Monday, November 26, 2012

Muscle Pains and Statins

 I have attached an abstract published by PUB Med this morning.  Their finding  are about the same as my own clinical experience. Notice that they defined myopathy as muscle symptoms and an elevated lab test , CPK( creatine kinase). Many people have mild muscle aches without abnormal lab test and these symptoms usually these symptoms subside over time. Myopathy risk increases with higher doses of statins. I have attached a link to a previous post regarding Zocor( simvastatin )

Simvastatin 80 mg FDA report

I have also attached links to previous post regarding myopathy and Statins below.


 2012 Oct;30(5):e212-8. doi: 10.1111/j.1755-5922.2011.00267.x. Epub 2011 Apr 1.

Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge.

Source

Department of Clinical Biochemistry and Metabolic Medicine, University Hospital Lewisham, London, UK. efung@nhs.net

Abstract

INTRODUCTION:

Statin myopathy is a generally encountered side effect of statin usage. Both muscle symptoms and a raised serum creatine kinase (CK) are used in case definition, but these are common manifestations of other conditions, which may not be statin related. Statin rechallenge assuming no contraindication in selected cases is an option before considering a different class of lipid-lowering agent.

AIMS:

We aim to characterize retrospectively the patients referred to our Lipid Clinic with a diagnosis of statin myopathy. The tolerability of different statins was assessed to determine a strategy for rechallenging statins in such patients in the future.

RESULTS:

Patients with statin myopathy constitute 10.2% of our Lipid Clinic workload. They are predominantly female (62.0%), Caucasian (63.9%), with a mean age of 58.3 years and mean body mass index (BMI) of 29.3 kg/m(2). The serum CK and erythrocyte sedimentation rate (ESR) were statistically higher compared to patients with statin intolerances with no muscular component or CK elevations. Secondary causes of statin myopathy were implicated in 2.7% of cases. Following statin myopathy to simvastatin we found no statistical difference between the tolerability rates between atorvastatin, rosuvastatin, pravastatin, and fluvastatin. Fibrates, cholestyramine, and ezetimibe were statistically better tolerated in these patients.

CONCLUSIONS:

Statin rechallenge is a real treatment option in patients with statin myopathy. Detailed history and examination is required to exclude muscle diseases unrelated to statin usage. In patients developing statin myopathy on simvastatin, we did not find any statistical difference between subsequent tolerability rates to rosuvastatin, pravastatin, and fluvastatin.
© 2011 Blackwell Publishing Ltd.


Wednesday, November 21, 2012

Does lowering A1c result in increased hypoglycemia risk


The take home message from the previous discussion a few days ago.
    Epinephrine produces the early warning symptoms of a dropping blood sugar. The loss of the
    epinephrine response to a falling glucose results in " hypoglycemia unawareness " and the 
    progression to the more severe stages of hypoglycemia.

Questions:
   #1-  Does lowering A1c result in increased risk of hypoglycemia in type 1 and type 2 diabetes ?

  Answer:
              Generally the answer is yes for patients with type 1 and type 2 diabetes but their are some
              interesting  caveats.

             The association of hypoglycemia with A1c  test below 7 occurs more often
             in people with type 1 diabetes .

             The association is a little different for people with type 2 diabetes and is , I believe 
              related the severity of their insulin deficiency. 

          Low risk
              Some people , with diet control ,  and those taking* Glucophage , *Byetta , *Victoza  or a
              *DPP4 inhibitor,  can achieve an A1c of 6 with minimal risk of hypoglycemia.

          Higher risk
              Hypoglycemia risk increases for patients taking *sulfonylureas .

              The risk increases depending on the  type of insulin needed to control their glucose levels .
              The addition of a basal insulin such as Lantus or levemir to oral medications
              ( metformin and/ or Byetta, Victroza , or  **DPP4 inhibitors ) does not add much  risk.
           
            Highest risk 
             The addition of  insulin to the treatment regimin of a peson taking a sulfonylurea.

                 The risk goes definitely increases when short acting insulin ( Humalog ,Novologi,Aphidra )
                  is needed to control meal time  glucose increases.

             
  The take home messages


         The difficulty of controlling  blood glucose levels increases with with the duration of type 2

         diabetes and the associated  increasing insulin deficiency. 
          

          An older person  with a longer duration of diabetes struggling  to control a high A1c is usually 
          at a greater risk of hypoglycemia than a younger person who easily achieves and A1c of less
          than 7 .
        
      Have fun, Be Smart  and remember A1c target goals depend on each individuals 
      circumstance
      David Calder, MD

Question #2 tomorrow.       
   #2 --Does age effect a persons awareness of hypoglycemia ?

   #3 --74% of unrecognized hypoglycemia occurs at night .       True or false

For your review .

****************What is GPL-1 ?   , DPP4 inhibitors , Sulfonylureas ****************

What is GPL-1 (Glucagon like peptide -1 )

Type 2 Diabetes is a complex game with many players.
Most of us are aware of  Beta cell dysfunction and failure causing insulin deficiency and we are familier with the term insulin resistance and its association with weight gain and obesity.
 We are less familier with the dysfunction of the pancreatic alpha cells and inappropriate Glucagon releasetriggering the liver to release glucose resulting in higher fasting and after meal glucose levels

GPL-I
The , newest member of  this group  , is a deficiency of a hormone made in our intestineGlucagon like Peptide -1 (GPL-1 ). 
This hormone is released in response to eating and has a powerful influence on our ability to manage  blood glucose levels.

Effects of GPL-1
 #1  Glucose - Dependent insulin secretion. This hormone allows insulin secreting Beta Cells to
        produce insulin in response to an increase in glucose levels.
  #2  Decreases glucagon levels resulting in lower fasting and after meal glucose levels
  #3   Appetite suppression and Slows  gastric emptying

Products Available to replace GLP-1 deficiency

GLP-1 agonist
 Exenatide ( Byetta )     a twice daily injection
 Liraglutide ( Victoza )  one injection per day
 Exenatide ( Bydureon ) weekly injection

Chart summary
                                        GLP1 agonist      DPP4 inhibitors    acarbose   Insulin    sulfonylureas

Effectively reduce A1c           YES                      YES                  YES       YES          YES

Preserve Beta cell function    YES                      ?                       NO        NO            NO

Promotes weight loss             YES                      No                     + -          NO            NO

Promotes weight gain              NO                      NO                     + -         YES           YES

Do not cause hypoglycemia   YES                     YES                   YES        NO            NO

Once a week injection             YES                     NO                     NO          NO           NO

Glucagon suppression            YES                     YES                   NO         NO           NO

Most expensive                         YES                        +-                     NO          + -            NO



Sunday, November 18, 2012

Diabetes and the Devil of low blood sugars

I have always felt that people with diabetes have to work a little harder each day to preserve their good health while being forced to walk a narrow path between 2 devils .  The Devils of high and the Devils of low blood sugars .The devil of high high glucose comes with known long term risk and the devil of low glucose levels , on the other side of the path , comes with immediate often severe consequences. This is the beginning of a 4 part discussion of hypoglycemia. Today, I will lay the ground work with a few definitions and  a little physiology .


 The American Diabetes Association's discussion of hypoglycemia. Position statement 2012
"Hypoglycemia is the leading limiting factor in the glycemic management of type 1 and type 2 diabetes.

