Incretin Mimetics and DPP-4 Inhibitors: New Approach to Treatment of Type 2 Diabetes Mellitus.

Type 2 diabetes constitutes the main bulk (85-90%) of diabetic population. It is a chronic metabolic disorder with progressive ?beta-cell dysfunction, impaired insulin actions and various other abnormalities. Insulin response of beta-cell is more after oral glucose or following meal than intravenous infusion of glucose. Gut related peptides, the incretin hormones released after meal following activation of the enteroinsular axis plays an important role in glucose homeostasis by pancreatic and extrapancreatic glucoregulatory effects and helps in preservation of beta-cell function. In type 2 diabetes, there is progressive decline of these incretins level, glucagons like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) with loss of beta-cell mass, beta-cell function and glycemic deterioration. These peptides are rapidly degraded by endogenous proteases, dipeptidyl peptides-4 (DPP-4) giving a very short half life of 2-3 minutes. Currently available anti-diabetic drugs do not address these arms of glucoregulatory dysfunction of type 2 diabetes. Modern therapeutic strategy should be targeted at preservation of beta-cell mass and function by exploiting the incretin hormones and enteroinsular axis. DPP-4 resistant incretin analogues/mimetics (e.g. exenatide, liraglutide) that have been developed by modifications/ substitutions in the polypeptide chain may be an effective alternative of the existing therapy of type-2 DM. DPP-4 inhibitors (e.g. sitagliptin, vindagliptin) prevent the degradation of endogenous GLP-1 and GIP, thereby potentiate their actions and help in glycemic control. Distinctive features of incretin mimetics are: their action is glucose dependent, do not produce hypoglycemia, help in preservation of beta-cell mass and function, help in weight reduction. DPP-4 inhibitors are weight neutral. Ongoing studies will reveal newer avenues and long term outcome of these molecules.

Drug abuse and addiction.

Among the social and medical ills of the twentieth century, substance abuse ranks as on one of the most devastating and costly. The drug problem today is a major global concern including Bangladesh. Almost all addictive drugs over stimulate the reward system of the brain, flooding it with the neurotransmitter dopamine. That produces euphoria and that heightened pleasure can be so compelling that the brain wants that feeling back again and again. However repetitive exposure induces widespread adaptive changes in the brain. As a consequence drug use may become compulsive. An estimated 4.7% of the global population aged 15 to 64 or 184 million people, consume illicit drug annually. Heroin use alone is responsible for the epidemic number of new cases of HIV/AIDS, Hepatitis and drug addicted infant born each year. Department of narcotic control (DNC) in Bangladesh reported in June 2008 that about 5 million drug addicts in the country & addicts spend at least 17 (Seventeen) billion on drugs per year. Among these drug addicts, 91% are young and adolescents population. Heroin is the most widely abused drugs in Bangladesh. For geographical reason like India, Pakistan and Myanmar; Bangladesh is also an important transit root for internationally trafficking of illicit drug. Drug abuse is responsible for decreased job productivity and attendance increased health care costs, and escalations of domestic violence and violent crimes. Drug addiction is a preventable disease. Through scientific advances we now know much more about how exactly drugs work in the brain, and we also know that drug addiction can be successfully treated to help people stop abusing drugs and resume their productive lives. Most countries have legislation designed to criminalize some drugs. To decrease the prevalence of this problem in our setting; increase awareness, promoting additional research on abused and addictive drugs, and exact implementation of existing laws are strongly recommended. We should also deserve renewed attention on prescription drug abuse. It is imperative that as a nation we make ourselves aware of the consequences associated with drug abuse. Otherwise devastating effects of drug will destroy the manpower and economic growth of the country.

Development of insulin delivery systems.

Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems.

Evaluation of inhaled insulin therapy for diabetes mellitus.

