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Pancreatic cancer and soda consumption:

Jacob Schor ND FABNO

February 13, 2010

 

An odd coincidence in timing: 

Perhaps it is because soda and candy have been a big story in Colorado legislative news over the last few months, that an article in an obscure epidemiology journal caught my attention this past week.  Back in November 2009 Colorado’s currently democratic leadership announced plans to add a 2.9% tax to carbonated beverages and candy as part of a comprehensive plan to balance the state budget.  The bill to turn Governor Ritter’s soda tax proposal into law was passed by the Colorado Senate just a few days ago. The lead up debate to this vote brought forth vocal opponents that made it apparent that many people believe unfettered access to soft drinks is a fundamental right guaranteed in the Constitution.

Coincident with these Colorado legislative debates, but unmentioned, is a fascinating paper by Noel Mueller et al. that appeared in the February issue of Cancer Epidemiology, Biomarkers & Prevention.  According to their analysis, drinking two or more sodas a week almost doubles a person’s risk of getting pancreatic cancer.

Their data was collected from a prospective cohort made up of 60,524 people who are taking part in the Singapore Chinese Health Study. Information on consumption of soft drinks, juice, and other dietary items, as well as lifestyle and environmental exposures, was collected through in-person interviews at recruitment.

 

Following these people for 14 years yielded 648,387 person-years of data and 140 cases of pancreatic cancer (PC). Individuals who consumed two or more soft drinks a week experienced a statistically significant increase in risk of pancreatic cancer (hazard ratio, 1.87; 95% confidence interval, 1.10-3.15) compared with individuals who did not consume soft drinks. There was no association seen between drinking fruit juice and risk of PC.

A hazard ratio of 2.0 would mean soda drinkers were twice as likely to get pancreatic cancer.  This ratio of 1.87 is just a little less than 2.0.

 

Background is essential to understand the results of this study.   This is just the latest in a series of studies on the subject that have yielded sometimes conflicting and confusing results.  Yet the bottom line consensus appears to be that soda or other concentrated forms of sugar, such as candy bars, do increase risk of pancreatic cancer.

 

The first thing we have to understand with PC is that it’s one of the bad cancers; five-year survival even with modern treatment is less than 5%.  Treatment does little good; a better approach is to focus on prevention.  Cigarette smoking is the one accepted risk factor consistently associated with increased risk of pancreatic cancer.  Type 2 diabetes also increases risk.  This led to a theory that producing high levels of insulin might somehow lead to malignant transformation of pancreatic cells.

In most cancers, the cells that become cancerous have been somehow overworked, irritated, or in some way abused prior to becoming cancer cells.  They have been pushed by something to grow faster, work harder, secrete more or in some manner live harder lives.  Estrogen pushes both breast and uterine cells to become cancerous.  Testosterone pushes prostate cells to become prostate cancer. Infections push lymph cells to become lymphoma. Chronic inflammation pushes colon cancer cells, etc.  This theory about pancreatic cancer suggests that high sugar intake pushes the pancreas.   Granted, this is a vast oversimplification of both a complex process and a complicated hypothesis, but it works for my simple mind.

 

Diabetes has been associated with pancreatic cancer for decades. A study on Seventh Day Adventists published in 1988 reported that,A prior history of diabetes was associated with increased risk of subsequent fatal pancreas cancer….”   Overwork cells or abuse them and they aren’t happy.

A Kaiser Permanente study published that same year, found that while cigarette smoking increased risk of pancreatic cancer by a factor of 2.5, people who had been treated for diabetes had 4.5 times the risk. (Smoking: relative risk, 2.5; 95% confidence interval, 1.3-4.7.  Diabetes: relative risk, 4.5; 95% confidence interval, 1.2-16.7).)

 

A Dutch paper published two years later in 1990, that analyzed data on 164 patients with pancreatic cancer, found, “…a significant, positive association between pancreatic cancer and past habitual intake of simple sugars…. (OR 1.95; 95% confidence interval 1.24-3.07).”  This led the study authors to, “… suggest that the development of exocrine pancreatic carcinoma is positively related to past habitual intake of total energy, total carbohydrates and simple sugars, …”  

 

A 1991 Australian paper that analyzed the habits of 104 people who developed PC also found a link to sugar consumption. “For the top quartile of refined sugar intake, the estimated relative risk was 2.21 (95% confidence interval 1.07-4.55).” 

