The “Other” Forms of Diabetes:Latent Autoimmune Diabetes of Adults

Cystic Fibrosis Related DiabetesPost-Pancreatectomy Diabetes

EMILY BRENNAN

PGY-4 ENDOCRINOLGY

WEDNESDAY, MARCH 11, 2015

Objectives At the end of the lectures you will:

◦ Understand the definition of LADA, CFRD, and post-pancreatectomy diabetes

◦ Understand the pathophysiology behind LADA,CRFD and post-pancreatectomy diabetes

◦ Understand the implications for screening/diagnosis of these forms of diabetes

◦ Understand the clinical relevance and the differences in clinical management of these forms of diabetes

Case Mr. L.D. 57 year old male is referred by his family doctor for poorly controlled diabetes.

He was diagnosed about 4 months ago, and despite significant lifestyle modification and compliance with metformin and gliclazide, his sugars are still poor.

His BP is 124/78, HR 78. BMI 24.6. Unremarkable physical exam.

Most recent A1c is 9.1%

Started on insulin. Energy level much improved.

Sugars now controlled are low doses of MDI

LATENT AUTOIMMUNE DIABETES IN ADULTS

Diabetes and Antibodies Islet cell antibodies were discovered in 1974 in type 1 diabetes by Bottazzo et al.

Provided evidence that beta-cell destruction was autoimmune in nature, and leads to insulin deficiency

Thought to offer ‘evidence’ to differentiate between type 1 and type 2

Diabetes and Antibodies In 1978, Irvine et al, showed that 11% of patients with “type 2” diabetes were also positive for islet-cell cytoplasm antibodies (ICA)

Groop et al. 1986 found islet-cell antibodies in 14% of 154 patients aged 35 to 75 years who had been treated with diet and oral agents for at least 1 year

◦ Preserved beta-cell function◦ this subgroup had lower basal and stimulated C-peptide levels than ‘type 2s’◦ progressed more rapidly to insulin therapy

LADA: Definition Difficult to ‘define’

◦ Described over thirty years ago, but still a clinical controversy

Latent Autoimmune Diabetes in Adults (LADA)

Term coined in 1994 to describe patients with a slowly progressive form of type 1/autoimmune diabetes who could initially be treated without insulin

Heterogeneous disease that shares biochemical, genetic and phenotypic characteristics with both type 1 and 2 diabetes

Nomenclature

Latent Autoimmune Diabetes in Adults (LADA)

Progressive insulin-dependent diabetes

Latent type 1

Type 1 diabetes masquerading as type 2 diabetes

Type 1.5 diabetes

LADA DefinitionIn general, 3 criteria for “diagnosis of latent”:

◦ Adult age of diagnosis

◦ The presence of circulating islet autoantibodies

◦ No requirement for insulin for at least 6 months after diagnosis

Autoantibodies GAD (typically GAD65 isoform)

Insulinoma-associated (also called protein tyrosine phosphatase) antigen (IA-2A)

Cytoplasmic islet cell antibodies (ICA)

Zinc transporter 8

LADA: Pathophysiology Less understood than either type 1 or type 2 diabetes

Natural history of ‘pre-clinical’ LADA is unknown◦ Two extremes: longstanding islet cell autoimmunity and slowly progressive beta cell damage over many

years vs onset of islet autoimmunity in adult life with a shorter pre-clinical stage

LADA appears to be have both progressive autoimmune destruction of the beta-cells; however, insulin resistance may also contribute to the presentation of LADA

LADA: Pathophysiology

LADA: Genetics Less genetic epidemiology available for LADA; the focus is primarily on T1D and T2D

Family-based designs in linkage studies have had limited success to identify genetic factors

International HapMap project has offered new insight◦ Showed that T1D and T2D are distinct biological mechanisms; and none of the genes identified to date

in each of these disorders are associated with the other disease

LADA: Genetics T1DM Widely believed that LADA shares susceptibility genes with type 1 diabetes; small studies only available

