Arab Association for the Study of Diabetes & metabolism

By

Prof. Ragaei HenryProfessar of Internal Medicine, Mansoura University

What is Leptin ?• Leptin is a hormone like protein produced by white adipose cells, so amount of leptin in blood is generally proportional to weight of person and amount of adipose tissue.• Leptin secretion is stimulated by insulin, glucocorticoids and estrogens.• Leptin is found in gastric epithelium, placenta and adipose tissue. Most abundant in white adipose tissue.• Involved in several pathways including : 1) Appetite regulation. 2) Energy intake and expenditure. 3) Involves NYP, glucagon-like peptide-1, melanocortins, CRH, and Other hypothalamic systems. 4) Decreases weight through its role in a feedback loop that affects the satiety and appetite centers of the brain. 5) Many obese patients are resistant to leptin, secondary to a low CSF : blood level ratio.

The Function of the Protein Leptin :• Reduces appetite.• Speeds up metabolism.• Makes people more active.

Leptin peripheral effects :• Stimulates fatty acid oxidation in non-adipose tissue.• Inhibits lipid accumulation is non-adipose tissue.

Leptin

Leptin, A key factor in body energy status :• Short-term energy restriction leads to a marked fall in circulating Leptin levels.• Fall is associated with increased hunger, which may be an early impediment to compliance with a low-energy diet to achieve weight loss.• Fall is associated with increased hunger, which may be an early impediment to compliance with a low-energy diet to achieve weight loss.• Plasma insulin concentrations in parallel with leptin levels in this condition.

Leptin and appetite control :• Leptin acts on several neuronal subtypes within the arcuate nucleus, which inhibits the production of neuropeptied-Y (NPY) and GRP peptide ( an excitatory neuropeptide ) and galanin.• It stimulates production of POMC, CART, and neurotensin.• When leptin levels are high, food intake decrease, mediated by the pro-opiomelanocortin (POMC)-alpha-melanocyte stimulating horm-one (MSH) and melanocortin 4 receptor pathway.• When Leptin levels are low, appetite increases mediated by the secretion of neuropeptide Y, eventually leading to stimulation of food intake.• Insulin also inhibits arcuate nucleus expression of neuropeptide Y.

How does leptin work in obesity ? Obese humans lack leptin? May not have enough receptors.• Leptin is generaly ineffective as signal for excessive body fat, since obese people generally have higher, not lower, levels of leptin, but yet remain obese.• More Important role of leptin is to signal to body that body fat has fallen to dangerously low levels (for example during starvation ) & thus signal that appropriate metabolic changes should occur to preserve metabolic resources.

LEPTIN + INSULIN(1) STIMULATE POMC?CART NEURONS CART AND AMSH LEVELS.(2) INHIBIT NPY/AGRP NEURONS NPYNET EFFECTS : SATIETY AND APPETITE

Lipodystrophy :• Have no fat cells : Usually store huge amounts of lipids (fat) in inappropriate places like muscle or liver & have extremely high levels of lipids in their blood.• They are likely to be insulin resistant-meaning their bodies don’t readily respond to insulin that allows muscle & fat cells to properly use glucose.• Chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipody strophic patients.• Improvement in insulin action leads to reduction in hepatic and muscle triglycerides.• Leptin therapy could reverse severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Leptin

Adipose tissue

Placenta

CentralNervousSystem

Periphery

Neuroendocrine effects

Metabolic effectsEnergy expenditureFood intake

Hemopoiesis

AngiogenesisImmune effectsFetal effects

Honorary PresidentsProf. Ragaei Henry

Prof. Rafat Rashwan

AASD PresidentProf. Inass Shaltout

AASD VicePresidentProf. Abbas Oraby

AASD SecretaryProf. Amr Abdel Wahab

TreasurerProf.

Abdel Khalek Hamed

Board Members

Prof. MohamedKamarProf. Mohamed AsyProf. Amr Gad

Arab Association for the Study of Diabetes & metabolism

By

Prof. Inas ShaltoutProfessar of Internal Medicine & Diabetes, Cairo University

Diabetes Mellitus : Geriatric Times

Advancesin medical care and improved social conditions led to increase life expectancy. About 10% of population in developed countries are above the ageof 60 while 5 - 8 % of population in developed contriesare above the same age. In india alone in 2001 there was million individual above the age of 60.

