CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, FACP,Director, Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in. Co-authors: Dr. Vaibhav Agnihotri, (DCH, DNB (Pediatrics), Fellowship Neonatology (IAP), PGPN, Boston, PCBD USA), Jaipur; Dr. Leena Singh, MBBS, DCH, Lecturer, PMCH, Dept. of Pathology, Dhanbad; Dr. Richa Agnihotri, MBBS, DGO, DNB (Obs & Gynae), FGES (lap surgeon), Jaipur.

Abstract

At present, most common endocrine condition found in children and young adults is type 1 diabetes. There have been amazing advances in the understanding of type 1 diabetes and new techniques have brought smile, still we are far from optimal goal of achieving HbA1c.

It is now well established that improved blood glucose leads to reduction of the increased morbidity. But another formidable fact is that cardiovascular-renal risk management is lagging far behind.

Approach to type 1 diabetes needs meticulous planning and proper DSME (Diabetes self-monitoring education).So far, a cure is not in sight. Lifelong insulin injections are the cornerstone in management. The inter play of insulin pens, insulin pumps, continuous glucose monitoring, hybrid closed-loop systems, social and political factors are not sufficient to prevent occurrence of complications. A basic approach to counterbalance all odd factors is the most needed modality. By new targets of immunotherapies, islet-cell transplant and new techniques scientific world is expected to win the battle.

Introduction

“True, it is a fight, but there is pleasure in the struggle. Victory comes to the courageous; and without courage and common sense, success awaits no one. I look upon the diabetic as charioteer and his chariot as drawn by three steeds named Diet, Insulin, and Exercise. It takes skill to drive one horse, intelligence to manage a team of two, but a man must be a very good teamster who can get all three to pull together.”- Joslin, 1933[1]

Joslin statement in 1933 is a testimony to the fact that type 1 diabetes poses a unique burden. It is interplay of adjusting complex medication regimens,  behavioral and social modifications and  need of considerable  knowledge and skill so that patient can  navigate between hyper- and hypoglycemia.

Understanding why and how beta cells fail

Many studies are being conducted to understand the etiology of type 1 diabetes. From T cell-mediated autoimmune disease notion which still holds true , now a role of beta cells that goes beyond being a non-provoking victim of an autoimmune attack, is on horizon. The role of autoantibodies in destruction of beta cells is not clear. It is mystery that why some β-cells resist or escape the immune attack and why  new β-cells are formed.

New concept considers that it is not a single autoimmune disorder. It is thought to result from a complex interplay between environmental factors and microbiome, genome, metabolism and immune system.

Still the working understanding is that T-cell-mediated destruction of  beta cells occurs. There is evidence that biomarkers of type 1 diabetes-associated autoimmunity are found months to years before symptom onset. This fact has been applied to identify the individuals who are at risk to develop diabetes. [2]

Table 1

Some interesting facts about environmental and genetic factors [3,4]
There is also genetic component in Type 1 DM.Monozygotic twins – 60% life time concordance for developing T1DM.Dizygotic twins – 8% life time concordance for developing T1DM.
DR3 expression – Also risk for developing other autoimmune endocrinopathies and celiac disease.
DR4 expression-Usually younger, more likely to have positive antibodies, unlikely to have other autoimmune endocrinopathies.
Both   DR3 and DR4 expression- Greatest risk of type 1 diabetes, have characteristics of both the DR3 and DR4 groups.
Viral infections may be the most important environmental factor in the development of type 1 diabetes.
 No single factor has been identified, but infections and diet are considered the two most likely environmental candidates.
Paradoxically, type 1 diabetes mellitus incidence is higher in areas where the overall burden of infectious disease is lower.
Breastfed infants have a lower risk for type 1 diabetes.Direct relationship is observed between per capita cow’s milk consumption and the incidence of diabetes. Some cow’s milk proteins (e.g., bovine serum albumin) have antigenic similarities to an islet cell antigen.
Smoked foods and some water supplies having Nitrosamines, chemicals are known to cause type 1 diabetes mellitus in animal models only.No definite link has been made with humans. No definite link has been established with Persistent Organic Pollutants.
The known association of increasing incidence of type 1 diabetes mellitus with distance from the equator is interesting.It may be due to reduced exposure to ultraviolet (UV) light and lower vitamin D levels.
Early probiotic use and islet autoimmunity in infants predisposed to T1DM. New data from the multinational Environmental Determinants of Diabetes in the Young (TEDDY) study suggests. Probiotic supplementation before the age of 3 months in infants with type 1 diabetes (DM1)–associated HLA-DR-DQ alleles is linked to a reduction in the risk.
Although the incidence rates tend to be similar between boys and girls, it has been observed that the peak for girls precedes that for boys.
The incidence is highest in Scandinavian countries, followed by European countries (such as the United Kingdom), North America and Australia.  In Asian countries — such as China, Korea and Japan — T1DM is a rare disease.
The prevalence of diabetes in India is variable, and three sets of data show 17.93 cases/100,000 children in Karnataka, 3.2 cases/100,000 children in Chennai, and 10.2 cases/100,000 children in Karnal (Haryana).

