MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 357amputations, blindness,and end-stage renal disease occurs in diabetic patients.3This chapterwill provide an in-depth account ofdifferent treatment options and latest advancement indiabetes care. Managing diabetes complications and screening is a part ofcomprehensivediabetes care , but cannot be covered in this chapter because of limited space.MANAGEMENT OF DIABETES MELLITUSThe major objectives of proper diabetes management are to alleviate the symptoms,achieve good glycemic control and prevent the micro and macrovascular damage. Datafrom the United Kingdom Prospective Diabetes Study (UKPDS), DCCT and ADVANCEstudies demonstrated the substantial impact of good glycemic control on vascularcomplications.r "It isestimated that a 1% decrease in HbA Ic results in significantreductionin diabetes related deaths (21%) , reduction in microvascular complications (37%) andreduction in myocardial Infarction (14%).Diabetes EducationDiabetes education is the most important obligation on the part ofa clinician. Patientsand their families are the best persons to manage a disease that is affected so markedlyby daily fluctuations in environmental stress, exercise, diet and infections. The teachingshould include explanations by the physician or educator of diabetes and its potentialacute and chronic complications and how they can be recognized early and prevented ortreated. Self-monitoring of blood glucose (SMBG) should be emphasized, especially inType I diabetes mellitus (T IDM) and insulin-requiring Type 2 diabetes mellitus (T2DM)patients, and instructions must be given on proper testing and recording of the data.v?Patients taking insulin should be taught how to adjust the insulin dose for thecarbohydrate content of a meal. Strenuous exercise can precipitate hypoglycemia andpatients must therefore be taught to reduce their insulin dosage in anticipation ofstrenuousactivity or to take supplemental carbohydrate.The targets for blood glucose control in elderly patients should be flexible since theyhave much higher risk of hypoglycemia if subjected to tighter glycemic control. Adviceon personal hygiene, including detailed instructions on foot and dental care, shouldbe provided. Finally, vigorous efforts should be made to persuade all diabetics to quitsmoking since large vessel peripheral vascular disease and debilitating retinopathy aremore common in diabetic smokers.Medical Nutrition Therapy (MNT)Medical nutrition therapy (MNT) is the process by which the nutrition prescriptionis tailored for people with diabetes based upon medical, lifestyle, and personal factors. toA well-balanced diet remains a cornerstone oftherapy.The American Diabetes Association(ADA) recommends about 45-65% of total daily calories should be taken in the formof carbohydrates, 25-35%, in the form offat (of which <7% are from saturated fat), and10-35% in the form ofprotein.!:" Patients with TIDM orT2DM who take insulin shouldbe taught "carbohydrate counting," so they can administer their insulin bolus for eachmeal based on its carbohydrate content. In obese individuals with diabetes, an additionalgoal is weight reduction by calorie restriction.
358 DIABETESThe current recommendations for both types ofdiabetes continue to limit cholesterolto 300 mg daily, and individuals with LDL cholesterol more than 100 mg/dL should limitdietary cholesterol to 200 mg/day .High protein intake may cause progression ofkidney disease in patients with diabeticnephropathy; for them, a reduction in protein intake to 0.8 kg/day (or about 10% oftotalcalories daily) is recommended. Diabetic patient should also be instructed to take dailyfibers in their diet. Fibers have good beneficial effects on cholesterol in the body.ExerciseExercise isbeing increasingly promoted as part ofthe therapeutic regimen for diabetesmellitus. In addition to its cardiovascular benefits, exercise can also improve glycemiccontrol. The beneficial effect on glycemic control largely results from increased tissuesensitivity to insulin .Based on the literature ,ifcompletely sedentary and underactive individuals participatein moderate physical activity 30 minutes a day, they would obtain at least a 30% reductionin risk not only for T2DM but also for other chronic diseases such as coronary arterydisease, stroke and colon cancer. The American Heart Association and The AmericanDiabetes Association recommend at least 150minutes ofmoderate-intense aerobic activityor at least 90 minutes of vigorous aerobic exercise per week." The activity should bedistributed over at least three days each week, with no more than two consecutive daysof inactivity.Weight LossMore than 80 percent of cases of T2DM can be attributed to obesity, which mayalso account for many diabetes-related deaths. Despite the clear benefit of weight loss,only a small percentage ofpatients with T2DM are able to attain and maintain substantialweight IOSS.1 5 This difficulty results from limited success in long-term adherence tocalorie-restricted diets. However, impressive successes reported with intensive dietaryintervention.Pharmacotherapy for weight loss may be effective in patients with T2DM, andgenerally is associated with high dropout rates due to medication side effects and is notrecommended as primary therapy for diabetes. Orlistat, a pancreatic lipase inhibitor, isthe only FDA approved drug for the long term management ofobesity. Other weight lossdrugs such as rimonabant and sibutramine have been withdrawn from the market becauseof increase suicidal thoughts and cardiovascular side effects, respectively.Bariatric Surgery for ObesityBariatric surgery may be considered for adults with BMI >35 kg/m-, especiallyif the diabetes or associated co-morbidities are difficult to control with lifestyle andpharmacologic therapy. Gastric bariatric surgery results in the largest degree ofsustainedweight loss and improvements in blood glucose control and should be considered inmorbidly obese diabetics.f-" Bariatric surgery has been shown to lead to near- or completenormalization of glycemia in more than 55-95% of patients with T2DM, depending onthe surgical procedure."
MANAGEMENT AND TREATMENT OF DIABETES MELLITUSTable 1. Glycemic targets: Current recommendationsIDF359ADAI-1bAlc %Pre prandial glucose mg/dLPost prandial glucose mg/dL<6.5<110<140<7.090-130<180Table 2. Lipids and blood pressure targets: Current recommendationsTotal cholesterol mg/dL <200Triglycerides mg/dL <150LDL-C mg/dL <100<70 with many CV risk factorsHDL-C mg/dL Man : >40Woman: >50Blood pressure mm I-1g <130/80Cardiovascular Risk Factor ManagementIn addition to glycemic control, vigorous cardiac risk reduction includes smokingcessation, use ofaspirin, secondary prevention, blood pressure control , and reduction inserum lipids these should bethe top priority for all patients with diabetes (Tables I and 2).12VaccinationInfluenza and pneumoniaare common, preventable infectious diseases associated withhigh mortality and morbidity in the elderly and in people with chronic diseases. Diabeticpatients should receive influenza vaccination yearly and pneumococcal vaccination,repeatingthe pneumococcal vaccination once after 65 years ofage ifthe initial vaccinationwas prior to age 65.19,20Psychological Assessment and CarePsychological and social problems can impair the individuals or familys abilityto carry out diabetes care and may lead to compromised health status. Therefore, it isimportant for the clinicians to assess psychosocial status in a timely and efficient mannerso that referral for appropriate services can be accomplished.v-"PHARMACOLOGICAL TREATMENT OF DIABETESEarly institution ofpharmacological treatmentfor diabetes isassociated with improvedglycemic control over time and decreased long-term complications. Pharmacologictherapy is often not initiated soon enough, resulting in poor glycemic control. After asuccessful initial response to oral therapy, patients fail to maintain target HbAl c levels«7 percent) at a rate of 5 to I0 percent per year." An analysis from the UKPDS foundthat 50 percent of patients originally controlled with a single drug required the addition
360 DIABET ESFirst Lin e App roachLifestyle+Metformin Lifestyle+Metformin+ +Basal Insnlin Intensive InsnlinAt Diagnosis:Lifestyle + Metformi n tLifestyle+Metformin+Sulfonylurea sStep 3Step 1 Step 2Second Line App roachLifestyle+Metfo rm in Lifestyle+Metform in+ +Pioglitazone Pioglitazon e-----+ Caution: Heart failure r+ +At Diagnosis: Sulfonylur easLifestyle + Metformin f---+Lifestyle+Metformin/ 4 Lifestyle+Metformin-----+ + +GLP 1 agonist Basal Insulin I--Step 1 Step 2 Step 3Figure 1. Treatment flow sheet for Type 2 diabetes.of a second drug after three years; by 9 years 75% of patients needed multiple therapiesto achieve the target HbA IC.24Figure I illustrates a flow sheet of a consensus statementfrom the American Diabetes Association (ADA) and the European Association for theStudy of Diabetes (EAS D) for the treatment of T2DM.25Anti-Diabetic DrugsThey fall into two broad categories; oral and injectable.Oral Anti-Diabetic MedicationsA. Insulin secretagogues1. SulfonylureasFirst generation sulfonylureas: includes tolbutamide, chlorpropamideand acetohexamideSecond generation sulfonylureas: includes glimepiride, glibenclamide/Glyburide, gliclazide and glipizide2. Meglitinides includes repaglinide and nateglin ideB. Insulin sensitizersI. Biguanides: includes metformin and phenformin2. Thiazolidinediones: includes pioglitazone and rosiglitazoneC. a -Glucosidase inhibitors: includes acarbose and migl itolD. Dipeptidypeptidase IV inhibitors:includes sitagliptin,vidagliptinandsaxag liptin.
