Letter to editor: Malnutrition-related diabetes mellitus: Rushing toward "type 5" amid unresolved questions and limited evidence.

Genetic studies of Malnutrition related diabetes are few. We have analyzed HLA class II gene polymorphism in different types of diabetes mellitus patients from Cuttack in Eastern India. Patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and malnutrition-related diabetes mellitus (MRDM), which is subdivided into protein-deficient diabetes mellitus (PDDM) and fibrocalculous pancreatic diabetes (FCPD), were studied and their associations with autoantibody markers. IDDM and PDDM were associated with DR3 and DQ2 but not DR4 and DQ8. FCPD was positively associated with DQ9 (A*0201-B*0303). The association of DQ9 with FCPD suggests differences in the genetic background for susceptibility between IDDM and MRDM in the Cuttack population. There is no association seen between HLA-DR-DQ and NIDDM patients from Eastern India. Clinical classification of diabetes into IDDM, NIDDM and MRDM does not identify the underlying pathological mechanisms. Presence of autoantibodies to IDDM autoantigens in clinical MRDM and NIDDM identifies the slow-onset form of IDDM. Due to the absence of autoantibody assays for diagnosis of IDDM in India, slow onset IDDM is not diagnosed and the patients are classified as NIDDM or MRDM. Our study demonstrates that the presence of GAD65 antibody and DR3-DQ2 positivity in MRDM and NIDDM patients in Eastern India would suggest the presence of slow-onset IDDM. Our data would indicate alternatively that MRDM can coexist with IDDM in these patients and malnutrition could be one of the reasons for the slower onset in IDDM-prone individuals.

Immunogenetic and nutritional profile in insulin-using youth-onset diabetics in Korea

Obesity and increased dietary intake of high fat are considered important factors involved in the development of type 2 diabetes, as they correlate to the prevalence of diabetes in different populations and are both associated with insulin resistance, which is an important pathogenic event for diabetes (1,2). However, epidemiological studies have shown that diabetes is common also in populations where obesity is not a major concern for health (3). In fact, in some developing countries, the prevalence of diabetes exceeds that of more developed countries, as, for example, has been shown in studies in Bangladesh (4) and India (5). The question of whether also malnutrition is detrimental for glucose metabolism and may contribute to the development of diabetes has therefore been raised. This would also be supported by clinical studies showing distinct and specific clinical characteristics of diabetes in malnourished subjects when compared to nonmalnourished subjects, such as early age of onset, requirement of insulin to control hyperglycemia in conjunction with ketosis resistance in the absence of insulin therapy, and the presence of pancreatic calculi, in addition to the clinical manifestations of malnutrition (6–9). Based on these epidemiological and clinical observations, WHO recognized, in 1985, malnutrition-related diabetes mellitus (MRDM) as a special subtype of diabetes, different from type 1 (IDDM) and type 2 diabetes (NIDDM) (6). However, using malnutrition in the classification of diabetes has been questioned, because malnutrition has also been considered to be a mere coincidence with diabetes, which exaggerates or modulates the clinical feature of the disease (10,11). In fact, several arguments have been put forward against the use of MRDM as a distinct entity of diabetes. One argument is that it has not been convincingly demonstrated that malnutrition results in permanent diabetes and another argument is that the classification of diabetes into type 1 or type 2 relies on clinical aspects, not pathogenesis (6,10). In addition, malnutrition by itself is a vague condition that is difficult to define, as it is usually assessed by combined interpretation of data from the dietary history, anthropometric data, clinical examination, and laboratory investigations without strict criteria. Malnutrition is also inhomogeneous, because it includes both single and combined nutrient deficiencies as well as global energy deficiency. Moreover, the clinical characteristics thought to be specific for MRDM may also be identified in diabetic subjects without a history of malnutrition (10,12). Therefore, the new classification system of the American Diabetes Association does not consider MRDM a distinct entity of diabetes (11). Instead, fibrocalculus pancreatic diabetes (FCPD), being a former subgroup of MRDM, has been classified as an exocrine pancreatic disease, and protein-deficient diabetes mellitus (PDDM) is considered a condition modulating the clinical features of existing diabetes. Nevertheless, apart from the issue of classification, the role of malnutrition on glucose homeostasis remains elusive and needs further studies to designate it as a modulating factor in diabetes. As previously reviewed by Rao (7), malnutrition may cause diabetes as a priInternational Journal of Pancreatology, vol. 26, no. 3, 125–130, December 1999 © Copyright 1999 by Humana Press Inc. All rights of any nature whatsoever reserved. 0169-4197/99/26:125–130/$11.50

Malnutrition-related diabetes mellitus: Rushing toward "type 5" amid unresolved questions and limited evidence.