 

[Of course sugars aren’t the only dietary culprit in the pancreatic cancer story.  High fat diets have also been identified as a factor. A November 1993 study reported that high fat foods tripled risk.   ]

A December 1995 study that looked at 179 cases of PC in French speaking Canadians found a similar effect of sugar consumption. Again, high sugar consumption nearly tripled risk.  Of interest in this paper was the pronounced effect of cooking with firewood, a habit that increased relative risk by a factor of almost 5, while cooking in a pressure cooker lowered risk to 1/3 the average. 

 

Sweetened carbonated drinks, what we call soft drinks, or soda, are a major source of simple sugars in western diets and as such, soda consumption provides a measure of overall sugar consumption. Soda consumption is associated with hyperglycemia and hyperinsulinemia, obesity and type 2 diabetes. 

 

Let us return to the current study by Mueller and colleagues.  Rates of developing pancreatic cancer have plateaued and are stable in the United States but they are rising among Chinese men and women in Singapore. From 1968 to 1998 they have almost doubled going from 3.7 to 5.4 per 100,000 for men and 1.5 to 3.4 per 100,000 for women. One explanation for this increase is the shift toward a more western diet and increased consumption of sugar and sugar sweetened sodas.  It may be that during this transition period between traditional diets and western diets that the effect of soda consumption is more pronounced.  Soda may be adopted into the diet while traditional foods and recipes still comprise the basic diet. 

 

On the other hand as soda consumption increases so do other behaviors linked to higher risk of pancreatic cancer.  For example in the Mueller study, people who drank more soda also consumed more red meat, total fat, sugar, candy, and alcohol.  They smoked more, exercised less and were more likely to become diabetic.  Is soda the cause of the increased risk or is it just a marker of overall poor lifestyle?  The intricate dissection of this data using statistical tools is a delicate task.  Simply gathering data on so rare a cancer is itself a challenge. 

 

In the last five years four other prospective cohort studies have been published that looked at this same equation of soda or sugar consumption and whether it is tied to pancreatic cancer risk. (Schernhammer, Larsson, Nothlings, Bao)  Results from the current Mueller paper are consistent with three out of four of these earlier studies.  One other study included fruit juice and found a positive association between juice intake and PC risk; this current study did not find an association. 

 

Eva Schernhammer and researchers from Harvard used data from two large cohorts, the Nurses' Health Study and the Health Professionals Follow-up Study, comprising 88,794 women and 49,364 men for their 2005 paper. These cohorts over the course of 20 years follow-up yielded data on 379 cases of pancreatic cancer.  Schernhammer’s analysis found that the women who consumed more than 3 sodas a week had a 57% greater risk of pancreatic cancer than women who drank one or less sodas a month. (RR, 1.57; 95% CI, 1.02-2.41; P for trend = 0.05).    No association was found in the 174 men who developed pancreatic cancer.

 

In November 2006, the American Journal of Clinical nutrition published a paper by Susanna Larsson et al, analyzing Swedish dietary data from a cohort of 77,797 people who were followed for 7 years, 131 of whom developed pancreatic cancer. Those who drank 2 or more soft drinks a day had a 93% increased risk of pancreatic cancer. (OR1.93 (1.18, 3.14; P for trend = 0.02)

 

A November 2007 study conducted by Nothlings and fellow researchers from the University of Hawaii analyzed data for 162,150 participants in the Hawaii-Los Angeles Multiethnic Cohort Study to investigate associations between glycemic load, dietary carbohydrates, sucrose, fructose, total sugars, and added sugars and the risk of pancreatic cancer.  During 8 years of follow-up, 434 pancreatic cancer cases occurred within the group.  Again the results though suggestive contradict, at least in part, other studies. The risk of PC increased with higher intakes of total sugars, fructose, and sucrose.  The association with fructose was significant when the highest and lowest quartiles were compared (relative risk: 1.35; 95% CI: 1.02, 1.80; P for trend = 0.046). An almost identical association was found with high fruit and juice intake (1.37; 1.02, 1.84; P for trend = 0.04).  But no association was seen with soda intake.  The researchers concluded that, “High fructose and sucrose intakes may play a role in pancreatic cancer etiology. Conditions such as overweight or obesity in which a degree of insulin resistance may be present may also be important.”