Mild hypoglycemia - plasma glucose below 70 mg/dl

Severe hypoglycemia -
  ( where the individual requires the assistance of another person and cannot be treated with oral
    carbohydrate due to confusion or unconsciousness) should be treated using emergency glucagon kits)
       
Hypoglycemia unawareness
  (In type 1 diabetes and severely insulin deficient type 2 )
  These people of lost their awareness of the early warning signals of hypoglycemia

Joslin's Diabetes Mellitus thirteenth edition has a good chart on page 495 . It matches our bodies response and symptoms to decreasing blood glucose levels. I have adjusted the medical terminology slightly to meet the needs of this discussion.

 Counter regulatory hormones .
 These are hormones our body releases in an attempt to correct a falling  blood glucose  level.  Some of these hormones produce the early warning symptoms that we associate with hypoglycemia.

    Glucose level               Increase counter regulatory hormone         Effects and symptoms 
    
      < 70 mg/dl                         increase glucagon                                   increase in glucose from liver
      < 70  mg/d/                        increase Epinephrine                               increase glucose, feeling of 
                                                                                                                anxiety, sweating , shaking,
                                                                                                                pallor
     < 65 mg/dl                          increase cortisol and growth hormone     increase glucose levels

     < 60 mg/dl                                                                                           neurological symptoms
                                                                                                                     confusion, dizzy
                                                                                                                     headache,weakness
                                                                                                                     irritability , sleepy
                                                                                                                     belligerent behavior
      < 40                                                                                                        lethargy , Coma
                                                                                                                     seizures

Take home message
    Epinephrine produces the early warning symptoms of a dropping blood sugar. The loss of the
    epinephrine response to a falling glucose results in " hypoglycemia unawareness " and the 
    progression to the more severe stages of hypoglycemia.

Have Fun , Be Smart and avoid hypoglycemia
David Calder,MD

Questions
     Does lowering A1c result in increased risk of hypoglycemia in type 1 and type 2 diabetes ?
     Does age effect a persons awareness of hypoglycemia ?

      74% of unrecognized hypoglycemia occurs at night .       True or false

                                                                                             
                                                                             



Tuesday, November 13, 2012

Insulin resistance , a different perspective" inbrainertia"

Insulin resistance , a different perspective

The usual perspective.
Most people with type 2 diabetes are familiar with the term insulin resistance.  Insulin resistance is commonly associated with obesity.

 Wikipedia defines "insulin resistance" as a physiological condition in which cells fail to respond to the normal action of the hormone insulin.
            Fat and liver cells require insulin to absorb glucose.
            Liver cells respond to insulin by decreasing its secretion glucose .
            Insulin resistance also decreases the the storage of triglycerides in fat cells.

 The combination of insulin resistance and insulin deficiency is called Type 2 Diabetes

The different perspective  " inbrainertia "
We recently discussed the idea of treatment inertia. Treatment inertia is basically a form of insulin resistance that begins in our minds of patients with type 2 diabetes and their doctors. People with Type 1 Diabetes , especially children, are also victims of this form of insulin resistance.
The failure on the part of patients and their doctors to fully accept the reality of insulin deficiency and the need for insulin replacement comes with an often silent cost to their lives. Primary care doctors are  often slower than specialist in recommending insulin. Many patients are even more resistant to the idea of starting insulin.

In a recent continuing education class, Dr. Rubin reviewed data now in press for Diabetes care.
 Medication non-adherence is associated with a 58% increased in all-cause mortality

Another article pointed out  ;
 57% of patients with type 2 diabetes are very worried about having to start insulin.
                   Diabetes Care 2005;28:  2673-2679

Patients have many reasons for resisting the idea of starting insulin including;
   * My diabetes is worse
   * I failed to follow my doctors recommendation on diet and oral medications
   * Insulin won't help
 None of the above are correct .
 Type 2 diabetes is associated with a progressive loss of the ability to produce adequate insulin over time. There is hope that some of the newer diabetes medication will slow this process.

Other concerns include;
    * Fear of pain
    * Fear of hypoglycemia
    * Embarrassment
    * life style changes will be needed

All of the above are real concerns for every person with diabetes. I also know that the above concerns are over shadowed by the reality of diabetes silently stealing precious moments of our lives

Most of us have lived long enough to experienced some of the challenges life provides. The health problems most of us face are not by choice but we are often guilty of enabling the disease process. This is especially true for people with diabetes.

My approach to health issues has been framed by lessons I learned from my patients.

The practice of medicine is a rare privilege , allowing physicians to share moments in peoples lives when the "chips are down" and the reality of a situation requires a decision. I have had the privilege of observing the frailest persons make make some of the toughest decisions involving their loved ones or themselves.
These experiences helped me realize that every one of us has the hidden inner strength and courage that will rise to the surface to do what every is necessary when" chips are really down".

Well !!!
When you have diabetes , " the chips are down",  and it is time play the game .

Have fun , Be Smart  and take your insulin and don't be a victim of "Inbrainertia "
David Calder,MD


    


Saturday, November 10, 2012

Diabetes and Pancreatic Cancer . No simple answer.


Diabetes and pancreatic cancer continued discussion.  I have attached copies of 2 articles for your review.  The article by Suresh Chari, M.D., Gastroenterology, Mayo Clinic, Rochester, Minn. is a well done easy read that will help with your understanding of the problem. The second article is longer and I have hjghlighted some areas of interested.

Have fun Be Smart and remember poorly treated diabetes is a greater risk than Than the risk of developing pancreatic cancer
David Calder,MD

2012 2011 2010 2009
Link Between Pancreatic Cancer and Diabetes Not Fully Understood

July 31, 2009
Dear Mayo Clinic:
Does having diabetes increase the chance of pancreatic cancer? Would a test at the time diabetes is diagnosed help in the early detection of pancreatic cancer? Does going from diabetes pills to insulin increase the chance of getting pancreatic cancer?

Answer:
Considerable research has been done to examine the complex relationship between pancreatic cancer and diabetes. While long-standing diabetes may slightly increase the risk of pancreatic cancer, new-onset diabetes is more likely tosignal the presence of underlying cancer. However, distinguishing those who have pancreatic cancer-induced diabetes from the more common type 2 diabetes is a significant challenge. Complicating the issue further are results of recent studies suggesting that certain treatments for diabetes may decrease or increase the risk of pancreatic cancer.

Your pancreas makes insulin, a hormone that regulates blood sugar levels. Diabetes is a state in which blood sugar levels are high. Diabetes develops when your pancreas produces little or no insulin or when your body becomes resistant to insulin.

Studies focusing on people with long-standing diabetes (five or more years) have found that their risk for pancreatic cancer is slightly elevated. This phenomenon has been of interest to scientists who are trying to understand why some people get pancreatic cancer. However, since pancreatic cancer is rare, this small increase doesn't represent a significant health risk, nor does it call for increased cancer screening of patients with long-standing diabetes.

On the other hand, new development of diabetes after age 50 may be a harbinger of pancreatic cancer. Recently, Mayo Clinic researchers studied people who developed diabetes after age 50. They examined the participants' medical records to determine when their blood sugar levels were elevated to the point of becoming diabetic. Then, they reviewed the medical records for three years thereafter. The rate of pancreatic cancer in the study group was eight times higher than in the general population.

The researchers theorize that in some people who developed pancreatic cancer within this group, diabetes was actually caused by the cancer. They believe that pancreatic cancer reduced the pancreas' ability to produce insulin, resulting in diabetes.