Dose the Epidemic of Diabetes Involve Older Individuals ? By year 2050 there will be 336% increase in DM above the age 75, while during the NHANES percentage of diabetics above the age of 25 was 7.7 -8.4 % compared to 17.5 - 21 % above the age of 75. Among geriatric population, diabetes is somewhat different due to the changed metabolism, danger ofhypoglycemia and different goals of therapy and drug choice.Most studies of carbohydrate metabolism in the elderly showed that there was riseof blood glucose, especially the post prandial directly correlating with age Fasting blood glucose increases 1 - 2 mg/dL per decade while post prandial blood glucose increases up to 15 mg/dL per decade due to impaired insulinrelease with age and delayed suppression of hepatic glucose output. Clinical presentation of diabetes in the aging population may be totally asymptomatic, or may present with dramatic symptoms . So routine screening isrecommended . Presentation may be with onset of urinary in continence, meno occular neuropathy, onset of sexual dysfunction or with minor but difficult tocontrol infection . Diabetes Mellitus in geriatric population is a risk factor for dementia, falls, hip fractures, immobility and disability including house work, preparing meals ormoney managing . In the Fremantle study done on 223 subjects (Table 1), the incidence of dementia was found to be 2 - 4 times in diabetics compared to nondiabetic geriatrics.Depression was found to be seven times increased in geriatric diabetics . Some macrovascular complications e.g. coronary artery disease and strokes are doubled geriatric diabetics. Amputations are heroically increased up to ten times. There is also evident increased prevalence of microvascular complications.The most common symptomatic complication in geriatric diabetics is neuropathy and clinical diagnosis is often difficult due to age related peripheral andautonomic dysfunction. Bladder dysfunction is also common and symptoms have to be differentiated from that of sinile enlargement of the prostate. High prevalence of nephropathy occure in advancing age due to gradually falling creatinine clearance and coexisting hypertension and atherosclerosis,so planning treatment may include ACI started at the stage of microalbuminuria.

Coronary heart disease constitutes one of the major causes of death in geriatric diabetics, Myocardial infarction may be asymptomatic or sudden cardiacdeath may occur . Infectious complications in old age may occur. There is usually a high risk of tuberculosis and the presentation may be in the form of lowerlobe infection or fulminant tuberculous pneumonia. Other types of infections may occur in the form of frequent urinary tract infections, necrotizing fasciitis,candidiasis or malignant external otitis media.

Geriatric Diabetes : Some Unique Syndromes :1 - Diabetic cachexia which present with weight loss, depression, painful peripheral neuropathy.2 - Diabetic Amyotrophy.3 - Malignant otitis externa.4 - Pyelonephritis with papillary necrosis.5 - Intradermal bullae of the feet.6 - Periarthritis with painful limitation of shoulder movements and,7 - Hypothermia.

Hyperosmolar nonketotic coma may occur in up to 50% of newly diagnosed cases of geriatric diabetics due to impaired maintenance of serum osmolality,decreased thrist perception and possible decreased access to water. Acute infection is a frequent precipitating factor. Difficulties in management may occuras rapid fluid replacement may not be feasible due to commonly associated cardiovascular diseases. When we approach management of diabetes in griatric population we have to ask ourselves the following question: Do older patients require less intensiveor more intensive diabetes control ? Two theories are feasible, the first theory is to treat older diabetics with a goal of postprandial blood glucose of 200 mg/dLand the other theory is about euglycemia with fasting blood glucose of 110 m/dL and Hb AIC < 7%. According to the ADA (American Diabetes Association), although age per-se should not be an excuse for suboptimal control of blood glucose, it may beneither feasible nor appropriate to achieve such tight control in old diabetics, so goals should be individualized according to life expectancy and current medicalproblems.

Dietary Management : It is usually difficult to adhere to strict dietary regimen in elderly individuals due to possible financial difficulties, mobility problems, old individuals may acquirepoor food preparation skills, may have long standing dietary habits which are difficult to change. Usually no strict dietary guidelines needed. Vitamins and minerals supplements may be given when caloric intake is less than 1000 Kcal/day . Exercise:Benefits Should Usually Be Weighed Versus Exercise is benificial roimprove exercise to lerance, glucose to lerance and muscle shength and helphil todecrease blood pressure and body fat, improve lipid profile and sense of well being . The risks include hayard of sudden cardiac deth, foot and joint injuriesand hypoglycemia.Pharmacotherapy : Oral hypoglycemic agents :* Sulphonylureas seem to be popular and constitute 70% of prescriptions for diabetics above the age of 60.20 % of sulphonylurea patients develophypoglycemia due to altered metabolism. Drugs wich may accentuate incidence of hypoglycemia include blockers, salicylate, warfarin and tricyclicantidepressants.* Biguanides should not be used in renal insufficiency, hepatic disease, alcoholism, severe congestive heart failure and severe peripheral vascular disease* Repaglinide; efficacy and safety is similar to younger individuals.* Thiazolidinediones : care should be taken for cardiac function and liver condition. Insulin treatment is mandatory when needed but possible medication error may occur due to possible visual impairment, impaired manual abilities and limited access to injection sites. Rapidly acting analogues with shorter duration are safe because of less possiple hypoglycemia.

