Dr. S. G. Deodhare

OUTLINE

1.Type 1 Diabetes

A novel subtype of Type 1 diabetes

Advances in Pancreas and Islet Transplantation

Increasing Prevalence of Diabetes in Children and Adolescents

Islets Amyloid and Type 2 Diabetes Mellitus

Glucose Transporters and Insulin Action

Obesity Genes and Type 2 Diabetes

PPAR-gamma, the Ultimate Thrifty Gene

Gestational Diabetes is a Form of Type 2 Diabetes

Foetal Origins of Adult Disease

Inflammation markers and Type 2 diabetes

The post-prandial state and risk of cardiovascular disease

Diabetes is increasing worldwide. The World Health Organisation stated in 1998 that a 122 % rise in the number of adults with diabetes is projected by 2005, to reach 300 million adults worldwide.

There are four reasons for this two-fold global increase: Firstly, we are living longer (which increase our chance of experiencing the disease); over-nutrition and lack of exercise are prevalent (which promotes the manifestation of diabetes); the disease being transmitted in a hereditary fashion; and finally, the WHO and ADA (American Diabetes Association) are tightening diagnostic criteria (more people are being identified as diabetic).

Such transformations have taken place within the Indian population, which has undergone demographic change associated with affluent diet and a sedentary lifestyle, especially following emergence of green revolution in the region.

Type I diabetes is caused by autoimmune destruction of pancreatic islets; this immunologic process seems to be genetically determined, at least in parts. Since antibodies against islet or insulin can be detected in the pre-diabetic stage and some predisposing genetic factors - such as certain HLA alleles are known, immunologic interventions to prevent Type I diabetes are of great interest.

Imagawa et al (2000) classified 56 consecutive Japanese adults with Type I diabetes according to the presence or absence of glutamic acid decarboxylase antibodies (their presence is a marker of autoimmunity) and compared their clinical serologic and pathological characteristics.

Some patients with idiopathic Type I diabetes have nonautoimmune, fulminent disorders characterised by the absence of insulinitis and diabetes related antibodies, a remarkably rapid onset, and high serum pancreatic enzyme concentrations.

Remarkable advances in technology and clinical outcomes lend renewed promise to the success of pancreas and islet transplantation for patients with Type 1 diabetes.

Several emerging technologies have the therapeutic potential to enhance the success of future islet transplantation including the development of bioartificial pancreas through engineered islet cell lines, bone marrow stem cell-induced and monoclonal antibody-induced tolerance, and use of combination of new drugs. "Bioartificial pancreas" is an islet-surrogate model consisting of encapsulated islet cells that are protected from immune attack by a selectively permeable membrane barrier, and capable of releasing molecules of interest such as insulin into the bloodstream in response to metabolic stimuli. Ideally, such a closed-loop system would obviate the need for exogenous insulin and could be of significant benefit for islet transplantation (Thoren B 2000).

Pancreas transplantation is associated with an improvement in cardiovascular and atherosclerotic risk. Hypoglycaemia counter regulation is preserved following both short-term and long-term pancreas transplantation (Larsen JL, Ratanasuwan T, Lynch G et al, 2000).

Autoislet transplantation should be considered to prevent diabetes and preserve beta-cell function in patients with chronic painful pancreatitis undergoing pancreactomy. The islets are introduced into the portal vein shortly (within 2 hours) after isolation.

The intrahepatic autoislet transplantation with more than 300,000 islets can preserve metabolic stability of beta cell function and prevent diabetes in patients with chronic pancreatitis and previously non-diabetic for up to 13 years following pancreactomy (Robertson RP, Kendall DM, Sutherland DER et al, 2000).

Edmonton protocol is a novel islet transplantation regimen that has made several modifications to existing protocols and resulted in a dramatic 100% success rate to-date for solitary islet transplantation (Shapiro AMJ, Lakey JRT, Rajan E et al, 2000). The new Edmonton islet transplant is likely to be a landmark advance in the field.

The earlier results from the islet transplant registry showed rather poor outcomes for islet transplant recipients, with only 8% showing insulin independence beyond 1 year. The poor success rate was attributed to less than ideal use of immunosuppressants (including steroids, cyclosporine and azathioprine), which were unsatisfactory for islet use based on in vitro studies. Based on recently available drugs and antibody therapies, a new approach was devised that allowed a steroid-free combination regimen of anti-CD 25 (interleukin-IL-2 receptor antibody), sirolimus and tacrolimus. The latter 2 agents have now been shown to act synergistically in vivo and dramatically reduce acute rejection rates from 40% to 4 %.