Inhaled insulin (INH) is a novel, non-injectable alternative route of delivery of insulin for the management of diabetes mellitus (DM). It is an important breakthrough in the history of diabetes mellitus and an attractive means of treatment for many patients. Though insulin is one of the fundamental tools for management of DM, many patients and physicians are reluctant to initiate and intensify the insulin regime in appropriate time due to various reasons called psychological insulin resistance (PIR). Exubera, one of the inhaled insulin devices has been approved by FDA and European Union in early 2006. It delivers short acting human insulin powder in aerosol form. There are lot of ongoing studies regarding the efficacy and safety of INH. Inhaled insulin showed similar pharmacokinetic and glucodynamic behavior like that of subcutaneously administered rapid acting human insulin analogues like aspart, lispro and glulisine. It consistently improves glycemic control when used in combination with longer acting subcutaneous insulin regime in patient with type 1 and type 2 DM. It may be used to replace or supplement oral antidiabetic therapy in type 2 diabetic patients. Available study reports showed its tolerability and safety with an overall similar risk of hypoglycemia to that of subcutaneous insulin. So far, no significant clinically meaningful pulmonary functional changes have been noted with the use of INH. Various reports showed high level of patients satisfaction and an acceptable new modality of non-invasive treatment. However, long term follow up studies are needed to evaluate the safety profiles of inhaled insulin.

Insulin analogues: new dimension of management of diabetes mellitus.

Insulin is one of the fundamental tools for the management of diabetes mellitus. All type 1 diabetic patients and most of the type 2 require the appropriate support of insulin for good glycemic control, long term healthy outcome and also to overcome the acute crisis. It is almost impossible to mimic the endogenous physiological insulin secretion curve by external administration of short acting human insulin and conventional intermediate acting insulin, neutral protamin Hagedorn (NPH), the so called basal insulin. Short acting human insulin has got a delayed onset of action, late peak and a long tail leading to postprandial hyperglycemia and late hypoglycemia. The so called basal insulin (NPH) is not truly a basal or peakless insulin. Its onset of action takes about 2 - 4 hours with a peak action and a tail. It can not maintain a constant basal level leading to premeal and fasting hyperglycemia and chance of hypoglycemia during peak action, particularly after night injection. To overcome the limitations of human insulin, during the last decade, three ultrashort acting and two long acting basal analogues have been developed by modifications of primary molecule of human insulin. The ultrashort acting analogue insulins are insulin lispro, insulin aspart and insulin glulisine. The basal analogues are insulin glargin and insulin detemir. The pharmacokinetic profiles of novel analogue molecules provide a better opportunity to mimic a physiological pattern of insulin administration, better glycemic control, less chance of hypoglycemia, greater flexibility and a healthy longterm outcome.

Risk of cardiovascular diseases with oral contraceptives.

Oral contraceptive pills (OCs) are widely used method of contraception for its effectiveness and easier compliance. However, adverse effects associated with OCs use notably the increased risk of cardiovascular diseases (CVD), manifesting as ischaemic and haemorrhagic stroke, myocardial infarction (MI) and venous thromboembolic diseases were reported soon after their introduction to the market in the early 1960s. Various modifications were made in an attempt to lower these risks including a reduction in the estrogen dose and changes in the progestogen compound. Currently used OCs containing the new progestin (Levonorgestrel, Desogestrel, gestodene or norgestimate) classified as low dose because all contain less than 35 microg of ethinyl estradiol. Despite their low steroid content, all have proved to be highly effective. The rationale of this reviewed study based upon cardiovascular risks in relation to these monophasic low-dose oral contraceptives. To review all relevant articles it is concluded that the risk for cardiovascular disease is lower with current preparations of oral contraceptives. Cardiovascular diseases occur mainly among oral contraceptive users who smoke or have predisposing factors--such as age more than 35 years, overweight, diabetes & hypertension.

Combined occurrence of hyperthyroid Graves' and Hashimoto's thyroiditis.

A 40 years old, married Govt. servant from Sadar upazila, Mymensingh was admitted in Mymensingh Medical College Hospital on 9(th) February, 2005 with the complaints of excessive sweating for 1 year, gradual loss of weight for 6 months, swelling in front of the neck for 1(1/2) months, and hoarseness of voice for 1 month. He was nervous, irritable, emotionally labile. Thyroid gland was symmetrically enlarged, firm in consistency with scalloped surface. Palms were warm and sweaty with fine tremor in outstretched hands. Lid lag, lid retraction and proptosis were the occular manifestations. All the reflexes were exaggerated. Radioactive iodine uptake showed enlarged gland with homogenously increased radiotracer concentration, ultrasonogram findings were enlarged gland with hypoechoic parenchyma with fibrous septa, T(3), T(4), TSH values were 6.56 nmol/L, 241.09 nmol/L and 0.14 mIU/L respectively. Thyroid microsomal antibody level was 32.87%. Thyroid FNAC findings were sheets of regular follicular cells, some large cells with granular basophilic cytoplasm, macrophages, a few inflammatory cells and giant cells. All the above findings were in favour of a diagnosis of hyperthyroid Graves' with Hashimoto's thyroiditis.