Undernutrition is a preeminent feature of the two major clinical syndromes, protein dependent diabetes mellitus (PDDM) and fibrocalculous pancreatic diabetes (FCPD) that has been grouped together under the term malnutrition related diabetes mellitus (MRDM).[l] Although, MRDM represents only a few percent of the world population suffering from diabetes, it is a major health problem within developing countries. Investigation of these forms of the disease indicates that a genetic predisposition cannot be clearly established, and several hypotheses related to dietary-deficiency and environmental chemical exposure have been proposed. Oxidative stress induced by oxygen free radicals has been implicated in the pathogenesis of many human diseases in recent years.[2] It is becoming increasingly plausible that antioxidant deficiency leading to the exposure of pancreatic B-cells to increased oxidative stress may be implicated in the aetiology and pathogenesis of MRDM. increased oxidative stress (a high prooxidant/antioxidant ratio) which is based on evidence of increased lipid peroxidation and reduced antioxidant reserve.[3] A deficiency in the nutritional supply and availibility of antioxidants which may occur in MRDM may have consequences in terms of failure of the first line of defence against oxygen radical induced damage.[4] The aim of the study was to assess the antioxidant status and levels of oxidative stress and DNA damage in malnourished patients displaying PDDM (n=24), FCPD (n=14), non-insulin dependent diabetes mellitus (NIDDM) (n=46), and age matched controls (n=67). All diabetic patients were under 30 years and newly diagnosed to avoid complicating variables such as insulin therapy and control subjects were matched for age, BMI and socioeconomic status. Plasma vitamins A, C, and E were measured by HPLC [5,6], whilst antioxidant enzymes in red cell concentrate were measured on the Cobas Fara autoanalyser[7-10]. DNA damage within nucleated blood cells was measured using a sensitive ELISA.[11]

Thirty Ethiopian malnutrition-related diabetes mellitus (MRDM) patients were HLA typed and their HLA antigen frequencies were compared to those of 31 previously typed insulin-dependent diabetes mellitus (IDDM) patients and to 84 controls from the same ethnic background. In comparison to controls, a striking association between MRDM and HLA-DR3 (X2 = 15.15, p = 0.0001) was observed, whereas the frequency of HLA-DR4 was non-significantly increased (RR = 1.72). The frequency of DR2, DQw1, and DQw6 was decreased among MRDM. In comparison to IDDM that is associated with both DR3 and DR4 in this population, MRDM showed no significant differences in HLA class II antigens frequencies. Therefore, the genetic basis of susceptibility to MRDM and IDMM in Ethiopia is at least partially identical.

High frequency of autonomic as well as peripheral neuropathy in patients with malnutrition-related diabetes mellitus

Some diabetics in the Tropics are young undernourished and ketosis resistant at presentation yet require high doses of insulin for control from onset suggesting insulin resistance. They usually have histories suggestive of past childhood malnutrition. WHO categorized them as malnutrition-related diabetes mellitus (MRDM) taking into account the preceding and presenting protein energy malnutrition (PEM). PEM has been reported to cause insulin deficiency and glucose intolerance as well as insulin resistance. However the PEM preceding the onset of diabetes is hardly ever documented in such cases and hence is open to question. PEM at presentation with diabetes which is frequently documented can result to some extent from uncontrolled hyperglycaemia and hence is also found in Type 1 and Type 2 diabetics. Thus the identification of young insulin requiring ketosis resistant diabetics as MRDM is difficult and sometimes doubted. In this context we are reporting three diabetic children =5 years old who in addition to strong ketosis resistance and high insulin requirement had documented PEM which preceded and was unrelated to diabetes. (excerpt)