The second component of the procedure captures the recent advances in islet isolation technology, including the use of the Ricordi chamber for automated pancreas dissociation, islet-cell purification by a COBE cell processor, and the use of endotoxin-free Liberase enzyme for pancreatic digestion.

The actual implant was effected through a simple procedure using percutaneous trans-hepatic access to deliver islet cells into a portal vein via a catheter. Researchers injected islet-cells beneath the liver in 8 diabetic patients. The cells took up residence in the liver and began producing the long-lost insulin. An examination of metabolic parameters in the transplant recipients showed normal mean 24-hours glucose levels with progressive improvement in pre-transplant high-range glucose levels and elimination of hypoglycaemia. The mean amplitude of glucose excursions remained in the normal range following transplantation. HbA1c were normal at 3 and 6 months post-transplant. The preserved C-peptide stimulation tests indicated that the graft exhibited no autoimmune or acute rejection of the graft. No serious complications were seen except superficial mouth ulceration that resolved with time and adjustment of drug dosage. No alteration in creatinine, lipid levels, or insulin sensitivity was observed. A significant reduction in islet cell antibodies was observed in transplanted patients. These results demonstrate that the solitary islet cell transplantation works because the success rate has been increased from 8% to 100% with no evidence of autoimmune or acute rejection, excellent metabolic control with insulin independence with minimal surgical risk to patients.

These successful results have initiated the development of world wide multicenter network (Immune Tolerance Network [ITN]) to repeat this protocol. If the results are confirmed in a larger study and physicians can find better source of the islet cells, which must now be harvested from cadavers, it could mean the end of insulin-dependent diabetes mellitus.

Type 2 diabetes, which is more prevalent than Type I, is a multifactorial disease. The genetic basis of Type 2 diabetes is complex, and so far it is understood only in a subtype of diabetes known as maturity-onset diabetes of the young, which is caused by a single gene defect. By contrast most cases of Type 2 diabetes appear to be polygenic in origin. Moreover, insulin resistance caused by factors such as obesity and ageing is an important precipitating factor for diabetic states. Type 2 diabetes is one of the most prevalent metabolic disorders worldwide and a major risk factor for cardiovascular disease.

Type 2 diabetes has generally been believed to be rare in children, adolescents, and young adults; however, this is no longer the case (Pinhas-Hamiel O, Zeitler P 1998). Although the most common form of diabetes in children was Type 1 diabetes, the picture has changed. An important and alarming feature of the diabetes epidemic is that Type 2 diabetes is increasing in these younger age groups. In China, Japan and the Pacific Islands more than 70 % of children presenting the diabetes have the Type 2 form.

Obesity and lack of exercise have been implicated in this trend, which has been labeled as "nintendonization". Children are often driven to and from the school and then come home and race to the computer or computer- game station instead of playing games or sports outdoor. This new phenomenon of obesity and Type 2 diabetes in children and adolescents poses significant problems for treatment because the safety of therapies used in treating obesity and Type 2 diabetes (apart from insulin) have not been tested in this age group. In addition, the age of the onset of Type 2 diabetes is moving downward. Whereas most cases in 1960s were diagnosed in people over 65 years, particularly in highsusceptibility groups, now onset of diabetes in those aged 35 years and over is not unusual.

It has long been questioned whether the deposition of islet amyloid is involved in or merely a consequence of the pathogenesis of Type 2 diabetes. Because islet amyloidosis in patients with Type 2 diabetes is associated with a reduced mass of insulin-producing beta cells, it is most likely an important factor in the development of beta-cell failure. Patients who require insulin treatment have the greatest reduction in islet mass and the most prominent amyloid deposits, indicating that the degree of islet amyloidosis may be related to the severity of the disease. A causal link between islet amyloidosis and Type 2 diabetes is further supported by the finding of islet amyloid in other species in which Type 2 diabetes is known to develop - notably monkeys and cats. Islet amyloid is absent in rodents with Type 2 diabetes, in which the course of disease is very similar to that in humans. Also the absence of detectable islet amyloid in approximately 10 % of patients with Type 2 diabetes indicates that islet amyloidosis cannot account for all cases of Type 2 diabetes. (Hoppener JO, Ahren, BO, Lips CJM 2000).