The honeymoon period in Type 1 diabetes is possible. At diagnosis,15-40% of beta cell function remains as suggested by DCCT, Medalist studies, T1D Exchange and TrialNet. Beta cells function can serve the patient well till honeymoon period lasts. Prolonging the honeymoon is under intense research. It has been found that immunotherapy works. Cyclosporine experience from the 80s is still valid but requires continuous immunosuppression and not all respond.

Staging of the disease

Three stages help to understand the course of the disease, standardising taxonomy and helping in research. Stage 1 consists of autoimmunity, normoglycemia and presymptomatic. Stage 2 consists of autoimmunity,dysglycemia (IFG and /or IGT) and presymtomatic. Stage 3 consists of new-onset hyperglycaemia and is symptomatic. Now stage 4 is stated as long-standing type 1 diabetes.

Approach and Diagnosis of type 1 diabetes is not straightforward in many cases

It is a herculean task to diagnose especially when it occurs in adults. In adults if the history of diabetes is very short it baffles and can be diagnosed as type 2 diabetes. Another big issue is to differentiate it from monogenic diabetes. Although clinical presentations differ widely but gold standard is the classical triad of the thirst, polydipsia and polyurea. It is very important to understand that an accurate diagnosis opens a new door for assessment of the risk of diabetes in the first-degree relatives for appropriate counselling and to take measures to prevent or delay the onset of diabetes. Many times, type 1 diabetes is misclassified and over 40% of that developing diabetes after age of 30, have been found to be treated as type 2 diabetes. As no single clinical feature confirms type 1 diabetes, a proper history and approach is very much needed. We seldom require a glucose tolerance test. In atypical cases and in very early disease when plasma glucose values may be normal or mildly abnormal, it can be done. [5] It is worth to remember that these patients are prone to other autoimmune disorders (like, Hashimoto thyroiditis, Graves’ disease, Celiac disease, Addison disease, Vitiligo, Autoimmune hepatitis, Myasthenia gravis and Pernicious anaemia)

Table 2 – Type 1 diabetes diagnosis is a challenge (4)  

100% predictive value of islet autoantibodies has not been found
High C-peptide at diagnosis may be found
More type 1 diabetes people are developing obesity
Many type 2 diabetes cases are detected at younger age
Only a minority of cases with type 1 diabetes presents with DKA
DKA can occur in type 2 ketosis prone cases
Monogenic forms can disguise
Type 1 diabetes may be found in older people and islet autoantibodies in the older people do not equate type 2 diabetes

What investigations make a difference?

Role of Islet auto-antibodies and C-peptide

It is important that Glutamic Acid Decarboxylase (GAD) is the primary antibody measured. But if we suspect a case as type 1 diabetes and GAD is negative it should be followed by islet tyrosine phosphatase 2 (IA2) and/or Zinc transporter 8 (ZNT8) where available. Now Islet cell antibody (ICA) measurement is no longer recommended by ADA. The significance of the presence of one or more positive islet autoantibodies is in regard to prediction of highly rapid progression. It denotes severe insulin deficiency. But the absence of autoantibodies does not exclude type 1 diabetes. Approximately 5 to 10% of type 1 diabetes patients have negative islet antibodies. So, if there is clinical suspicion of type 1 diabetes, insulin must be started.

Table 3 – Diagnostic Pearls [4]

ADA Diagnostic Criteria:

In patients with classic symptoms, blood glucose measurement is sufficient to diagnose diabetes (symptoms of hyperglycemia or hyperglycemic crisis and random plasma glucose ≥200 mg/dL.)