HLA locus seen in T1DM is at 6p21◦ variation in this region accounts for half of the genetic risk for T1DM◦ this region coincides with the HLA class II genes which encode for the highly polymorphic antigen-

presenting proteins (primarily HLA-DRB1, DQA1, DQB1)◦ INS, CTLA4, and the protein tyrosine phosphatse-22 also confer susceptibility

HLA locus seen in T1D has also be seen in LADA; however, with some differences:◦ DQB1 *0201/*02302 is more common in T1DM than in LADA◦ Whereas the ‘protective genotypes’ *0602/X and 0603/X are more common in LADA◦ INS short class I variable number of tandem repeats has shown to confer equally strong susceptibility in

both T1DM and LADA

LADA: Genetics T2DM Transcription factor 7 (TCF7L2 gene) is the strongest locus for T2DM

TCF7L2 is also associated with LADA; interestingly, this has not been conclusively seen in T1DM

UKPDS Cohort UKPDS 70 - 2005

◦ Question: examine the prevalence of islet autoantibodies and their relationship to glycemic control over 10 years in patients diagnosed clinically with new onset type 2 diabetes

◦ Method: patient clinical characteristics and autoantibody status were determined at entry to the USPDS; before randomization to different glucose control policies.

◦ Follow-up: 10 years

◦ Patients had a clinical diagnosis of type 2 diabetes, defined as the absence of ketonuria

UKPDS 70 Cohort with 5102 newly diagnosed type 2 diabetes patients

UKPDS Baseline Characteristics

UKPDS 70

Ab+ closed circles

UKPDS 70

Ab+ on SU

Ab- on SU

Ab+ SUAb+ ConAb- SUAb- Con

UKPDS: Take Home Patients with autoantibody positivity exhibit:

◦ A phenotype closer to T1DM (lower BMI, lower BP, better lipid profile)

◦ Increased need for insulin to achieve glycemic control earlier than antibody negative patients

◦ Those who are antibody positive and on a SU had a higher rate of progression to insulin

Zhou et al (2013) In 2013:

◦ Multicenter study, retrospective analysis◦ Objective: characterize the Chinese LADA population ◦ 4880 subjects in China

◦ diabetes diagnosed at age > 30 years◦ enrolled within 1 year of diagnosis◦ did not develop DKA or insulin dependence for at least 6 months after diagnosis

Zhou et al (2013) LADA diagnosed in 5.9% based on + GAD65, the rest were classified as type 2

◦ LADA were leaner; lower fasting C-peptide, and less metabolic syndrome◦ North-South gradient (more LADA in the north)◦ HLA diabetes-susceptible haplotypes were more frequent in LADA◦ High GADA titer patients were phenotypically different than low GADA titer patients

Andersen et al (2013) Is there a difference in glycemic control in individuals with LADA versus T2DM and is it influenced by time on insulin therapy?

◦ Retrospective trial of 372 patients with LADA in Sweden◦ Age and sex-matched patients with type 2 DM were included as controls◦ Followed for 107 months

Andersen et al (2013) Outcomes

Andersen et al (2013) LADA were leaner than Type 2; longer time on insulin (53.3 vs 28.8)

LADA had poorer control at follow-up

They did not look at clinical outcomes; however, one can extrapolate more microvascular complications with higher A1c

Buzzetti et al (2007) Does the antibody titre matter?

2007 Italian trial:◦ Objective: define heterogeneity of LADA based on characterization of the antibodies◦ Used the NIRAD population and assessed antibody body status, HLA typing, and clinical characteristics◦ 4250 patients with T2DM

Buzzetti et al (2007)

Buzzetti et al (2007) Patients with high GAD antibody titers displayed:

◦ prominent traits of insulin deficiency ◦ a profile of more severe autoimmunity resulting in significantly higher A1C◦ significantly lower BMI◦ Lower total cholesterol, triglycerides◦ Lower prevalence of the metabolic syndrome

They look more like type 1 than type 2!