In vivo, islet amyloidosis is correlated with a loss of up to 40 to 50 percent of beta-cell mass in the pancreatic tissue of patients with Type 2 diabetes as well as in diabetic cats and transgenic ob/ob mice that produce human islet amyloid polypeptide. Longitudinal studies in monkeys revealed that the degree of islet amyloid formation was associated with the degree of reduction in insulin secretion, indicating that islet amyloid polypeptide-induced islet amyloidosis is causally related to the death of beta cells.

In recent years, there has been new insight into the formation of islet amyloid and its effects on the function and viability of beta cells. Overproduction of human islet amyloid polypeptide is an important factor in inducing the formation of islet amyloid, the process may also involve local membrane components as well as stabilizing or protective components supplied through the circulation. Overproduction of human islet amyloid pollypeptide and islet amyloid formation have been implicated in beta-cell cytotoxicity. In transgenic mice that produce human islet amyloid polypeptide the formation of islet amyloid leads to impaired insulin secretion as a result of the loss of beta cells. Thus, the formation of islet amyloid is a diabetogenic factor. Besides being a common pathogenic factor in an otherwise heterogeneous and multifactotial disease, islet amyloidosis seems to be an attractive therapeutic target. Potential therapies might involve inhibition of the production of human islet amyloid polypeptide or the formation of amyloid fibrils. Additional advantages of the former approach are that they inhibit the formation of prefibrillary, pathogenic aggregates and diminish the potential diabetogenic effects of human islet amyloid polypeptide on insulin secretion and glucose clearance.

Because the lipid bilayers that make up cell membranes are impermeable to carbohydrates, carbohydrate-transport systems are required. In recent years, two distant families of cellular transporters of glucose (and other hexoses, including fructose and lactose) have been cloned. The sodium-link glucose transporters are largely restricted to the intestine and the kidney, where they actively transport glucose against glucose-concentration gradient by using sodium cotransport as an energy source. The other group of transporters conveys glucose by facilitated diffusion down glucose-concentration gradients. This consist of five homologous transmembrane proteins, GLUT-1, 2, 3, 4,and 5, that are encoded by distinct genes.

The GLUT proteins have distinct substrate specificities, kinetic properties and tissue distribution that dictate their functional roles. Studies that have examined regulation of the expression of glucose-transporter genes as well as cell-biologic characteristic of the GLUT protein have led to a better understanding of the mechanism by which carbohydrate metabolism is regulated (Shepherd PR, Kahn BB 1999).

GLUT-4 is the main insulin-responsive glucose transporter and is located primarily in muscle cells and adipocytes. The importance of GULT-4 in glucose homeostasis is best demonstrated by studies of mice in which one allele of GLUT-4 gene has been disrupted. These mice have approximately a 50% reduction in GLUT-4 concentration in skeletal muscle, heart and adipocytes; they have severe insulin resistance; and in at least half the males, frank diabetes develops with age.

In normal muscle cells and adipocytes, GLUT-4 is recycled between the plasma membrane and intracellular storage pools. GLUT-4 differs from other glucose transporters in that about 90 percent of it is sequestered intracellularly in the absence of insulin or other stimuli such as exercise. In the presence of insulin or another stimulus, the equilibrium of this recycling process is altered to favour the translocation (regulated movement) of GLUT-4 from intracellular storage vesicles to the plasma membrane and, in the case of muscle, to the transverse tubules as well. The net effect is a rise in the maximal velocity of glucose transport into the cell.

Insulin resistance is a major factor in the pathogenesis of obesity. Diabetes, and the insulinresistance syndrome is associated with an increased risk of cardiovascular disease. In skeletal muscle, insulin resistance may be caused by defects in glucose transport, which results from impairments in the translocation, fusion, or exposure and activation of GLUT-4 glucose transporters. These abnormalities in GLUT-4 translocation in muscle appear to result from defects in intracellular signaling. These defects may be inherent in the tissue or may be due to circulating or paracrine factors such as hyperglycaemia itself (glucose toxicity) or increased serum concentrations of free fatty acids or TNF-alpha. Insulin-stimulated glucose uptake in adipose sites is also defective, largely as a result of the down-regulation of GLUT-4 expression. Studies in transgenic mice indicate that increase intracellular concentrations of GLUT-4 can ameliorate diabetes.

