CME INDIA Presentation by Dr. N.K. Singh, MD, FICP, Director, Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.

This presentation is based on the talk by Dr. N. K. Singh at APICON -2022, Jaipur on 14th April.

Facts worth Pondering

• Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas.
• Although onset frequently occurs in childhood, the disease can also develop in adults.
• Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person.
• This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans.
• These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

What we need to know about Genetics?

• Clear evidence: Monozygotic twins have a 60% lifetime concordance for developing type 1 diabetes mellitus
• The frequency of diabetes development in children with a mother who has diabetes is 2-3%; this figure increases to 5-6% for children with a father who has type 1 diabetes mellitus. The risk to children rises to almost 30% if both parents are diabetic.
• Human leukocyte antigen (HLA) class II molecules DR3 and DR4 are associated strongly with type 1 diabetes mellitus. More than 90% of whites with type 1 diabetes mellitus express 1 or both of these molecules, compared with 50-60% of the general population.

Be aware about Prediction Risk

• Patients expressing DR3 are also at risk for developing other autoimmune endocrinopathies and celiac disease.
• Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies.

Story with Covid now a new entry

Environmental Factors: Not more, not less?

• No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates.
• Viral infections may be the most important environmental factor in the development of type 1 diabetes mellitus, probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella.
• One survey suggests enteroviral infection during pregnancy carries an increased risk of type 1 diabetes mellitus in the offspring.
• Paradoxically, type 1 diabetes mellitus incidence is higher in areas where the overall burden of infectious disease is lower.

Probiotic Use and Type 1 Diabetes?

Dietary factors are also relevant

• Breastfed infants have a lower risk for type 1 diabetes.
• Some cow’s milk proteins (e.g., bovine serum albumin) have antigenic similarities to an islet cell antigen.
• Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause type 1 diabetes mellitus in animal models; however, no definite link has been made with humans.
• Persistent organic Pollutants: Emerging role.

Interesting: The known association of increasing incidence of type 1 diabetes mellitus with distance from the equator.

Staging of Type 1: Do it to delay it

Diagnostic Challenges

(API Medicine Update 2022)

What history matters the most?

Never miss DKA symptoms

Additional symptoms

• Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract.
• Candidiasis may develop, especially in the groin and in flexural areas.

Differential Diagnosis: Many times, no definite clues

Auto-antibody testing could be a mirage

Glutamic acid decarboxylase of 65 kDa (GAD65): Take-Aways

1. The first signs of beta-cell autoimmunity might appear already during the first year of life.
2. It is one of the major autoantigens for type 1 diabetes mellitus.
3. The predictive sensibility of GAD antibodies for type 1 DM in general population is approximately 50%.
4. Detection of GAD antibodies before clinical onset of diabetes provides evidence that these antibodies can be used as diagnostic and predictive tool for type 1 DM and latent autoimmune diabetes of adults

Islet cell antibody (ICA) measurement is no longer recommended

Do not miss to do Thyroid function tests and antithyroid antibodies

• In children with type 1 diabetes, consider testing for antithyroid peroxidase and antithyroglobulin antibodies soon after diagnosis.
• Measure TSH concentrations when the patient is clinically stable or once glycemic control has been established; if normal, suggest rechecking every 1-2 years (or sooner if the patient develops symptoms or signs that suggest thyroid dysfunction, thyromegaly, an abnormal growth rate, or unexplained glycemic variability).
• Because early hypothyroidism has few easily identifiable clinical signs in children, children with type 1 diabetes mellitus may have undiagnosed thyroid disease.
• Untreated thyroid disease may interfere with diabetes management.
• Typically, hypothyroid children present with reduced insulin requirements and increased episodes of hypoglycemia.
• Hyperthyroid children have increased insulin needs and a tendency toward hyperglycemia. Caution, therefore, is needed when initiating treatment as insulin requirements can change quite quickly.
• Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present). 
• Antithyroid antibody tests indicate the risk of present or potential thyroid disease.

Why and when to do Antigliadin antibodies?

ADA-2022 / 10 must know points

A higher HbA1c goal (in most cases below 7.5% is appropriate in the following contexts:

Best Advice You give to your Type 1 DM cases

Insulin is always required to treat type 1 diabetes mellitus.

