• Amiodarone is an iodine rich drug having a benzofuranic derivative with the structural formula closely resembling thyroxine and is one of the commonest causes of drug-induced thyroid dysfunction. 15-20 % of patients on amiodarone develop thyroid dysfunction in the form of either amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT).
• Amiodarone has a very long plasma half-life (60-142 days). In addition, its liposolubility leads to prolonged storage in fat and muscle tissue.Amiodarone has an active metabolite N-desethylamiodarone (DEA), whose half-life is longer than that of Amiodarone. All these factors lead to the persistence of the adverse effects long after discontinuation of the drug.
• In presence of high iodine load, because of Wolff-Chaikoff effect, inhibition of organification is observed resulting in reduced synthesis of T3 and T4. Subsequently, there is escape from the Wolf-Chaikoff effect with normalisation of thyroid hormone synthesis. However, failure to escape from the Wolff- Chaikoff effect results in hypothyroidism.
• On the other hand, some patients exhibit the opposite of Wolff – Chaikoff effect which is called the “Jod – Basedow phenomenon. Here, instead of reduction of thyroid hormone synthesis, the thyroid gland escapes the physiologic negative feedback mechanism of the Wolf-Chaikoff and actually produces inappropriately high levels of thyroid hormone leading to hyperthyroidism.

  Amiodarone-induced hypothyroidism (AIH)

  • AIH is more common than AIT.
  • Women are more prone to develop AIH with a female: male ratio of 1.5:1
  • The hypothyroidism may be subclinical (TSH levels between upper reference value and 10 mU/L, normal FT4 levels) or overt (serum TSH > 10 mU/L, low FT4 levels). The subclinical form is more common, occurring in about 26% of amiodarone treated patients, as opposed to overt hypothyroidism occurring in 5 %.
  • In about 60% of AIH, the hypothyroidism is transient, resolving on its own 2 to 4 months after stoppage of amiodarone.
  • Similar to overt hypothyroidism from other causes, AIH can be treated with levothyroxine. Subclinical hypothyroidism may not need treatment, especially in the elderly, given their propensity for cardiovascular events.

  Amiodarone-induced thyrotoxicosis (AIT)

  • AIT is commoner in males (0.4% females: 3.9 – 8.5% males)
  • Clinical manifestations of AIT can vary from an asymptomatic presentation unearthed on routine follow-up of biochemical tests to typical hyperthyroid symptoms like unexplained weight loss, palpitations, excessive sweating and heat intolerance.
  • It is to be noted that the β-blocker-like property of amiodarone may mask the autonomic symptoms of tremor, excessive sweating and tachycardia.
  • Recurrence of previously controlled atrial and/or ventricular tachyarrhythmias or symptoms suggestive of them like palpitations, episodic light-headedness and syncope, is one of the commonest presenting clinical features.
  • There are two forms of AIT – AIT 1 and AIT 2.
  • Attempt to distinguish between AIT 1 & AIT 2 should be made right at the beginning from history, physical examination and investigations.
  • It is useful to remember that AIT1 behaves like Graves disease and AIT2 like thyroiditis
  • On many occasions, it may be difficult to distinguish between AIT 1 and AIT 2.
  • It is important to point out that characteristics of both AIT1 and AIT2 may coexist giving rise to a mixed form of AIT, and on occasions,mixed/indefinite AIT often represents an exclusion diagnosis.
  • Table 1 highlights the important differences between AIT 1 and AIT 2.
  • Figure 1 depicts the treatment algorithm of AIT treatment
  • The iodine replete thyroid gland is less responsive to thionamides (carbimazole, methimazole, propylthiouracil) and hence higher doses (40-60 mg methimazole or equivalent doses of propylthiouracil) for longer than usual duration may be needed to achieve euthyroidism.
  • 

  • Figure 1.  Algorithm of treatment of amiodarone induced thyrotoxicosis

    

    Source:

    1. Source: 2. Bartalena L, Bogazzi F, Chiovato L, Hubalewska-Dydejczyk A, Links TP, Vanderpump M :2018 European Thyroid Association (ETA) guidelines for the management of amiodarone-associated thyroid dysfunction..Eur Thyroid J. 2018;7:55–66
    1. Ylli D, Wartofsky L, Burman KD: Evaluation and treatment of amiodarone-induced thyroid disorders. J Clin Endocrinol Metab. 2021;106:226–236.
    2. Elnaggar MN, Jbeili K, Nik-Hussin N, Kozhippally M, Pappachan JM. Amiodarone-Induced Thyroid Dysfunction: A Clinical Update.Exp Clin Endocrinol Diabetes. 2018 Jun;126(6):333-341.