Serum zinc status of rural women taking combined OC.

This prospective case-control study was undertaken on 78 women between 15 to 45 years of age from rural area to see alteration of serum zinc due to oral contraceptive (OC) use. Of the subjects, 34 women was taken as controls having no history of taking any form of hormonal contraceptives neither during the time of selection nor during one-year period prior to the study. All of the women in the control group were advised to start consuming oral pill (Sukhi) for 3 consecutive cycles and at the 3(rd) month, 25 women were taken as cases on longitudinal basis. Another 44 women were randomly selected as cases on the basis of using combined oral contraceptives (Sukhi) for 4 months onwards. Subjects were classified as follows on the basis of duration of oral contraceptive use: Group I (n=34) -- controls, Group II (n=25) -- 3 months, Group III (n=17) -- 4 months -- 2 years and Group IV (n=27) -- >2 years. Finally, 103 samples of blood (34 from controls and 69 from oral contraceptives users) were collected for estimation of Serum Zinc (microg/dl) by Atomic Absorption Spectrometry using UNICAM - AA Spectrometer. MeanSD of Serum Zinc significantly reduced in all 3 contraceptive groups in comparison to controls (p<0.001). It was recommended to carry out further study including larger population from rural area to elucidate alteration in serum zinc and other trace elements to correlate with side effects caused by hormonal contraceptive so that attempt could be made to mitigate those.

Evaluation of hormone replacement therapy.

Hormone Replacement Therapy (HRT), once considered as the gold standard of treatment of menopausal symptoms and osteoporosis, introduced about seventy years ago still continuing with lot of controversies. Menopause, a transitional period of women's life, is not an illness when oestrogen level falls leading to its consequences. Results of earlier observational studies showed beneficial effects of HRT including cardiovascular protection. But all recent randomized controlled trials have failed to prove these positive effects, rather increases the cardiovascular risk and breast cancer. Women's Health Initiative(WHI), one of the recent randomized controlled trials was stopped prematurely in 2002 due to unfavorable risk-benefit ratio. HRT is not the only way of treating the menopausal symptoms and other consequences of estrogen deficiency. There are suitable alternatives without bearing the risk of HRT. Vasomotor symptoms with hot flushes and sweating experienced by about 75 percent of menopausal women can be treated with alternatives like phyto-estrogens, selective estrogen receptor modulators (SERMs), clonidine, selective serotonin reuptake inhibitors, acupuncture, exercise, behavioral therapy etc. HRT is no longer considered as the first line of treatment of postmenopausal osteoporosis. It can be treated with alternatives like regular weight bearing exercise, balanced calcium rich diet, maintaining weight, avoidance of bone robbers, (like excess alcohol, caffeine, smoking), use of SERMs etc. Use of HRT should be individualized and rationalized considering its risks and benefits.

Budd-Chiari syndrome.

A 30 years old, non-alcoholic farmer from Trishal, Mymensingh was admitted in Mymensingh Medical College Hospital on 7 February, 2004 with the complaints of gradual swelling of abdomen, both legs and upper abdominal pain for 3 months. For the last 6 years, he was treated as a case of chronic liver disease (CLD) with spironolactone and frusemide. He was non-icteric, mildly anaemic with mild oedema, clubbing, gynaecomastia and engorged vein over anterior abdominal wall, flanks and back. Direction of venous flow was from below upward. There were mild hepatosplenomegaly, ascites and bilateral testicular atrophy. He was diagnosed as a case of Budd-Chiari Syndrome (BCS) on the basis of physical examination and it was confirmed by the findings of ultrasonography, liver scan and doppler study. The patient was managed by medical therapy alone.