MANAGEMENT AND TREATMENT OF DIABETES MELLITUSInjectable Anti-Diabetic Medications361A. Glucagon-like peptide I receptor agonist ( GLP-I analogue): includes exenatideand liraglutideB. Pramlintide (amylin analogue)C. InsulinI. Conventional insulin: includes regular and intermediate acting (NPH)2. Insulin analoguesUltra short acting: includes lispro, aspart and glulisineLong acting analogues: includes glargine and detemirCommonly Prescribed Oral Anti-Diabetic Medications (see Table 3)There are different classes oforal anti-diabetic medications exerting clinical effectsvia different mechanisms. These medications are commonly prescribed world wide andhave shown effectiveness while used alone or in combination.v-"Table 3. Oral anti-diabetic drugsDrug Potency Dail y Dosage DurationSu Ifonylu reasGlimepirideGlibenclamide/GlyburideGliclazideGliclazide MR*GlipizideTolbutamideMeglitinideRepaglinideNateglinideBiguanidesMetforminMetformin XR**1,2,3,4 mg1,25, 2,5, 5 mg80 mg30,60 mg5, 10 mg500 mg0,5, 1,2 mg60-120 mg250, 500, 850,1000 mg500 mg1-8 mg once a day1.25-20 mg single or twodivided dosages80-320 mg two divided dos es30-120 mg once a day2.5-20 mg two divided doses0.5-2 g in three divided doses0,5-4 mg thrice a day60-120 mg three times a day1000-2500 mg two to threedivided doses500-2000 mg once a dayUp to 24 hoursUp to 24 hoursUp to 12 hoursUp to 24 hours6-12 hours6-12 hours3 hours1.5 hours6-12 hoursUp to 24 hours15-45 mg onc e a day4-8 mg once a dayThiazolidinedionesPiogl itazon e 15, 30, 45 mgRosiglitazone 2,4,8 mga-Glucosidase inhibitorsAcarbose 50-100 mg 25-100 mg three times a dayMiglitol 25,50, 100 mg 25-100 mg th ree times a dayDipeptidyl peptidase 4 (DPP-4) inhibitorsSitalgliptin 25,50, 100 mg ***100 mg onc e a dayVildagliptin 50 mg 50-100 mg/daySaxagliptin 2,5 and 5 mg 2,5-5 mg once dailyUp to 24 hoursUp to 24 hou rs4 hours4 hou rs24 hours24 hours24 hours* Modified release; ** Extended release; *** 50 mg/day if creatinine clearance 30-50 mLimin and25 mg/day ifclearance <30 mL/min.
362 DIABETESFollowing is the detail description ofthe use of different oral agents in T2DM withtheir pharmacokinetic and pharmacodynamic properties .SulfonylureasSulfonylureas are most commonly prescribed and well tolerated oral hypoglycemicdrugs.They are moderately effective,lowering blood glucose concentrations by20 percentand HbA Icby 1-2%. However,their effectiveness decreases overtime.AIthough the onsetofthe glucose lowering effect ofsulfonylurea monotherapy is relatively rapid comparedwith the thiazolidinediones (TZDs), maintenance of glycaemic targets over time is notas good as monotherapy with a TZD or metformin. Generally sulfonylureas are saferwith in the group, use ofglyburide/glibenclamide has been shown to be associated withhigher mortality than other sulfonylureas."Primary andSecondary Failure. The reported rate ofprimary failure ofsulfonylureatherapy (i.e.,the inability to achieve a good or adequate glucose response) variesfrom 5-30%. The rate of secondary failure in patients who have an initial response totreatment with sulfonylureas ranges from 5-10% each year; after 10 years, only 50%have satisfactory control.":"Mechanism ofAction. Sulfonylureas exert clinical effects via receptors.Sulfonylureasreceptor is a component of the ATP-dependent potassium channel in the pancreatic~ cells. Binding leads to inhibition of these channels, which alters the resting potentialof the cell, leading to calcium influx and stimulation of insulin secretion. The net effectis increased insulin secretion from ~ cells of pancreas. Thus, sulfonylureas are usefulonly in patients with some ~-cell function.Pharmacokinetics. Approximately 50% ofthe sulfonylurea dose is rapidly absorbed;its level can be detected in serum one hour after administration. Ninety to 99% ofthe drugis bound to plasma proteins, especially albumin. Binding ofsecond-generation agents islimited to non-ionic sites; hence, they are less likely to interact with other medicationsthan are first-generation agents.Glipizide, glyburide (glibenclamide), gliclazide, and glimepiride are so-calledsecond-generation sulfon ylureas. They have structural characteristics that allow them tobe given in much lower doses than the first-generation sulfonylureas. Nevertheless, thedifferent sulfonylureas are equally effective in lowering blood glucose concentrations.There are,however,differences inabsorption and metabolism,as well as ineffectivedosage(Table 3). Comparison of plasma half-lives is misleading, since the biological effect isoften much longer. For example, the hypoglycemic action ofglibenclamide can last formore than 24 hours, due in part to the formation ofactive metabolites. Glibenclamide isunique among all sulfonyureas in that it becomes sequestered in ~ cells. This may explainits prolonged duration despite short plasma half life.Chlorpropamide, glibenclamide and glimepiride can be given once daily because oftheir long half-lives. They also cause greater suppression of overnight hepatic glucoseoutput, thereby lowering fasting blood glucose concentrations more. Sulfonylureas aremetabolized by the liver and excreted through kidneys and, in case ofsecond generationsulfonylureas, partly excreted in the bile. Metabolites ofacetohexamide are more activethan othersulfonylureaswhos e metabolites are either inactive or partly active. Glimepiride
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 363achieves blood glucose lowering with the lowest dose ofany sulfonylures,thus, increasingits cost-effectiveness.Side Effects. Hypoglycemia is the most common side effect and is more commonwith long-acting sulfonylureadrugs such as chlorpropamide,glyburide/glibenclamide.32,33Elderly patients are more prone to develop hypoglycemia; therefore, short actingsulfonylureas are more preferable, such as gliclazide and glipizide.One study has shown that patients receiving second generation sulfonylureas suchas glyburide, glipizide, or glimepiride at the time of myocardial infarction did not havegreater mortality rates than patients treated with insulin." Chlorpropamidehas a prolongedbiologic halflife and may cause severe hypoglycemia especially in elderly. Its other sideeffects include alcohol-induced flushing and hyponatremia.Factors Contributing Drug-Induced Hypoglycemia in Elderly. Drug-inducedhypoglycemia is most likely to occur in the following circumstances in older patientsand may be a limiting factor for use of these drugs in older adults:After exercise or missed mealsInadequate oral intakeImpaired renal functionsImpaired hepatic functionsPoor left ventricular functionAlcohol abuseDrug therapy with salicylates, gemfibrozil, warfarin etc.Weight gain may occur insome patients using sulfonylurea. Hypersensitivity reactionto sulfonylureas may occur in the first 6-8 weeks oftherapy. It consists mainly ofallergicskin reaction which progress rarely to erythema multiforme, exfoliative dermatitis, feverand jaundice.Contraindications. Sulfonylureas should not be given in severe liver disease, chronickidney diseases and porphyria. They should be avoided in pregnancy and lactation sincedata are not sufficient to ensure safety of drugs in these conditions.":"MeglitinidesMeglitinides are oral hypoglycemic agents derived from benzoic acid and chemicallyunrelated to the sulfonylurea agents.Repaglinide, which is rapidly absorbed after oral administration, reaches peakplasma levels within I hour and is rapidly eliminated by oxidation and conjugation withglucuronic acid in liver, therefore, can be given safely in renal failure because it has nosignificant renal excretion.Meglitinides stimulate insulin secretion like sulfonylureas but they bind to a differentsite within the sulfonylurea receptor." They have a shorter circulating half-life thanthe sulfonylureas and must be administered more frequently. Repaglinide is almost aseffective as metformin and decreasing HbA 1e levels by 1.5%. Nateglinide is somewhatless effective in lowering HbA Ie than repaglinide when used as monotherapy or incombination therapy."