Treatment Apart from the UKPDS, studies on LADA have been small and underpowered

No consensus regarding ‘optimal’ treatment

Follow the CDA/ADA guidelines for T1DM

Suggested that patients with LADA should be initiated on insulin

Cochrane Review (2011) Objective: to compare interventions used for treatment of LADA

Selection criteria: RCT and controlled clinical trials evaluation interventions for LADA or T2DM with antibodies included

15 publications (10 studies) looking at 1019 who were followed for 3 months to 10 years◦ poor quality reporting◦ Small numbers of participants◦ No studies reported development of diabetic complications (looked at A1c and fasting blood glucose)◦ Significant heterogeneity

Cochrane Review (2011)

Cochrane Review Metabolic control (HbA1c) is improved using insulin compared to SU

Early pilot data that GAD65 may improve control

Insulin combined with Chinese medicine improved metabolic control when compared to SU

Vitamin D may protect beta-cells when given with insulin compared to insulin alone

LADA Adult-onset autoimmune diabetes is prevalent!

◦ likely more prevalent than T1DM

There is uncertainty regarding if the pathophysiology is distinct from T1DM or is there a clinical spectrum to ‘autoimmune diabetes’

It is not known whether the increasing prevalence of Type 2 diabetes is associated with an increasing prevalence of LADA

Does it matter? From a practical standpoint,

◦ If we are monitoring glucose, does measuring the antibodies matter?◦ No hard evidence that patients have more complications? (not studied)

◦ They do have worse HbA1c control post which would imply more microvascular complications

A list of diagnostic features for screening and defined clinical management regimens are unlikely to improve outcomes for adult-onset autoimmune patients who benefit from regular and careful clinical care with flexible treatment plans

Case: Ms. CF 42 year old female with a history of cystic fibrosis. She has had a prior lung transplant.

She is being followed for her diabetes. Last exacerbation was 2 months ago, required hospital admission. She struggles with frequent lows.

Physical exam: BP 112/62 HR 87. Weight 48.1. BMI 18.3

Her most recent A1c is 7.2%.

CYSTIC FIBROSIS RELATED DIABETES

Cystic Fibrosis Caused by mutations in the cystic fibrosis transmembrane conductance regulator (CRTR) protein

◦ Complex chloride channel and regulatory protein found in all exocrine tissues◦ Deranged transport of chloride and other CFTR-affected ions (Na and HCO3) result in thick, viscous

secretions in the lungs, pancreas, liver, intestine, and reproductive tract

CF is the most common recessive autosomal disease among Caucasians (1/2500-1/4000)

Cystic Fibrosis Related Diabetes (CFRD)

Significant advances in medical and nutritional treatments have led to improved survival, but increased the prevalence of other comorbidities:

◦ DM, bone diseases, depression

Diabetes is the most common morbidity in subjects with cystic fibrosis

CFRD: Epidemiology Can appear in infancy or adolescence

Increasing prevalence with age

Estimated to occur in approximately 50% of adult patients

CFRD: Pathophysiology

Certain mutations have higher occurrences of CRFD and more severe CF and pancreatic exocrine insufficiency

No known correlation with T1DM gene susceptibilities; however, some correlations with genes linked in T2DM have been found

CFRD: Pathophysiology

Pancreatic dysfunction is due to alterations in chloride channels◦ Viscous secretions cause obstruction of the exocrine pancreas with progressive fibrosis and fat

infiltration◦ This may lead to destruction and rupture of islets, which leads to loss of beta, alpha, and polypeptide

cells ◦ Postmortem studies have not found a greater loss of islets; however, amyloid polypeptide (seen in T2DM) was found in 69% of

CRRD patients and absent in non-DM patients

CFRD: Pathophysiology Primary issue that leads to DM is severe insulin deficiency (not absolute!)