The importance of obesity as a risk factor for a number of diseases, including Type 2 diabetes, cardiovascular disease, hypertension, gallstone disease and certain cancers is well documented.

There is now enormous interest in search for the gene(s) contributing to obesity Type 2 diabetes and insulin resistance. The thrifty gene has recently received a great deal of attention.

Neel described the thrifty genotype 35 years ago. Neel suggested that the propensity of Pacific Islands and Pima Native American Islanders obesity and diabetes may have an anthropological basis, and hypothesised that the marked tendency to obesity in traditional living populations (e.g. hunter-gatherers, experiencing modernisation) was the result of a "thrifty genotype". This trait would promote efficient storage of fat in times of plenty and allow a survival advantage at times of hardship (i.e, the "feast and famine" that may have been encountered with long canoe voyage and uncertain climatic conditions). In modern times, with abundance of food and a sedentary life-style, however, this genotype has become disadvantageous, favouring the development of obesity and Type 2 diabetes.

So the hunt is now for the thrifty gene. Psammonys obesus (the Israeli sand rat is possibly the best animal model of thrifty genotype insulin resistance, obesity, and Type 2 diabetes). Studies in this species suggest hyperinsulinemia / insulin is the initial metabolic lesion in the development of obesity and Type 2 diabetes. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance and diabetes.

Incidentally, it also develops hyperleptinemia and leptin insensitivity. (The recent discovery of leptin has been an important advance in obesity research.) Leptin is a protein product of the obese (ob) gene and produced by adipocytes. It plays an important role in the management of fat stores and regulates appetite and energy expenditure. It was identified in 1994 as the product of a gene that is defective in the obese (ob / ob) strain of mouse. These animals are massively obese and exhibit a syndrome similar to that seen in morbidly obese humans. Leptin hit the news headlines because, when it was injected into these mice their weight returned to normal).

Diabesity in Psammomys provides a unique opportunity for molecular biology research in the hunt for Type 2 diabetes and obesity genes. (The term "Diabesity " is used to link the common metabolic backgrounds of obesity and diabetes.) Polymorphisms and mutations discovered in this animal model can be the basis of the search in obese human individuals and populations. Potential new and exciting opportunities exist with a better understanding of the physiological role not only of leptin but also of the newly discovered "beacon" gene reported by Zinatf et al 2000 at Deakin University, Melbourne, Australia. The product of this novel gene, discovered in obese Psammoys, increases food consumption and body weight in animal studies. The combination of beacon protein with neuropeptide Y (NPY) has an even greater effect on appetite and weight. Beacon, leptin, NPY, and other hypothalamic genes, and their receptors and pathways have become important targets in the area of phamacogenetics for drug discovery and will play an important role in the more rational treatment of obesity, the Type 2 diabetes, and the Metabolic syndrome.

The discovery of the nuclear receptor PPAR (peroxisome proliferator activated receptor) and its role in fat metabolism and insulin sensitivity provide important clues concerning the pathogenesis of diabetes. (Peroxisomes are subcellular organelles that contain oxidising enzymes called peroxidases.) The creation of a new class of drug, the thiazolidinediones, that act through this receptor, has been an added new agent to the treatment of Type 2 diabetes (Auwerex J 1999).

There are three family members of the PPAR: PPAR-gamma, PPAR-alpha and PPAR-delta. Each is thought to have unique as well as some overlapping biological roles. The natural ligands, or activators of these receptors are fatty acids derivatives.

PPAR-gamma was first identified as a part of a transcriptional complex essential in adipocyte differentiation. The key role of PPAR-gamma is in adipogenesis, the process by which adipocytes differentiate from precursor cells or adipoblasts. Mice that have defective gene for PPAR-gamma have absent adipose tissue. The case for involvement of PPAR-gamma in adipogenesis has been strengthened by the report of a gain of function mutation in three human subjects with severe obesity. PPAR-gamma is also involved in modulating insulin sensitivity, and two human families with severe insulin-reacted diabetes and early-onset hypertension have recently been shown to have a loss of function mutations. Thus this receptor would appear to be potentially important in the pathogenesis of diabetes (Willson T M et al 2000). In contrast, PPAR-alpha, the first PPAR to be identified, had been thought to play primarily a role in fatty acid metabolism, in particular in beta oxidation, with expression previously thought to be primarily in the liver.