 

The Bao study published in 2008 is the one report that did not find an association between sugar and PC.  This is despite the fact that it was the largest of the studies.  Rather than soda they calculated the total consumption of added sugar and sugar-sweetened foods and beverages, examining data from 487,922 men and women calculating total added dietary sugar intake. During 7.2 years of follow-up, 1,258 pancreatic cancer cases were found within the group. The lowest sugar consumers averaged about 3 tsp/day while the high consumers averaged almost 23 tsp/day.  No difference in risk was seen between these two groups.  We should clarify; no statistically significant difference was seen.  The low sugar consumers had a relative risk of 0.85 compared to the high sugar eaters but this did not reach statistical significance. Thus these results did not support the sugar hypothesis.

 

Just a year later in August 2009, another study reported different results, a positive but still confusing, association.  June Chan and colleagues from the University of California in San Francisco reported in the journal Cancer Causes and Control on a comparison of the dietary habits of 532 people who developed PC with people who didn’t. “Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk…” that ranged from an overall risk of 1.9 for total sweets to 3.3 for candy bars but in this study,  “…Sweets were not consistently associated with risk among women.”  In contrast to other soda studies they also reported that,  “Sweetened beverages were not associated with increased pancreatic cancer risk.”  But to confuse things further,  “… low-calorie soft drinks were associated with increased risk among men…”

 

In November 2009 an Italian study was published that once again supported a link between sugar consumption and pancreatic cancer.  Polesel et al. worked with data from 326 patients with pancreatic cancer comparing them to 652 control patients. Comparing the diets of the two groups they found that, “Frequent meat consumption was associated to a twofold increased risk of pancreatic cancer (95% CI: 1.18-3.36). Added table sugar (OR = 2.23; 95% CI: 1.34-3.71) and potatoes (OR = 1.79; 95% CI: 1.12-2.86) were related to pancreatic cancer.”  Leading them to conclude that, “The increased risk for table sugar suggests that insulin resistance may play a role in pancreatic carcinogenesis.”

 

Thus the results of the Mueller study do not stand-alone but are one of a series of studies that have parsed out this relationship between sugar and pancreatic cancer.  If we are to accept these findings though we need an explanation to explain this relationship.

 

There are two types of pancreatic cancer, endocrine or exocrine; endocrine tumors develop in the hormone producing tissues for secretion into the blood while exocrine cancers develop from the tissues that make digestive enzymes for secretion into the intestine.  “Of pancreatic tumors, 95% develop from the exocrine portion of the pancreas, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.”   These exocrine derived are the focus of this discussion.

 

“It is tacitly assumed that the endocrine and exocrine parts of the pancreas are independent of each other, almost as though they were anatomically related by some sort of celestial coincidence.”  But this is not the case.  Instead, “…the two components are functionally related, and that the endocrine gland exerts a profound effect upon the digestive activities of the organ.”  Blood and with it, insulin, are carried from insulin producing cells to exocrine cells in what has been named the Insulin-Pancreatic Acinar Axis.  Insulin regulates the exocrine function of the pancreas. Exocrine cells are exposed to insulin concentrations that are 20-fold higher than in general circulation. Insulin has an effect on these cells increasing cell division and stimulating production of amylase.      These high insulin levels may increase free insulin-like growth factor (IGF) by lowering levels of IGF-binding proteins.  Low levels of IGF-binding proteins are suggested in some research to be risk factor for pancreatic cancer.  

 

[It should be noted that not all studies support this idea; an August 2009 paper found no link between IGF-1 or IGF-binding proteins and PC. ]

 

The Mueller paper found no association between fasting plasma insulin levels and pancreatic cancer risk. “This suggests that postprandial insulin may be a better measure for the association with cancer risk than fasting insulin levels and is consistent with the independent role of soft drink consumption in the development of pancreatic cancer….” In other words it may be the surge of insulin produced after eating concentrated sugars that is the problem.