364 DIABETESSide Effects . Side effects ofmeg litinides include weight gain and hypoglycemia. Anadditional drawback to this drug is the dosing schedule since it must be taken with meals .BiguanidesMetformin, phenformin and buformin are the derivatives of biguanides and haveglucose-lowering effects. Metformin is the commonly used biguanide and lowers HbA Ielevels by 0.5_1 .0%.41,42Metformin is an effective monotherapy and may be an ideal drugfor overweight patients since it does not cause weight gain and has been seen to causemodest amounts of weight loss when first administered.vv v" Diarrhea and abdominaldiscomfort are the main side effects that can be alleviated by changes in diet and slowincreases in metformin dosage.In the absence of contraindications, metformin is considered the first choice fororal treatment of T2DM . American Diabetes Association (ADA) and the EuropeanAssociation for the Study of Diabetes (EASD) proposed that metformin therapy (in theabsence of contraindications) be initiated, concurrent with lifestyle intervention, at thetime of diabetes diagnosis.Mechanism . The mechanism of action of metformin is not entirely understood, butits predominant effect is to suppress hepatic glucose production and to enhance insulinsensitivity in peripheral tissues .v-" At cellular level metformin activates adenosinemonophosphate-activated protein kinase, which acts as an intracellular energy sensorand has a critical role in regulating gluconeogenesis."Pharmacokinetics. Metformin is partially absorbed from the gastrointestinal tractand has a bioavailability of50-60%. The drug is stable, does not bind to plasma proteins,and is not metabolized. It is excreted in the urine unchanged and has a plasma half-lifeof 1.7 to 4.5 hours. Ofa given dose, 90% is cleared within 12 hours. Metformin does notcause hypoglycemia if used as monotherapy. Absorption of vitamin B12 appears to bereduced during long-term metformin therapy, but the serum vitamin B12 levels usuallyremain in the normal range. However, periodic screening with serum vitamin B12levelsshould be considered, especially in patients with symptoms of peripheral neuropathy.Contraindications. Renal dysfunction (serum creatinine> 1.5 mg/dL in man and>1.4mg/dL inwomen or creatinine clearance <30 mL/min) isconsidered acontraindicationto metformin use because it may increase the risk of lactic acidosis, an extremely rare(less than I case per 100,000 treated patients) but potentially fatal complication."Its use should be avoided in acute medical conditions like ketoacidosis, sepsis ,hepatitis, respiratory failure , heart failure. It should be withdrawn one day prior to givingradio contrast agent or general anesthesiaand restart when renal function returns to normalor at least three days after giving these agents.Thiazolidinediones (TZDs)Pioglitazone and rosiglitazones are two drugs ofthis class , effective as monotherapyand in combination with sulfonylureas or metformin or insulin. When used asmonotherapy, these drugs lower HbA Ic by about 0.5-1.4%.49 TZDs can be used in
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 365combination with oral anti-diabetic drugs and insulin." When used in combination withinsulin, they can result in a 30-50% reduction in insulin dosage, and som e patients cancome off insulin completely."Mechanism ofAction. The thiazolidinediones increase insulin sensitivity by actingon adipose tissues, muscle and liver to increase glucose utilization and decrease glucoseproduction.P-" The mechanism by which the thiazolidinediones exert their effect is notfully understood. It is postulated that they bind a nuclear receptor called peroxisomeproliferator-activated receptor gamma (PPAR-y) and affect the expression of a numberofgenes.>> Observed effects ofthiazolidinediones include increased glucose transporterexpression (GLUT I and GLUT 4), decreased free fatty acid levels, decreased hepaticglucose output, increased adiponectin and decreased release of resistin from adipocytes,and increased differentiation of pre-adipocytes into adipocytes.This class of drugs has also been shown to lower blood pressure and decreasevascular inflammation in vitro." Rosiglitazone and pioglitazone have similar effects onglycaemic control, but their effects on serum lipid concentrations are different. Mostrandomized trials found that pioglitazone produces a more favorable lipid profile andcard iovascular safety.53,56-58Cardiovascular Safety. Several meta-analyses have suggested a 30-40% relativeincrease in risk for myocardial infarction with rosiglitazone.v" Although subsequentstudies have cast doubt on this finding; the FDA required the manufacturer to include aboxed warning about the potential risk ofheart attacks on the drug label. A meta-analysisofclinicaltrials with pioglitazone did not show a similarfinding.Many physicians, becauseof these findings, have stopped prescribing rosiglitazone and instead use pioglitazone,if indicated.Side Effects. Adverse effects ofTZDs include weight gain, edema, a possible increasein alanine aminotransferase levels (AL T), anaemia due to hemodilution and farcture riskat atypical sites. Recently increased risk of bladder cancer has also been reported afterone year of piogl itazone therapy.63,64Contraindications. TZDs are contraindicated in patients with advanced forms ofcongestive heart failure . Due to reported cases of liver failure and liver toxicity caused bythe increase inALT levels,TZDs should be avoided in patients with abnormal liver function.They should also be avoided in pregnancy and lactation since no safety data available.a-Glucosidase InhibitorsAcarbose and miglitol are the drugs included in this group. A fundamental differencebetween acarbose and miglitol is in their absorption. Acarbose has the molecular massand structural features of a tetrasaccharide, and very little (about 2%) crosses themicrovillar membrane. Miglitol, however, has a structural similarity with glucose andis absorbable.Clinical studies with these agents have demonstrated a reduction in postprandialglucose elevations in both T 10M and T2DM.65,66In older patients with T2DM, acarbosemay also increase insulin sensitivity."?
366 DIABETESMechanism ofAction. Alpha-glucosidase inhibitors (AGls) work by blocking theenzyme in the small intestine that breaks down complex carbohydrates, a-glucosidase.By blocking this enzyme these drugs prevent starches from being absorbed into thebloodstream and in doing so lower blood glucose levels. AGls are the only drug classused to treat T2DM that does not specifically target the pathology of the disease.Because AGls work in the digestive tract , they are more effective at loweringpostprandial glucose levels than fasting plasma glucose levels. AGls are less effectiveat lowering HbA Ic levels than biguan ides or sulfonylureas." >" a-glucosidase inhibitorsare associated with weight loss and less hypoglycemia.Side Effects. Flatulence is the principal adverse effect, seen in more than two thirdofpatients." This is caused by undigested carbohydrate reaching the lower bowel , wheregases are produced by bacterial flora. In 3% ofcases, troublesome diarrhea occurs. Thisgastrointestinal discomfort tends to discourage excessive carbohydrate consumptionand promotes improved compliance of T2DM patients with their diet prescriptions.A slight rise in hepatic aminotransferases has also been noted. Acarbose should beavoided in inflammatory bowel disease, severe renal and hepatic impairment, pregnancyand lactation.Dipeptidyl Peptidase IV Inhibitors (DPP-IV inhibitors)Dipeptidyl peptidase IV(DPP-IV)isanenzyme expressed onthesurface ofmostcellsanddeactivatesglucagon-likepeptide-l (GLP-I). Therefore, DPP-IV inhibition could potentiallyaugment the effects of endogenous GLP-1. GLP-I exerts its main effect by stimulatingglucose-dependent insulin release from the pancreatic islets. It restores both first phase andsecond phaseinsulinresponsetoglucose.lthasalsobeenshowntoslowgastricemptying, inhibitinappropriate post meal glucagon release, and reduce food intake."DPP IV inhibitors, unlike other GLP-I based therapies, can be administered orally.Metformin has been shown to modestly enhance GLP-I secretion, making it an attractiveoption for combination therapy with DPP-IV inhibitors." DPP IV inhibitors are weightneutral and generally do not cause hypoglycemia. Currently available DPP IV inhibitorsare sitagliptine, vildagliptin and saxagliptin.Sitagliptin. This drug is effective in lowering glucose when used alone and incombination with metformin and pioglitazone and sulfonylureas in T2DM.73-76Dose ofsitagliptin should be reduced to 50 mg/day if creatinine clearance is 30-50 mUmin and25 mg/day if clearance <30 mUmin. In various clinical trials, improvements in HbA 1cranged from 0.5-1.4%.74Adverse Effects. The main adverse effects ofsitagliptin appears to be a predispositionto nasopharyngitis or upper respiratory tract infection, a small increase in neutrophi Icountof-200 cells/me. Aanaphylaxis, angioedema, and exfoliative skin conditions includingStevens-Johnson syndrome have also been reported. There have also been reports ofpancreatitis (88 cases including 2 cases of hemorrhagic or necrotizing pancreatitis).Saxagliptin. Saxagliptin is approved as a monotherapy for the treatment of T2DMor in combination with sulfonylurea, metformin, or a thiazolidinedione.":" The dose is2.5 mg or 5 mg once a day. The 2.5-mg dose should be used in patients with calculatedcreatinine clearance <50 mUmin. The drug is weight neutral.
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 367Adverse Effects. The main adverse effects are upper respiratory tract infection,nasopharyngitis, headache, and urinary tract infection. There is also small reversibledose-dependent reduction in absolute lymphocyte count, which remains within normallimits . Hypersensitivity reactions, such as urticaria and facial edema, occurred in1.5% of patients taking the drug.Vildagliptin. Like the other DPP-4 inhibitors, vildagliptin lowers HbA Ie by about0.5-1% when added to the therapeutic regimen of patients with T2DM .80-83The dose is50 mg once or twice daily.Adverse Effects. Adverse reactions include upper respiratory tract infections,nasopharyngitis, dizziness and headache. Rare cases of hepatic dysfunction, includinghepatitis, have been reported. Liver function testing is recommended quarterly duringthe first year of use and periodically thereafter.Injectable Anti-Diabetic DrugsGLP-I AnaloguesGLP-I is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and cleared rapidly bythe kidney rendering their half-lives to only 1-2 minutes. The native peptide, therefore,cannot be used therapeutically and GLP-I receptoragonists are made to escape degradation.Two GLP-I receptor agonists, exenatide and Iiraglutide are currently available for clinicaluse for T2DM.Exenatide. Exenatide is a synthetic exendin-4. Exendin-4 is a naturally occurringcomponent of the Gila monster saliva." It is resistant to DPP-IV degradation andtherefore exhibits a prolonged half-life." It is approved for the treatment of T2DM asmonotherapy or in combination with oral agents. Exenatide binds to the GLP-I receptorand exerts same effects like GLP-I and has been shown to promote ~-cell regenerationand differentiation in animal models.86,87 Exenatide is not currently approved for usewith insulin therapyIn clinical trials, adding exenatide therapy to patients with T2DM already takingmetformin, or sulfonylurea, or a thiazolidindione, further lowered the HbA Ie value by0.4-0.6%. These patients also experienced a weight loss of3-6 pounds.P-"Side Effects. Nausea is the major side effect affecting over 40% of the patients.The nausea was dose-dependent and declined with time . In post marketing surveillancepancreatitis has been reported." Patients taking exenatide should be advised to seekimmediate medical care ifthey experience unexplained persistent severe abdominal pain.Other side effects include renal impairment, acute renal failure , and delayed absorptionof the drugs . Low-titer antibodies against exenatide develop in over one-third (38%) ofpatients, but of no clinical significance. High-titer antibodies develop in approximately6% of patients, and in about half ofthese cases, an attenuation ofglycemic response hasbeen seen.?Exenatide is dispensed as two fixed-dose pens (5 ug and 10 ug). It is administeredsubcutaneouslytwice daily immediately before orwithin one hourofmorning and eveningmeals." Patients should be prescribed the 5 f.-lg pen for the first month and, if tolerated,the dose can then be increased to 10 ug twice a day. The drug is not recommended inpatients with glomerular filtration rate <30 mUmin.