Given the role of PPAR-alpha and PPAR-gamma in adipogenesis and lipid metabolism as well as the activity of PPAR against insulin-sensitizer and lipid-altering drugs, PPARs have received attention as possible critical components of the insulin resistance syndrome (also known as syndrome X and the cardiovascular metabolic syndrome) and as pathways involved in the powerful association between diabetes and atherosclerotic vascular disease. The evidence continues to mount implicating PPARs as important in determining vascular responses through direct effects on cells present within the vessel wall. The potential for PPARs as the key transcriptional regulators in the insulin resistance syndrome is underscored by recent data suggesting that mutation in PPAR-gamma caused insulin resistance among 2 different kindred (Marx N et al 2000).

Gestational diabetes (GDM) mellitus results from the womans inability to mount sufficient insulin secretion to compensate for the increased nutritional needs of gestation, the increased adiposity of pregnancy, and the anti-insulin hormones, specifically human placental lactogen, prolactin, cortisol and progesterone. In normal pregnancy, the insulin secretory response increases up to 4-fold to compensate for the diabetic forces of pregnancy. Women who were either small-for-dates at birth or large-for-dates at birth are at increased risk for gestational diabetes. In addition, if height is reflection of size at birth, it has been shown that both very short women and very tall women are also at risk of gestational diabetes, reflecting the result of the intrauterine environment and subsequent pancreatic exhaustion. Gestational diabetes is thus a metabolic status similar to Type 2 diabetes. When the insulin resistance is not counterbalanced by the pancreatic ability to secrete insulin, hyperglycaemia develops.

Gestational diabetes mellitus is defined as glucose intolerance or diabetes mellitus diagnosed for the first time during pregnancy. There is convincing evidence that mild maternal hyperglycaemia is a risk factor for foetal morbidity (Kjos SL, Buchanan TA 2000). Because diabetes can have serious consequences for the foetus as well as mother, it is now routine for the obstetrician to test for GDM as soon as the diagnosis of pregnancy is made. 24 to 28 weeks of pregnancy is the optimal time for screening for GDM because at this time its frequency peaks and there is still sufficient time for appropriate therapy. This screening test consists of a 50-gram oral glucose load without regard to time of the last meal or the time of the day, followed by a blood glucose test one hour later. If the 1-hour serum glucose level is more than 140 mg, a 100-gram pregnancy oral glucose tolerance test is performed (Naylor C D et al 1997).

The normal upper limit of fasting serum glucose in pregnancy is 105 mg / dl. To diagnose GDM, two or more of blood sugar levels after a 100-gram oral glucose load must exceed the following values:

Sample 1 Fasting 105 mg/ dl

Sample 2 1 Hour 190 mg/ dl

Sample 3 2 hours 165 mg/ dl

Sample 4 3 Hours 145 mg/ dl

Type 2 diabetes shares several risk factors with atheroscleorosis. Markers of inflammation are a risk factor for atheroscleorosis and now Davis TME et al (1999) have shown that they are also associated with increased risk of Type2 diabetes.

A cohort of 12330 men and women aged 45-64 was recruited in 1987-89 and followed for 7 years, during which 1335 developed diabetes. Raised white cell count, low serum albumin, and raised fibrinogen each increased the risk of diabetes by 20 to 90%. In a subgroup of 610 subjects, raised concentrations of orosomucoid and of sialic acid increased the risk 8- and 4-fold. After adjustment for BMI and waist-hip ratio only the associations with white cell count, orosomucoid, and sialic acid remained significant.

A total of 3776 patients aged 25-65 with newly diagnosed Type 2 diabetes were followed up for an average of 8 years. Ninety-nine developed a stroke. The risk of stroke was related to age. Other risk factors were male sex (63% increase), hypertension (15% increase), and atrial fibrillation (eight-fold increase). Obesity, smoking, lack of exercise, poor diabetes control, dyslipidaemia and microalbuminuria were not significantly related to stroke risk.

These workers conclude that that anti-hypertensive therapy and anticoagulants for atrial fibrillation are the main measures to prevent strokes in these patients.

Metabolism in man is regulated by complex hormonal signals and substrate interactions, and for many years the focus has centered on the metabolic and hormonal picture after an overnight fast. More recently, the post-prandial state, (i.e. the period that comprises and follows a meal), has received more attention (Lefebvre PJ, Scheen AJ 1999).

India is the country with the largest number of people with diabetes. It is estimated that 19 million cases occurred in India in 1995, rising to a projected 57 million by the year 2025 (one-sixth of the world total).