Angiographic severity and extent of coronary artery disease in patients with type 2 diabetes mellitus.

Coronary angiographic characteristics of fifty patients with type 2 diabetes mellitus and coronary artery disease (CAD) were compared with fifty non diabetic patients with CAD. Type 2 diabetic patients undergoing clinically indicated elective coronary angiography were individually matched with fifty non diabetic coronary artery disease patients for age, sex and major risk factors. No significant difference was present between the mean age, presenting complains and other coronary risk factors between the two groups. Severity and extent of coronary artery involvement was assessed by a coronary artery score (CAS) using the segmental distribution method for coronary artery lesions and morphometric analysis of atherosclerotic lesion was done. Type 2 diabetic patients had a higher CAS (11.74+/-5.04 vs 8.72+/-4.87; P<0.001) as compared to the non-diabetic patients. Multivessel disease were more prevalent in both the groups (82% vs 68%; P>0.05) but diabetic patients had significantly higher number of triple vessel disease (58% vs. 38%; P<0.001). Normal coronary arteries and single vessel disease were more prevalent in non-diabetic patients (32% vs. 18%; P<0.05). As compared to non-diabetic group diabetic patients had a higher total number of diseased vessels (78.66% vs. 68%; P<0.01), a higher lesion per patient ratio (3.94+/-1.80 vs 3+/-1.67:P<0.001) and more proximal lesions (40.83% vs. 34.70%; P>.05) though not statistically significant. Morphometric analysis of coronary artery lesions revealed that diabetic patients had significantly higher number of multiple irregularity lesions (24.37% vs. 15.33%; P<0.01) and lesions were more obstructive (lesion involving 70-90% of coronary lumen: 70.53.% vs. 57.33%; P<0.05). Though there was no significant difference between the systolic left ventricular function between the two groups but significant higher regional wall motion abnormality was found more in diabetic patients (76%vs 62%; P<0.01). So type 2 diabetic patients had more severe and extensive atherosclerotic lesion in their coronary arteries than the matched non diabetic control on coronary angiography suggesting an independent effect of diabetic mellitus on atherosclerotic process specially in our population.

Effects of prolonged use of injectable hormonal contraceptive on serum lipid profile.

The current study was carried out to determine serum levels of total cholesterol, triacylglycerol (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in human female volunteers taking injectable hormonal contraceptives. For this purpose, 200 (two hundred) subjects with age range of 20-35 years were selected. Out of them, 140 (one hundred and forty) were experimental subjects and 60 (sixty) were control. Women without hormonal contraceptive were selected as the subjects of control group. The experimental subjects were taking injectable hormonal contraceptive, DMPA (depo-medroxyprogesterone acetate) for 3-5 years uninterruptedly. The mean serum total cholesterol and mean serum triacylglycerol levels of the DMPA users were significantly (P<O.05 and P<0.01 respectively) elevated in comparison to that of the non-users. The mean serum HDL-cholesterol was decreased in subjects using DMPA in comparison to that of the control group. But the decrease was not significant (P>0.05). The mean serum LDL-cholesterol level of the subjects of DMPA users was significantly (P<0.05) elevated in comparison to that of the control.

A case report on Klinefelter syndrome.

An 18 year old boy presented with small genitalia, failure of eruption of secondary sex hairs, female like voice with eunachoid body habitus, bilateral gynecomastia, infantile external genitalia, small testes and poorly developed musculature. He was diagnosed as a case of 47XXY Klinefelter syndrome on the basis of hormone assay and karyotyping. He has given androgen replacement therapy with the aim to relieve symptoms of androgen deficiency, to reproduce physiological levels of plasma testosterone and to prevent long term consequences of androgen deficiency.

Ketosis resistance in under thirty diabetic subjects.

