DR. N.S. NEKI PROFESSOR OF MEDICINE GOVT. MEDICAL COLLEGE, AMRITSAR (INDIA)

Diabetes mellitus is a chronic metabolic disorder with adverse effects on all organs of body Type 1Type 2 Age Type I At any age but usually before 30 years Type 2 At any age but usually after 30 years Body constitutionMostly lean90% overweight Pathogenesis Autoimmune distruction of beta cells Insulin resistance Insulin deficiencyAsolute insulin deficiencyRelative insulin deficiency Lifelong exogenous insulin required Endogenous insulin levels below normal or high More prone to develop DKALess prone to DKA Greater “glucose variability

PREVALENCE OF T 1 DM In US About 1 million individuals. Overall prevalence of diabetes has been increasing steadily. Lifetime prevalence of type1 diabetes United states 0.4% High incidence in countries such as Finland & Sweden 1%. Lowest incidence in Japan. Incidence of type1 DM is increasing. An average of 3.4% increase per year No difference in trend between boys and girls No known explanation for this increasing incidence

Treatment Goals: Juveniles Plasma blood glucose and Hb A1c goals by group. Plasma blood glucose goal range ( mg/dl) HbA1cRational Before meals Bed time/overnight Toddlers and preschoolers <6 yrs %) High risk and prone to hypoglycemia School age 6-12 yrs <8% Risk of hypoglycemia and relatively low risk of complication before puberty Adolescents and young adults yrs <7.5%Risk of hypoglycemia developmental and psychological issues.

Treatment Goals:Adults DefinitionADA guidelines AACE guide lines HbA1c 1.Measures the amount of glycosylated Hb in patients blood 2.Estimates how well diabetes is managed over time. 3.Tested every 3-6 months <7% <6.5% Pre-prandial glucose Blood glucose level taken before a meal mg/dl <110 mg/dl Post-prandial glucose Blood glucose level taken 1-2 has after a meal <180mg/dl <140 mg/dl Blood Pressure<130/80

Major challenge in type 1 DM is the patient is on insulin therapy for lifelong I.Barriers in achieving glycemic targets: 1.Hypoglycemia. Risk of hypoglycemia is a significant barrier in achieving aggressive blood glucose targets in T 1 DM. Education of patient to recognize the signs of hypoglycemia and its treatment. -Parents must be made familiar with the signs and symptom of hypoglycemia and its treatment. -Positive reinforcement for cooperation with regimen. -Reassure the child that diabetes is no one ’ s fault. -Making diabetes regimen flexible to allow for participations in school/peer activities. -Allowing patient to live normal life. -Managing increased insulin requirement during puberty. -Monitoring for signs of depression, eating disorders and risky behaviours. -Select once or twice daily regimen. -Self monitoring of blood glucose levels Intensified regimens result in 3-4 times higher incidence of causing hypoglycemia. 2.Weight gain 3.Genetic susceptibility 4.Environmental factors. 5.Appearance of islet autoantibodies

II.ISLET CELL TRANSPLANTATION Following the introduction of Edmonton transplant protocol in 1999, developed at the university of Alberta in Canada, major islet transplant centre have developed and refined new procedures. There are sufficient data to conclude that there is a high rate of technical success for islet cell transplantation. Recent clinical trials have shown that 50% - 90% of patients are free from insulin after 1 year. Side effects (from long term immunosuppression with cyclosporine) include mouth ulcers, diarrhoea, neutropenia. But there are limitations Need for chronic immunosupression will limit transplantation to only the most brittle patient. Organ availability will limit the number of procedures performed. Each transplant requires at least 2 pancreas. III.TREATMENT ALGORITHM FOR PATIENTS WITH T2 DM ADA/EASD CONSENSUS Ideal drug for T 2 DM (oral or otherwise) should have the following properties. It should reduce blood sugar levels by facilitating insulin secretion from the failing beta cells. It should facilitate insulin action by reducing insulin resistance. It should suppress uncontrolled hepatic glucose output. Avoid hypoglycemia, which is a consequence of fight glycemic control. It should be weight neutral or facilitate weight loss. It should preserve beta cell and if possible generate beta cells.