• The majority of children and adolescents with type 1 diabetes should be treated with intensive insulin regimens, either via multiple daily injections or continuous subcutaneous insulin infusion.
• All children and adolescents with type 1 diabetes should self-monitor blood glucose levels multiple times daily, including premeal and prebedtime; as needed for safety in specific clinical situations, such as exercise or driving; and for symptoms of hypoglycemia.
• Continuous glucose monitoring should be considered in children and adolescents with type 1 diabetes, whether they are using injections or continuous subcutaneous insulin infusion, as an additional tool to help improve glycemic control; benefits of continuous glucose monitoring correlate with adherence to ongoing use of the device.
• Automated insulin delivery systems improve glycemic control and reduce hypoglycemia in adolescents and should be considered in adolescents with type 1 diabetes.
• Insulins lispro, glulisine, and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia.
• Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates.

Insulin Pump: A leap much Ahead

Artificial Pancreas

Insulin Replacement Not Always Sufficient for Glucose Control in T1DM

• Normal glucose regulation involves multiple hormones (e.g., insulin, glucagon, amylin, incretins) and multiple organ systems (e.g., pancreas, liver, stomach, brain)
• Insulin replacement therapy does not fully mimic the actions of insulin secreted by the pancreas in a healthy individual
• Insulin exposure in the liver is lower with replacement therapy than with natural production, resulting in inadequate suppression of endogenous glucose production.
• Higher doses of insulin are required to achieve sufficient suppression of endogenous glucose production, but these are associated with hypoglycemia and weight gain
• Pramlintide
  • FDA approved for T1 &T2
    • Human amylin analog with pharmacokinetic and pharmacodynamic properties similar to endogenous hormone.
  • Mechanism of action
    • Promotes satiety and reduces caloric intake
    • Slows gastric emptying
    • Inhibits inappropriately high postprandial glucagon secretion

Never Forget to assess CVD in T1 DM

GLP-1 receptor agonists in type 1 diabetes: a MAG1C bullet?

SGLT2 Inhibitor: Intelligent use, need of the time?

How Future is Unfolding 2022 onwards?

Exciting Future Indeed

Final Points

CME INDIA Tail Piece

Dr. Rajkamal Chaudhary, Asso. Prof. of Medicine, Bhagalpur:

• How is the Equator going to make our lives more prone to Diabetes? That means people who live near Equator are going to suffer less such as Africa, Kenya and so many. Kindly Explain if you have something secret to reveal.

Dr. N. K. Singh:

• No secrets
• Human observational studies indicate
• But no definite conclusion
• Studies corelate with vit D exposure
  • The incidence of T1D is positively related to distance north of the equator (i.e., the so-called North–South Gradient) (Karvonen et al. 2000).
  • In terms of extremes, T1D is uncommon in China, India, and Venezuela, where the incidence is only 0.1 per 100,000 per year (for review, see Maahs et al. 2010).
  • In contrast, the disorder is far more common in Finland, with recent incidence rates of more than 60 cases per 100,000 per year being noted, and to a slightly lesser degree, Sardinia, with rates approximating 40 per 100,000 per year. Rates of more than 20 cases per 100,000 per year are observed in Sweden, Norway, Portugal, Great Britain, Canada, and New Zealand (Vandewalle et al. 1997; Patterson et al. 2009; Maahs et al. 2010.
  • The highest incidence of T1D occurs in Finland and in Sardinia—the incidence is about 400 times higher than in Venezuela, a country located near the equator.
  • Low levels of Vitamin D may be associated with T1D because it is an autoimmune disease and Vitamin D plays a role in the development and functions of the immune system along with other functions in maintaining bone strength and the processes of inflammation.

References:

1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190;
   Brown L, et al. Sci Transl Med. 2010;2:27ps18; Lebovitz HE. Nat Rev Endocrinol. 2010;6:326-334.
2. Johansen NJ, Dejgaard TF, Lund A, et al. Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2020; published online March 2. https://doi.org/10.1016/S2213-8587(20)30030-9
3. Diabetes Obes Metab. Published online August 31, 2021. doi:10.1111/dom.14532
4. von Scholten et al (2021) Diabetologia DOI 10.1007/s00125-021-05398-3
5. https://drc.bmj.com/content/7/1/e000591
6. Seidu, X. Cos, S. Brunton, S.B. Harris, S.P.O. Jansson, M. Mata-Cases, A.M.J. Neijens, P. Topsever, K. Khunti,2022 update to the position statement by Primary Care Diabetes Europe: a disease state approach to the pharmacological management of type 2 diabetes in primary care,Primary Care Diabetes,2022,https://doi.org/10.1016/j.pcd.2022.02.002.
7. Are low sun exposure and/or vitamin D risk factors for type 1 diabetes?Photochem. Photobiol. Sci., 2017,16, 381-398
8. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia (2008) 51:1391–1398 DOI 10.1007/s00125-008-1061-5

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