99mTc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. Conclusion: patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric. MacIsaac et al, Diabetes Care Jan;27(1):

45 Blood Pressure Target Goals in CKD patients
CHEP 2014 (BP target)¹ Target Blood pressure Should be less than 140/90 mmHg in most patients, including those with chronic kidney disease. ESC 2013 (BP target)² Target Blood pressure <140/90 mmHg should be considered in patients with diabetic or non-diabetic CKD. JNC IV (BP target)³ In patients with CKD, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg, and treat to achieve SBP <140 mmHg and DBP <90 mmHg. 1: Canadian Hypertension Education Program (CHEP) 2014 Recommendation, adopted from: Accessed at 5/2/2014 2: Mancia G, et al. J Hypertens Jul;31(7): 3: James PA, et al. JAMA Dec 18. [Epub ahead of print]

46 ACE inhibitors in Hypertensive diabetic patients

47 Weight loss Exercise Smoking cessation BP & Lipid targets
Intensive group n=80 Weight loss Exercise Smoking cessation BP & Lipid targets Aspirin, Statin, ACEI CV morbidity & mortality -50% Compared to usual diabetic care 8 years follow up Progression to proteinuria -60% We highlighted early on the CVD risk increase in both types of DM with nephropathy. Aggressive CV risk factor management is vital and will also reduce the progression of renal disease and other diabetic complications of diabetes. In a small study in type 2 diabetics with micro albuminuria patients were randomised to usual diabetic care or Intensive care. The intensive group followed a protocol driven intensive life style and medical intervention regimen Progression to Retinopathy -60% Gaede P et al. Multifactorial intervention , N Engl J Med 2003; 348:

48 Steno-2 Trial: multiple risk factor intervention in T2DM
Steno-2: Number needed to treat Number of microalbuminuric patients with type 2 diabetes needed to treat for 13 years to prevent one ….. Death patients Cardiovascular death patients Major cardiovascular event patients Progression to nephropathy 5 patients Dialysis patients Laser treatment 7 patients Steno-2 Trial: multiple risk factor intervention in T2DM

49 RAS MANAGEMENT CAUTION: avoid combined therapies


51 Caution : ACEi or ARB in combination with RENIN inhibitor ALTITUDE – Murray JJ Eur J Heart Fail (4) 341-3 Aliskerin 300mg increased urinary albumin excretion Dual caused reduction of e GFR Stroke placebo 85 Aliskerin 112 Study discontinued

52 Diabetic Kidney disease guidelines
CKD 1-2 CKD 3-4 Same as CKD1-2 CKD group education: -Bone mineral disease - phosphorus mg/day - salt intake <6g/day - anaemia Hb 10-12g/dl - ferritin >100ng/ml Preparation for renal replacement therapy including transplantation Life style modification Protein intake 0.8g/kg Treat all risk factors HbA1C <7% BP < 140/80 Refer to Nephrologist : -rapid progressors - nephrotic syndrome - haematuria - e GFR < 40ml/min

53 Can we identify patients at risk using biomarkers?
Microalbuminuria remains the gold standard Other candidate markers associated with microalbuminuria or low e GFR: - Neutrophil gelatinase associated lipocalin (NGAL) - Kidney Injury Molecule 1(KIM 1), -Transforming Growth Factor Beta -Cystitis C -Tumour Necrosis Factor -oocytes Adipocytokinine Zinc alpha 2 glyco protein (ZAG) in non-albuminurics

54 Meta-analysis in primary prevention 2009 ASA and diabetes

55 Meta-analysis in primary prevention 2009 ASA and diabetes: Total mortality

56 Efficacy of Antiplatelet Therapies in ACS Results in the Diabetes Mellitus Subgroups (Adapted from Ferreiro JL et al. Circulation 2011; 123: )

57 Diabetes and heart failure Current knowledge
Piccini JP et al,Am J Med 2004: 116: 64s-75s Trost S, LeWinter M. Curr Treat Options Cardiovasc med. 2001: 3:

58 Glucose management strategy

59 Clinical management of diabetic foot

60 Clinical management of diabetic foot

61 Evidence based management of diabetic foot
Glycaemic control Control oedema Debridement Dressings

62 Erectile dysfunctiom Incidence and prevalence is high worldwide
Effects up to 52% of men (40-70yrs) Aetiology - Organic - Hormonal - Anatomical - Drugs - Psychogenic

63 Treatment Oral therapy PDE-5 inhibitors improve relaxation of smooth muscle. Contraindicated in patients receiving nitrates, recent stroke/MI, unstable angina Intracavernosal injection Papaverine Phentolamin PGE1 Atropine Vacuum devices Penile prosthesis

64 PACD Diabetes continues to be a global epidemic particularly effecting the Middle East The ultimate goal of the congress is to support thaw commitment of health professionals to fight against diabetes. We hope you have gained more knowledge yet again this year and see you again at PACD in Cairo.

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