368 DIABETESLiraglutide. Liraglutide is albumin bound with a half-life ofapproximately 12hours,allowing the drug to be injected once a day. It is available for use as monotherapy as anadjunct to diet and exercise or in combination with oral agents in adults with T2DM. Itis not considered a first-line therapy.v-" HbAl c decline is in the range of0.6-1.5%. Thepatients may have sustained weight loss of 1-6 pounds.Side Effects. Frequent side effects are nausea and vomiting and found in 28% and10% of users respectively. There is also an increased incidence of diarrhea. In clinicaltrials, there were seven cases ofpancreatitis in the liraglutide treated group with one casein the comparison group.Liraglutide stimulates C-cell neoplasia and causes medullary thyroid carcinomain rats. Human C-cells express very few GLP I-receptors, and the relevance to humantherapy is unclear; however, because of the animal data, the drug should not be usedin patients with personal or family history of medullary thyroid carcinoma or multipleendocrine neoplasia (MEN 2).95The dosing is initiated at 0.6 mg daily , increased after I week to 1.2 mg daily. Ifneeded, an additional increase in dose to 1.8 mg is recommended for optimal glycemiccontrol. No dose adjustment is recommended in renal failure.PramlintideThis drug is a synthetic analogue ofislet amyloid polypeptide or amylin. When givensubcutaneously, pramlintide delays gastric emptying, suppresses glucagon secretion, anddecreases appetite. It is approved for use both in TI DM and in insulin-treated T2DM.96,97Nausea is the major side effect but hypoglycemia can occur specially in T IDM and it isrecommended that the short-acting or premixed insulin doses be reduced by 50% whenthe drug is started.In patients with T IDM, the initial dose ofpramlintide is 15 ug before each meal andtitrated up by IS ug increments to a maintenance dose of30 ug. In patients with T2DM,the starting dose is 60 ug pre meals increased to 120 ug in 3 to 7 days .InsulinInsulin is indicated for all types of diabetes. Initiation of insulin therapy is oftendelayed, owing to physician or patient reluctance and fear of injection, thus exposingpatients to the physiological consequences of prolonged hyperglycemia.Insulin is a reasonable choice for initial therapy in patients who present withsymptomatic or poorly controlled diabetes, and is the preferred second-line medicationfor patients with HbA Ie> 8.5% or with symptoms of hyperglycemia despite initialtherapy with metformin and life-style intervention. The ADA/EASD have developed aflow diagram for initiating and titrating insulin in the management ofT2DM.25Pharmacokinetics. Insulin is secreted in a pulsatile manner; pulses occur under basalconditions and in response to meals.98 Basal insulin secretion represents approximately 50%of24-hour insulin production, with the remainder accounted for by prandial excursions.Half-life ofintravenous insulin appears to be 5-10 minutes in normal persons. The liver isthe major site ofinsulin clearance, accounting for ~5 0% ofthe total ; the kidney accountsfor ~3 0%, and skeletal muscle account for most of the rest."Insulin pharmacokinetics is complicated by many factors that alter insulin absorptionfrom the subcutaneous site.
MANAGEMENT AND TREATMENT OF DIABETES MELLITUSTable 4. Conventional insulin s pharmacokinetics369TypesRegularNPHPremixed 30/70Onset Peak30-60 min 2 hr2-4 hr 4-6 hrFollows combined pharmacokineticsDuration4-6 hr12-18 hrFactors Causing Increased Insulin AbsorptionLow doses of insulin.Diluted insulin solution.Increased subcutaneous blood flow (exercise, massage, heat) .Local tissue injury.Abdominal injection and intramuscular injection.Factors Causing Decreased Insulin AbsorptionConcentrated insulin solution.Decreased subcutaneous blood flow (shock, cold, standing).Lipohypertrophy.Intradermal injection, and injection into limbs (at rest).Conventional InsulinRegular Insulin. Regular insulin is short-acting soluble crystalline zinc insulinwhose effect appears within 30 minutes after subcutaneous injection and lasts 4-6 hours(Table 4). Intravenous infusions ofregular insulin are particularly useful in the treatmentof diabetic ketoacidosis, hyperglycemic hyperosmolar state, critically ill patient andduring the perioperative management of diabetics.100NPH (Neutral Protamine Hagedorn) Insulin. Isan intermediate-acting insulin whoseonset ofaction is delayed by combining 2 parts soluble crystalline zinc insulin with I partprotamine zinc insulin . Its onset ofaction is delayed to 2-4 hours, and its peak response isgenerally reached in about 4-6 hours .? (Table 4). Because its duration ofaction is often<24 hours (with a range of 10-20 hours), most patients require at least two injectionsdaily to maintain a sustained insulin effect.Rapidly-Acting Insulin Analogues (see also Tables 5 and 6)Insulin Lispro. Insulin lispro is an insulin analogue produced by recombinanttechnology, wherein two amino acids near the carboxyl terminal of the f)-chain havebeen reversed in position; proline at position B28 has been moved to B29 and lysinemoved from B29 to B28.Insulin Aspart. This insulin is a single substitution of proline by aspartic acid atposition B28.Insulin Glulisine. This insulin differs from human insulin in that the amino acidasparagine at position B3 is replaced by lysine and the lysine in position B29 byglutamic acid.Alterations of the amino acids sequences in these analogues result in formation ofmonomers when injected subcutaneously in contrast to regular human insulin, whosehexamers require considerably more time to dissociate and absorbed.Pv?
370 DIABETESTable 5. Pharmacokinetics of analoguesType s Onset Peak DurationRapidly actingLisproAspartGlulisine5-15 min5-15 min5-15 min60min60 min60min2 hr2 hr2 hrPremixed Lispro 25%, Neutral Protamine Lispro 75% ( Humalog Mix 25)Lispro 50%, Neutral Protamine Lispro 50% ( Humalog Mix 50)Aspart 30%, Protamine Aspart 70% (Novo Mix 30)These follow combined pharmacokinetics of ultra short actingand NPH insulinLong actingGlargineDetemir2-4 hr2-4 hrNoneNone24 hr20-24 hrTable 6. Compares some features of conventional and analogue insulin typesConventional AnaloguesLess physiologic time action profile More physiologic time action profileStrong affinity for self dissociation Easy dissociationUnpredictable hypoglycemia Less hypoglycemiaLow cost High costLong-Acting Insulin AnaloguesInsulin Glargine. Insulin glargine is an insulin analogue in which the asparagine atposition 21 ofthe A chain in the human insulin molecule is replaced by glycine and twoarginines are added to the carboxyl terminal of the B chain.? The arginines raise theisoelectric point of the molecule closer to neutral, making it more soluble in an acidicenvironment. Insulin glargine is a clear insulin which, when injected into the neutral pHenvironment ofthe subcutaneous tissue, forms microprecipitates that slowly release theinsulin into the circulation. It lasts for about 24 hours without any pronounced peaks andis given once a day to provide basal coverage.Insulin glargine has got a six fold greater affinity for IGF-I receptor comparedwith the human insulin. There has also been a report that insulin glargine had increasedmitogenicity compared with human insulin in a human cell line. The significance oftheseobservations is not yet clear. lOSInsulin Detemir.lnsulin detemir isan insulin analogue inwhich the tyrosine at position30 of the j3-chain has been removed and a 14-C fatty acid chain is attached to the lysineat position 29 by acylation. The fatty acid chain makes the molecule more lipophilic thannative insulin and the addition of zinc stabilizes the molecule and leads to formation ofhexamers. After injection, self-association at the injection site and albumin binding in thecirculation via the fatty acid side chain, leads to slower distribution to peripheral targettissues and prolonged duration of action.!"It is recommended that the insulin be injected once or twice a day to achieve astable basal coverage. This insulin has been reported to have lower within-subjectpharmacodynamic variability compared with NPH insulin and insulin glargine.