While these results may seem to call for everyone diagnosed with diabetes after age 50 to be screened for pancreatic cancer, it isn't that easy. There is no simple screening test for pancreatic cancer. No blood test exists to determine if a person has pancreatic cancer, and imaging tests — such as computerized tomography (CT) scans — can't reliably detect pancreatic cancer in its early stages.

The search for a marker that could be detected by a blood test and distinguish between diabetes caused by pancreatic cancer and other forms of diabetes is an important area of research. If such a marker could be found, some cases of pancreatic cancer could be diagnosed in the early stages of the disease and treatment started promptly, when it's most effective.

One test that can reliably detect pancreatic cancer, endoscopic ultrasonography, is an invasive and expensive procedure. Many insurance companies won't cover the cost of this study based on a diabetes diagnosis alone. In addition, having large numbers of people undergo this type of invasive test isn't feasible in many medical centers.

Further complicating matters, people who develop diabetes as a result of pancreatic cancer usually have diabetic symptoms similar to individuals who develop diabetes for other reasons. But prior to the onset of cancer symptoms, there does seem to be one subtle clue that may hint at a difference. People who develop diabetes because of pancreatic cancer tend to experience unexplained weight loss at the onset of diabetes. Those who have type 2 diabetes often gain weight. So, endoscopic ultrasonography or other testing for pancreatic cancer does seem appropriate for patients diagnosed after age 50 who experience weight loss after developing diabetes.

Recently, diabetes treatment has also come under scrutiny for a possible link to cancer. These studies have examined the risk of pancreatic cancer in diabetic individuals taking specific anti-diabetic medications. One study conducted in Germany concluded that a newer form of insulin (glargine) may increase cancer risk, but that other forms — including human insulin and other new insulins (aspart and lispro) — do not. However, the study didn't take into account the fact that pancreatic cancer is more common shortly after a diagnosis of diabetes. Other recent studies suggest that subjects on the oral antidiabetic drug metformin were less likely to develop pancreatic cancer. These findings are intriguing, as metformin is known to inhibit cancer growth in the laboratory. More research is necessary to determine what, if anything, the findings mean for the treatment of diabetic patients.

As you can see, there are many more questions than answers regarding the connection between diabetes and pancreatic cancer. A significant amount of research is ongoing. If you're a diabetic patient concerned about your risk of cancer, talk to your doctor. And remember, never discontinue treatment or change medication without consulting your doctor first.

— Suresh Chari, M.D., Gastroenterology, Mayo Clinic, Rochester, Minn.
----------------------------------------------------------------------------------------------------------------------------------


The relationship between diabetes and pancreatic cancer
Feng Wang1, Margery Herrington1,2, Jörgen Larsson1 and Johan Permert1*
* Corresponding author: Johan Permert johan.permert@cfss.ki.se
Author Affiliations
1 Surgery Department, Karolinska Institute at Huddinge University Hospital, 141 86 Stockholm, Sweden
2 Department of Biology, Adams State College, Alamosa, CO 81102, USA
For all author emails, please log on.
Molecular Cancer 2003, 2:4 doi:10.1186/1476-4598-2-4

The electronic version of this article is the complete one and can be found online at: http://www.molecular-cancer.com/content/2/1/4

Received: 12 November 2002
Accepted: 6 January 2003
Published: 6 January 2003

© 2003 Wang et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. 
Abstract
About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes. This observation has led to the following two hypotheses: i. pancreatic cancer causes the associated diabetes and ii. the conditions associated with diabetes promote the development of pancreatic cancer. Evidence supporting both hypotheses has been accumulated in previous studies. This article reviews these studies, especially those that have been conducted recently.

Review
The early symptoms of pancreatic cancer, such as abdominal pain, weight loss, fatigue, jaundice, and nausea, are nonspecific and may occur late in the course of the disease [1,2]. As a result, pancreatic cancer is usually diagnosed at an advanced stage, frequently after the tumor has already metastasized. Pancreatic cancer is insensitive to pharmacological and radiological intervention and often recurs after apparently curative surgery. All these factors contribute to the dismal prognosis of the disease [3].

About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes [4,5]. This observation has led to the following two hypotheses: i. pancreatic cancer causes diabetes and ii. diabetes is a risk factor for the development of pancreatic cancer. Numerous studies have been performed in order to elucidate the relationship between these two diseases.

Evidence suggesting that pancreatic cancer causes diabetes
The majority of diabetes associated with pancreatic cancer is diagnosed either concomitantly with the cancer or during the two years before the cancer is found [6]; 71% of the glucose intolerance found in pancreatic cancer patients is unknown before the cancer is diagnosed [5]. These suggest that recently-developed glucose intolerance or diabetes may be a consequence of pancreatic cancer and that recent onset of glucose intolerance or diabetes may be an early sign of pancreatic cancer. Several studies have demonstrated that diabetes in pancreatic cancer patients is characterized by peripheral insulin resistance [4,5,7]. Insulin resistance is also found in non-diabetic or glucose intolerant pancreatic cancer patients, though to a lesser degree [7]. Insulin sensitivity and overall diabetic state in pancreatic cancer patients who undergo tumor resection are markedly improved three months after the surgery [7]. These data suggest that pancreatic tumors are causally related to the insulin resistance and diabetes seen in pancreatic cancer patients. In their study of sera from patients with pancreatic cancer and culture media conditioned by human pancreatic cancer cells, Basso et al. found a 2030 MW peptide that they considered to be a putative pancreatic cancer associated diabetogenic factor [8].

A number of investigators have studied insulin resistance at the organ, tissue, and cellular levels in pancreatic cancer [7-13]. Studies of the initial steps in the insulin signaling cascade in human skeletal muscles showed no significant differences in insulin receptor binding, tyrosine kinase activity, and insulin receptor substrate-1 content between pancreatic cancer patients and healthy controls [9]. However, phosphatidylinositol 3-kinase (PI3-K) activity and glucose transport, which are located downstream to the initial insulin signaling steps, were impaired in pancreatic cancer patients [10]. In addition, glycogen synthase activity was reduced in skeletal muscles of humans and rodents with pancreatic carcinoma [9,11] and in isolated rat skeletal muscles exposed to human pancreatic tumor extracts in vitro [7]. These data show that the insulin signaling cascade in skeletal muscle is impaired at multiple steps by pancreatic cancer.

An Italian group has performed a series of studies to investigate the effects of pancreatic cancer cells on hepatic insulin sensitivity. When mice were treated with culture medium conditioned by the human pancreatic cancer cell line Mia PaCa2, blood glucose was elevated compared to the control value seen in mice treated with unconditioned medium [12]. In addition, isolated rat hepatocytes showed impaired glycolysis when incubated in culture media conditioned by four human pancreatic cancer cell lines [13].

Islet dysfunction is another etiological component underlying the diabetes associated with pancreatic cancer. Because the islet mass destroyed by the tumor is only a small proportion of the whole islet mass, the islet dysfunction is unlikely to be the result of decreased total islet volume. In fact, endocrine pancreatic function can be maintained even with a larger loss of pancreatic islets [14]. Reduced insulin release is seen in pancreatic cancer patients in response to classic stimuli [5,15,16]. Insulin release was also reduced when isolated rat pancreatic islets were incubated in culture media conditioned by the human pancreatic cancer cell lines Panc-1 and HPAF or co-cultured with Panc-1 and HPAF cells [17,18]. Studies of chemically-induced pancreatic cancer in hamsters found that glucose-stimulated insulin release was impaired in vivo [19] but not in isolated perfused pancreata [20]. Ishikawa et al. found an increase in proinsulin relative to insulin in pancreatic cancer patients [21], suggesting that the maturation of proinsulin may also be affected by the tumor.