Fasting plasma glucose (FPG) ≥126 mg/dL

In asymptomatic children and adolescents at high risk for diabetes, if FPG ≥126 mg/dL if 2-hr PG ≥200 mg/dL, or if Hb1Ac ≥6.5%, testing should be repeated on a separate day to confirm the diagnosis.
Try to achieve HbA1c target of less than 7.5%, but it should be individualized.
Hypoglycemia: Tackling Rule of 15 – Glucose (15 g) is preferred treatment for conscious individuals with hypoglycemia (blood glucose < 70 mg/dL) If glucose not available, any form of carbohydrate may be used.

Repeat self-monitoring blood glucose 15 minutes after treatment, if shows hypoglycemia, give 15 gm glucose.

When blood glucose concentration returns to normal, consider a meal or snack and/or reduce insulin to prevent recurrence of hypoglycemia.
Measure TSH when the patient is clinically stable or once glycemic control has been established.

Even the first TSH report is normal, suggest rechecking every 1-2 years.

Consider testing for anti-thyroid peroxidase and antithyroglobulin antibodies soon after diagnosis.
Do screen children for celiac disease by measuring IgA tissue transglutaminase antibodies.

Autoantibodies and disease correlation

The high prevalence of autoantibodies in type 1 diabetes helps in predicting natural history, disease prediction in high-risk cases. It is used for diagnostics and prognostics too.[6]

Table 4 – Unique Facts with Autoantibodies in Type 1 diabetes [6,7]

Indian studies

Shiva prasad et al.: GAD antibody was present in 64.7%, IA2 antibody in 19.3%, and ZnT8 antibody is present in 31.8%. Antibody positivity may reach up to 80% with inclusion of ZnT8 antibody.(2014)

Basu et al: Anti‑GAD antibody was found to be the commonest (79.3%) followed by IAA (63%), and ZnT8 antibody was found to be positive in only 20.65% in this study (2020)

Bhatia et al.: 45% recent onset T1DM were negative for GADA and IA2A(2003)

Valam Puthussery Vipin et al.(SGPGI-Lucknow): The prevalence of GADA, IA-2A, and ZnT8A was 53%, 34%, and 29% respectively, while IAA (measured in 61 patients) was detected in 31%. All four antibodies were absent in 17 of 61 (28%) patient (2020)    
Some Unique Facts

IAA (Insulin Autoantibodies) – First to appear. IAA is common in young children. It may be associated with fulminant course due to total destruction of β cells and complete insulin deficiency with rapid onset of T1DM.

IA-2 are very specific for the development of T1D.

GAD and IAA are most frequent antibodies in childhood.

GADA is the hallmark of adult-onset T1D.

ZnT8A is more frequent in recent onset young (≤10 years) with acute-onset T1D, but it decreases with increasing duration of T1DM.

Although GADA is most common and most persistent IA in T1DM, it peaks later, being more common in older children and adolescent with T1DM and LADA. It suggests more persistent but less intense autoimmune process.

High level of multiple autoantibodies (mAbs) especially at earlier age is associated with loss of beta cell mass and progression to overt T1DM, thus predictive of early onset T1DM  

C peptide is an important test and a persistent C-peptide >600 pmol/L tells strong possibility of type 2 diabetes. Getting a low or absent C-peptide, confirms the diagnosis of type 1 diabetes.

In 2021, we must consider molecular genetic testing for neonatal diabetes for neonatal diabetes in those cases of type 1 diabetes who got diagnosed under 6 months of age regardless of the age of the patient.

Thyroid function tests and antithyroid antibodies should be tested. It is of high probability that type 1 diabetes cases may have undiagnosed thyroid disease which may interfere with diabetes management. Hypothyroid children have typically reduced insulin requirements and tendency to increased episodes of hypoglycemia while hyperthyroid cases have increased insulin needs and tendency to have hyperglycemia.

Screening children for celiac disease by measuring IgA tissue transglutaminase antibodies is another important consideration which in routine practice is usually missed. Positive antigliadin antibodies, especially specific antibodies (e.g., antiendomysial, antitransglutaminase) are important risk markers. A jejunal biopsy is required to confirm or refute a diagnosis of celiac disease once positive antigliadin antibody is detected as the individual should remain on a gluten-free diet for life once celiac disease is confirmed.

Monitoring Issues

In type 1 diabetes we need to know glycemic variability and hypoglycemia occurrence. HbA1c has been found inappropriate as the only method of glucose evaluation. Self-Monitoring blood glucose (SMBG) metrics are important in real life setting to guide insulin dosage, food intake and prevention of hypoglycemia with exercise. 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 as per ADA.