Young onset diabetic subjects in tropical developing countries include a group of subjects who exhibits a characteristic ketosis resistance termed as Malnutrition Related Diabetes Mellitus (MRDM) by the WHO Study Group. The mechanism for this resistance to ketosis is still uncertain. To understand this mechanism we have studied the serum responses of glucose, non-esterified fatty acid (NEFA) and triglyceride (TG) to intravenous fat emulsion in newly diagnosed 8 fibrocalculous pancreatic diabetes (FCPD) and 11 low insulin secretory (LIS) subjects under 30 years of age along with 27 age-matched Non Insulin Dependent Diabetes Mellitus (NIDDM) subjects. Overnight fasting subjects were given a 90 min infusion of intralipos 10% (2.5 mg/kg body weight/min) and serum was collected at 0, 60, 90, 120 and 150 min. The fasting NEFA in the 3 groups were almost similar (micromol/l, M +/- SEM: 486 +/- 58, 564 +/- 76 and 559 +/- 34 in FCPD, LIS and NIDDM respectively). Fasting TG also showed a close similarity among 3 groups (mg/dl, M+/-SEM: 117 +/- 11, 110 +/- 22 and 123 +/- 4 in FCPD, LIS and NIDDM respectively). Intravenous fat caused a steady rise of NEFA as well as TG in all groups during the 90 minutes of infusion followed by a gradual fall. No two groups significantly differed regarding NEFA and TG at any time point. Fasting glucose was markedly higher in FCPD (22.9 +/- 2.5, mmol/l, M+/-SEM) and LIS (20.8 +/- 1.6) than NIDDM (11.0 +/- 1.0). In all the 3 groups glucose showed a slow but steady fall. Fasting C-peptide was very low in FCPD (0.42 +/- 0.08, ng/ml, M +/- SEM) and LIS (0.55 +/- 0.09) whereas it was within normal range in NIDDM patients (2.99 +/- 0.24). The results suggest the following: (a) Depleted body fat store do not lead to a decreased supply of NEFA in FCPD and LIS subjects at the fasting state; (b) Increased supply of NEFA in these subjects lead to a normal esterification response as evidenced by a parallel rise of TG; (c) Inspite of markedly low level of the antilipolytic hormone insulin, FCPD and LIS subjects are capable to maintain NEFA and TG responses similar to NIDDM subjects. This may indicate that factor (s) other than substrate and esterification is (are) probably involved in the ketosis resistance of FCPD and LIS subjects; and (d) Although FCPD and LIS differ regarding generalized pancreatic damage (which raises the possibility of involvement of glucagon producing alpha-cells in the FCPD group) the two groups do not differ regarding the ketogenic substrate and esterfication responses.

Studies on clinical pattern of glomerulonephritis.

A prospective study of primary glomerulonephritis covering two and half years period was done at Dhaka Medical College Hospital & IPGMR, Dhaka from June 90 to July 92. A total of 100 cases were included in this study. All of the patients were of 13 years and above, clinically diagnosed, and by laboratory investigations, the diagnoses were established. In this study, we have tried to find out age incidence, sex ratio, possible aetiological factors, common clinical presentation, biochemical parameters and histological typing of primary glomerulonephritis.

Tuberous sclerosis.

Tuberous sclerosis - also called tuberous sclerosis complex (TSC) - is a rare, multi-system genetic disorder affecting cellular differentiation & proliferation, which results in hamartoma formation in many organs. The classic triad of clinical features comprises mental retardation, epilepsy & skin lesion, but these three features are not always present. Mrs. Jahanara Khatun, a 30 years old lady presented with maculo-papular skin lesions over the face, neck, shoulder since her six years of age, a lump in the right lumber region for four years, pain in the right lumber region associated with passage of blood clot in urine for 15 days. Her family history was very characteristic. One of her elder brother had developed same type of skin lesions. Again her 13 years old daughter had developed same type of skin lesions since seven years of age & she was mentally retarded. Clinical examination revealed normal mentation, pin head sized yellowish red translucent discrete waxy papules situated in the face, neck, shoulder. A large tender firm irregular mass in the right lumber region, which was ballotable & moved with respiration. USG revealed bilateral retroperitoneal masses with the involvement of right kidney & formation of renal artery aneurysm. The patient undergone right sided nephrectomy & histopathology of the specimen showed features suggestive of renal angiomyolipoma. The patient was diagnosed as a case of definite tuberous sclerosis complex as she had two major feature of revised diagnostic criteria - facial angiofibromas & renal angiomyolipoma.