MANAGEMENT AND TREATMENT OF DIABETES MELLITUSGENERAL PRINCIPLES OF INSULIN THERAPY371The need for insulin depends upon the balance between insulin secretion and insulinresistance. All patients with TI OM need long term insulin treatment and many patientswith T20M will require insulin as their ~-cell function declines over time.Therapy should begin with diet, weight reduction, and exercise, which can frequentlyinduce normoglycemia if compliance is optimal. For many patients with T20M, a basalsupplement is often adequate for good glycemic control as endogenous insulin secretionwill control the postprandial excursions. Some patients with T20M may require additionalpremeal boluses, similar toTI OM.The use of premixed insulin is not recommended for patients with TIOM sincethese offer little glycemic advantage compared with adequately titrated basal and bolusinsulin. Many patients with T20M can use premixed preparations with reasonable effect.Theterm "intensive insulin therapy" has been used to describe complex regimens thatseparate basal insulin delivery with superimposed doses of short or rapid-acting insulinthree or more times daily . Intensive regimens more nearly approximate normal insulinphysiology. While intensive regimens were initially used for patients with TI OM, theyare used for patients with T20M as well.Basal InsulinAlthough intermediate-acting NPH insulin has been used commonly at bedtimeto supplement oral hypoglycemic drug therapy, longer acting insulin, such as insulinglargine and detem ir,added to oral agents are equally effective for reducing HbA Icvaluesand may cause less nocturnal hypoglycemia.t"! " Meta-analyses oftrials in patients withT20M comparing once-daily insulin glargine or detemir to once- or twice-daily NPHinsulin report similarglycemic controIbetween groups. However,the rates ofsymptomaticoverall and nocturnal hypoglycemia were lower in patients treated with either insulinglargine or detemir compared with NPH .Bolus InsulinFor patients with T20M, a basal supplement is often adequate for good glycaemiccontrol, but for others premeal boluses are needed as they are in T 10M.The newer rapid-acting analogue insulin may have a minor glycemic advantage overshort-acting (regular) insulin in patients with TI OM, but not in patients with T20M.No significant differences were seen in serum HbA Ic concentrations or the number ofhypoglycemic episodes between short acting and analogs. However, the ability to injectthe rapid-acting insulin immediately before meals, as opposed to the 30 to 45 minutesbefore the meal recommended for short-acting insulin, may provide improved conveniencefor patients.109Setting Insulin DosagesBasal InsulinIf a bedtime dose of NPH, detemir or glargine insulin is being added to oralhypoglycemic drug therapy, it is recommended to start at 10 units or 0.2 units per kg.
372 DIABETESFasting blood glucose (FBG) should be measured every day. An increase of2 to 4 units inthe bedtime insulin dose should be made approximately every 3 days ifthe mean fastingplasma glucose is more than 130 mg/dl..!?Bolus InsulinA typical starting dose is approximately 4 to 6 units. The dose can be increasedby 2 to 3 units every three days until the postprandial blood glucose target is achieved.A more complex method for adjusting premeal insulin is to match insulin deliveryto the anticipated glucose excursion with meals. With this approach (called carbohydratecounting), insulin-to-carbohydrate ratios are determined based upon an individualsusual insulin requirements and carbohydrate intake.II ISide Effects of Insulin TherapyHypoglycemiaHypoglycemia is the most frequently occurring side effect of insulin treatment."The common causes of hypoglycemia include missed meals or erratic meal timing,excessive insulin dosage, and unplanned exercise. Renal impairment, cortisol deficiency,hypothyroidism and alcohol intoxication should also be considered as the potential causesof hypoglycem ia.Post Hypoglycemic Hypergly cemia (Somogyi effect) . Many years ago, Somogyipostulated that over-treatment with insulin produces late night hypoglycemia, which isfollowed by fasting hyperglycem ia caused by activation ofcounter regulatory hormones.Unexplained Fasting Hyp erglycemia (Dawn phenomenon) . The dawn phenomenonoccurs in persons with and without diabetes. In the early morning hours , a transient stateof insulin resistance occurs that may be partially due to nocturnal secretion of growthhormone and cortisol. In persons without diabetes, this early morning insulin resistanceis limited by compensatory insulin secretion, but in patients with T1OM, troublesomehyperglycemia can occur.Weight Gain and EdemaSodium and fluid retention is a common occurrence after insulin therapy. Insulin ssodium-retaining effect on the kidney could be the best explanation for this phenomenon.Another contributor could be glucagon, which is known to have natriuretic effect. Plasmaglucagon levels are increased in uncontrolled diabetes, and a fall in glucagon with insulintreatment could contribute to the sodium retention.Insulin AllergyThe problem of insulin allergy has been greatly reduced by the introduction andwidespread use of human insulin. There have been case reports of successful use ofinsulin lispro in those rare patients who have a generalized allergy to human insulin orinsulin resistance due to a high titer of insulin antibodies.l?
MANAGEMENT AND TREATMENT OF DIABETES MELLITUSLipoatrophy373Lipoatrophy is characterized by a loss ofsubcutaneous fat at insulin injection sites.This phenomenon is rarely seen since then purified human insulin is being used . Thecause of this complication is unknown but is suspected to be immunologic.LipohypertrophyLipohypertrophy is a non- immune phenomenon,consistingofa localized hypertrophyof subcutaneous fat that develops from repeated injections of insulin into a highlycircumscribed area and resolves spontaneously with the use ofother insulin injection sites.Orthostatic HypotensionNormally, insulin stimulates the cardiovascular sympathetic nervous system. In thepresence of autonomic neuropathy, however, insulin has a direct vasodilator effect onthe vascular bed that can lead to hypotension.NEW ADVANCEMENTS IN DIABETES MANAGEMENTCure from diabetes remains an elusive dream so far. The greatest success in diabetesresearch has been inthe treatmentofdiabetes, with Iittle progress toward a cure . Followingis the brief discussion regarding the latest advancements and research towards diabetestreatment and cure.Artificial PancreasAn artificial pancreas system combines a continuous glucose monitor and an insulinpump and uses a sophisticated algorithm to calculate the appropriate amount ofinsulin todeliver based on the real-time glucose readings. Using an artificial pancreas system cansignificantly reduce the risk of hypoglycemia, a major concern for children and adultswith TI DM. In a small study conducted in TI DM, results showed the artificial pancreaskept blood glucose levels in the normal range for 60% of the time, compared with 40%for the continuous subcutaneous insulin infusion.!Islet Cell Regeneration TherapyIn human pancreas, it now seems clear that there is a slow rate of 13-cell turnoverwhereby 13 cells replicate and new islets are formed , probably from exocrine duct cellsthrough the process of neogenesis. In the future, islet cell replacement or regenerationtherapy may thus offer therapeutic benefit and potentially a cure to people with diabetes.Islet cell regenerative therapy could be achieved by in situ regeneration or implantation ofcells previously derived in vitro.I 14 Both approaches are being explored, and their ultimatesuccess will depend on the ability to recapitulate key events in the normal development ofthe endocrine pancreas to derive fully differentiated islet cells that are functionally normal.However, these approaches are at an early stage ofpreclinical development and should notbe offered to patients until shown to be safe as well as more efficacious than existingtherapy.
374Islet Cell TransplantationDIABETESIslet cell transplantation isthe transplantation ofisolated islets from a donor pancreasto a recipient. It is an experimental treatment for TI DM patients; the islets begin toproduce insulin and actively regulating the level of glucose in the blood. The purifiedislets usually are infused into the patients liver via the portal vein. Since body perceiveislets tissues as foreign body , therefore, the patient needs to undergo treatment withimmunosuppressants.Recentstudies have shown that islettransplantation has progressedto the pointthat58%ofthe patients in one study were insulin independent one year after the operation. lI S Twoofthe most important limitations are the currently inadequate means for preventing isletrejection, and the limited supply ofislets for transplantation. Current immunosuppressiveregimens are capable of preventing islet failure for months to years, but the agents usedin these treatments are expensive and may increase the risk for specific malignanciesand opportunistic infections.Pancreas TransplantationPancreas transplantation continues to evolve as a strategy in the management ofdiabetes mellitus. In most cases, pancreas transplantation is performed on individuals withT IDM with end-stage renal disease. The majority ofpancreas transplantations (>90%) aresimultaneous pancreas-kidney transplantations.I" In the absence ofindications for kidneytransplantation, pancreas transplantation should only be considered a therapy in patientswho exhibit a history of frequent hypoglycemia, ketoacidosis, clinical and emotionalproblems with exogenous insulin therapy that are so severe as to be incapacitating andconsistent failure of insulin-based management to prevent acute complications.!" Theprognosis after pancreas transplantation is very good. One year after transplantation morethan 95% of all patients are still alive and 80-85% of all pancreases are still functional.After transplantation patients need lifelong immunosuppression which increases the riskof infection and malignancy.Gene TherapyGene therapy can be used to manufacture insulin. In this modality viral vectorcontaining the insulin sequence, is digested and delivers its genes to the upper intestines.By delivering [3-cell DNA to the intestine cells in the duodenum, a few intestinecells will turn into [3 cells, and subsequently adult stem cells will develop into [3 cells.This makes the supply of [3 cells in the duodenum self replenishing, and the [3 cells willproduce insulin in proportional response to carbohydrates consumed. Gene therapy mighteventually be used to cure the cause ofp-cell destruction, thereby curing the new diabetespatient before the [3-cell destruction is complete and irreversible.!"Sodium-Glucose Co-Transporter Inhibitors (SGLT2)Sodium-glucose co-transporter 2 [SGLT2 (Dapagliflozin, Sergliflozin)] expressedin the proximal renal tubules accounts for about 90% of the re-absorption of glucosefrom tubular fluid. SGLT2 is almost exclusively expressed in the proximal renal tubules.Preclinical studies with selective SLGT2 inhibitors show dose-dependent glucosuria
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 375and lowering of blood glucose in models of T2DM . Preliminary clinical studies of upto 3-month duration show dose-dependent lowering of glycosylated hemoglobin up to0.9% along with modest weight loss.!"Side effects include an increase in genital fungal infection, increased urine volume ,and evidence ofvolume depletion consistentwith mild diuretic effect. SGLT2 inhibitors areshowing promise as a useful addition to the current therapeutic options in TIDM. Resultsofongoing Phase 11 clinical trials are awaited and will determine whether the risk-benefitratio will allow approval of this new class of drug for the management ofTIDM.ColesevelamColesevelam is a bile acid sequestrant that lowers LDL cholesterol in patients withprimary hypercholesterolemia. Colesevelam modestly reduces HbA lc levels 0.3 to 0.4 %in patients with T2DM inadequately treated with oral agents or insulin.?" Colesevelamsmechanism ofaction to improve glycemic control is uncertain. One possibility is that bileacid sequestrants act in the gastrointestinal tract to reduce glucose absorption.Piragliatin (Glucokinase Activator)Glucokinase plays a key role in glucose homeostasis. Glucokinase activators canlower glucose levels in both animal and human T2DM. In a study, Piragliatin caused adose-dependent reduction ofglucose levels in both fasting and fed states.? In the fastingstate, piragliatin caused a dose-dependent increase in ~-cell function, a fall in endogenousglucose output, and a rise in glucose use. In the fed state, the primary effects ofpiragIiatinwere on ~-cell function .Oral Insulin!"Insulin isa protein,which isdigested inthe stomach and gut and inorderto be effectiveat controlling blood sugar, cannot be taken orally in its current form. Investigators haveattempted to devise ways ofmoving enough intact insulin from the gut to the portal veinto have a measurable effect on blood sugar.Oral-Lyn isan oral spray formulation ofhuman insulin indicated forthetreatmentofTlDM and T2DM. Having secured regulatory approval in 2005 for clinicaluse ofOral-Lyn in T2DM in Ecuador, ongoing Phase 11 clinical trials are beingconducted in North America and many European countries.Oral insulin analogue (NN 1952). Trial has already initiated on December 2009 .The aim ofthe trial is to investigate the safety, tolerance, pharmacokinetics andpharmacodynamics in people with TI DM and T2DM. Results from the trial,which is planned to enroll about 80 people, are expected to be reported in thefirst half of 20 II.VIAtab isan oral formulation ofinsulin designed to be administered sublingually.This therapy is a tablet that dissolves in minutes when placed under the tongue.In a Phase I study, VIAtab delivered insulin to the blood stream quickly andresembled the first-phase insulin release spike found in healthy individuals.Oral insulin capsule (ORMD-080 I). Results substantiated the safety andtolerability of ORMD-080 I and demonstrate that oral insulin has a relevantclinical impact at the tested dose .