Continuous glucose monitoring (CGM) devices have changed the landscape of Type 1 diabetes management. CGM should be considered in children and adolescents with type 1 diabetes, especially if they are using injections or continuous subcutaneous insulin infusion. This should be used as an additional tool to help improve glycemic control. At present Time in Range (TIR) metric appears important but will not replace HbA1c. ADA has recommended TIR as an important glucose measure in 2021 update. Maintaining TIR above 70% should be the goal.

Currently, two types of CGM devices are available-(1) real-time CGM (rt CGM) (2) intermittently scanned CGM (is CGM). New data is in favor of rt-CGM as it improves HbA1c and reduces hypoglycemia when used with either insulin pumps or multiple injections. [8]

Table 5 – ADA: Position statement on type 1 diabetes in children and adolescents [4]

Consult a pediatric endocrinologist before diagnosing type 1 diabetes when isolated glycosuria or hyperglycemia is discovered in patients with acute illness in the absence of classic symptoms
Differentiating type 1 diabetes, type 2 diabetes, monogenic diabetes, and other forms of diabetes is based on patient history and characteristics, as well as on laboratory tests, such as an islet autoantibody panel
The majority of children with type 1 diabetes should be treated with intensive insulin regimens using multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion
HbA1c should be measured every 3 months
Blood glucose levels should be monitored up to 6-10 times daily
Continuous glucose monitors (CGM) should be considered in all children and adolescents with type 1 diabetes; the benefits of CGM correlate with adherence to ongoing use of the device
Blood or urine ketone levels should be monitored in children with type 1 diabetes in the presence of prolonged/severe hyperglycemia or acute illness
Individualized medical nutrition therapy is recommended for children and adolescents
Exercise is recommended, with a goal of 60 minutes a day of moderate to vigorous aerobic activity, along with vigorous muscle-strengthening and bone-strengthening activities at least 3 days a week
It is important to frequently monitor glucose before, during, and after exercise (with or without CGM use) to prevent, detect, and treat hypoglycemia and hyperglycemia
All individuals with type 1 diabetes should have access to an uninterrupted supply of insulin; lack of access and insulin omissions are major causes of diabetic ketoacidosis
Glucagon should be prescribed for all individuals with type 1 diabetes, and caregivers or family members should be instructed regarding administration
Once the child has had diabetes for 5 years, annual screening for albuminuria, using a random spot urine sample (morning sample preferred to avoid effects of exercise) to assess the albumin-to-creatinine ratio, should be considered at puberty or at age greater than 10 years, whichever occurs earlier
Once the youth has had diabetes for 3-5 years, an initial dilated and comprehensive eye examination is recommended at age 10 years or after puberty has started, whichever is earlier, and an annual routine follow-up is generally recommended
For adolescents who have had type 1 diabetes for 5 years, consider an annual comprehensive foot exam at the start of puberty or at age 10 years, whichever is earlier
Blood pressure should be measured at each routine visit; children who have high-normal blood pressure (systolic blood pressure [SBP] or diastolic blood pressure [DBP] at 90th percentile for age, sex, and height) or hypertension (SBP or DBP at 95th percentile for age, sex, and height) should have blood pressure confirmed on 3 separate days
Initial treatment of high-normal blood pressure (SBP or DBP consistently at the 90th percentile for age, sex, and height) includes dietary modification and increased exercise for weight control; if target blood pressure is not reached within 3-6 months after lifestyle intervention, consider pharmacologic treatment
Because of their potential teratogenic effects, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should be considered for initial pharmacologic treatment of hypertension after reproductive counseling
The blood pressure treatment goal is consistently less than the 90th percentile for age, sex, and height
If low-density lipoprotein (LDL) cholesterol is within an acceptable risk level < 100 mg/dL, a lipid profile every 3-5 years is reasonable
If lipid levels are abnormal, initial therapy should consist of optimizing glucose control and initiating a Step 2 American Heart Association diet (restricting saturated fat to 7% of total calories and dietary cholesterol to 200 mg/day)
After age 10 years, consider adding a statin if, despite 6 months of medical nutrition therapy and lifestyle changes, LDL cholesterol remains greater than 160 mg/dL or LDL cholesterol remains greater than 130 mg/dL with one or more cardiovascular disease (CVD) risk factors present (after reproductive counseling because of the potential teratogenic effects of statins)
The LDL therapy goal is less than 100 mg/dL

Management strategies: Need to adapt new therapies and technologies

Dietary management is very important.