Islet hormone profiles are changed in the circulation of pancreatic cancer patients, suggesting that secretion by different types of islet cells is disrupted by pancreatic cancer [22]. Changes in islet hormone concentrations in the circulation can also be seen in hamsters after induction of pancreatic cancer [23]. Human pancreatic islets adjacent to pancreatic carcinoma show morphological abnormalities characterized by abnormal co-localization of islet hormones in islet cells [24].

The diabetogenic potential of islet amyloid polypeptide (IAPP or amylin) has been investigated by several groups. IAPP is normally produced in islet beta cells and co-released with insulin at a constant ratio. In 1994, Permert et al. found elevated circulating levels of IAPP in patients with pancreatic cancer [25]. Similar results have been reported in more recent studies by other groups [26,27]. The islets adjacent to human pancreatic carcinomas show reduced IAPP staining. In contrast, the expression of IAPP mRNA in these islets is unchanged, suggesting normal production but increased release of IAPP [25].

The molar ratio of IAPP/insulin was increased when rat pancreatic islets were co-cultured with Panc-1 and HPAF cells or cultured in media conditioned by these cell lines [17,18]. The ratio was normalized after the co-cultured cancer cells were removed [18]. In a similar co-culture model, Ding et al. found that culture media conditioned by human pancreatic cancer cells contained a soluble molecule that selectively enhanced IAPP release from BRIN-BD11 beta cells [28]. Increased IAPP/insulin ratios were also seen in rats with azaserine-induced acinar pancreatic tumors and in hamsters with ductular pancreatic tumors induced by carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) [29]. However, exposure of isolated rat pancreatic islets to hamster pancreatic cancer cells did not change the secretion of insulin and IAPP [17].

A physiological study of isolated rat pancreatic islets has shown that endogenous IAPP reduces arginine-stimulated insulin, glucagon, and somatostatin release [30]. Also, the improvement in glucose tolerance seen after tumor removal is associated with normalization of IAPP levels in the circulation [25]. Therefore, the increased IAPP release seen in pancreatic cancer patients may be responsible, at least in part, for the islet dysfunction seen in these individuals. However, when IAPP is infused in rats to create circulating concentrations comparable to the circulating IAPP levels in pancreatic cancer patients, the rats have normal glucose disposal [31]. Thus, the increased IAPP secretion found in pancreatic cancer patients is unlikely to be responsible for their peripheral insulin resistance.

Evidence for diabetes as a risk factor for pancreatic cancer
Everhart et al. examined 30 of the epidemiological studies that have looked at the association between diabetes and pancreatic cancer and used 20 of them in a meta-analysis [32]. The pooled relative risk from these studies was 2.1 for diabetes with a duration of at least l year prior to cancer diagnosis or death and 2.0 for diabetes with a duration of at least 5 years [32]. The authors concluded that pancreatic cancer could be added to the list of complications of diabetes [32]. Several epidemiological studies have analyzed relative risks associated with the different periods of time after the diagnosis of diabetes and have found a relatively modest but persistent increased risk of death from pancreatic cancer even when the diagnosis of diabetes preceded death by many years [32-37]. A population-based case-control study in the United States with 526 incident cases and 2,153 population controls showed a significant positive trend (P = 0.016) in risk with increasing years prior to diagnosis of cancer [36]. In other studies, the relative risk decreased with increasing follow-up time but remained significant [34,35,37]. However, other epidemiological studies have concluded that diabetes is not a risk factor for pancreatic cancer or else that it is not a risk factor if recently-diagnosed cases are excluded [6,38-40].

Studies of the relationship between diabetes and pancreatic cancer are complicated by the fact that diabetes has two major forms that are different entities in terms of pathophysiology [41]. A number of studies have suggested that Type I diabetes is not associated with an increased risk for pancreatic cancer [37-39]. Most epidemiological studies, however, have not distinguished between Type I and Type II diabetes. It is likely that the large majority of diabetics in the studies have Type II diabetes because this form of the disease constitutes 80–90% of the cases and is typically found in older individuals [32,35,41].

In patients with Type II diabetes (non-insulin-dependent diabetes), the pancreas is generally exposed to substantial hyperinsulinemia for years [33], suggesting that insulin may be involved in the association between long-standing diabetes and pancreatic cancer. A number of experiments have tested the hypothesis that insulin may stimulate the growth of pancreatic cancers. Binding studies have shown the presence of insulin receptors on pancreatic cancer cells [42-45]. In vitro studies have shown that insulin promotes growth of the hamster pancreatic cancer cell line H2T [42], the rat acinar pancreatic cancer cell line AR42J [45], and numerous human pancreatic cancer cells lines [44,46-51]. However, the human pancreatic cancer cell line SOJ-6 was not stimulated by insulin [46], and one of the studies using PANC-1 cells reported no response to exogenous insulin [49]. In addition to hyperinsulinemia, the increased blood glucose and free fatty acids in diabetes may also promote the growth of pancreatic cancer [52].

The genesis of the cancer is also influenced by the endocrine pancreas. In vivo studies concerning the effects of administration of exogenous insulin and/or induction of diabetes on pancreatic cancer have provided inconsistent data that reflect the complex interactions that may be involved in tumor growth [53-56]. Exogenous insulin significantly reduced the induction of benign and malignant pancreatic lesions in hamsters when given 2 hours before BOP, but the reduction in incidence was not significant when insulin was given simultaneously with BOP or 2 hours after BOP [53]. Cancer incidence in hamsters receiving insulin twice daily starting before BOP administration and continuing through the experimental period did not differ significantly from that in controls that received BOP only [54].

When hamsters were given streptozotocin (SZ) injection to diminish insulin cells and given insulin from the following day untill the end of the experiment, the inhibition of carcinogenesis in hamsters receiving SZ+BOP+insulin treatment was greater than that seen in the SZ+BOP group, compared to group treated by BOP only [54]. Hamsters receiving SZ+insulin had significantly fewer insulinomas than SZ-only animals [54]. Because insulin administration was associated with inhibition of beta cell regeneration and persistence of severe diabetes in hamsters treated with SZ [57], the investigators in the SZ/BOP/insulin study concluded that intact islet cells, rather than the availability of insulin, are prerequisite for triggering the neoplastic effects of BOP [54]. The association of intact islets with pancreatic cancer induction is also shown in transplantation studies in which tumors develop in the submandibular gland after BOP treatment if normal islets are transplanted to that site but not when pancreatic ductal cells, thyroid, heart muscle, or starch are introduced into the gland [58-60]. Submandibular gland tumor incidence was not changed when hamsters were pre-treated with SZ before islet transplantation [60].

A study of pancreatic cancer in hamsters fed a high-fat diet that potentiated pancreatic cancer provided data suggesting that islet proliferation associated with insulin resistance enhances carcinogenesis [61]. In that study, high-fat-fed hamsters had elevated insulin levels but normal glucose levels, which was consistent with a state of insulin resistance [61]. The turn-over rate of cells in islets is significantly increased in the high-fat animals, suggesting a compensatory islet cell proliferation [61]. Administration of metformin, starting 2 weeks before the administration of BOP and continuing throughout the experiment, normalized insulin concentrations and the rate of islet cell turnover [61]. Malignant pancreatic lesions were found in 50% of the high-fat/BOP animals and none in the high-fat/BOP/metformin group (P < 0.05) [61].