Malnutrition Related Diabetes Mellitus (MRDM), a separate clinical class of diabetes mellitus recognized by WHO Study Group on Diabetes Mellitus in 1985 exhibits peculiar metabolic characteristic of ketosis resistance. To explore the role of cortisol and growth hormone in the development of ketosis resistance, a cross sectional study was carried out involving 21 newly diagnosed MRDM patients, 19 NIDDM patients, and 16 age matched non-diabetic control at BIRDEM, Dhaka. MRDM patients presented with significantly lower Body Mass Index (P<0.001) and significantly higher level of serum glucose (P<0.001) in comparison to NIDDM and control subjects. The mean serum cortisol was significantly higher in MRDM and NIDDM subjects compared to that of control (P<0.05). Therefore, regarding cortisol, MRDM patients behave exactly like NIDDM patients The serum growth hormone levels were similar in MRDM, NIDDM and control subjects. So it can be suggested from the study that cortisol and growth hormone may not play any significant role in the development of ketosis resistance in MRDM patients. doi: 10.3329/taj.v18i1.3295 TAJ 2005; 18(1): 5-9

The profile of diabetes mellitus seen in the developing countries differs from that seen in the developed world with regards to clinical, genetic and etiological features. Type 1 or insulin-dependent diabetes mellitus (type 1 DM or IDDM) and type 2 or non-insulin-dependent diabetes mellitus (type 2 DM or NIDDM) are the most common forms of diabetes encountered in the developing countries1. A distinct form of diabetes mellitus with characteristic features of malnutrition with or without pancreatic damage termed malnutrition-related diabetes mellitus (MRDM) is peculiar to tropical countries and is a relatively uncommon cause of diabetes mellitus. Even though MRDM has been frequently reported from the Indian subcontinent, it accounts for less than 1% of all diabetics2 MRDM with clinical features, which are different from the type 1 and 2 DM had generated a lot of controversies, and its study has helped in better understanding of the pathogenesis of diabetes mellitus. Economic constraints of the developing countries have important implications in management policies for diabetic children.

Malnutrition related diabetes mellitus (MRDM) is rare type of diabetes associated with long term malnutrition and is not uncommon in India. Diabetes mellitus is the most common endocrine disorder of multifactorial aetiology and has been linked to both chronic under nutrition and obesity. Malnutrition is often related to deficient micro and macro nutrients, unhealthy behaviours and low socioeconomic status. Various clinical studies have underlined the relationship between malnutrition and diabetes mellitus. In the present review, we mainly explored malnutrition related diabetes mellitus in Indian population. Maternal under nutrition during pregnancy causes a decrease in the fetal intrauterine development rate known as intrauterine growth retardation (IUGR). Malnutrition majorly causes persistent insulin deficiency, glucose intolerance and insulin resistance and there by increases the risk of diabetes in Indian population. In this study we have also discussed the pathogenesis of MRDM and their management like self- dietary management and evidence based individualized nutritional therapy.

Cases of malnutrition-related diabetes mellitus conforming to the description of the protein deficient pancreatic diabetes type in Ethiopian patients were compared with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic. Fourteen of 39 malnutrition-related diabetes mellitus patients had fat malabsorption compared with only two of ten Type 1 diabetic patients and one of nine control subjects. Xylose absorption was normal favouring a pancreatic cause for the malabsorption. Plasma C-peptide during oral glucose tolerance test was significantly lower than that in Type 2 diabetic patients and normal control subjects (p less than 0.01 to 0.001) and was also consistently but not significantly higher than in Type 1 diabetic patients. Glucagon secretion patterns were similar in malnutrition-related and Type 1 diabetic patients. Of 23 new malnutrition-related diabetic patients treated with glibenclamide after nutritional rehabilitation and insulin treatment, only three responded, 14 were unresponsive but remained ketosis free for over eight days while another six developed ketoacidosis or significant ketonuria within two to six days during the trial. Sixteen unselected Type 1 diabetic patients who discontinued their insulin therapy all developed frank ketoacidosis after a mean of 5.5 days. The similarity of the malnutrition-related and Type 1 diabetes mellitus in age of onset, insulin requirement for diabetic control and appearance of ketosis-proneness in some cases, together with the similarity of C-peptide and glucagon secretion patterns suggest that the protein deficient pancreatic diabetes variant of malnutrition-related diabetes mellitus may be Type 1 diabetes mellitus modified by the background of malnutrition rather than an aetiologically separate entity.(ABSTRACT TRUNCATED AT 250 WORDS)

To compare the pancreatic exocrine and beta-cell function in the two variants of malnutrition-related diabetes mellitus (MRDM): fibrocalculous pancreatic diabetes (FCPD) and protein-deficient pancreatic diabetes (PDPD). Fecal chymotrypsin (FCT) and fasting C-peptide levels were measured in 20 consecutive patients with FCPD and 19 with PDPD. FCPD was diagnosed by pancreatic calcification on ultrasonography, while the diagnosis of PDPD was made on the basis of low body mass index, severe diabetes requiring insulin therapy, and ketosis resistance on interruption of insulin. Twenty patients with type I diabetes and 32 healthy subjects served as control subjects. Both FCPD and PDPD patients had diminished levels of FCT when compared with those of control subjects and patients with type I diabetes. However, FCT levels were significantly lower in subjects with FCPD (median 0.4 U/g, range 0-8.9 U/g), in comparison with those with PDPD (4.7 U/g, 0.6-40.5 U/g; P < 0.001). Of the FCPD patients, 13 of 20 (65%) had severe exocrine pancreatic deficiency (FCT < 1 U/g) vs. 3 of 19 (15.8%) PDPD subjects (P < 0.01). In comparison with control subjects, fasting serum C-peptide levels were significantly diminished in both MRDM groups. However, C-peptide levels in subjects with FCPD (mean +/- SE, 0.22 +/- 0.04 nmol/l) and PDPD (0.26 +/- 0.04 nmol/l) were comparable. Among the two variants of MRDM, subjects with FCPD have severe pancreatic exocrine deficiency in comparison with those with PDPD, even though their C-peptide levels are comparably diminished. This suggests that the pathogenesis of these two entities may differ or that the genetic and/or environmental factors leading to exocrine damage are different.

Background: Malnutrition-Related Diabetes Mellitus (MRDM) formerly called “Tropical Diabetes” is a rare type of diabetes mellitus (DM), associated with long-term malnutrition. Objective: To create awareness about this rare disease in the phase of a dwindling global economy and the need for a more focused screening in vulnerable groups. Methodology: We reviewed the case records of the patient in terms of clinical presentation, imaging and laboratory parameters. Case Summary: A 19-year-old destitute male, resident in a rural-community in Nigeria, presenting with abdominal pains for 6 months, bilateral leg swelling for 5 months and lower limbs paresthesia for a month. He was diagnosed with DM a year previously, took insulin for a month, thereafter resorted to herbal remedies due to financial constraints, but later left home to beg in the streets due to hunger. Examination: Chronically-ill looking, markedly dehydrated and pale, with fluffy and pluckable hairs, peripheral oedema, multiple oral ulcers and bilateral parotid fullness. Weight was 35kg, height 1.65m and BMI was 12.9 kg/m2.Laboratory parameters: Marked glycosuria, absent ketonuria, beside random blood glucose (RBG) was unrecordably high (&gt; 33 mmol/L), laboratory RBG was 63mmol/L, normal E/U/Cr and lipid profile, HbA1c of 13.8%, elevated alanine transaminase, low total serum proteins and albumin. Abdominal USS revealed normal-sized pancreas with diffuse echogenicity and multiple faint calculi. Plain abdominal x-rays showed multiple pancreatic calculi. A diagnosis of MRDM, fibro-calculous pancreatic (FCPD) type was made. Treatment: Insulin, antibiotics, anti-neuropathic drugs, high-calorie/high-protein diet were given, with good clinical improvement within two months. Conclusion: Regular screening for MRDM in vulnerable groups will allow early detection and treatment of affected individuals.

Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes. State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy. The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D. These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.