376CONCLUSIONDIABETESTreatment of patients with any type of diabetes requires a comprehensive approachincluding education, normalization ofglycemia, minimization ofcardiovascularand otherlong-term risk factors , and avoidance ofdrugs that can aggravate abnormalities ofinsulinor lipid metabolism. The core objective of diabetes management is to prevent acute andlong term diabetes complications. Current treatment modalities focus on increasing insulinsecretion, responsiveness, or both, or decreasing the rate of carbohydrate absorption,and mimeting incretin effects. Monotherapy with metformin is considered a drug offirstchoice for all T2DM (especially obese), ifno contraindication.Insulin is indicated for all types of diabetes, is the first choice in acute diabetescomplications and critically ill patients. Diet and exercise are an essential component ofdiabetes management and significantly affect the glycemic control. Majority of TIDMpatients fail to achieve glycemic control on life style modification alone and requireoral combination therapy with or without insulin . Obesity is very common in T2DMand contributes greatly to insulin resistance, therefore, weight reduction and exerciseshould be greatly emphasized in obese T2DM patients. In addition, a strong partnershipbetween the patient and the treating physician is ofparamount importance inthe successfulmanagement of diabetes.Some T2DM eventually fail to respond to oral medications and must proceed toinsulin therapy. GLP I analogues and DPP IV inhibitors are relatively new addition tooral therapy and a reasonable option in obese T2DM patients, while TZDs , the insulinsensitizers, should be used very carefully in those patients with poor left ventricularfunction, and in those who are prone to develop soteoporosis.Current therapeutic modalities are unable to cure diabetes, but we hope for a betterfuture for diabetic as new advancements and technologies are coming to cure diabetes.REFERENCESI. Steven RG.Emergingepidemic:diabetes inolderadults:demography,economicimpact,and pathophysiology.Diabetes Spectrum 2006; 19:221-228.2. Norris SL, Zhang X, Avenell A et al. Long-term effectiveness of lifestyle and behavioral weight lossintervention s in adults with type 2 diabetes: a meta-analysis. Am J Med 2004; 117:762.3. Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health riskfactors. JAMA 2003; 289():76-79.4. Effect of intensive blood-glucose control with metformin on complications in overweight patients withtype 2 diabetes (UKPDS 34). Lancet 1998; 352(9131):854-865.5. Patel A et al. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes inpatients with type 2 diabetes . N Engl J Med 2008; 358(24):2560-2572.6. White NH, Danis RP, Davis MD et al. Long-term renal outcomes of patients with type I diabetes mellitusand microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology ofDiabetes Interventions and Complications cohort. Arch Intern Med 2011; 171(5):412-420.7. Funnell MM, Brown TL, Childs BP et al. National standards for diabetes self-management education .Diabetes Care 2007; 30:1630.8. Karter AJ, Parker MM, Moffet Hh et al. Longitudinal study of new and prevalent use of self-monitoring ofblood glucose. Diabetes Care 2006; 29(8):1757-1763.9. Goldstein DE, Little RR, Lorenz RA et al. Tests of glycemia in diabetes. Diabetes Care 2004; 27:1761.10. Miller CK, Edwards L, Kissling G et al. Nutrition education improves metabolic outcomes among olderadults with diabetes mellitus. Prev Med 2002; 34(2):252-259.II . Bantle Jl>, Wylie-Rosett J, Albright AL et al. Nutrition recommend ations and interventions for diabetes:a position statement of the American Diabetes Association. Diabetes Care 2008; 31 Suppl I:S61.12. Standards of medical care in diabetes. Diabetes Care 2010; 33 Suppl LS I .
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 37713. Masharani U. Diabetes mellitus & hypoglycemia. In: McPhee SJ, Papadakis MA, eds. Current MedicalDiagnosis and Treatment 2010. McGraw-Hill : New York City, 2010:I079-1122.14. Buse JB, Ginsberg HN, Bakris GL et al. Primary prevention of cardiovascular diseases in people withdiabetes mellitus: a scientific statement from the American Heart Association and the American DiabetesAssociation. Circulation 2007; 115(): 114-126.15. Klein S, Burke LE, Bray GA et al. Clinical implication s of obesity with specific focus on cardiovasculardisease:a statement for professiona ls from the American Heart AssociationCouncil on Nutrition, PhysicalActivity and Metabolism. Circulation 2004; 110( 8):2952-2967.16. Lawson ML, Kirk S, Mitchell T et al. One-year outcomes of Roux-en-Y gastric bypass for morbidly obeseadolescents. J Pediatr Surg 2006; 41():137-143.17. OBrien PE, Sawyer SM, Laurie C et al. Laparoscopic adjustable gastric banding in severely obeseadolescents: a randomized trial. JAMA 20 I0; 303(6):519-526.18. Buchwald H, Estok R, Fahrbach K et al. Weight and type 2 diabetes after bariatric surgery. Am J Med2009; 122:248-256.19. Colquhoun AJ, Nicholson KG, Botha JL et al. Effectiveness of influenza vaccine in reducing hospitaladmissions in people with diabetes. Epidemiol lnfect 1997; 119:335-341.20. Bridges CB, Fukuda K, Uyeki TM et al. Prevention and control of influenza. Recommendations of theAdvisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2002; 51:1-31.21. Fisher L, SkaffMM, Mullan JT et al. Clinical depression versus distress among patients with type 2 diabetes:not just a question of semantics. Diabetes Care 2007; 30:542-548 .22. Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and meta-analysis of randomized controlledtrials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet2004; 363:1589.23. Turner RC, Cull CA, Frighi V et al. Intensive blood-glucose control with sulphonylureas or insulincompared with convention al treatment and risk ofcomplications in patients with type 2 diabetes. Lancet1998; 352(9131):837-853.24. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus:progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281(2 1):2005-2012.25. Nathan DM, Buse JB, Davidson MB et al. Medical Management of Hyperglycemia in Type 2 Diabetes:A Consensu s Algorithm for the Initiation and Adjustment of Therapy : A consensus statement of theAmerican Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care2009; 32:193.26. Monami M, Lamanna C, Marchionni N et al. Comparison of different drugs as add-on treatments tometformin in type 2 diabetes: Diabetes Res Clin Pract 2008; 79:196.27. Bolen S, Feldman, L Vassy J et al. Comparative Effectiveness and Safety ofOral Medications for Type 2Diabetes Mellitus. Ann Intern Med 2007; 147:386.28. Zeller M, Danchin N, Simon D et al. Impact of type of pre-admission sulfonylureas on mortality andcardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab20 I0; 95( 1):4993-5002.29. Eurich DT, Simpson SH, Majumdar SR et al. Secondary failure rates associated with metformin andsulfonylurea therapy for type 2 diabetes. Pharmacotherapy 2005; 25:810-816.30. Groop LC, Pelkonen R, Koskimies S et al. Secondary failure to treatment with oral antidiabetic agents innon-insulin-dependent diabetes. Diabetes Care 1986; 9:129-133.31. Matthews DR, Cull CA, Stratton 1M et al. UKPDS 26: sulphonylurea failure in non-insulin dependentdiabetic patients over six years. Diabet Med 1998; 15:297-303.32. Tessier D, Dawson K, Tetrault JP, Bravo G et al. Glibenclamide vs gliclazide in type 2 diabetes of theelderly. Diabet Med 1994; 11(10):974-980.33. Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 200 I; 17(6):467-473.34. Arruda-Olson AM, Patch RK et al. Effect ofsecond-generation sulfonylureas on survival in patients withdiabetes mellitus after myocardial infarction. Mayo Clin Proc 2009; 84( I):28-33.35. Langer 0 , Conway DL, Berkus MD et al. A comparison ofglyburide and insulin in women with gestationaldiabetes mellitus. N Engl J Med 2000; 343(16): 1134-1 138.36. Langer 0 , Yogev Y, Xenakis EM et al. Insulin and glyburide therapy: dosage, severity level ofgestationaldiabetes, and pregnancy outcome. Am J Obstet Gynecol 2005; 192():134-139.37. Conway DL, Gonzales 0 , Skiver D. Use of glyburide for the treatment of gestational diabetes: the SanAntonio experience. J Matern Fetal Neonatal Med 2004; 15:51.38. Rochon M,Rand L, Roth Let al. GIyburideforth emanagement ofgestationaldiabetes: risk factorspredictiveof failure and associated pregnancy outcomes. Am J Obstet Gynecol 2006; 195:1090.39. Fuhlendorff J, Rorsman P, Kofod H et al. Stimulation of insulin release by repaglinide and glibenclamideinvolves both common and distinct processes. Diabetes 1998; 47(3):345-351.