Well-Validated core therapies Step 1Step2 Step3 Life style+metformin+basal insulin Life style +metformin+ instensive insulin At diagnosis life style +metformin ` Life style + metformin + sulfonylurea

Less well-validated therapies Life style+metformin +pioglitazone Life style+metformin + pioglitazone+sulf onylurea At Diagnosis life style + metformin Life style +metform in+ intensive insulin Life Style + Metformin + GLP 1 Agonist  No hypoglycemia  Weight loss  Nausea/vomiting Life style+metformin + Basal insulin Step1 Step2 Step3

Life style management LSM People with T 2 DM often have life styles (eating and physical activity) which lead to disease. Evidence supports the effectiveness of nutrition therapy and exercise in the prevention and management of T 2 DM Studies of medical nutrition therapy reported HbA1c decrease by Intervention included reduced CHO intake and healthy food choices. Metaanylisis of exercise reported an HbA1c reduction of 0- 66%, independent of changes in body weight, in T 2 DM as well as improvement in insulin sensitivity. As the gain from LSM, in term of glucose control is more and less expensive than any individual therapy, so LSM is greatly promoted. But sometimes LSM is difficult to maintain.

Therapeutic Agents for T 2 DM Drug classMechanism of action 1.SulfonylureasStimulate cell in pancreas to release more insulin 2.MeglitindesStimulate cell in pancreas to release more insulin 3.Biguanides Decrease the amount of glucose production by liver. Make muscle tissue more sensitive to insulin, so glucose can be absorbed 4.Thiazolidinediones ↑ insulin sensitivity by increasing the efficiency of glucose transporters 5.DPP-4 inhibitors (dipeptidyl peptidase 4 ) Prevent breakdown of GLP-1, which reduces blood glucose levels in the body 6.Glycosidase inhibitors Lower blood glucose levels by blocking breakdown of starches and sugars in the intestine 7.GLP-receptor agonists (glucagen like peptide) Increase glucose dependent insulin secretion from the pancreas.  Slow gastric emptying  Reduce post prandial glucagen secretion  Reduce food intake InsulinCompensates for inadequate endogenous insulin production

Exenatide (Exendin-4) is a GLP-1 recptor agonist. Synthetic version of salivary protein found in the gila monster. About 50% identity with human GLP-1 Binds to known GLP-1 receptors on cells in vitro. Resistant to DPP-4 inactivation. Exenatide remains in the circulation longer than GLP-1 Reduce fasting hypoglycemia in T 2 DM. Reduces post prandial hyperglycemia in T 2 DM Reduces the beta cell workload and post prandial glucagon secretion in T 2 DM. Exenatide infusion actutely restores first phase insulin response in T 2 DM. Reduces body weight and food intake. Side effect of exenatide: usually well tolerated. It causes antibody production, nausea (34%), vomiting (24%). But it is given subcutaneously twice daily as compared to Liraglutide (given once daily). Fasting glucose reduction is more with liraglutide than exenatide.

DPP-4 Inhibitor Sitagliptin – used as monotherapy. 1.It improves insulin secretion after OGTT. 2.Prevents degradation of active GLP-1. 3.Decreases glucagon level after OGTT. 4.Reduces fasting, postprandial hyperglycemia Vildagliptin is weight neutral reduces HbA1c. Side effects As add on therapy with glimepride, metformin, insulin, it causes hypoglycemia. As add an therapy with sitagleptin, pioglitazone, metformin, glimepride/metformin – sitagliphtin it causes URC, Headache. A DPP-4 inhibitor (vildagliptin) does not have affect on gastric emptying. Videgliptin as monotherapy can cause commonly dizziness. But headache, constipation, arthralgia, hypoglycemia, URC are rare Sitagliptin causes nausea in 12% and vomiting in 3%, usually well tolerated

