The Obesity Paradox in Type 2 Diabetes

Summary of a guest lecture given today by Dr P Costanzo an Interventional radiologist working in the UK. You can find him on pubmed here and on twitter here: 

Increasing BMI has been shown to increase all cause mortality in this NEJM study in 1.46 million white patients. Further extrapolation showed this was mainly due to cardiovascular death. 

Furthermore obesity levels are on the rise. So too are the levels of type 2 diabetes. However, the mortality levels for patients with type 2 diabetes has not shown the same rise infact it has been petty stable for many years. 

A large cohort of type 2 diabetic patients (T2DM) was taken by Costanzo et al. and divided into categories of weight and then following up over 10 years for mortality. The kaplan meier survival curve was interesting, displaying the so called obesity paradox. Patients who were underweight with a low BMI (less than 20 or 18.5) had the highest mortality. Increasing BMI showed a protective effect with the highest BMI values having the lowest mortality. A paradox indeed. 

Further extrapolation of the data by cause of death showed a protective effect of obesity in T2DM in sepsis and cancer (again paradoxical, considering cancers relationship with obesity). 

Dr Costanzo went on to explain possible mechanisms of this, citing the important relationship between low birth weight and increased lifetime risk of T2DM. And how this may be part of the so called evolutionary Thifty phenotype, a phenotype in which high blood sugar can be maintained in starvation providing a survival advantage. It is well known that subsaharan populations (and also indian populations) who move to say the UK  (or anywhere) and start a western diet are likely to develop diabetes. He mentions the lipgenic model of T2DM and how subcutaneous fat is neutral to us but visceral fat is the fat that as it accumulates increases cardiovascular mortality. There is a kind of tipping point where when lets say SC fat is full, visceral fat begins to accumulate (where is the level?). 

The last part of Dr Costanzos talk was incredibly interesting. HB1AC levels documented across all values of BMI is more or less the same in his cohort (unreleased data unfortunately, paper release in 2017), except for the underweight BMI values in which it generally higher. You can postulate that HB1AC is therefore not linked to mortality, and infact other studies confirm this. My notes run out at this point, I guess I was trying to concentrate, but the final part of this section he shows that good BP control in T2DM can reduce mortality in T2DM and perhaps glycemic control has little to do with cardiovascular mortality. 

In fact a nice point was that two new anti-diabetic drugs being studied at the moment; Liraglutide and Empagliflozin, are the only drugs that have been shown to reduce cardiovasuclar mortality in T2DM. These two drugs also have a blood pressure lowering effect. 

Pancreas Transplantation BMJ State-of-the-Art Review Summary

(Another medical student orientated summary of a recent review, this time Pancreas Transplantation.)
Successful pancreas transplantation can result in durable glycemic control and improved survival for patients with diabetes. There seems to be no other treatment in medicine that has the same improving success rates over time and is being applied less and less (the number of pancreas transplants performed in the US has decreased every year during the past decade). In other words, more patients could probably benefit from pancreas transplantation than currently undergo the procedure. 

Most people are diagnosed with type 2 diabetes, with type 1 diabetes accounting for 8-10% of all diabetes cases.
In the UK 3.5 million people are diagnosed with diabetes, with approximately 0.5 million still to be diagnosed. The incidence is increasing.

First successful pancreas transplant was in 1966, at the University of Minnesota.
The number of transplants increased steadily until 1996.
Survival at this point (1996) was 91% at one year and 84% at three years.
The introduction of ciclosporin in the 1980s dramatically increased survival, further efficacy of transplant was enhanced with introduction of tacrolimus and mycophenolate in the 1990s.

Between 2005 and 2014 pancreas transplantation number decreased by 20%. Reasons for this decline were probably; improved medical management of diabetes, decline in organ donor quality (more obese and old), lack of consistent referral of transplant candidates from endocrinologists.

Three main pancreas transplantation types:

• PAK = pancreas after kidney transplant (the main role of this type is avoid the morbidity and mortality asociated with dialysis therapy; patients with type 1 diabetes have at least a 33% mortality in teh first five years after starting dialysis). 
• PTA = pancreas transplantation alone (has higher rates of technical graft loss and acute cellular rejection, however a very small number of this type are performed, no no reports have rigorously studied the efficacy or quality of life benefits)
• SPK = simultaneous pancreas kidney transplant (most common type of pancreas transplant, typically both organs from the same donor)

Success rates of pancreas transplantation have improved with time likely due to increasing experience with these complex patients.

UK current survival rates SPK five year survival 88%, Pancreas only transplants five year survival 78%.

No real studies have directly compared the costs of pancreas transplant vs conventional medical therapy but there have been theoretical models that concluded that SPK is the most cost effective strategy after accounting for varying probabilities of patient and graft survival.

• To date there have been no randomised controlled trials comparing the different forms of pancreas transplantation against for example intensive insulin therapy, islet transplantation. 
• However many single centre studies and registry analyses suggest that pancreas transplantation provides a net benefit compared to kidney transplant alone for patients with both diabetes and chronic kidney disease. 
• More controversial is the impact of pancreas transplantation on patient survival in patients with diabetes and preserved renal function. One analysis of transplant registry data reported a survival disadvantage for PAK and PTA recipients. 

Because pancreas transplantation can also establish normoglycemia it is reasonable to infer that this intervention would also improve or stabilise end organ complications (eg. retinopathy, nephropathy).

Complications:
Diabetic nephropathy (a microvascalur complication of diabetes) is one of the most important complications of diabetes.
Single centre studies with small cohorts have suggested that pancreas transplantation has a beneficial effect on secondary complications of diabetes.
Data is limited on the long term complications, have been reports of increased infections and hematologic cancers after transplantation.