The rapid increase in diabetes prevalence can already be seen in India. According to recent epidemiological studies there has been a 40 % increase in diabetes prevalence amongst urban Indians during the last five years.

Considering the magnitude of the population, the number likely to suffer from morbidity due the condition is very high. Studies also show that southern Indians have an increased risk of diabetes through inheritance as well as through the changes in dietary habits and less physical activity as a result of urbanisation and modernisation. Likewise, recent studies indicate that the prevalence of Type 1 diabetes in India is also increasing (Shera AS, Etu-Seppala L 1999). According to recent studies the prevalence of micro- and macro-vascular complications in Indian people with diabetes is high.

One out of every 12 Indians above the age of 40 is a diabetic. Type 2 diabetes mellitus usually has an onset in adult life, but unlike Europeans in whom it usually occurs above 50 years, in Indians it starts even by 20 or 30 years of age (Ahuja MMS 1997).

It appears that Indians have a genetic susceptibility to develop Type 2 diabetes. The high prevalence of impaired glucose tolerance (IGT) suggests the presence of a pool of susceptibility, which becomes exposed, when they migrate and achieve improved socio-economic status.

The incidence of Type I diabetes in Bangalore district urban, South India is about 1.68%, 100,000 a year with mortality of 2.33%. The age group most commonly affected is between 5 and 9 years. Diabetes ketoacidosis is the most common cause of death (Mala D etal 2000).

Dyslipidaemia including low HDL is highly prevalent in Asian Indians, especially females with Type 2 diabetes and other coronary risk factors (hyperinsulinaemia, hypertension, hyperglycaemia etc) are likely to account for the very high burden of coronary heart disease and mortality. The premature menopause, and oestrogen replacement therapy are some of the other risk factors in females.

Increased albumin excretion is common in Type 2 diabetes Indian patients at diagnosis and may occur without associated risk factors and other microvascular complications (Arvind SR et al 2000). Syndrome X appears to be more common among South Indian women than men. The presence of severe peripheral neuropathy in Type 2 diabetes indirectly indicates the presence of cardiovascular neuropathy and therefore these patients are at a increased risk of sudden cardiac death (Godbole SA et al 1997).

Recently Baker et al reported that babies born at term, but lighter than expected, have health problems such as diabetes and heart disease later on in life. This newly described association between poor intrauterine growth and adult diabetes may be particularly relevant in India.

Proper isolation and identification of organisms and use of appropriate therapeutic agents can be of great value in the management of diabetic foot lesions (Sathe SR et al 1997).

The Western Indian population behaves differently in its manifestations of tropical pancreatitis and malnutrition related diabetes as compared to classical features as described in South India. Abdominal pain predominates. The overall prognosis was good in the Western Indian population (Joshi SR et al 1997). Malnutrition related diabetes mellitus (MRDM) comprises 35% of the diabetic population in Calcutta. Impotency was detected in 30% of male diabetics (Majumdar A, Ganguly D 1997). Retinopathy and nephropathy occurs in initial 5 years.

Indian women with polycystic ovary syndrome (PCOS) suffer diabetic metabolic syndrome, even though a large proportions are non-obese. High prevalence of parenteral hyperglycaemia suggests that the insulin resistance in PCOS may be familial (Sardesai SB, Shelgikar KM, Coyagi K et al 1997).

The metabolic control and complications are not different in lacto-vegetarians and non-vegetarians groups in Type 2 diabetes urban patients in Western India. Thus equal efforts are required to improve control and minimise complication in both groups.

Though yoga interventions tend to induce beneficial effects in Type 2 diabetes patients, the significance will have to be proved by more randomised trials (Simha V et al 1997).

The impediments to the effective diabetic care in India include patients perception that diabetes is curable, diabetic tablets and insulin are addictive to the body and faith in alternative system of medicine (Goenka S et al 1997). Only a small fraction (approx 2.5%) of Indian patients with diabetes are taking allopathic medications (Pardeep G, Talwalkar GV et al 1997). The dual task of identifying undiagnosed and untreated persons with diabetes and providing with appropriate medications need to be tackled on a war footing.

Awareness about diabetes mellitus and its complications in diabetic population coupled with better management and health care facilities have significantly reduced the occurrence of severe diabetic ketoacidosis (DKA) in the western diabetic population. However, it is still encountered quite frequently in Indians due to illiteracy, poverty and poor health care facilities. This is reflected in the finding of 14 episodes of DKA per 100 of Type 1 diabetes cases in India. DKA is a major preventable cause of death in diabetic population.