Carbohydrates should provide 50-55% of daily intake (10% from sucrose or other refined carbohydrates). Fat should provide 30-33% of daily energy intake and protein should provide 10-15%. Medical nutrition therapy provided by a qualified dietitian has been found with a reduction of HbA1c by 1.0-1.9%. No one eating pattern has been recommended.

Exercise is boon

Exercise is a neglected but one of the most important aspect of management. A combination of aerobic and resistance exercise on most days has numerous benefits. [9]

Table 6 – Benefits of Exercise [9]

Improved fitness
Increased insulin sensitivity leading to reduced insulin requirement
Improved cardiovascular health with better lipid profile and endothelial function
Decreased mortality 
Improvement in HbA1c
Reduced risk of microvascular complications, osteoporosis, and cancer in people with type 1 diabetes Helps maintain a healthy BMI and promotes sleep quality and mental wellbeing

Exercise-induced Hypoglycemia

It is a major hurdle in type1 diabetes. It is due to rapid increase in glucose uptake and Insulin sensitivity which is known to persist for up to 48 hours following exercise. To prevent exercise induced hypoglycaemia proper education  must be given such as withholding pre-exercise insulin, increasing carbohydrate intake during or following exercise and reducing basal or night time insulin.

Insulin therapy

In type 1 diabetes management proper insulin regimen selection is the key to success of therapy. Choosing basal insulin to restrain glucogenesis and ketogenesis in the pre-prandial state is the one aspect. The patient needs mealtime insulin to cover the intake of carbohydrate. To match the physiological kinetics of Insulin, either multiple daily injections (MDI) of subcutaneous basal insulin analogues and meal time rapid-acting insulin analogues is considered the best option. Another way is to use continuous insulin infusion of a rapid acting insulin analogue via a pump, delivered as continuous basal insulin combined with manual mealtime boluses.

At present time clearly Insulin analogues are considered the insulins of choice as these may reduce hypoglycemia and achieve better mealtime coverage. [10]

Ultra-rapid analogues have not been shown to reduce HbA1c or hypoglycemia to a greater extent than rapid-acting analogues. In spite of all emerging science in favor of insulin analogues, a great barrier of cost prevails. No wonder, subcutaneous regimens of human regular insulin and NPH insulin or premixed insulin dominate as preferred choice worldwide.

Cardiovascular disease(CVD) Issues

It is more common in T1 diabetes cases than non-diabetes cases. It occurs 10-15 years earlier in patients with T1. Subclinical markers of CVD in T1 diabetes are- 1.Higher coronary artery calcium scores 2.Increased CIMT and plaque 3.Endothelial dysfunction and 4.Cardiac autonomic neuropathy.

If patient is obese, weight loss is needed. Avoiding hypoglycaemia and appropriate glycaemic control is the key. If hypertensive, requires ACE/ARBs and BP control. Statin and other lipid lowering drugs might be needed.

Aspirin as a secondary prevention strategy has level A evidence and it may be considered as a primary prevention strategy in those who are at increased risk.

New agents such as SGLT2-inhibitors and GLP-1 RA have been not studied in paediatric group.

Adjunctive therapies

Metformin, Pramlintide, an amylin analogue (approved in USA), Glucagon like peptide-1 receptor agonists and Sodium-glucose co-transporter (SGLT) inhibitors are under intense interest due to desirable benefits. These drugs have limited effectiveness, hence must be individualized after optimizing insulin therapy. [11]

Table 7 – Emerging Adjunctive therapies in T1DM [11]

DrugHb1Ac reductionBodyweightHypoglycemiaSide effectsApproval Status EU/USSpecific Indications
Metformin0.1%Modest(1Kg)GastrointestinalWomen with polycystic disease
Pramlintide0.3%Modest(1kg)Potential increaseGastrointestinalFDA
SGLT2-i0.2-0.4%Moderate (2-3 kg)-Genital mycotic infections -Increase risk of DKAEU in low dose when BMI>27kg/m2
GLP-1-RA0.2-0.3%Significant(5kg) -GI -Increase in ketosis Overweight -Obesity -High Insulin dose -Risk of CVD and renal disease

Covid Pandemic and Type1 Diabetes

The incidence of may have increased over the past year in certain populations.  At present we have no sufficient data to state that SARS-CoV-2 infection is the direct cause. The increase in severe DKA at the time of diagnosis could be possibly directly linked. Nausea and vomiting with Covid may mask DKA onset and delay DKA diagnosis.

Newer avenues on horizon

Delaying the onset of diabetes

JDRF-funded TrailNet in 2019 showed that the monoclonal antibody Teplizumab is effective to delay the onset of type 1 diabetes. Half of the Teplizumab cohorts remained diabetes -free after 3 years, compared to 22% of placebo cohorts. It also reversed the loss of C-peptide, indicating improved beta cells function. Updated analysis in 2020 showed continued benefit. It extended median delay of stage 3 up to 32.5 months. Its disease modifying intervention led FDA approval in June 2021[11]

Islet cell transplantation

US FDA has now endorsed a pancreatic islet cell transplant therapy for the treatment for patients of type 1 diabetes. It can be offered to those patients who cannot managed with current therapies. It has potential for insulin independence and elimination of Hypoglycemia. Such patients will need life-term immunosuppression. [12]

Conclusion

A proper Approach to type 1 diabetes is essential to a disease for which no cure exists. In meticulously managed type 1 diabetics, longevity has now improved and there is no gloomy scenario.

 Now strong evidence points that in individual with certain combinations of genes and particular environmental influence leads to autoimmunity and initiates stages of type 1 diabetes.

With genomic sequencing and new insights prevention and cure might be possible in future. By stopping immune attack and getting new beta cells through death -defying insulin producing islets for transplantation, future may be exciting.

References:

  1. Joslin EP: The treatment of diabetes with diet and exercise. In Diabetic Manual for the Mutual Use of Doctor and Patient. 5th ed. Philadelphia, Pa., Lea & Rebiger, 1933, p. 100-120
  2. Roep, B.O., Thomaidou, S., van Tienhoven, R. et al. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat Rev Endocrinol.2021;17:150–161.
  3. Praveen PA, Madhu SV, Viswanathan M, Das S, Kakati S, Shah N, Chadha M, Bhadada SK, Kaur T, Dhaliwal RS, Das AK, Yajnik CS, Tandon N. Demographic and clinical profile of youth onset diabetes patients in India-Results from the baseline data of a clinic based registry of people with diabetes in India with young age at onset-[YDR-02]. Pediatr Diabetes. 2021 Feb;22(1):15-21. doi: 10.1111/pedi.12973. Epub 2020 Feb 6. PMID: 31885113.
  4. American Diabetes Association. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes 2021. Diabetes Care 2021;44(Suppl. 1): S152S33
  5. Thomas NJ, Lynam AL, Hill AV, Weedon MN, Shields BM, Oram RA, et al. Type 1 diabetes defined by severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes. Diabetologia. 2019 Jul;62(7):1167–72.
  6. Sanyal D. Current perspective on auto-antibodies in type 1 diabetes. Indian J Endocr Metab.2020 ;24:233-4.
  7. Basu M, Pandit K, Banerjee M, Mondal SA, Mukhopadhyay P, Ghosh S. Profile of auto‑antibodies (disease related and other) in children with type 1 diabetes. Indian J Endocr Metab 2020; 24:256-9.
  8. Beck RW, Bergenstal RM, Cheng P, Kollman C, Carlson AL, Johnson ML, et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c. J Diabetes Sci Technol. 2019 Jul;13(4):614–26.
  9. Wu N, Bredin SSD, Guan Y, Dickinson K, Kim DD, Chua Z, et al. Cardiovascular Health Benefits of Exercise Training in Persons Living with Type 1 Diabetes: A Systematic Review and Meta-Analysis. J Clin Med. 2019 Feb; 17:8(2).
  10. Danne T, Matsuhisa M, Sussebach C, Goyeau H, Lauand F, Niemoeller E, et al. Lower risk of severe hypoglycaemia with insulin glargine 300 U/mL versus glargine 100 U/mL in participants with type 1 diabetes: A meta-analysis of 6-month phase 3 clinical trials. Diabetes Obes Metab. 2020 Oct;22(10):1880–5.
  11. Chair, Richard I.G. Holt, Anne L. Peters.Management of Type 1 Diabetes in Adults—2021 Draft ADA/EASD Consensus Report. 81st Scientific Sessions. American Diabetes Association Virtual, June 25-29. 2021; Monday June 28th 2021: 5:30 PM – 7:30 PM.
  12. Chair, Jay S. Skyler. Implementing Type 1 Diabetes Immune Intervention in Clinical Practice. 81st Scientific Sessions.American Diabetes Association Virtual, June 25-29,2021; Saturday, June 26th:1:45 AM – 3:45 AM.


Preview - Untold Story of Fructose: Friend vs Foe
Read Next – Untold Story of Fructose: Friend vs Foe

Discover CME INDIA

Discover CME INDIA