* Maturity-Onset Diabetes of the Young (MODY) typically presents in children and young adults, resulting from a single-gene mutation that disrupts the function of pancreatic beta cells.

* Inheritance: autosomal dominant.

* Prevalence: 1-2% of all diabetes cases.

* Features:

- Early Onset: Usually diagnosed during adolescence or early adulthood.

-Family History: Diabetes through multiple generations.

 -Absence of Autoimmunity.

 -Absence of Insulin Resistance.

-Mild Hyperglycaemia.

* Diagnosis: By genetic testing.

* Most common subtypes:

* MODY 3 (Mutation in the HNF1α gene): The most common, making up 50-70% of cases.

* Features-Progressive beta-cell failure and pronounced sensitivity to sulfonylureas. Often managed by low-dose SU.

* MODY 2 (Mutation in the GCK gene): The second most common, accounting for 30-50% of cases.

* Features -Mild, stable fasting hyperglycaemia from birth, with a slight rise after eating. Often found by a flat OGTT curve during pregnancy. Complications are rare. Usually, no treatment is needed except during pregnancy.

* MODY 1 (HNF4α-MODY): Rare, less than 5-10% of MODY cases.

* Features- progressive diabetes and good response to sulfonylureas.

* MODY 5 (HNF1β-MODY): Is associated with renal cysts, pancreatic problems, genital tract abnormalities, and gout. Insulin is often needed early, as sulfonylureas are less effective.

* Conclusion:

* Consider genetic testing for MODY in young, non-obese patients with a strong family history of diabetes, especially those who are autoantibody-negative or have atypical features.

* A correct diagnosis of MODY transforms management, improves quality of life, and enables predictive testing for at-risk relatives.

* Misdiagnosing MODY as type 1 diabetes condemns a patient to lifelong, unnecessary insulin injections. Misdiagnosing it as type 2 diabetes may lead to ineffective treatments like metformin when a simple, low-dose sulfonylurea could provide perfect control.

Malnutrition-Related Diabetes Mellitus (MRDM) is a rare form of diabetes, closely linked to chronic malnutrition and specific pancreatic damage

MRDM is found almost exclusively in low- and middle-income tropical countries, such as:

• Sub-Saharan Africa
• South and Southeast Asia (including India and Bangladesh)
• Latin America
• Papua New Guinea

It is especially prevalent in populations where poverty, food insecurity, and repeated famines are common.

The condition usually affects young people—often under 30 years old—and is seen more frequently in males.

Pathophysiology: Is not fully understood, but it seems to result from an interaction between chronic malnutrition and exposure to certain dietary toxins.

• Chronic Malnutrition: Long-term protein and micronutrient deficiencies damage the pancreatic beta cells, reducing insulin production.
• Dietary Toxins: Foods like cassava can release cyanide if not prepared properly. Chronic, low-level exposure to cyanide is believed to damage pancreatic cells.
• Insulin Deficiency and Resistance: People with MRDM have significant insulin deficiency, and some degree of insulin resistance, likely due to their body's adaptation to starvation.
• Historically, MRDM was divided into two types:
• Fibro calculous Pancreatic Diabetes (FCPD): The main form, marked by pancreatic duct calcifications and stones, leading to tissue destruction and scarring.
• Protein-Deficient Pancreatic Diabetes (PDPD): Characterized by severe protein deficiency and malnutrition, but without pancreatic calcification.

WHO (1985) diagnostic criteria:

• Onset before age 30
• Past malnutrition or low BMI
• Need for insulin therapy
• No ketosis despite low insulin

Management:

1. Nutritional support: Correcting malnutrition with a high-calorie, high-protein diet is essential, alongside insulin therapy to avoid complications like refeeding syndrome.
2. Most patients need insulin, though their requirements may be low due to sensitivity.
3. Metformin can be used if insulin resistance is significant.
4. Pancreatic enzyme supplements and rarely surgery for patients with severe pain and large pancreatic stones.