Conclusion
Recent studies indicate that there is no simple answer to the question of which of the two hypotheses stated at the beginning of this review is right. However, it appears that these hypotheses are not mutually exclusive, since there is considerable experimental and epidemiological evidence in support of both of them. Clearly, the relationships between pancreatic cancer and alterations in glucose metabolism are very complex.

List of abbreviations used
PI3-K: phosphatidylinositol 3-kinase,

IAPP: islet amyloid polypeptide,

BOP: N-nitrosobis(2-oxopropyl)amine,

SZ: streptozotocin.

Authors' contributions
This article was drafted by WF and MH and revised by JL and JP. All authors read and approved the final manuscript.

Acknowledgements
Our research discussed in this article was supported by grants from the Swedish Research Council, the Swedish Medical Research Council, and the Swedish Cancer Society.

References
Nix GA, Schmitz PI, Wilson JH, van Blankenstein M, Groeneveld CF, Hofwijk R: Carcinoma of the head of the pancreas. Therapeutic implications of endoscopic retrograde cholangiopancreatography findings.
Gastroenterology 1984, 87:37-43. PubMed Abstract | Publisher Full Text 
Gullo L, Tomassetti P, Migliori M, Casadei R, Marrano D: Do early symptoms of pancreatic cancer exist that can allow an earlier diagnosis?
Pancreas 2001, 22:210-213. PubMed Abstract | Publisher Full Text 
Gudjonsson B: Cancer of the pancreas. 50 years of surgery.
Cancer 1987, 60:2284-2303. PubMed Abstract 
Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnqvist HJ, Larsson J: Pancreatic cancer is associated with impaired glucose metabolism.
Eur J Surg 1993, 159:101-107. PubMed Abstract 
Schwarts SS, Zeidler A, Moossa AR, Kuku SF, Rubenstein AH: A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma.
Dig Dis 1978, 23:1107-1114.  
Gullo L, Pezzilli R, Morselli-Labate AM: Diabetes and the risk of pancreatic cancer. Italian Pancreatic Cancer Study Group.
N Engl J Med 1994, 331:81-84. PubMed Abstract | Publisher Full Text 
Permert J, Adrian TE, Jacobsson P, Jorfelt L, Fruin AB, Larsson J: Is profound peripheral insulin resistance in patients with pancreatic cancer caused by a tumor-associated factor?
Am J Surg 1993, 165:61-67. PubMed Abstract 
Basso D, Valerio A, Seraglia R, Mazza S, Piva MG, Greco E, Fogar P, Gallo N, Pedrazzoli S, Tiengo A, Plebani M: Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide.
Pancreas 2002, 24:8-14. PubMed Abstract | Publisher Full Text 
Liu J, Knezetic JA, Strömmer L, Permert J, Larsson J, Adrian TE: The intracellular mechanism of insulin resistance in pancreatic cancer patients.
J Clin Endocrinol Metab 2000, 85:1232-1238. PubMed Abstract | Publisher Full Text 
Isaksson B, Strömmer L, Friess H, Büchler MW, Herrington MK, Wang F, Zierath JR, Wallberg-Henriksson H, Larsson J, Permert J: Impaired insulin action on phosphatidylinositol 3-kinase and glucose transport in skeletal muscle of pancreatic cancer patients.
Pancreas, in press.  
Liu J, Kazakoff K, Pour PM, Adrian TE: The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model.
Pancreas 1998, 17:359-366. PubMed Abstract 
Basso D, Brigato L, Veronesi A, Panozzo MP, Amadori A, Plebani M: The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice.
Anticancer Res 1995, 15:2585-2588. PubMed Abstract 
Basso D, Valerio A, Brigato L, Panozzo MP, Miola M, Lucca T, Ujka F, Zaninotto M, Avogaro A, Plebani M: An unidentified pancreatic cancer cell product alters some intracellular pathways of glucose metabolism in isolated rat hepatocytes.
Pancreas 1997, 15:132-138. PubMed Abstract 
Bonner-Weir S, Trent DF, Weir GC: Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release.
J Clin Invest 1983, 71:1544-1553. PubMed Abstract 
Cersosimo E, Pisters PW, Pesola G, McDermott K, Bajorunas D, Brennan MF: Insulin secretion and action in patients with pancreatic cancer.
Cancer 1991, 67:486-493. PubMed Abstract 
Fox JN, Frier BM, Armitage M, Ashby JP: Abnormal insulin secretion in carcinoma of the pancreas: response to glucagon stimulation.
Diabet Med 1985, 2:113-116. PubMed Abstract 
Wang F, Larsson J, Abdiu A, Gasslander T, Westermark P, Adrian TE, Permert J: Dissociated secretion of islet amyloid polypeptide and insulin in serum-free culture media conditioned by human pancreatic adenocarcinoma cell lines.
Int J Pancreatol 1997, 21:157-164. PubMed Abstract 
Wang F, Adrian TE, Westermark G, Gasslander T, Permert J: Dissociated insulin and islet amyloid polypeptide secretion from isolated rat pancreatic islets cocultured with human pancreatic adenocarcinoma cells.
Pancreas 1999, 18:403-409. PubMed Abstract 
Ahrén B, Andren-Sandberg A: Glucose tolerance and insulin secretion in experimental pancreatic cancer in the Syrian hamster.
Res Exp Med 1993, 193:21-26.  
Bell RH Jr, Place S, McCullough P, Ray MB, Rogers DH: Pancreatic insulin secretion in exocrine pancreatic cancer.
J Surg Res 1986, 40:588-596. PubMed Abstract 
Ishikawa O, Nakamori S, Ohigashi H, Immaoka S: Increased secretion of proinsulin in patients with pancreatic cancer.
Int J Pancreatol 1994, 16:86-89.  
Permert J, Larsson J, Fruin AB, Tatemoto K, Herrington MK, von Schenck H, Adrian TE: Islet hormone secretion in pancreatic cancer patients with diabetes.
Pancreas 1997, 15:60-68. PubMed Abstract 
Permert J, Herrington M, Kazakoff K, Pour PM, Adrian TE: Early changes in islet hormone secretion in the hamster pancreatic cancer model.
Teratog Carcinog Mutagen 2001, 21:59-67. PubMed Abstract | Publisher Full Text 
Pour PM, Permert J, Mogaki M, Fujii H, Kazakoff K: Endocrine aspects of exocrine cancer of the pancreas. Their patterns and suggested biologic significance.
Am J Clin Pathol 1993, 100:223-230. PubMed Abstract 
Permert J, Larsson J, Westermark GT, Herrington MK, Christmanson L, Pour PM, Westermark P, Adrian TE: Islet amyloid polypeptide in patients with pancreatic cancer and diabetes.
N Engl J Med 1994, 330:313-318. PubMed Abstract | Publisher Full Text 
Chari ST, Klee GG, Miller LJ, Raimondo M, DiMagno EP: Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer.
Gastroenterology 2001, 121:640-645. PubMed Abstract | Publisher Full Text 
Makimattila S, Hietaniemi K, Kiviluoto T, Timonen T, Yki-Jarvinen H: In vivo glucose-stimulated amylin secretion is increased in nondiabetic patients with pancreatic cancer.
Metabolism 2001, 5:1036-1042.  
Ding X, Flatt PR, Permert J, Adrian TE: Pancreatic cancer cells selectively stimulate islet beta cells to secrete amylin.
Gastroenterology 1998, 114:130-138. PubMed Abstract | Publisher Full Text 
Oosterwijk C, van Hulst KL, Visser CJ, Woutersen RA, Lips CJ, van den Tweel JG, Hoppener JW: Pancreatic cancer in rats and hamsters does not induce IAPP-related hyperglycaemia.
Int J Cancer 1997, 72:637-641. PubMed Abstract | Publisher Full Text 
Wang F, Adrian TE, Westermark GT, Ding X, Gasslander T, Permert J: Islet amyloid polypeptide tonally inhibits beta-, alpha-, and delta-cell secretion in isolated rat pancreatic islets.
Am J Physiol 1999, 276:E19-E24. PubMed Abstract | Publisher Full Text 
Arnelo U, Permert J, Larsson J, Reidelberger RD, Arnelo C, Adrian TE: Chronic low dose islet amyloid polypeptide infusion reduces food intake, but does not influence glucose metabolism, in unrestrained conscious rats: studies using a novel aortic catheterization technique.
Endocrinology 1997, 138:4081-4085. PubMed Abstract | Publisher Full Text 
Everhart J, Wright D: Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis.
JAMA 1995, 273:1605-1609. PubMed Abstract 
Gapstur SM, Gann PH, Lowe W, Liu K K, Colangelo L, Dyer A: Abnormal glucose metabolism and pancreatic cancer mortality.
JAMA 2000, 283:2552-2558. PubMed Abstract | Publisher Full Text 
Calle EE, Murphy TK, Rodriguez C, Thun MJ, Heath CW Jr: Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults.
Cancer Causes Control 1998, 9:403-410. PubMed Abstract | Publisher Full Text 
Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, Borch-Johnsen K, Olsen JH: Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark.
J Natl Cancer Inst 1997, 89:1360-1365. PubMed Abstract | Publisher Full Text 
Silverman DT: Risk factors for pancreatic cancer: a case-control study based on direct interviews.
Teratog Carcinog Mutagen 2001, 21:7-25. PubMed Abstract | Publisher Full Text 
Chow WH, Gridley G, Nyren O, Linet MS, Ekbom A, Fraumeni JF Jr, Adami HO: Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden.
J Natl Cancer Inst 1995, 87:930-931. PubMed Abstract 
Gullo L: Diabetes and the risk of pancreatic cancer.
Ann Oncol 1999, 10(Suppl 4):S79-S81.  
Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A: Cancer and diabetes – a follow-up study of two population-based cohorts of diabetic patients.
J Intern Med 1997, 241:471-475. PubMed Abstract 
Frye JN, Inder WJ, Dobbs BR, Frizelle FA: Pancreatic cancer and diabetes: is there a relationship? A case-controlled study.
Aust NZJ Surg 2000, 70:722-724. Publisher Full Text 
Saltiel AR: New perspectives into the molecular pathogenesis and treatment of type 2 diabetes.
Cell 2001, 104:517-529. PubMed Abstract | Publisher Full Text 
Fisher WE, Muscarella P, Boros LG, Schirmer WJ: Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse.
Surgery 1998, 123:315-320. PubMed Abstract | Publisher Full Text 
Fisher WE, Boros LG, O'Dorisio TM, O'Dorisio MS, Schirmer WJ: GI hormonal changes in diabetes influence pancreatic cancer growth.
J Surg Res 1995, 58:754-758. PubMed Abstract | Publisher Full Text 
Fisher WE, Boros LG, Schirmer WJ: Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors.
J Surg Res 1996, 63:310-313. PubMed Abstract | Publisher Full Text 
Mossner J, Logsdon CD, Williams JA, Goldfine ID: Insulin, via its own receptor, regulates growth and amylase synthesis in pancreatic acinar AR42J cells.
Diabetes 1985, 34:891-897. PubMed Abstract 
Takeda Y, Escribano MJ: Effects of insulin and somatostatin on the growth and the colony formation of two human pancreatic cancer cell lines.
J Cancer Res Clin Oncol 1991, 117:416-420. PubMed Abstract 
Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger HG, White MF, Korc M: Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer.
Cancer Res 1998, 58:4250-4254. PubMed Abstract 
Ding XZ, Fehsenfeld DM, Murphy LO, Permert J, Adrian TE: Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression.
Pancreas 2000, 21:310-320. PubMed Abstract | Publisher Full Text 
Beauchamp RD, Lyons RM, Yang EY, Coffey RJ Jr, Moses HL: Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines.
Pancreas 1990, 5:369-380. PubMed Abstract 
Wang F, Larsson J, Adrian TE, Gasslander T, Permert J: In vitro influences between pancreatic adenocarcinoma cells and pancreatic islets.
J Surg Res 1998, 79:13-19. PubMed Abstract | Publisher Full Text 
Liehr RM, Melnykovych G, Solomon TE: Growth effects of regulatory peptides on human pancreatic cancer lines PANC-1 and MIA PaCa-2.
Gastroenterology 1990, 98:1666-1674. PubMed Abstract | Publisher Full Text 
Fisher WE, Boros LG, Schirmer WJ: Reversal of enhanced pancreatic cancer growth in diabetes by insulin.
Surgery 1995, 118:453-8. PubMed Abstract 
Pour PM, Stepan K: Modification of pancreatic carcinogenesis in the hamster model. VIII. Inhibitory effect of exogenous insulin.
J Natl Cancer Inst 1984, 72:1205-1208. PubMed Abstract 
Pour PM, Kazakoff K, Carlson K: Inhibition of streptozotocin-induced islet cell tumors and N-nitrosobis(2-oxopropyl)amine-induced pancreatic exocrine tumors in Syrian hamsters by exogenous insulin.
Cancer Res 1990, 50:1634-1639. PubMed Abstract 
Bell RH Jr, McCullough PJ, Pour PM: Influence of diabetes on susceptibility to experimental pncreatic cancer.
Am J Surg 1988, 155:159-164. PubMed Abstract 
Povoski SP, Fenoglio-Preiser CM, Sayers HJ, McCullough PJ, Zhou W, Bell RH Jr: Effect of streptozotocin diabetes on development of nitrosamine-induced pancreatic carcinoma when diabetes induction occurs after nitrosamine exposure.
Carcinogenesis 1993, 14:961-967. PubMed Abstract 
Pour PM, Duckworth W, Carlson K, Kazakoff K: Insulin therapy prevents spontaneous recovery from streptozotocin-induced diabetes in Syrian hamsters. An autoradiographic and immunohistochemical study.
Virchows Arch A Pathol Anat Histopathol 1990, 417:333-341. PubMed Abstract 
Ishikawa O, Ohigashi H, Imaoka S, Nakai I, Mitsuo M, Weide L, Pour PM: The role of pancreatic islets in experimental pancreatic carcinogenicity.
Am J Pathol 1995, 147:1456-1464. PubMed Abstract 
Pour PM, Weide L, Liu G, Kazakoff K, Scheetz M, Toshkov I, Ikematsu Y, Fienhold MA, Sanger W: Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans.
Am J Pathol 1997, 150:2167-2180. PubMed Abstract 
Fienhold MA, Kazakoff K, Pour PM: The effect of streptozotocin and a high-fat diet on BOP-induced tumors in the pancreas and in the submandibular gland of hamsters bearing transplants of homologous islets.
Cancer Lett 1997, 117:155-160. PubMed Abstract | Publisher Full Text 
Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM: Prevention of pancreatic cancer induction in hamsters by metformin.
Gastroenterology 2001, 120:1263-1270. PubMed Abstract | Publisher Full Text 

Tuesday, November 6, 2012

Diabetes, Januvia and Cancer

I have attached a email exchange that you find interesting.  Dr. Calder

Info@diabetesofficevisit.com
Nov. 1, 2012

Hello Dr. Calder,
  Recently I came across your very informative diabetes site, and after reading through many of your articles I decided to email you regarding a question I have about Janumet.  By the way, I am a 49 year old male with type 2 diabetes.  About a month ago my doctor decided that Metformin was not working as well as it used to in keeping my A1C down,  so he prescribed Janumet twice daily. Within a day or two of taking Janumet, I noticed a vast improvement in my blood sugar levels.  However, being the inquisitive person I am, I began researching Janumet and Januvia online, and quickly came across many articles warning that these medications can cause pancreatic cancer.  Do you have any updated information regarding this?  I certainly appreciate the fact that Janumet is working wonders for my blood sugar levels, but of course I do not desire to increase my odds of getting pancreatic cancer in the process.  Anything you might be able to share with me regarding this would be greatly appreciated.  Thank-you for your time.

   Sincerely,
 Jody 
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NOV.4, 2012
Hello Jody
I apologize for not getting back to you sooner. I have an excuse , my wife and I are in the process of buying and remodeling a new home and selling the one we are in now. I had forgotten what a hassle this process is. 

Thank you for this very timely question. I will give you my initial reaction today and provide a more informed discussion later. 

Pancreatic cancer and its relationship to Type 2 Diabetes and diabetes medications is not clear.Even the  time of diagnosis of Type 2 diabetes and the diagnosis of pancreatic cancer is not clear . Did the cancer cause the elevated sugar and the diagnosis  of diabetes or did the diabetes cause the cancer?  Attaching a certain diabetes medication as a cause of pancreatic cancer is even more difficult .

In any case , pancreatic cancer is very rare in every one including people with type 2 diabetes. The complications  death and disability ( especially heart disease )from poor diabetes management is very common. 

My gut reaction is , the benefits of taking Janumet ( januvia combined with metformin ) are much greater than the risk of developing cancer.
Metformin has also been shown to reduce the risk of developing some cancers.

I will get more specific information for you and me.
Dr. Calder

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Hello Dr. Calder,

  Please do not apologize for the delay in getting back to me, it is I who am honored that you took the time to respond.  After reading so many scare stories online about Januvia and Janumet, I temporarily stopped taking my twice daily Janumet.  After reading your reassuring and very logical response I resumed taking my medication today.  Although I think the internet is a Godsend, I am also aware that it is rather easy to misuse it when it comes to researching medications.  After reading the multitude of horror stories about patients having terrible side effects after taking a prescription drug, it is no wonder many patients become non-compliant.  You have the websites ranting about big bad pharma, and how the prescription drug makers are out simply to make a buck without regards to public safety.  There are even diabetes blogs where diabetics are warned about how dangerous taking their prescribed medication can be.  Many believe all diabetics can stop the disease in its tracks by diet and exercise alone.  Unfortunately that did not work for me.  Even with a low-carb diet my fasting blood sugars were well above normal.  

  Anyhow, I have rambled on enough.  Once again I thank-you for responding, and most likely saving me from an early death.  In all honesty, I had no intention of ever taking my Janumet again until I read your response.  You cut through all the crap I was reading and gave me an honest and very well thought out response.  I doubt I will ever be able to thank-you enough Dr. Calder.

  Good luck with your house.

     Sincerely,
     Jody
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info@diabetesofficevisit.com

 Thanks . Can I use your question and answers  as a post. I will remove your name and email address and have you approve it before it is published. I think we did a good job with a real problem that other people may be dealing with .  Dr. Calder

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info@diabetesofficevisit.com

Please feel free to use my question, and using my name and email is fine.  I do not have to proof read it, I certainly have full trust in you Dr.  Thanks again. jody

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I want to thank Jody for initiating this exchange about the risk of cancer associated with diabetes.

This is a complex issue with less than perfect answers. Type 2 diabetes and people with Pre-diabetes seem to have a slight increase cancer risk .  I don't think the increased risk applies to people with type 1 diabetes.

My personal experience as diabetes specialist in an endocrine group supports my thoughts about how rare cancer is in patients with diabetes. I can recall the the few people that I saw with cancer and type 2 diabetes. I am also sure that a cancer specialist has probable had a different experience.

My experience with diabetes associated complications , especially heart disease , was a frequent daily experience. Our endocrine group managed the in hospital diabetes care for the cardiovascular surgeons. We followed 5 to 10 people with primarily type 2 diabetes and undiagnosed diabetes daily admitted  for coronary bypass surgery.
This story reminds me of the child hood story of  blind men examining and describing an elephant.

Have Fun, Be Smart and remember your personal doctor is still your best source of medical advise.
David Calder, MD

I have attached links to some of my previous post discussing cancer and diabetes


Monday, November 5, 2012

Diabetes Office Visit up date is on the way

The Diabetes Office visit  iphone and ipad app is still having problems with the Risk Management Section. We are working to correct the problem . I suggest not using this section until we get the bugs worked out.

The  ebook, goal setting and glucose management sections are working without problems. I hope to get the problem resolved soon.

 Dr. Calder

Sunday, November 4, 2012

Avoid Desiccated thyroid hormone replacement is still a good idea

I am repeating this post from almost 1 year ago because it continues to get  comments with varying opinions  from my readers. Please review this including the comments  below. I have
also attached 2 articles discussing the small percentage of people who do have a genetically caused problem with an enzyme system that reduces T3, the active form of thyroid hormone .

Have fun , Be smart  study any health problem you may have . Having an informed discussion with your doctor may improve your overall health.
David Calder,MD

Avoid Desiccated Thyroid Hormone Replacement

Avoid Desiccated Thyroid Hormone Replacement

Desiccated thyroid hormone , Armour thyroid and Thyroid USP is listed as obsolete by the FDA but continues to be prescribed and used by some people . I recently saw a video promoting the use of desiccated thyroid which prompted me to write this note.

Our thyroid gland produces thyroid hormone in a response to TSH ( thyroid stimulating hormone ) from our pituitary gland. The primary form of thyroid hormone produced and released into our blood is T4 . This T4 is slowly converted to the active hormone T3 in our tissues,primarily the liver . The T3 Hormone in correct amounts helps keep all of the cells of our body running at peak efficiency.

A deficiency of T4 and T3 results in a slow down of all of the machinery in our body and an excess of T4 and T3 can have toxic effects especially for our heart causing arrhythmia , heart failure , angina or even cardiac arrest. The effect of excess T3 is a concern for anyone with heart disease.
( many of us have a little silent coronary heart disease ).

So, why is desiccated thyroid hormone not a recommended treatment for hypothyroidism ?

Desiccated Thyroid Hormone is of animal thyroid tissue origin. This means that it contains a mixture of T4 and T3. The T3 is almost 100% absorbed rapidly producing abnormally high levels of T3 in the blood stream and potentially a toxic effect on that persons heart.

Levothyroxine ( L-thyroxine , levothyroid , synthyroid and others) is T4 and is much safer to use. The T4 is absorbed and converted slowly to the active T3 , similar to the function of a normal thyroid gland. Be safe . If you need thyroid hormone replacement, use T4.
Dr. Calder


7 comments:

  1. Hey very interesting blog!
    Look into my page : Adrenal Fatigue Mild anxiety
    ReplyDelete
  2. This doctor or whatever he is...doesn't know what he's talking about. Most who suffer from hypothyroidism have found that T4 only treatment is horrible and that we DO NOT convert T4 to T3 readily. It has also been proven that taking NDT (Natural Desiccated Thyroid) helps prevent heart problems and heart attacks. Do the research Dr. Calder. I tried T4 only treatment and still felt like crap. Adding T3 into my regime only made things worse. It wasn't until I started taking NDT that I got optimized and all my hypo symptoms went away. Try looking up Janie Alexander Bowthorpe's STTM page on Facebook. 7000 of us strong and 90% of those on this board take NDT and have found it far superior to T4 only treatment. You are just like the 5 or 6 Endo's that I have fired who told me..."here take this one little pill (T4) and it will make you feel all better. To that I say BS! T4 does nothing but make most people sicker. Adding in T3 helps...but it is NDT that really makes the difference
    ReplyDelete
  3. Thanks for your comment. We are fortunate to have a variety of options available to help manage the various medical problems we all deal with in our lives. It is good that you found something that works for you. Dr. Calder
    ReplyDelete
  4. Hi, it seems to be very complex. I think a lot of people who are hypothyroid, most of whom have autoimmune disease, do not respond well to T4 alone. I appreciate you bringing up concern about risks, but going untreated or unsuccessfully treating with T4 is also risking heart problems. Not to mention many untreated or T4-supplemented patients whose lives have come to a standstill because of extreme fatigue, memory problems, and mood swings. So treating immune and adrenal imbalance and its possible causes with diet and safe herbs and supplements, and if necessary proceeding cautiously with whatever form of thyroid hormone works to improve life in general, seems imperative.
    ReplyDelete
  5. I have hashi and 2 months ago tried a combination of t4/t3 at 76mcg/18mcg split. I am 34, super fit and I recently took a ride in the back of an ambulance twice for cardiac arrythmia!!!! It was very, very scary. Today I skipped my dose and my resting heart rate immediately returned to normal at 60bpm versus the last two months of 80-90. We are all different but I think it's disrespectful and wrong to say the doc doesn't know of what he speaks. I also tried dedicated and my hr went the other way to 42bpm. So, guess who is going back to t4 only? Me. Thanks doc- this is important information.
    ReplyDelete
  6. also the chinese have been using desiccated for 2100 years yes that's 900BC so I am going to buy it off the net instead of t4/t3 which is all we get in the uk as it's CHEAP! crap life for thirty years, don't forget desiccated adrenal which so farr is saving my life.
    ReplyDelete
  7. Thanks for your comment.
    I would use caution in buying any medication from the internet, especially desiccated thyroid. You have no idea of where or under what conditions the internet medications are produced.( see my post above)
    Treating the lab test TSH , free T4 is easier than treating the symptoms of hypothyroidism . The symptoms of tiredness and fatique may have other causes. Many people with hypothyroidism have Hashimotos Thyroiditis ( a chronic autoimmune inflammation of the thyroid gland) causing the symptoms .
    T3,has 3 iodine molecules,and is the active form of Thyroid hormone . It is produced in our body by by an enzyme that removes one iodine molecule from T4 . T4 has 4 iodine molecules and is the less active precursor to T3. A small percentage of people with Hypothyroidism may also have genetically cause malfunction of the enzyme system responsible for removing an iodine molecule from T4 resulting in a deficiency of
    T3. This person will benefit from taking a thyroid replacement containing both T4 and T3.

    I recommend seeing an endocrinologist for an opinion and using FDA approved thyroid from your local pharmacy and avoiding desiccated thyroid.
    Dr. Calder
    ____________________________________________________________________________
    The attached articles that may add to your understanding of some of the problems of thyroid hormone replacement.
    Dr. Calder
    #1
    J Clin Endocrinol Metab. 2009 May;94(5):1623-9. Epub 2009 Feb 3.
    Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.
    Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM.
    Source
    Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, United Kingdom.
    Abstract
    INTRODUCTION:
    Animal studies suggest that up to 80% of intracellular T(3) in the brain is derived from circulating T(4) by local deiodination. We hypothesized that in patients on T(4) common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T(4)/T(3) without necessarily affecting serum thyroid hormone levels.
    METHODS:
    We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T(4)/T(3) in 552 subjects on T(4) from the Weston Area T(4) T(3) Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).
    RESULTS:
    The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T(4) (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T(4)/T(3) therapy compared with T(4) only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.
    CONCLUSIONS:
    Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T(4) and enhanced response to combination T(4)/T(3) therapy, but did not affect serum thyroid hormone levels.

    #2
    Resistant Hypothyroidism? Consider Adding Liothyronine
    By: BRUCE JANCIN, Internal Medicine News Digital Network

    09/04/12 
    EXPERT OPINION FROM AN UPDATE ON INTERNAL MEDICINE SPONSORED BY THE UNIVERSITY OF COLORADO  
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    In a secondary analysis of a study involving 552 hypothyroid patients randomized to LT4 or LT4/LT3, the prevalence of Thr92Ala homozygosity was 16%, and psychological well being in patients with the deiodinase 2 polymorphism improved significantly more on combination therapy than with LT4 alone (J. Clin. Endocrinol. Metab. 2009;94:1623-9).

    The fact that the Thr92Ala polymorphism is present in only 16% of individuals on thyroid hormone therapy might explain why so many randomized trials of LT4 versus combination therapy were negative: With study populations of only 20-141 patients, the trials would have been underpowered to detect a significant difference in treatment effect. Unfortunately, genetic testing for deiodinase polymorphisms is not commercially available, the endocrinologist observed.

    When he does resort to combination therapy, Dr. McDermott prescribes it in an LT4:LT3 ratio of 10-14:1 to mimic normal thyroid secretion. He generally has patients take LT3 twice daily, with the second dose no later than about 6 p.m. so it doesn’t interfere with sleep. Once-daily slow-release formulations of LT3 are available in Europe and work very well. Several companies are interested in developing a slow-release LT3 for the United States, which would be a welcome development, according to Dr. McDermott.

    Another option, once all else has been tried and failed, is to switch to another brand of LT4, he continued. Some patients may have adverse reactions to the various dyes and fillers contained in LT4 pills. When this is a potential concern, levothyroxine sodium (Tirosint), approved by the Food and Drug Administration a couple of years ago, is an attractive option. The LT4 in Tirosint is contained in oil in a liquid gelcap with no dyes or fillers, differentiating it from all other brand name and generic products, Dr. McDermott noted.

    He emphasized the importance of avoiding overtreatment with LT4 in an attempt to improve quality of life in patients with residual symptoms despite a TSH of 0.5-2.0 mU/L. Subclinical hyperthyroidism as defined by a TSH below 0.1 mU/L has been shown to significantly increase the risk of hip and spine fractures, atrial fibrillation, and cardiovascular mortality.

    Dr. McDermott reported having no financial conflicts.