Quality of life:
QoL improved rapidly after transplantation (measured at four months), the effect did however flatten out later. A minority had decreased QoL emphasising the importance of pre-transplant education to establish realistic expectations for the patient.

Clinical trials:
No multicentre trial has been designed to truly evaluate the true efficacy of transplant compared to best medical therapy in type 1 diabetes.

Islet transplantation (ITA):
ITA is less invasive.
Has good short term results but five year insulin Independence rate are around 11%, despite this these patients achieved avoidance of hypoglycemia and near normal glucose control.
Comparison of ITA vs PTA; PTA has higher morbidity, authors of mentioned study concluded that ITA produces similar outcomes to PTA.

Artificial pancreas:
A closed loop system with a subcutaneous sensor that transmits glucose measurements to an external insulin pump that deliver insulin subcutaneously when needed.
Addition of glucagon in the future could prevent hypoglycemia.
The use of such devices requires the patient reaches a certain level of understanding.
Results from international diabetes closed-loop trial conducted on real patients will be out in 2019.

Future directions:

"Pancreas transplantation stands at a crossroads—without a systematic approach to the procedure and its outcomes, transplant volumes, especially those for PTA and PAK, may continue to decline and the procedure take second stage to therapies such as islet transplantation and closed loop insulin and glucagon delivery systems..... a more systematic approach to characterizing the successes and limitations of pancreas transplantation is needed."

Need to develop a uniform definition of graft failure. The most common definition of graft failure at the moment is the requirement of exogenous insulin therapy.
Need the development of biomarkers to diagnose rejection and monitor patient immune status.

UK guidelines:

In the UK, patients with the following conditions are considered for pancreas transplantation135: 

•  Pancreas transplantation alone or islet transplantation alone: patients with severe hypoglycemic unawareness but normal or near normal renal function

•  Simultaneous pancreas and kidney transplantation or simultaneous islet and kidney transplantation: patients with renal failure and insulin dependent diabetes 

•  Pancreas after kidney transplantation or islet after kidney transplantation: patients with functioning kidney transplants and diabetes. Most patients who are considered have type 1 diabetes but some patients with insulin dependent type 2 diabetes may also be suitable candidates.

This summary was for the following paper: http://www.bmj.com/content/357/bmj.j1321
(all the information and images were from the above paper).

Fever Of Unknown Origin (FUO)

I am sure you have all watched at least one episode of House, the series in which a witty Hugh Laurie is presented with difficult to solve cases almost every day. Obviously in reality these kind of cases are incredibly rare, but there is one kind of 'difficult to solve' problem in medicine which appears far more often than you think, the febrile illness without an obvious origin, FUO.

Definition and Diagnosis:

Fever greater than 38.3 degrees on several occasions, persisting without diagnosis for at least 3 weeks despite of at least 1 week investigation in hospital. (Later updated to 3days Inpatient investigation or 3days of Outpatient investigation).

Can be further classified into:

Classical (as defined above)

Nosocomial (the fever was absent on admission to the hospital)

Neutropenic (Patient is neutropenic as well, less than 500 neutrophils per mm3)

HIV associated (Patient has confirmed HIV infection)

You cannot conclude a patient has a FUO until you have performed the following basic investigations:

History, Physical exam, Complete blood count, Blood Cultures, Complete metabolic panel and Liver function tests, Urinanalysis and culture, Chest X-ray.

Etiology:

Three catergories of illness can cause FUO; 

infections, malignancies and connective tissue disorders.

There is a long list of the possible causes (See image) but don’t forget Drug Fevers in which a fever can be the sole feature of an adverse drug reaction (most commonly with antibiotics).

Age is very important when considering the etiology, for example in younger patients infections will be much more common (in children around one third of FUO are caused by self limited viral illnesses) and in the elderly (haematological malignancies and solid tumours will be much more common).

Also neutropenia associated FUO will be much more likely linked to a bacterial infection (although never forget genetic neutropenia exists such as cyclic neutropenia and benign familial neutropenia).

Malaria and respiratory infections are a common cause in returned travellers.

First steps:

Re do history and physical exam, a careful history is critical for diagnosis! 

Ask about: animal exposure, immunosupression, drugs and toxins, localising symptoms (for example, jaw claudication is consistent with giant cell arteritis, nocturia with prostatitis etc.). 

Note that the degree of fever, nature of fever curve and response to antipyretics has no specificity to guide the diagnosis. 

After a careful history the following exams will be useful (obviously performed in a targeted nature, guided by your suspiscions):

LEVEL 1 testing:

ESR, CRP, LDH, TST/IGRA, HIVab/RNA, 3 blood cultures for separate sites, Rheumatoid factor, creatine phosphokinase, heterophile antibody test, antinucleaur antibodies, serum protein electrophoresis, procalcitonin can be helpful

LEVEL 2 testing:

CT abdomen, CT chest (if these turn out to be negative move to FDG-PET, although be aware of its high false positive rate)

Level 3 testing: 

Biopsies and Endoscopies

Treatment:

Treatment should be withheld as long as possible until the cause of the fever is determined and empirical antibiotic treatment is not appropriate! However you must obviously consider the patients condition and febrile neutropenic patients have a much higher percentage of bacterial infections and so empiric treatment can be appropriate after cultures have been obtained.

Summary:

• Most cases of FUO are due to unusal represantations of common diseases rather than exotic diseases
• Reassess the patient frequently and the don’t underestimate the importance of a very careful history and physical exam (it is in fact critical).
• Almost any infective agent can be responsible for FUO
• Look out for Malignancy red flags in the history and physical exam such as symptoms (night sweats, weight loss, pruritus, rectal bleeding), radiation exposure, cigarette smoking, lymphadenopathy, hepatosplenomagaly, petechiae.

A long list of the possible causes of FUO #fever #medicine #fuo #medED #study #medicalschool