Sir Fredrick Banting , 5th child of parents of British Northern Irish origin, Canadian born Orthopedic surgeon, was trying to set up his own practice in his home town (Ontario)..post First World War, 1914 to 1918,where he fought for the Canadian army.from 1916 to 1918.He.obtained enormous experience in surgery in the battle field..suffered injuries himself with wounds which took months to heal.

Anyway with no luck in private practice, he took up a job as a demonstrator in Western Ontario Hospital , where something struck him while preparing an article on the pancreas. He rushed to their research team, who then referred him to University of Toronto to the lab of a Scottish physiologist, John Mcleod..who provided him a space and an assistant Charles Best(a student of Biochemistry/Medicine, having some experience working in that lab).
Banting’s surgical skill helped to keep the pancreactomised dogs  remain alive after surgery long enough to receive the pancreatic extract. The extract (often called ‘thick brown muck’ by their colleagues)was isolated and injected into these dogs.  to demonstrate its effect on blood sugar.Charles Best’s tedious job was to draw the blood and to check blood sugar levels at regular intervals and to keep  records meticulously!..ProfessorMcleod was initially sceptic, but he straightened up a little bit when he returned from summer holidays in Scotland in 1921 and asked them to present their data in the journal club. Banting’s tenure was soon tofinish.and he could only continue his research with no pay. However, another researcher came forward to support him, of course, still under the patronage of Professor John Mcleod, who, by this time was more or less convinced. The longest survival in a dog reached 70 days. This  was considered the first landmark in the history of discovery of insulin.
James Collip, a biochemist was called to join the team to purify this extract for a safe use on humans.
January 11,1922, 14 year old Leonard Thompson , dying from diabetic ketoacidosis, received the first purified pancreatic extract . an allergic reaction with the first dose was followed by second dose on January 23. Leonard’s life was saved!. This was the second landmark in the history of discovery of insulin.
University of Toronto called the pharmaceutical company Elli Lilly &Co to manufacture this product at a larger scale for a bigger human trial.
In recognition with their work, Frederick Banting and John Macleod were awarded Nobel Prize in Medicine and physiology in 1923, which they shared with Best and Collip, respectively.

Frederick Banting was knighted in 1934. He joined Royal Canadian Army again in the Second World War .Sir Frederick Banting died in a plane crash in Feb 21,1941 in the coast of Newfoundland, Canada.

Thanks to Carbon dating and gene testing of the excavated earthenwares and teeth of domesticated animals, that enabled us to obtain ideas about dietary patterns of olden days.
Ancient Indian civilisation has never observed vegetarian diet and except Jainism , no other religion has ever mandated vegetarianism.It was only after the Kalinga war, when Ashoka, the Mauryan king put a ban on the killing of animals, many civilians, including upper caste Hindus adopted vegetarianism in a large scale.Mr B R Ambedkar, in a commentary, once mentioned that Brahmins gave up eating beef to restore and maintain their social prestige.Jain merchants played a vital role in India’s economic development between 9th and 14th centuries and are thought to be instrumental in promoting vegetarianism among other Indians(particularly south Indians).
Free communal kitchens in Gurdwaras(Langar) serve only vegetarian meals.Many Sufis are vegetarian as their personal choice.
Currently 30% of 1.4 billion Indians(Highest in the world) are vegetarian.Our average per capita meat consumption per annum is only 5kg as opposed to 80kg in the west…but certainly’Hindu meal’ in the international air lines is a misnomer!

OTHER CULTS
Ancient Greek philosopher, Pythagoras was a strong proponent of vegetarianism (abstention from meat, fish and beans), which he connected to personal spiritual belief of transmigration of souls.He had many followers.In fact, vegetarianism in the west until Roman era was popularly known as Pythagorian diet.

In China, vegetarianism became common after introduction of Buddhism and Daoist ascetism from 1CE, again mainly from Imperial influences, particularly among monks and nuns and not from Buddhist Precepts(Like King Ashoka in India).