378 DIABETES40. Moses R, Siobodniuk R, Boyages S et al. Effect of repaglinide addition to metformin monoth erapy onglycem ic control in patients with type 2 diabetes. Diabetes Care 1999; 22(1) :II :9-24.41. DeFronzo RA, Goodman AM. Efficacy of metformin in patient s with non-insulin-dependent diabetesmellitus. N Engl 1 Med 1995; 333(9):541-549.42. Bailey C.I, Turner RC. Metformin. N Engl 1 Med 1996; 334:574.43. Effect of intensive blood-glucose control with metformin on complic ations in overweight patients withtype 2 diabetes (UKPDS 34). Lancet 1998; 352(9131):854-865.44. UKPDS13: Relativeefficacyofrandomly allocated diet,sulphon ylurea, insulin,ormetformin in patients withnewly diagnosed non-insulin dependent diabete s followed for three years. BMl 1995; 310(6972):83-88.45. Stumvoll M, Nurjhan N, Perriello G et al. Metabolic effects ofmetformin in non-insulin-dependent diabete smellitus. N Engl .I Med 1995; 333(9):550-554.46. Bailey C.I, Turner RC. Metformin. N Engl 1 Med 1996; 334:574.47. Zhou G, Myers R, Li Y, Chen Y et al. Role ofAMP-activated protein kinase in mechanism of metforminaction..1 Clin Invest200 I; 108(8):1167-1174. http://reference.medscape.comlmedline/abstract/20702526.48. Kasia Jl., Clifford lB, Silvio EI. Use ofMetformin in the Setting ofMild-to-Moderate Renal Insufficiency.Diabetes Care 20 I I; 34:1431-1436.49. Schernthaner G,Matthews DR, Charbonnel Bet al. .IClin Endocrinol Metab 2004 ; 89(12) :6068-6076.50. Kipnes MS, Krosnick A, Rendell MS et al. Pioglitazone hydrochloride in combination with sulfonylureatherapy improves glycemic control in patients with type 2 diabete s mellitus. Am 1 Med 200 I; 111:1O.5 1. Schwartz S, Raskin P, Fonseca V et al. Effect oftroglitazone in insulin-treated patients with type II diabete smellitus. Troglitazone and Exogenous Insulin Study Group . N Engl .l Med 1998; 338( 13):861-866.52. Iwamoto Y, Kosaka K, Kuzuya T et al. Effects of troglitazone: a new hypog lycem ic agent in patients withNIDDM poorly controlled by diet therapy . Diabetes Care 1996; 19(2):151-156.53. Yki-Jarvinen H. Thiazolidinediones. N Engl 1 Med 2004; 351:1106.54. Vidal-Puig A.I, Considine RV, .Iimenez-Linan M et al. Peroxisome proliferator-activated receptor geneexpression in humantissues. Effectsofobesity, weight loss, and regulation by insulin and glucocorticoids.1 Clin Invest 1997; 99( 10):2416-2422.55. GervoisP, Fruchart.lC, Staels B. Drug Insight: mechanismsofaction and therapeutic applications for agonistsof peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab 2007; 3(2):145-156.56. Chiquette E, Ramirez G, Defronzo R. TI A meta-analysis comparing the effect ofthiazolidinediones oncardiovascular risk factors. Arch Intern Med 2004 ; 164(19):2097-2 I04.57. Goldberg RB, Kendall DM, Deeg MA et al. A comparison oflipid and glycemic effects ofpioglitazone androsiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005; 28(7): 1547-1554.58. Winkelmayer WC, SetoguchiS, Levin Ret al. Comparisonofcardiovascularoutcome sinelderly patients withdiabetes who initiated rosiglitazon e vs pioglitazone therapy. Arch Intern Med 2008; 168(21):2368 -2375.59. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocard ial Infarction and Death fromCardiovascular Causes. N Engl 1 Med 2007; 356:2457-2471. http://www.n ejm.org/toc/nejm/356/24/.60. Rosen C.I. The Rosiglitazone Story: Lessons from an FDA Advisory Committee Meeting. N Engl.l Med2007 ; 357:844-846. http://www .nejm.org/toc/nejm/357/9/.61. Singh S, Loke YK, Furberg CD.Long-term risk ofcardiovascular events with rosiglitazone:ameta-analysis.lAMA 2007; 298(10) :1189-1195.62. Winkelmayer WC, SetoguchiS, Levin Ret al. Comparisonofcardiovascular outcome sinelderly patients withdiabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008; 168(21):2368 -2375.63. Lewis.lD, FerraraA , PengT etal. RiskofBladder Cancer Among Diabetic PatientsTreated With Pioglitazone:Interim report of a longitudinal cohort study. Diabetes Care 20 II ; 34:9I6-922.64. SOl, Vector One": Total Patient Tracker (TPT). 2010-2010. Data extracted 10.65. Hollander P, Pi-Sunyer X, Coniff RF. Acarbose in the treatment of type I diabetes. Diabetes Care 1997;20(3):248-253 .66. McCulloch DK, Kurtz AS , Tattersall RB. A new approach to the treatment of nocturnal hypoglycemiausing alpha-glucosidase inhibition. Diabetes Care 1983; 6(5):483 -487.67. Meneilly GS, Ryan EA, Radziuk .Iet al. Effect of acarbose on insulin sensitivity in elderly patients withdiabetes. Diabetes Care 2000 ; 23(8) :1162-1167.68. Hoffmann .I, Spengler M. Efficacy of 24-week monoth erapy with acarbose, glibenclamide, or placebo inNIDDM patients. Diabetes Care 1994; 17(6):561-566.69. Holman RR, Cull CA, Turner RC. A randomi zed double-blind trial of acarbose in type 2 diabetes showsimproved glycemic control over 3 years. Diabetes Care 1999; 22(6) :960-964 .70. Chiasson Jl. , Josse RG, Hunt lA et al. The efficacy of acarbose in the treatment of patients withnon-insu lin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994;121(12):928-935.71. Demuth I-IU, Mclntosh CH, Pederso n RA. Type 2 diabetes-therapy with dipeptid yl peptidase IV inhibitors .Biochim Biophys Acta 2005 ; 1751(1):33-44.
MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 37972. Mannu cci E, Ognibene A, Cremasco F et al. Effect of metformin on glucagon-like peptide I (GLP-I) andleptin levels in obese nond iabetic subjects. Diabetes Care 2001 ; 24(3):489-494.73. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptid ase-4 inhibitor sitagliptin asmonotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006 ; 49( 1):2564-2571.74. Charbonnel B, Karasik A, Liu Jet al. Efficacy and safety of the dipeptidyl peptid ase-4 inhibitor sitagliptinadded to ongo ing metformin therapy in patients with type 2 diabetes inadequately controlled withmetformin alone. Diabetes Care 2006 ; 29(12) :2638-2643.75. RosenstockJ, Brazg R,Andryuk PJet al. Efficacy and safetyofthe dipeptid yl peptidase-4 inhibitor sitagliptinadded to ongo ing pioglitazone therapy in patient s with type 2 diabetes.ClinTher 2006; 28( I0):1556-1568 .76. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety ofthe dipeptidyl peptidase-4 inhibitor, sitagliptin,in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepirideand metformin. Diabete s Obes Metab 2007; 9(5):733-745.77. Rosenstock J, Sankoh S, ListJF.Glucose-Iowering activity ofthe dipeptidyl peptidase-4 inhibitor saxagliptinin drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008 ; 10(5):376-386.78. DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety ofsaxagliptin when added to metformintherap y in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care2009 ; 32(9):1649-1655.79. Chacra AR, Tan GH, Apanovitch A et al. Saxagliptin added to a submaximal dose of sulphonylureaimprove s glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes:a randomi zed controlled trial. Int J Clin Pract 2009 ; 63(9) :1395-1406 .80. Pratley RE, Jau ffret-Kamel S, Galbreath E et al. Twelve-week monotherapy with the DPP-4 inhibito rvildagliptin improve s glycemic control in subjects with type 2 diabetes. Horm Metab Res 2006 ;38(6):423-428.81. Pi-Sunyer FX, SchweizerA,Mills Detal. Efficacy and tolerabi lityofvildagliptin monotherapy indrug-naivepatients with type 2 diabetes . Diabetes Res Clin Pract 2007; 76():132-138.82. Fonseca V, Schweizer A, Albrecht D et al. Addition ofvildaglipti n to insulin improves glycaemic contro lin type 2 diabete s. Diabetologia 2007; 50(6): 1148-1155.83. Bosi E, Camisasca RP, Collober C et al. Effects ofvildagliptin on glucose control over 24 weeks in patientswith type 2 diabete s inadequ ately controlled with metformin. Diabetes Care 2007; 30(4) :890-895.84. Eng J, Kleinm an WA, Singh L et al. Isolation and characterization of exendin-4, an exendin-3 analogue,from Heloderma suspectum venom. Further evidence fo r an exendi n receptor on dispersed acini fromguinea pig pancreas. J Bioi Chern 1992; 267( I I):7402-7405.85. Parkes DG, Pittner R, Jodka C et al. Insulinotrop ic actions ofexend in-4 and glucagon-like peptide-I in vivoand in vitro. Metabolism 2001; 50(5) :583-589.86. Kolterman OG, Buse JB, Fineman MS et al.Synthetic exendin-4 (exenatide) significantly reducespostprandialand fasting plasmaglucosc in subjects with type 2diabetes.JClin Endocrinol Metab 2003;88(7):3082-3089.87. Xu G, Stoffers DA, Habener JF et al. Exendin-4 stimulates both beta-cell replication and neogenesis,resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48( 12):2270-2276 .88. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over30 weeks in patients with type 2 diabetes treated with metformin and a sulfonyl urea. Diabetes Care2005 ; 28(5): 1083- 109 1.89. Zinman B, Hoogwerf BJ, Duran GS etal.Theeffect ofadding exenatide to athiazolidinedione in suboptimallycontroll ed type 2 diabetes: a randomized trial. Ann Intern Med 2007; 146(7):477-485.90. www .fda.gov/CDER/Drug/lnfoSheets/HCP/exenatide2008HCP.htm. Accessed 2008.91. Stephen JM, Maxine AP. Diabetes mellitus and hypoglycemia. Current Medical Diagno sis and Treatment20 10; 1079- 1121.92. Linnebje rg H, Kothare PA, Skrivanek Z et al. Exenatide: effect of injection time on postprandial glucosein patients with Type 2 diabetes. Diabet Med 2006; 23(3):240-245.93. Vilsboll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human glucagon-like peptide-I analog,given as monotherapy significantly improv es glycemic control and lowers body weight without risk ofhypoglycemia in patients with type 2 diabetes. Diabetes Care 2007; 30:1608.94. Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-I analogIiraglutid e in combi nation with metformin and thiazolid inedione in patients with type 2 diabetes. DiabetesCare 2009; 32(7): 1224-1230.95. Bjerre Knudsen L, Madsen LW, Andersen S et al. Glucagon-like Peptide-I receptor agonists activate rodentthyroid C-cells causing calcitonin releaseand C-cell proliferation. Endocrinology 20 I0; 151(4):1473-1486.96. Ratner RE, Dickey R, Fineman M et al. Amylin replacement with pram lintide as an adjunctto insulin therapyimprov es long-term glycaemic and weight control in Type I diabetes mellitus: one year, randomizedcontrolled trial. Diabet Med 2004; 21( I):1204-1212 .
380 DIABET ES97 . Hollan der PA, Levy 1, Fineman MS et al. Pramlintide as an adjunct to insulin therapy improves long-termglycemic and weight control in patients with type 2 diabetes: a I-year randomized controlled trial.Diabetes Care 2003 ; 26(3):784-790 .98. Polonsky KS, Given BD, Van Cauter E.Twenty-fo ur-hour profiles and pulsatile patterns ofinsulin secre tionin normal and obese subject s. J Clin Invest 1988; 81(2):442-448.99 . Binder C, Lauritzen T, FaberO, Pramming S. Insulin pharmacokinet ics. Diabetes Care 1984 ; 7(2) :188-199.100. Kitabchi AE, Umpierrez GE, Murphy MB et al. Management of hyperglycemic crises in patients withdiabetes (Techn ical Review) . Diabetes Care. 200 1; 24: 131-153.101. Greenspan FS, Gardner DG. Basi c and Clinical Endocrinology. Sixth edition 2001 ; 66 1-668.102. Barnett AH, Owen s DR. Insuli n analogues. Lancet 199 7; 349:47.103. Singh SR, Ahmad F, Lal A et al. Efficacy and safety of insul in analog ues for the managem ent of diabe tesmell itus: a meta-analysis. CMAJ 200 9; 180:385.104. Heinem ann L, Linkeschova R, Rave K et al. Time-action profile of the long-acting insulin analoginsulin glargine (HOE901) in comparison with those ofNPH insul in and placebo. Diabetes Care 2000;23(5):644-649.105. Home ID, Lagarenne P. Combined randomi zed controlled trial expe rience of malignanc ies in studiesusing insul in glargi ne. Diabe tologia 200 9; 52(12):2499-506.106. Havelund S, Plum A, Ribel U et al. The mechanism of protraction of insulin detemi r, a long-acting,acylated analog of hum an insulin. Pharm Res 2004; 21: 1498.107. Philis-Tsimikas A, Charpentier G, Clauson I et al. Comparison of once-daily insulin detem ir with NP Hinsulin added to a reg imen of oral antidiabetic drugs in poorly contro lled type 2 diabetes. Clin Ther2006; 28(10):1569-1581.108. Riddle MC, Rosenstock J, Gerich 1. The treat-to-target trial: randomize d addition of glargi ne or hum anNPH insulin to oral thera py of typ e 2 diabetic patients. Diabetes Care 2003; 26(11 ):3080-30 86.109. Plank J, Siebenhofer A, Berghold A et al. Systematic review and meta-analysis of short-acting insulinanalogues in patien ts with diabetes mell itus. Arch Intern Med 2005; 165(12):1337-1344.110. Nat han DM, Buse JB , Davidson MB et al. Management ofhype rglycemia in type 2 diabetes: a consensusalgorithm for the initiation and adj ustmentoft herapy. A consensus statement from the American DiabetesAssociation and the European Association for the Study of Diabetes. Diabete s Care 2006 ; 29:1963.11I. Bergenstal RM, John son M, Powers MA et al. Adj ust to target in type 2 diabetes: comparison of a simplealgorithm with carbohydrate counting for adj ustment of me altime insulin glulisine. Dia betes Care 2008;3 I(7):1305-1 310.112. Castera V, Dutour-Meyer A, Koepp el M et al. Systemic allergy to human insulin and its rapid and longacting analogs: successful treatm ent by continuous subcutaneous insulin lispro infusion. Diabetes Metab200 5; 3 1:39 1-400.113. van Bon AC, Brouwer TB, von Basum G et al. Future Acceptance of an Art ificial Pancreas in Adults withType I Diabetes. Diabetes Technol Ther 20 11; 13(7):73 1-736.114. Nagaya M, Katsuta H, Kaneto H ct al. Adult mouse intrahepatic biliary epithelial cells indu ced in vitroto beco me insulin-producing cells. J Endocrinol 2009 ; 20 1:37-47.115. Alejandro R, Barton FB, Hering BJ et al. Update from the Co llaborative Islet Transplant Registry.Transplant ation 2008; 86 :I783-1788.116. Ojo AO, Meier-Kriesche HU, Hanson JA et al. The impact of simultaneo us pancreas-ki dney transplantationon long-term patient survival. Tran splant ation 200 I; 7 1:82-90.117. Larsen. Pancreas transplantation : indications and consequences.Endocr Rev 2004; 25:919-946.118. Lee HC, Kim SJ, Kim KS etal. Rem ission in models oftype I diabetes by gene therapy using asingle-chaininsuli n analogue. Nature 2000; 408 :483-4 88.119. Rahmo une H, Thompson PW, Ward JM et al. Glucos e transporters in hum an renal proxim al tubular cellsisolated from the urine of patient s with non-in sulin dependent diabetes . Diabetes 2005 ; 54:3427 -3434.120. Handelsman Y,Goldberg RB,Garvey WT et al.Colesc velam hydrochloride to treat hypercholesterolemiaandimprove glycemia in prediabetes: arandomized,prospective study.Endocr Pract20 10; 16(4):6 17-628. http://reference.medscape.com/m edline/abstract/20634 I76.121. Bonadonna RC, Heise T, Arbet-Engel et al. Piragliatin (R04389620), a novel gluco kinase activator,lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients withtype 2 diabetes mellitus: a mechani stic study . J Clin Endocrinol Metab 20 10; 95(1 1):502 8-5036. http://reference.medscape.com/m edl ine/abstract/20739378.122. http://en.wikipedia.orgiwiki/ln sulin_th erapy#cite_note-24.