Adverse events: DPP-4 inhibitors vildegliptin as add in therapy Adverse events Vildagliptin+met formin Vildagliptin _ sulphonylurea Vildagliptin + TZD TremorCommon HeadacheCommon Uncommon DizzinessCommon FatigueUncommon NauseaCommon HypoglycemiaCommon Uncommon NasophrengitisVery rare ConstipationUncommon AsthemiaCommonUncommon Weight gainCommon Oedema peripheralCommon

Psychological issues are involved in therapy Adults with depression have 37% increased risk of T 2 DM. Depression and distress missed by physicians in % of cases. Severity of symptoms and cognitive symptoms are underestimated. Increased costs. Anxiety disorders are prevalent in diabetics than the community at large. Always have fear of hypoglycemia a) Diabetes specific fear. b) Intense worrying about/fear of (being at risk for) low blood glucose level usually accompanied by excessive self monitoring of blood glucose and corrective behaviours. c) Continuous from mild to extreme (phobia) d) Higher risk in cases of hypoglycemia unawareness. e) Often comorbid anxiety and psychiatric disorders are present. f) Avoidance behaviours – active and passive with subsequent poor diabetes control. g) Also present in parents and spouses of patients -Can be higher in parents with patients. -Affected by recent severe hypoglycemia episodes.

Why does hypoglycemia cause anxiety Unpleasant symptom/disruptive Loss of control. Cause accident, harm others. Brain damage, death. Social embarrassment. Negative effect on relationships, burden to others. Negative effect on work performance, carrier Fear of hypoglycemia risk factors and assessment Risk factors for hypoglycemia Impaired hypoglycemia awareness i.e. reduced bodily signs such as shaking and sweating or not reacting to low blood glucose readings. High trait anxiety/phobia. Having witnessed one or more episodes of severe hypoglycemia in other patient, partner or child.

Assessment Observation Increasing HbA1c levels (following one or more hypoglycemic episodes). Report from patients and or significant others. Questionnaire Problem Areas in diabetes scale and Hypoglycemia Fear Survey. Patient adherence – general findings Adherence to life style recommendation is usually poor. Medication adherence drops with longer duration of treatment. Adherence is highest in HIV, arthritis and cancer. Adherence is lowest in diabetes, pulmonary disease and sleep disorder. Oral hypoglycemic agent adherence rates are 36-93% Higher adherence with once daily v/s multiple tablets. Suboptimal adherence in polypharmacy may be related to one medication instead of whole regimen. Insulin adherence is 63-71%.

Lifelong management stressors in diabetes Continuing need to self manage: always and everywhere. Self-care tasks are unpleasant. Future goals (secondary prevention), but immediate frustrations. Blood glucose fluctuation disrupt psychobehavioral functioning (fear of hypoglycemia). Good behavior ” does not always pay of (effort-reward imbalance). Minimal good news in diabetes: progressive disease and serious risk of developing complications. Social reactions (lack of understanding, discrimination, over/underinvolvement. Self Management Education: More than proving information. Promotes understanding of diabetes and health risks. Promotes intrinsic motivation to self manage/ engage in diabetes. Promotes behavioural strategies. Positively impacts metabolic outcomes. Psychological support options for self management education. Support groups. Stress Management training. Coping skills training. Psychotherapy/cognitive behavioural therapy. It will have significant effect on HbA1c control in T 2 DM and T 1 DM patients.