Vegetarianism has roots in Judaism, since the Torah’s first diet in Eden was plant-based. While eating meat is permitted under kosher laws, many Jewish teachings emphasize compassion for animals (tza’arba’aleichayim), avoiding waste (baltashchit), and health. Some Jews see vegetarianism as a return to the Edenic ideal and a way to live Jewish values of kindness, responsibility, and care for creation.Prominent Jewish writer like Franz Kafka and the 10th Israeli Prime minister , Reuven Rivlin
were among many other vegetarian eminent people of Jewish origin.

In short, vegetarianism grew out of the concept of compassion, love for animals, purity of souls across all races, globally at different times.In India, there was also significant geo-political influence, additionally, for its expansion in such a large scale.

Type 1 diabetes (Type 1D) is a condition where beta cells of pancreas are destroyed by an autoimmune process and patients need insulin for survival and control of diabetes.  Our general understanding is that it has a short or, quick process of development, but research has shown that the process of development of Type1D is much longer, spreading over months to years, and is divided in to several stages. Current research is focused on (1)  identifying subjects who are at high risk of developing the disease and (2) monitoring such patients closely to prevent complications. American Diabetes Association, in consultation with JDRF and Endocrine Society has emphasized on the importance of monitoring subjects who are IA-2 antibody positive.

In this short article we will discuss some salient features of Type 1 Diabetes and its stages.

Age of Onset: Although Type 1D can manifest at any age, most cases develop in children and adolescents, aged 4-14 years. It has also been observed that age of onset has a direct bearing on the course of the disease – earlier the onset, more severe is the disease.

Genetics: While nine out of ten patients with Type 1D do not have a positive family history of diabetes, recent researches have shown that some families have high prevalence of Type 1D. With a positive family history of Type 1 diabetes, the chance of developing Type 1D is very high, nearly 15 times more.

The Autoantibodies: -

The following five antibodies have been identified in patients with Type 1D: -

• GAD-65: glutamic acid decarboxylase 65 autoantibody
• IA-2A: insulinoma-associated protein 2 autoantibody
• ZnT8: zinc transporter 8 autoantibody
• IAA: insulin autoantibodies
• ICA: islet cell autoantibodies

There is no definite order of appearance of the antibodies, but most patients have two or more of the above antibodies.

The Stages: -

Stage 1: During this stage, patients have no symptoms. Blood sugar level is normal, but blood screening shows presence of two or more autoantibodies.

Stage 2: During this stage, patients have no symptoms, but blood sugar level start rising. Antibodies are present in blood.

Stage 3: During this stage, patients have one or more of 4T symptoms (Tiredness, Thinness – weight loss, Toilet – frequency of urination and Thirst). Blood sugar level is further high and antibodies are present. In most cases, clinical diagnosis is made at this stage and many patients present in ER with diabetic ketoacidosis (DKA).

Benefit of screening: -

1. Significant reduction of incidence of DKA: There are multiple benefits of screening and identifying people in the early stage of the disease. TrialNet, a National Institute of Arthritis, Diabetes and Kidney disease (NIADDK, a units of NIH) funded program has screened about 200,000 relatives of Type 1D patients. They have opened nearly 200 sites for screening across the world. Over the last two decades, TrialNet program has shown that the risk of DKA at diagnosis has reduced from 30 percent to only four percent for those who participated in the program. This was possible because trial participants were frequently monitored for development of dysglycemia, and when detected they were treated with insulin and monitoring continued. Such patients rarely developed DKA, in contrast to patients whose diagnosis manifests with DKA. It is important to note that Type 1D patients who are diagnosed with DKA have much worse prognosis than those who are not.
2. Disease Modifying Therapy: As many patients can be identified in Stage 1 or, in Stage 2, medicines to stop or, delay progression to next stage can be attempted. One such drug, teplizumab, has been approved by USFDA for delaying progression of Type 1D.

Another drug, baricitinib, given daily over 48 weeks to Stage 2 Type 1D patients, showed good control of diabetes in clinical trial.

Several other drugs are in clinical trials with the ultimate objective of cure of Type 1 diabetes.

1. Prevention Strategy: There is strong evidence that there are many environmental factors involved in triggering the autoimmune attack on the islet beta cells of pancreas. An Australian study, Environmental Determinants of Islet Autoimmunity (ENDIA study) have found that Enteroviruses are involved in triggering autoimmunity in many cases. An effective strategy to neutralize the triggering mechanism can abate the attack.

The ultimate objective of all these researches is to create a world free of Type 1 diabetes.