The ADA-revised criteria for diagnosis are:

• Typical symptoms of diabetes - polydipsia, polyuria, and unexplained weight loss - plus a casual serum glucose level greater than 200 mg/dl - "casual" meaning any random glucose obtained at any time of the day without respect or non-fasting.
• A fasting serum glucose greater than or equal to 126 mg/dl after no caloric intake for at least 8 hours.
• Two hours serum glucose greater than or equal to 200 mg/dl during a 75-gram oral glucose tolerance test is also diagnostic of diabetes.

Any of these initial findings confirmed on a subsequent day can be considered as diagnostic of diabetes, and any combination of the findings can be used for confirmation. For example, a physician may observe a casual serum glucose greater than 200 mg/dl in a patient with symptoms of diabetes on one day, and subsequently document a fasting serum glucose greater than 126 mg/dl on another day. This satisfies the requirement for confirmation by repeat testing.

The ADAs new criteria for diagnosing diabetes mellitus de-emphasize the glucose tolerance test and favour diagnosis by fasting serum glucose.

• Imagawa A et al (2000). A novel subtype type of Type 1 diabetes mellitus characterised by a rapid onset and an absence of diabetic related antibodies. N Engl J Med 342: 301-307

• Larsen JL, Ratansuwan T, Lynch G et al (2000). Carotid intima media thickness (IMT) decreases after pancreas transplantation (PTX). Program and abstracts of the 60^th Scientific Sessions of the American Diabetes Association, June 9-13,2000,San Antonio, Texas, Abstract 121-OR
• Robertson RP, Kendall DM, Sutherland DER et al 2(000). Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Program and abstracts of the 60^th Scientific Sessions of the American Diabetic Association, June 9-13,2000, San Antonio, Texas, Abstract 126-OR
• Shapiro AMJ, Lakey JRT, Ryan E et al (2000). Metabolic control after insulin dependence in solitary islet transplantation for type 1 diabetes mellitus, Program and abstracts of the 60^th Scientific Sessions of the American Diabetic Association, June 9-13,2000, San Antonio, Texas, .abstract 124-OR
• Thoren B (2000) Engineering tolerance into transplanted beta cells, Presented at the 6^th Sessions of American Diabetes Association. June 12 2000. San Antonio, Texas.

• Pinhas-Hamiel O, Dolan LM, Standford DS et al (1996). Increasing incidence of non-insulin-dependent diabetes mellitus in children and adolescents. J Pediatr 128: 608-615

• Hoppener JO, Ahren BO, Lips CJM (2000). Islet amyloid and Type 2 diabetes mellitus . N Engl J Med 343: 411-419

• Shepherd PR, Kahn BB (1999). Mechanisms of disease: Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248-257

• Zimmet P (2000). Diabetes and obesity world wide epidemic in full flight. Paper presented at the 60^th Scientific Sessions of the American Diabetes Association June 10,2000, San Antonio, Texas

• Auwrex J (1999). PPAR-gamma, the ultimate thrifty gene. Diabetologica 42: 1033-1049
• Marx N et al (2000). Perooxisome prolifertator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of T-cell active CXC chemokines IP-10, Mig, and I -TAC in human endothelial cells. J Immunol 164: 6503-6508
• Willson TM (2000). The PPARs: from orphan receptors to drug discovery. J Med Chem 43:1527-550

• Baker DJ (1999). Foetal origins of cardiovascular disease. Ann Med 31 (suppl) 3-6
• Gluckman PD, Harding JE (1999). Foetal growth retardation: underlying endocrine mechanisms and postnatal sequences. Acta Pediatr 422 (suppl) 69-72

• Kjos SL, Buchanon TA (1999). Current Concepts: Gestational diabetes mellitus N Engl J Med 341: 1749-1756
• Naylor CD, et al (1997). Selection Screening for gestational diabellitus, N Engl J Med 337: 1591-1596.

• Davis TME et al (1999). Risk factors for stroke in Type 2 diabetes mellitus, Arch Intern Med 1999: 159:1097-1103.

• Lefebvre PJ, ScheenAJ (1999). The postprandial state and the risk of cardiovascular diseases. Diab Metab 15 (supp 4) S 63- S 68