VIIGlycosylated Hb : Extensive evidence support the benefits of treating to HbA1c goal both in terms of health and economic outcomes. In UKPDS & DCCT trial, the risk of patient with T 2 DM developing vascular complications is strongly correlated with HbA1c levels and the duration of poor glycemic control.Good glycemic control significantly reduces the risk of complication. HbA1c – how low do we go? It is an important challenge. Regarding this ACCORD (Action to Control Cardiovascular Risk in diabetes) trial and Advance trials were conducted in USA and Canada. ACCORD Trial T 2 DM patients from USA and Canada enrolled. Subjects randomized to intensive glucose control with a target of HbA1c<6% of and standard glucose control with a target of HbA1c 7-7.9%. All subjects provided with diabetes education glucose monitoring equipment and diabetes medication. Doses of medication increased every month if HbA1c levels exceed 6% or if more than 50% of the pre-post meal blood glucose values were >100mg or >140 mg/dl respectively. After a median 3.2 year followup, a 1.1% difference in mean HbA1c was observed between groups.

ADVANCE Study: T2DM patients with high cardiovascular risk factors Europe, Asia and North America included. Subjects randomized to intensive glucose control with a target of HbA1c <6.5%. All subjects provided with diabetes medication gliclazide MR. After a 5 year followup, a 0.67% difference in mean HbA1c was obtained between groups (6.5% versus 7.3%; p<0.001) with no change in body weight. The trial showed significant reduction in overall risk of serious diabetes complications by 10%, with 21% reduction in kidney disease and 30% reduction in the development of proteinurea. This trial achieved a positive trend towards reduction in the risk of cardiovascular death (12%), although this did not achieve statistical significance. After a median 3.2 year followup, a 1.1% difference in mean HbA1c was observed between groups. This trial was stopped prematurely because subjects from intensified glucose lowering arm (n=5128) had 22% of higher relative risk for death compared with patients assigned to the standard glucose control arm.

Difference between two trials HbA1c goal for intensive group was <6% in ACCORD Trial and <6.5% in ADVANCE study. Glycaemic control was achieved more rapidly in ACCORD as compared with ADVANCE study. Use of insulin was significantly higher in ACCORD – 77% and 55% in the intensive and standard arms respectively as compared to 41% and 24% of intensive and standard arms of ADVANCE. Rosiglitazone was used in 92% and 58% in the intensive and standard arms respectively of the ACCORD Trial as compared with 17% and 11% of the comparable arms of ADVANCE. Gliclazide MR prescribed in all patients in ADVANCE trial while no patients in Accord Trial received it. Use of Aspirin and Statin was more in ACCORD than ADVNACE study. Hypoglycemia requiring assistance reported was more in ACCORD trial as compared to ADVACE trial. Weight gain reported more in ACCORD trial (3.5kg) while no weight gain in ADVANCE trial. *ADA & EASD have set targets for glycemic control of HbA1c <7% while AACE and ACE <6.5%.

VIII. Replacing amylin with pramlintide as an adjunctive therapy to insulin reveals potencyequal to that of human amylin, subcutaneous injection of premlintide before meals in addition to insulin therapy significantly reduced post prandial glucose excursion and lowered HbA1c levels in patients with type 1 and type 2 diabetes mellitus. There was significant reduction in body weight, no severe hypoglycemia without increases in total daily insulin use. Amylin is second beta cell hormone, consecreted with insulin in response to meals and is deficient in T 1 DM and insulin requiring T 2 DM, Pramlintide is soluble nonaggregating synthetic peptide analog of human amylin.

SUMMARY Current Challenges in diabetes management include: Optimizing the use of currently available therapies to ensure adequate glycemic, blood pressure and lipid control and to reduce complicates. Educating patients on diabetes self management Improving patients adherence to life style and pharmacological interventions. Reducing barriers to the early use of insulin. Improving the delivery of health care to people with chronic complications. The ultimate aim of diabetes therapy is to prevent diabetes complications macrovascular and such as nephropaty, retropathy and microvascular in order to improve quality of life and life expectancy. Order people are more prone to develop severe hypoglycemia as well as renal impairment and elderly people also take multiple pharmacological treatments, so it is difficult for them to adhere to all of their prescribed medications.

REFERENCES: 1.American Association of Clinical Endocrinologists Endo Prac 2007: 20 th Edition Nothan D et al Diabetes care 2006; 29: ADA diabetes care 2009; JAMA 2001, 280: