Remission of Type 1 Diabetes with Sitagliptin and Vitamin D

Original Case by Marcelo Maia Pinheiro1, Felipe Moura Maia Pinheiro2 and Margareth Afonso Torres3[1] Pharmaceutical Assistance Center of the State of Mato Grosso, Cuiaba, Brazil[2] Faculdade de Medicina da Universidade de Cuiabá-UNIC, Cuiaba, Brazil [3] Laboratório Clinico do Hospital Israelita Albert Eistein, São Paulo, SP, Brazil

Patient #1 was a 20-year-old woman with a history of hypothyroidism due to Hashimoto’s thyroiditis treated since the age of 6 years with levothyroxine. In April 2012, she presented with weight loss, polyuria, polydipsia and leg cramps. Her physical examination was normal; she weighed 62 kg, had a body mass index (BMI) of 21.7 kg/m2 and blood pressure of 100/60 mmHg. She had a grandmother with Hashimoto’s thyroiditis and type 2 diabetes mellitus.

Q What percentage of type 1 diabetic have autoimmune thyroid disorder ?

  • 2-5% have overt hypothyroidism
  • 20% have Anti TPO positive

Q What is the effect of subclinical hypothyroidism in type 1 diabetes ?

  • Reduced linear growth
  • Increased risk of Hypoglycemia

Q How and when if TFT monitoring done in children with type 1 diabetes ?

  • At the time of diagnosis
  • If normal repeat every 1-2 years

Q What percentage of type 1 diabetics have celiac disease ?

  • 5%

Q What are concerns with celiac disease in type 1  ?

  • Risk of hypoglycemia
  • Poor linear growth
  • Poor bone accural

Q How is screening for celiac done in type 1 diabetics ?

  • At the time of diagnosis
  • Every 1-2 years after diagnosis
  • Use Anti TTG antibody – if positive then do Duodenal biopsy

Q Which HLA in type 1 has higher risk of autoimmune disease ?

  • HLA DR3 > HLA DR4

Q Enlist some other autoimmune disorder in type 1 diabetes ?

  • Autoimmune adrenalitis
  • APS type 2
  • IPEX syndrome

Patient #2 was a 21-year-old woman who presented in May 2011 with weight loss, polyuria, polydipsia and leg cramps. Her physical examination was normal; she weighed 62.5 kg, had a BMI of 19.5 kg/m2 and blood pressure of 115/70 mmHg. Her mother had Hashimoto’s thyroiditis, and her brother had Crohn’s disease

The diagnosis of diabetes mellitus was confirmed in patient #1 based on her serum glucose and HbA1c levels (Fig. 1 and Table 1). The patient’s anti-GAD antibody was positive (Fig. 2)

Q Enlist the antibodies associated with type 1 diabetes ?

  • GAD 65
  • Insulinoma associated antibody – IA-2 (also called ICA5-12)
  • Insulin autoantibody – IAA
  • Zinc transporter 8 antibody- Znt8

Q Antibodies are formed against which part of GAD65 ?

  • Carboxy terminal of GAD65 antibody

Q What is the other name of Insulinoma associated antibody 2  ?

  • ICA512

Q Tell me something about GAD65 antibody ?

  • Present in 70% of type 1 diabetics
  • Does not reduce with age- most common antibody to check in adults
  • Slowly developing diabetes
  • HLA-DR3 associated

Q Which is the antigenic main target in type 1 diabetes ?

  • The main target seems to be Beta chain of Insulin

Q Which is the first antibody to appear in type 1 diabetes  ?

  • IAA- insulin autoantibody is the first to appear

Q  If IAA is the first to appear, why does it not have more importance compared to GAD65 etc  ?

  • Any person given insulin can develop IAA antibody
  • Hence measurement of antibody anytime after 2 weeks after insulin injection will give a positive result

Q Which is often the last antibody to appear ?

  • Znt8
  • It disappears also first
  • IAA first à then GAD à then IA2 à Last ZnT8

Q Summarize the prevelance of various antibodies in type 1 diabetes ?

  • IAA – almost 100% – but not reliable marker
  • GAD65- 70%
  • IA-2 – 68%
  • Znt8 – 60-80%

Q What do Indian studies say about Antibodies in type 1 ?

  • South Indian study – GAD65 was present in 70% – just like west
  • Cuttuck Study- ICA512 was more common – in 43% , GAD65 only in 7%
  • Her HLA typing was DQA1*01:01, 03:01, DQB1*03:02, 05:01, DRB1*04:01, 10:01. Of note, the occurrence of the haplotype HLA-DQA1*03:01, −DQB1*03:02, −DRB1*04:01 is associated with an increased risk of T1DM.

Q What is the role of MHC ?

  • MHC carry the antigen on the surface of antigen presenting cells and activate the T cells

Q Which 2 haplotypes of HLA  confer the highest risk of type 1 diabetes ?

  • HLA DR3,DQB1*0201 – Also called HLA DR3- DQ2
  • HLA DR4,DQB1*0302 – also called HLA DR4-DQ8
  • 90% of type 1 have either of these two haplotypes
  • 30% have both !
  • The risk of type 1 diabetes is you carry either of these two haplotypes is 5% compared to 0.4 % in controls

Q Which HLA haplotypes protect from type 1 ?

  • HLADRB1*0403
  • HLADPB1*0402
  • Additionally HLA DQB1*0602 – also protective

In patient #2, the diagnosis of diabetes mellitus was also confirmed by serum glucose and HbA1c levels (Fig. 1 and Table 1). The patient’s anti-GAD antibody was positive (Fig. 2), her urinalysis revealed glycosuria without ketonuria, and her serum levels of lipids, BUN and creatinine were normal. Antithyroid antibodies measurement (Table 1) and thyroid ultrasound evaluation confirmed the diagnosis of Hashimoto’s thyroiditis with a normal TSH level (1.83 µIU/mL). Her HLA typing was DQA1*01:01, 01:01, DQB1*05:01, 05:01, DRB1*01:01, 01:01, which is not associated with an increased risk of T1DM.

Q How will you treat these patients ?

  • I would start both the patients on Basal-bolus insulin regimen.
  • I would start with 0.5 unit/kg of total insulin dose with 50% basal and 50% bolus.
  • I would also screen these patients for Celiac disease at baseline.

Patient #1 started treatment with insulin glargine 35 IU once a day and insulin lispro 2 IU before breakfast and 6 IU before lunch and dinner.

On May 2012, she started treatment with sitagliptin 100 mg/day and vitamin D3 5000 IU/day, and on June 6, 2012, she interrupted the administration of insulin.

Patient #2 started treatment with insulin glargine 20 IU once a day, and insulin glulisine 6 IU before breakfast, lunch and dinner. In July 2011, she experienced a honeymoon phase in which she used only insulin glargine 6–10 IU/day. Two months later, she resumed a basal-bolus regimen with the same initial doses. In March 2012, she was started on sitagliptin 100 mg/day and vitamin D3 5000 IU/day.

Both patients were duly informed that treatment of T1DM with sitagliptin and vitamin D3 was off-label and signed an informed consent form, accepting this treatment.

Q What is the objective definition of Honeymoon phase of Type 1 diabetes ?

  • Partial remission of honeymoon phase of type 1 diabetes is defined as follows:
  • HbA1c <6.0%
  • Insulin requirement
  • Stimulated C peptide >0.9 ng/ml

Q How long does the honeymoon phase last ?

  • It lasts for several weeks to months. It rarely lasts beyond 1 year.

Q What is the recommended dose of Vitamin D daily in adults ?

  • Recommended Daily allowance of Vitamin D is 600 IU /day
  • For those having Vitamin D deficiency, it is recommended to give 60,000 IU once a week for 8 weeks followed by 2000 IU once a day.

Patient #1 continues treatment with sitagliptin and vitamin D3. Since June 6, 2012, she has not used insulin and her levels of capillary glucose and serum fasting glucose, HbA1c and C-peptide remain normal (Fig. 1). In May 2014, her glucose levels, determined with a continuous glucose monitoring system (CGMS-72 h), confirmed the persistence of normal glucose values (Fig. 2).

Q Patient #1 has vitamin D levels of 22 ng/ml. According to Endocrine society guidelines, how will you classify her Vitamin D status ?

  • Vitamin D values between 20-29 ng/ml are classified as Vitamin D insufficiency.

Q How will you convert Vitamin D ng/ml to nmol/l ?

  • Vitamin D value of 1 ng/ml is 0.4 nmol/l

After 1 month of treatment with sitagliptin and vitamin D3, patient #2 started decreasing her insulin dose, and in March 2015, she interrupted the administration of insulin glargine. At the time of this report, she was only administering insulin glulisine 2–4 IU before breakfast, lunch and dinner when eating carbohydrates and she maintains use of sitagliptin and vitamin D3. She chose not to interrupt the use of insulin glulisine to maintain flexibility in her diet. She has been maintaining normal levels of capillary glucose, fasting blood glucose, HbA1c and C-peptide (Fig. 1). Results from her CGMS-72 h in May 2014 were normal (Fig. 2).

Both patients maintained normal serum levels of calcium and 25(OH) vitamin D. No side effects related to sitagliptin use have been reported by the patients.

Q Where does the evidence of vitamin D action in type 1 diabetes come from ?

  • Mainly from observation studies which have shown that vitamin D deficiency is associated with increased risk of diabetes

Case control studies have shown that vitamin D reduces risk of type 1 diabetes by 30%

  • However there are no RCT for use of vitamin D in type 1 diabetes
  • Genetic polymorphism in vitamin D has been associated with diabetes

Q How does vitamin D reduce risk of type 1 diabetes ?

  • Immune modulation
  • Increase insulin secretion (see later)
  • Reduce beta cell apoptosis

Q How does vitamin D reduce beta cell apoptosis ?

  • Vitamin D activates- Nf- kb pathway which increase beta cell survival

Q What kind of immune modulation is seen with vitamin D which is beneficial for type 1 diabetes ?

  • Its actions mainly via 1,25 Dihydroxyvitamin D produced by the macrophages
  • Reduces Th1
  • Increases Th2
  • Reduces production of IgG by B cells
  • Increases Treg (Regulatory T cells) cell function
  • Reduce damaging cytokine production

Q What are the potential benefits of Sitagliptin in Type 1 diabetes ?

  • By its incretin effect Sitagliptin can increase the GLP1, which can potentially enhance beta cell survival and function
  • Sitagliptin may potentially have immunomodulatory effects in Type 1 diabetes.

Q What is the effect of Sitagliptin on Immune system relevant to type 1 diabetes ?

  • Sitagliptin is shown to reduce Th1 cytokine (IFN –gamma) and increase Th2 Cytokine (IL-4)

Q What is the effect of DPP IV inhibitors in type 1 diabetes ?

  • Meta-analysis by Guo et al shows that DPP IV use in type 1 diabetes reduces the insulin dose requirement without change in HbA1c.
  • It does not increase or reduce the risk of hypoglycemia.

Q Apart from this case, has it been shown before that DPP IV inhibitors can potentially reverse type 1 diabetes ?

  • In several studies in NOD mice which are models for type 1 diabetes it has been shown that DPP IV can delay the onset of type 1 diabetes or bring an early onset type 1 diabetes in remission.

Learning Objectives

  1. DPP IV inhibitors and Vitamin D have immunomodulatory effects which can potentially reverse and early onset type 1 diabetes and bring it to remission.
  2. Partial remission of type 1 diabetes (Honeymoon phase) is defined as Insulin requirement 0.9 ng/ml.

ENDOCRINE ROUNDS CASE 6- 6TH CASE IS OF 6TH NERVE PALSY !

A 66 year old female with long standing uncontrolled type 2 diabetes and hypertension presented to us with complaints of diplopia since last 2 months. There was no history of trauma and no other clinical complaints

On examination patient had esotropia in primary gaze in the left eye and reduced abduction of the left eye suggestive of lateral rectus palsy. Rest of neurological examination was normal. Patient had an isolated left 6th nerve palsy.

 

Q. What are the etiologies for 6th nerve palsy ?

1. Traumatic
2. Vascular- diabetic cranial mononeuropathy is one of them
3. ICSOL
4. Raised ICT including Idiopathic intracranial hypertension
5. Cavernous sinus involvement
6. Stroke
7. Vasculitis (including giant cell arteritis)
8. Sarcoidosis

Abducens nerve is the most common nerve involved in Diabetic patients.
Q Would a neuroimaging be required ?

This is controversial. Patel et al published a paper in 2004 in which they suggested that isolated non-traumatic sixth nerve palsy with no other neurological signs do not require a neuroimaging and require a close follow up. (1)

Q How common are diabetic and hypertension a cause of 6th nerve palsy

A population based study by Patel et al showed that diabetes was present in 23% of patients with isolate 6th nerve palsy which was more compared to controls. Isolated hypertension was similar to controls. Hypertension plus diabetes was present in 18% of patients with isolated 6th nerve palsy. (2)

Q What is the management of this condition ?

Diabetic Cranial neuropathy resolves on its own and requires no management apart from good glycemic and blood pressure control. It generally resolves over 6-12 months. Prisms may be used for symptomatic correction of the diplopia.
A paper by Broniarczyk-Loba et al suggest that injection of botulism toxin in the medial rectus can help in early resolution of the diabetic 6th nerve palsy. They suggest that this approach can be used for patients in whom the diplopia interferes with their work and function. (3)

REFERENCES:

1. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology2004;111(2):369-75.
2. Patel SV, Holmes JM, Hodge DO, Burke JP. Diabetes and hypertension in isolated sixth nerve palsy: a population-based study. Ophthalmology2005;112(5):760-3.
3. Broniarczyk-Loba A, Czupryniak L, Nowakowska O, Loba J. Botulinum Toxin A in the Early Treatment of Sixth Nerve Palsy-Induced Diplopia in Type 2 Diabetes. Diabetes Care2004 March 1, 2004;27(3):846-7.

ENDOCRINE ROUNDS CASE 5- PERIPHERAL ARTERIAL DISEASE

An elderly female with long standing history of uncontrolled diabetes mellitus presents with non-healing ulcer over the tip of the 2nd right toe with blackening of both left and forefoot since last 2-3 months.
The ABPI was 0.55 on the right side and 1.36 on the left

Q. What is the interpretation of the ABPI ?

On the right side ABPI is suggestive of significant PAD on the with ABPI >1.3 is difficult to interpret with ABPI alone and would suggest a non compressible vessel.
Right arterial doppler showed biphasic flow in the ATA with reduced pressure and PTA was found to be Stenosed at the origin.
The CT peripheral angiography of the lower limb was done and show below

Right

1- Popliteal

2- Anterior tibial

3- posterior tibial

4- peroneal

Left

1- Popliteal

2- Ant. tibial

3- tibioperoneal trunk

5- peroneal

6 – posterior tibial

Q. What is your interpretation of CT angiography ?
The posterior tibial on both side has attenuated lumen and significant reduction in flow

Q. What would be the next step for this patient ?
The next step would be to perform a revascularization procedure

Q. How to decide which revascularization procedure to perform in this case.
It depends on TASC classification of lesion.

Q. Which TASC stages would do well with Angioplasty
TASC A- single lesion < 5 cm
TASC B- multiple lesions, each <5 cm

Q. Is infrapopliteal angioplasty successful ? What is the long term patency rate ?
Success is >90%, however the term patency rate is 42% at 2 years with conventional balloon angioplasty.

Q. Which TASC lesions would require surgical revascularization ?
TASC C – Multiple stenosis with total length of occlusion > 10 cm
TASC D- Occlusion length >10 cm with dense lesion calcification and non visualization of collaterals

ENDOCRINE CASE 3- DIABETIC RETINOPATHY

A 60 year old type 2 diabetic with HbA1c of 10.3% presents to the OPD for glycemic control. We perform a routine target organ evaluation. On Dilated fundus examination we find the following:

DR3

Q1. What are the findings in this fundus examination ?
We can see the following:
1. Hard exudates close to Macula
2. Hemorrhages

Q2. What would the severity classification of Diabetic retinopathy in this case?

This would be classified as Moderate Nonproliferative Diabetic retinopathy with clinically significant macular edema
This is because the Hard exudates are close to the macula.

Q3. What would you do next for this patient ?
I would refer this patient to a retina specialist since clinically significant macular edema is considered as sight threatening.

Q4. What would be the management for this patient ?
1. Intensive glycemic and blood pressure control (with avoidance of Pioglitazone)
2. Intravitreal anti-VEGF would the treatment of choice for this patient.

CASE 17 A CASE OF DIABETIC KETOACIDOSIS IN AN ELDERLY MALE

Original Case by Satoshi Yamagata et al

An 81-year-old male had experienced vomiting, dizziness, and appetite loss for 2 weeks. There had not been recognition of diabetes prior to the onset of this illness. On admission, he showed impaired consciousness (Glasgow Coma Scale score, 12) with no neurologically abnormal findings or abdominal tenderness. However, he had a dry tongue and decreased skin turgor. His height was 158 cm, body weight 42.1 kg, and body mass index 16.7 kg/m2. His blood pressure was 138/78 mm Hg with an irregular pulse and heartbeat. His body temperature was 35.8°C. Electrocardiography revealed atrial fibrillation. He had no familial history of diabetes. There was no history of falling or bruising.

Q Which endocrine condition would you suspect here ?

Clinically I would suspect Thyrotoxicosis from this history. Points in favour are

  1. Low BMI
  2. Atrial fibrillation
  3. Loss of appetite- Apathetic thyrotoxicosis in elderly

Biochemical analysis revealed high levels of serum 3-hydroxybutyrate (6,296 μmol/L) and the presence of urine ketones and metabolic acidosis, which suggested DKA. His plasma glucose level and glycated hemoglobin level were 732 mg/dL (40.6 mmol/L) and 6.9% (56 nmol/mol), respectively. Urinary C-peptide excretion was <0.1 μg/day, and serum C-peptide level was <0.1 ng/mL after intravenous glucagon loading at onset.  Table 1

Q What is the interpretation of Glucagon stimulation test ?

C peptide 6 min after 1 mg of Glucagon, if the value is <1.8 ng/ml it is considered to be low.

Q What is your interpretation from the biochemical investigations ?

  1. The high blood sugar, low C peptide and presence of ketoacidosis go in favour of absolute insulin deficiency.
  2. Absence of GAD 65 and IA2 antibody go against the possibility of autoimmune etiology. However, presence of other antibodies cannot be ruled out.
  3. The low calcium and increase phosphorous are suspicious. I would consider going a vitamin D and PTH. Also the alkaline phosphatase is high
  4. Amylase is high. I would do a pancreatic imaging.
  5. The increase CPK gives a hint of Rhabdomyolysis
  6. As you can see from the chart, there is multiple organ involvement. A possibility of multi system involvement must be kept in mind

Q The high blood sugar with a low HbA1c suggests what ?

It suggests a possibility of Fulminant type 1 diabetes

Q What is Fulminant type 1 Diabetes ?

It is a severe form of diabetes in which rapid destruction of pancreatic beta cell occurs within no time leading to absolute insulin resistance.

Q What are the clinical characteristics of Fulminant Type 1 Diabetes ?

  1. Abrupt onset of action
  2. Negligible C peptide at onset
  3. Negative islet associated antibodies
  4. Ketoacidosis at onset
  5. Relatively short history of symptoms- <1 week
  6. Elevated pancreatic enzymes

It is described predominantly in Japan

Laboratory data on admission showed high concentrations of serum creatine kinase (CK) (31,084 U/L), myoglobin (122,335 ng/mL), and myoglobinuria, which indicated the onset of rhabdomyolysis. Blood urea nitrogen and serum creatinine (Cr) were both increased (101 mg/dL and 3.6 mg/dL, respectively), and the plasma osmolality level was high (370 mOsm/kg H2O). Glutamic acid decarboxylase and insulinoma-associated antigen 2 antibodies were undetectable.

Q Which are the important antibodies in Type 1 Diabetes ?

  1. Anti GAD65 antibody
  2. Anti Insulinoma associated antibody 2
  3. Anti Insulin autoantibody
  4. Anti Znt8

Thyroid hormones were within normal ranges: free triiodothyronine, 2.62 pg/mL; free thyroxine, 0.90 ng/dL; thyroid-stimulating hormone, 2.08 μIU/mL. The following serological markers for viruses were all negative: coxsackie A9, B2, B4, and B5; cytomegalo; mumps; herpes 6; Epstein-Barr; influenza; herpes simplex; echo 1, 3, and 7; varicella zoster; and rubella. A drug screen performed by Triage® DOA (Biosite Diagnostics Inc, San Diego, CA) was negative.

We treated the patient with 4,000 mL/24 hour saline and continuous venous insulin infusion on the first day (Fig. 1). Empiric broad-spectrum antibiotics were administered for a urinary tract infection. Blood glucose and pH levels normalized 1 day after treatment. However, he was treated with continuous hemodiafiltration on the second day because of anuria and elevated serum CK concentrations (78,225 U/L). Although his serum CK concentrations improved to within the normal range 1 week after treatment, daily urinary volume remained decreased (<50–100 mL/day).

HD was introduced on hospital day 10. After 16 HD sessions, his serum Cr concentrations transiently increased to 12.5 mg/dL and then decreased to 6 mg/dL. Daily urinary volumes gradually increased to >1,500 mL/day. Finally, HD was completed 46 days after starting continuous hemodiafiltration (CHDF). Two weeks after the final HD, his serum Cr concentrations had improved to 2.0 mg/dL

Q Is there a link between Rhabdomyolysis and DKA ?

Yes. Rhabdomyolysis may be associated with DKA.

Learning points from this case

  1. Fulminant Type 1 diabetes is an antibody negative type 1 diabetes which presents rapidly with diabetic ketoacidosis
  2. Rhabdomyolysis may be associated with diabetes ketoacidosis .