Table 1 . Fremantle Study (mean age 70 - 89) on Cognit ion and Mood FREMANTLE AUSTRALIAN DIABETICS SURVEYSDementia 70 - 74 7.2% 2.8% - 4.1% 75-79 20.8% 4.9% - 5.0% 80+ 27.5% 8.7% 11.1%Depression 14.2% 2.0%

Arab Association for the Study of Diabetes & metabolism

Dual Inhibition-A new, More Effective Approach to Lipid-Lowering Therapy

Low density lipoprotein cholesterol (LDL-C) levels represent a primary target in the overall risk management of patients with coranary heart disease(CHD). Statins have proven useful in effectively lowering LDL-C levels through single inhibition and play a pivotal role in primary and secondaryprevention of CHD. However, there is still a huge unmet need as many patients treated with statins alone do not attain target LDL-C levels establishedby various management guidelines, and thus, remain at increased risk for CHD.

Dual Inhibition of two sources of cholesterol - cholesterol production in the liver and absorption in intestine-by coadministering ezetimibe togetherwith a statin repesents a new, more effective therapeutic approach to cholesterol management. Ezzetimibe, the first in a new class of cholesterolabsorption inhibitors,provides markedly greater LDL-C efficacy together with any dose of a statin than a statin alone in patients with primaryhypercholesterolemia or mixed hyperlipidemia.

The Liver and Intestine - Two major Sources of CholesterolCholesterol comes mainly from two principal sources -cholesterol production in the liver and cholesterol absorption in the intestine.

cholesterol absorbed from cholesterol produced by the body and secreted in bile, and secondarily from dietary sources. Approximately half of thecholesterol pool in intestine is absorbed via a cholesterol-transporter protein (Niemann-Pick C1 Like 1 (NPC1L1) and re-circulated to the liver viathe entrohepatic cycle. the remainder is excreted in the feces.

Dual Inhibition Leads to Greater Reductions in LDL-C

statins inhibit cholesterol production in the liver. A logical and innovative progression in lipid-lowering therapy is to inhibit simultaneously bothcholesterol production and cholesterol absorption, resulting in significantly greater LDL-C reduction. Ezetimibe is a novel, selective inhibitor of theintestinal absorption of cholesterol and related plant sterols. By inhibiting intestinal chlesterol absorption,ezetimibe reduces the amount of cholesterolreaching the liver, depleting hepatic cholesterol stores, and therebyincreasing the clearance of cholesterol from the blood.

Patients with hypercholesterolemia treated with the usual starting dose ofany statin typically achieve 19% to 37% reductions in LDL-C levels.

Most of theLDL-C lowering effect ofstatins occurs at the starting dose, and doubling the dose of any statin usually results in approxi-mately a 6%incremental reduction in LDL-C. 12 this the “rule of 6” and is a characteristic of all statins.

Coodministering ezetimibe together with a statin is a more effective therapeutic alternative than doubling the statin dose, for many patients.

Doubling the dose of any statin results in approximately a 6% incremental reduction in LDL-C; coadministering ezetimibe together with a statinprovides approximately a 25% incremental reduction in LDL-C. coadministering ezetimibe together with atorvastatin at the starting dose of 10 mgdemonstrated a 50% reduction in baseline LDL-C levels, The superior LDL-C lowering efficacy of Dual inhibition allows more patients to achievethe recommended target LDL-C levels and, thereby, reduce their risk of cardiovascular disease,4 A similar pattern of LDL-C reductions occurs whenezetimibe is coadministered with other statins.6.8

The substantial additional reductions in LDL-C produced by ezetimbe together with ongoing statin helped significantly more patients achieve NCEPtreatment goals (71.5% VS. 18.9% on placebo, p<0.001).5 The greater LDL-C lowering efficacy of this regimen was generally consistent across statintypes regardless of their LDL-C lowering potency and across various patient subgroups, including those with diabetes mellitus and metabolic syndrome.5

By

Prof. Terje R. Pedersen,MDULLeval University Hospital

Oslo, Norway

Advaces in Cholesterol Management

Arab Association for the Study of Diabetes & metabolism

Impact on Guidelines

Dyslipidemia represents a major risk factor for cardiovascular disease and needs aggressive treatment to reduce cholesterol levels and to helpprevent cardiovascular disease. The 2003 European guidelines on cardiovascular disease prevention in clinical practice 9 state that, in general,total plasma cholesterol should be below 5 mmol/L (190 mg/dl) and LDL-C should be below 3 mmol/L (115 mg/di). However, for matients withclinically established cardiovascular disease and patients with diabetes,

The treatment goals should be lower- total cholesterol less than 4.5 mmol/L (175 mg / di) and LDL-C less than 2.5 mmol/L (100 mg/dl) .

This pattern of treatment goals generally similar to the 2002 NCEP Adult Treatment Panel (ATP) III guidelines.10Since publication of these guidelines, a number of major clinical endpoint trials of statin therapy have been published, including the Heart ProtectionStudy (HPS) and PROVE-IT.11,12 These studies indicate that additional cardiovascular benefits may beattainable when population LDL-C levelsare lowered substantially and even below 100 mg/di.

In the publication by O’Keefe, 2004, 13 where he speculates that lower is better for LDL-C, he raises the question of whether an LDL-C target levelof 50 to 70 mg/di is practical. Randomized trial data suggest that atherosclerosis progression and CHD events are minimized when LDL is loweredto <70 mg/dl. No major safety concerns have surfaced in studies that lowered LDL to this range of 50 to 70 mg/dl. The current guidelines settingthe target LDL at 100 to 115 mg/dl may lead to substantial undertreatment in high-risk individuals (Fig. 4 ).

This body of new, clinical evidence has resulted in recent amendments to the NCEP ATP lll guidelines (Table l ). 14 These new goals represent aconsiderable management challenge since many patients already fail to reach their current LDL-C targets with therapeutic lifestyle changes andstain monotherapy, and many might be unlikely to reach LDL-Clevels of <70 mg/dl . Dual Inhibition with ezetimibe together with a statin providessuperior LDL-C lowering efficacy to statin therapy alone and will be a valuable therapeutic option to help a greater proportion of patients withhypercholesterolemia achieve their LDL-C target goals.

Arab Association for the Study of Diabetes & metabolism

By

Prof. Abbas OrabyA. Prof of Internal Medicine and Endocrinology

Continuous Medical Education AASD CME

CALENDER

Complications of insulin therapy :

At the injection site :

(1) Fault intradermal injection ( Shallow, Oblique injection ) : Pain Abscess Scar “if repeated”

(2) Local allergic reactions (transient) & generalized allergy ( Very rare ).

(3) Fat lumps (lipohypertrophy) : With repeated injections at the same site.

Most of the local complications can be avoided by perpendicular, full-needle length injection with frequent change of the site of injection.

Insulin resistance (massive insulin doses > 100u./day)* Obesity * Immunogenic insulin (Beef insulin)* Behaviour abnormalities * Acanthosis nigricans

Weight gain : A frequent complication with insulin therapy.

Hypoglycemia : (1) Insulin over-dose (2) Insulin erratic absorption (3) Over-exertion (4) Under-feeding (5) Alcohol excess

(6) Honey-moon period : In type 1 diabetes : Some recovery of endogenous insulin secretion may occur over the 1st few months. So, insulin may need to be reduced oreven stopped for a period, otherwise hypoglycemia occurs.

(7) Somogyi phenomenon : Nocturnal hypoglycemia ( over- expression of counter-regulatory hrmones).

Dealing with nocturnal hypoglycemia:(1) Bedtime snack(2) reduction of evening soluble insulin(3) Splitting technique of soluble and intermediate insulin.(4) Insulin analogues: The rapid analogues aspart ( Novorapid ) short duration. The insulin glargine (Lantus) peakless insulin.

Hypoglycaemic unawareness: The patient lacks symptoms of hypoglycemia “unawereful” :(1) beta - Blockers(2) Autonomic neuropathy(3) Human insulins ?!