Fasting insulin and C peptide may be normal, but there is a delay in the peak secretion of insulin during the OGTT (impaired first phase insulin and C-peptide secretion)

◦ In normal individuals this occurs at 30 and 60 minutes, while in CRFD the peak is observed in 90-120 minutes

CF patients also have an element of insulin resistance ◦ ?related to increased energy needs of CR patients create a physiologic balance between elevated hepatic

glucose production and high glucose demand◦ ?frequent use of glucocorticoids and constant infections may worsen this condition

Insulin resistance likely does not play as large a role as insulin deficiency

CFRD: Clinical Presentation Generally asymptomatic and may remain undetectable for up to 4 years prior to diagnosis

Spectrum of impaired glucose tolerance CFRD

In contrast to T1DM, insulin secretion is never totally absent

CFRD: Definition 1998 North American CFRD Committee Consensus:

2-hour glycemia >= 11.1 mmol/L in the OGTT

Divides the patients into those with or without fasting hyperglycemia ◦ FBG greater than/equal to 7 or less than 7 mmol/L◦ This classification was based on the fact that the prognosis can be different from the two groups ->

although, this has now been shown otherwise

CFRD: Screening

2-hr 75 gram OGTT (morning, during period of stable baseline health, 6 weeks after acute exacerbation)

Fasting blood glucose not acceptable (will miss up to half of patients)

HbA1c not sensitive enough in CFRD ◦ 6 studies showed low degree of correlation between A1C and glucose tolerance status

Begin annual screening at age 10 in all CF patients

CFRD: Screening For patients with continuous enteral feeds:

◦ Measure mid- and immediate postfeeding plasma glucose levels◦ CFRD represent if BG >= 11.1 mmol/L on two separate days

For patients during an acute exacerbation: (requiring IV antibiotics +/- glucocorticoids)◦ Screen by monitoring fasting and 2-h postprandial plasma glucose levels for the first 48 hours◦ If elevated glucose levels are found by SMBG, results must be confirmed on venous bloodwork

CFRD: RelevanceCFRD is associated with significant greater mortality

6 x increase in morbidity and mortality in those patients diagnosed with CFRD

CFRD: Morbidity Insulin deficiency and hyperglycemic negatively affect pulmonary disease

Nutritional condition and pulmonary function begin to deteriorate several years before CFRD diagnosis

Modest increases in sugars may influence pulmonary function◦ May promote growth of respiratory pathogens ◦ Catabolic effects of insulin deficiency may increase morbidity

US CF Foundation 2005 In 21, 047 patients in the US CF Foundation patient registry, between 1988 and 1992

Showed 54% increased in the risk of death in female patients with CFRD

Black = female no DMGreen = male no DMBlue = male + DMRed = female + DM

This was not confounded byCFTR genotype, age at CF diagnosis, BMI, steroid use or resp microbiology results

CF Population at University of Minnesota

Moran et al 2009◦ 527 patients at University of Minnesota

Mortality over time has decreased in CF with DM

In, the most recent time period, overall mortality still remains significantly higher in those with CFRD compared with those without diabetes, but the gap has considerably narrowed

Importantly, the mortality in the sex differences has disappeared.

CF Population at University of Minnesota

The improvement in the mortality is thought to be related to earlier detection and more aggressive treatment.

Also, CFRD without FH is now treated aggressively.

CF Population at University of Minnesota

CFRD: ADA Position Statement 2010

Should be treated with insulin therapy (Grade A)

Oral DM agents are not as effective as insulin to improve nutritional and metabolic outcomes in CFRD and are not recommended (Grade A)

No need to distinguish between CFRD with and without fasting hyperglycemia◦ both groups improve with insulin, and should receive insulin treatment

Strive to attain plasma glucose goals as per the ADA recommendations for all people with diabetes; higher or lower goals may be appropriate and should be individualized (Grade E)

CFRD: Dietary Recommendations

Common complications Hypoglycemia is common

◦ Occurs in the fasting and post-prandial state (usually not severe)◦ May reflect malnutrition and/or increased energy needs due to inflammation and infection◦ May be due to delayed and disordered insulin secretion◦ May have impaired glucagon secretion (alpha cell dysfunction), but should have normal catecholamine

response and normal hypoglycemic awareness

Microvascular complications appear typically after 5 years of CFRD and only after fasting hyperglycemia has developed

Multi-Disciplinary Approach CFRD is an expected complication as patients with CF grow older

Need to remember that the presence of another diagnosis – diabetes – for the families and the patients with CF is frequently difficult to accept and sometimes devastating.

Existence of multi-disciplinary teams with respirologist, physiotherapy, psychology and dietitian in addition to the endocrinologists is essential to promote the understanding of, and the adherence to the treatment and control of CFRD

Case: Mrs. CR 62 year old female with pancreatic mass found on CT.

Patient went for OR summer of 2014, and difficulties with bile leak post-operatively. Placed on TPN 24 hours a day for nutrition.

Blood sugars in hospital are 12-15.

Endocrine consulted to implement plan for diabetes management.

POST-PANCREATECTOMY DIABETES

Pancreatogenic DM Insulin is secreted by the beta cells (distributed evenly throughout the pancreas)

◦ Decreases glucose by: suppressing hepatic gluconeogenesis and glycogenolysis◦ Facilitates hepatic glycogen synthesis

Alpha cells (glucagon secreting cells) are located predominantly in the body and the tail of the pancreas

◦ maintain adequate glucose production by hepatocytes through stimulation of glycogenolysis and gluconeogenesis that together function as counter-regulatory mechanism to control hypoglycemia

Pancreatogenic DM Pancreatic polypeptide (PP) 36 amino-acid polypeptide localized to specific cells called PP cells

◦ Located mostly in the ventral pancreatic head and uncinated process

◦ In patients with low levels of plasma PP following pancreatic resection, hepatic glucose is not suppressed as it was in controls during an insulin infusion

◦ administration of PP to patients with PP deficiency was shown to improve their hepatic response

Pancreatogenic DM Loss of pancreatic parenchyma resulting from pancreatic resection causes an ‘extreme’ disruption in glucose homeostasis – different from T1DM or T2DM

◦ Pancreatogenic DM seldom causes ketoacidosis or severe hyperglycemia◦ does not have the insulin resistance of T2DM

Exogenous insulin administration frequently causes hypoglycemia ◦ Due to insulin sensitivity and reduced/lack of glucagon

Pancreatogenic DM: Pathophysiology

Differentiating Features

Pancreatogenic DM

Relevance:◦ Since the improved surgical procedures, post-op care and capacity for early diagnosis of disease has

prolonged life expectancy

Maeda and Hanazaki 2011

Burkhart et al (2014) Retrospective analysis of 1107 patients who underwent an pancreatectomy between 2006-2013

in New Jersey, US◦ Examined the incidence and characteristics of diabetes post-surgery◦ 257 of 691 surviving patients completed the surveys◦ Separated the patients into two groups: those with pre-existing DM versus those without

Burkhart et al (2014)

Burkhart et al (2014) Factors identified that were associated with increased risk (either development of pancreatogenic DM or worsening of preexisting condition):

◦ Increased insulin usage during the index hospitalization◦ Higher fasting blood glucose◦ Higher pre-operative HbA1c

Treatment There are no specific recommendations for the treatment of pancreatogenic DM

Choice of insulin versus non-insulin therapy depends on clinical presentation

Use the targets and recommendations set for T1DM and T2DM

If “mild”:◦ Frequent monitoring, follow-up, and lifestyle modification

If total pancreatectomy: results in insulin dependent pancreatogenic DM◦ Use insulin◦ Hypoglycemic attacks are partly related to the deficiency in pancreatic enzymes (does not occur until over 90% of pancreatic

exocrine function is lost)◦ Give pancreatic enzyme supplementation

TreatmentMetformin remains the first line agent

In patients with high risk of developing pancreatic carcinoma (chronic pancreatitis):Pancreatic carcinoma is characterized by overexpression of IGF-1 and G-protein coupled receptors and chronic hyperinsulinemia, which may enhance the development and growth of cancer

Pancreatogenic diabetes in the setting of chronic pancreatitis is considered ‘pre-malignant condition’, and treatments that employ insulin, insulin analogs, and insulin secretagogues may increase the risk of carcinoma by enhanced activation of these signally pathways

Metformin is the preferred drug, and should be used in in combination with insulin to reduce the insulin requirement (avoid SU, GLP-1 agonists, DPP4 inhibitor)

Comments/Questions?

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