 

Abandoning these soda studies for a moment, this idea that elevated insulin levels increase cancer risk is supported by a paper published in September 2009 in Diabetologia. Currie and colleagues at Cardiff University looked for confirmation of this insulin theory by looking at the effects of different blood sugar lowering treatments on type 2 diabetics.

 

They analyzed a retrospective cohort of 62,809 people who developed diabetes after age 40 and who were treated with either oral agents or insulin. These patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. The outcome measures were progression to any solid tumor, or cancer of the breast, colon, pancreas or prostate.  “Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). …. Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10),…..  Sulfonylureas were associated with a similar pattern of risk as insulin.”   It appears anything that increases insulin levels whether it is oral hypoglycemic drugs or actual insulin increased risk of some cancers, especially pancreatic cancer risk.  

 

Back to Colorado’s ‘Soda Tax’ for a moment.  One of the arguments against taxing soda was that the price increase would dissuade consumers from purchasing it and therefore harm Colorado businesses and beverage dealers leading to job losses.  Ignorant as I am about the economics of junk food marketing, I find it difficult to believe that a 2.9% price increase would influence anyone’s purchase decision to such an extent. 

 

Given the concerns raised by these studies regarding the health impact soda has, the tax sounds far too low as it will do little to shift consumption patterns.   Perhaps my views are swayed by the task of sitting with people every day who ask me why they have cancer.  A better argument against the soda and candy tax might be that they will effectively lower consumption and eventually cut pancreatic cancer incidence by half leading to unemployment among oncologists We should be so lucky!

.

References:

[http://bulletin.aarp.org/states/co/2010/6/articles/colorado_senate_narrowly_passes_soda_candy_energy.html]

Cancer. 1988 Jun 15;61(12):2578-85.

Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists.

Mills PK, Beeson WL, Abbey DE, Fraser GE, Phillips RL.

Department of Preventive Medicine, School of Medicine, Loma Linda University, California 92350.

Epidemiologic studies of diet and pancreas cancer are few, and include ecologic comparisons and a limited number of prospective and case-control studies. Foods and/or nutrients that have been suggested to be associated with increased risk of this cancer include total fat intake, eggs, animal protein, sugar, meat, coffee and butter. Consumption of raw fruits and vegetables has been consistently associated with decreased risk. Dietary habits and medical history variables were evaluated in a prospective study of fatal pancreas cancer among 34,000 California Seventh-day Adventists between 1976 and 1983. Forty deaths from pancreas cancer occurred during the follow-up period. Compared to all US whites, Adventists experienced decreased risk from pancreas cancer death (standardized mortality ratio [SMR] = 72 for men; 90 for women), which was not statistically significant. Although there was a suggestive relationship between increasing meat, egg, and coffee consumption and increased pancreatic cancer risk, these variables were not significantly related to risk after controlling for cigarette smoking. However, increasing consumption of vegetarian protein products, beans, lentils, and peas as well as dried fruit was associated with highly significant protective relationships to pancreas cancer risk. A prior history of diabetes was associated with increased risk of subsequent fatal pancreas cancer, as was a history of surgery for peptic or duodenal ulcer. A history of tonsillectomy was associated with a slight, nonsignificant protective relationship as was history of various allergic reactions. These findings suggest that the protective relationships associated with frequent consumption of vegetables and fruits high in protease-inhibitor content are more important than any increase in pancreas cancer risk attendant on frequent consumption of meat or other animal products. Furthermore, the previously reported positive associations between diabetes and abdominal surgery and pancreas cancer risk are supported in these data.

Int J Cancer. 1988 Jun 15;41(6):794-7.

Pancreatic cancer, blood glucose and beverage consumption.

Hiatt RA, Klatsky AL, Armstrong MA.

Division of Research, Kaiser Permanente Medical Center, Oakland, CA 94611.

We studied the incidence of pancreatic cancer in 122,894 men and women who had previously reported amount and frequency of coffee, tea, and alcohol consumption; reporting was done at a multi-phasic health check-up (MHC) taken while subjects were members of a large prepaid health plan. We also tested the hypothesis that a pre-clinical effect of pancreatic cancer on glucose homeostasis leads to mild hyperglycemia and a generally increased thirst. If true, this could partially explain the increased consumption of beverages (particularly coffee) reported in association with pancreatic cancer in some case-control studies. However, in the 49 pancreatic cancer cases diagnosed during 6 years of follow-up, we found no evidence of increased risk associated with coffee, tea, or alcoholic beverages. We also found no evidence to support the increased-thirst hypothesis when we examined the 19 cases diagnosed within 12 months of having MHC. We did confirm a significantly increased risk among cigarette smokers (relative risk, 2.5; 95% confidence interval, 1.3-4.7) which was progressive with increasing levels of cigarette use. In addition, risk of pancreatic cancer was greater for persons previously under treatment for diabetes mellitus (relative risk, 4.5; 95% confidence interval, 1.2-16.7). Our results add to the growing body of evidence against a causal role of coffee in pancreatic cancer.

Int J Cancer. 1990 Sep 15;46(3):435-44.

Are energy and energy-providing nutrients related to exocrine carcinoma of the pancreas?

Bueno de Mesquita HB, Moerman CJ, Runia S, Maisonneuve P.

Department of Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.

During 1984-88 a population-based case-control study was carried out in The Netherlands in collaboration with the International Agency for Research on Cancer in order to further explore the possible relationship between diet and exocrine pancreatic carcinoma. Past habitual dietary intake was assessed in 164 cases and 480 controls. This is the first series of population-based studies of pancreas cancer to perform a comprehensive assessment of diet. The results of logistic regression analysis, controlled for age, gender and total cigarette consumption, suggested a positive association with past habitual intake of energy in directly interviewed patients (OR highest versus lowest quintile 3.35; 95% confidence interval 1.51-7.18). No indication of an effect of Quetelet index was found. When maximum-weight-ever-achieved was used, nonsignificantly reduced risks were observed for the upper 4 quintiles of "maximum" Quetelet index. After controlling for age, gender, response status and total cigarette consumption, a positive relationship with habitual past intake of total carbohydrates was observed (OR 2.40; 95% confidence interval 1.44-3.99). The effect decreased considerably when the analysis was restricted to subjects who reported stable long-term dietary intake. After controlling for age, gender, total cigarette consumption and response status, a significant, positive association between pancreatic cancer and past habitual intake of simple sugars was found (OR 1.95; 95% confidence interval 1.24-3.07). Among those who reported stable long-term dietary intake, no effect was seen. The positive effect of simple sugars was present in males only (OR 2.15; 95% confidence interval 1.18-3.93) and was smaller in men who reported long-term stable dietary intake. Our findings suggest that the development of exocrine pancreatic carcinoma is positively related to past habitual intake of total energy, total carbohydrates and simple sugars, whereas no relationship with body-mass index was observed.

PMID: 2394510 [Pu

Am J Epidemiol. 1991 Jul 15;134(2):167-79.

A case-control study of diet and cancer of the pancreas.

Baghurst PA, McMichael AJ, Slavotinek AH, Baghurst KI, Boyle P, Walker AM.

Division of Human Nutrition, Commonwealth Scientific Industrial Research Organisation, Adelaide, South Australia.

In a population-based case-control study carried out in Adelaide, South Australia, during the years 1984-1987, the diets of 104 cases of cancer of the pancreas 1 year prior to diagnosis were compared with the diets of 253 community controls. A quantitative food-frequency questionnaire was used to assess usual dietary intakes of 179 food items. Cases were compared with controls in terms of both the amounts of individual food items consumed and the estimated contributions of 48 nutrients to the diet. Food items consumed more by cases than controls included boiled eggs and omelettes as well as a number of items that could be collectively described as sweet and fatty. Food items consumed less by cases than controls included several vegetables and fruits. Conditional logistic regression analysis of nutrient intake adjusted for total energy and for alcohol and tobacco usage yielded an estimate of relative risk of 3.19, with a 95% confidence interval of 1.58-6.47 for the highest quartile of cholesterol intake (relative to the lowest quartile). For the top quartile of refined sugar intake, the estimated relative risk was 2.21 (95% confidence interval 1.07-4.55). Several nutrients derived principally from plant foods were statistically significantly associated with lower risks. Alcohol consumption was significantly lower among cases than controls. Current smokers had a relative risk of 1.76 (95% confidence interval 0.93-3.34) relative to those who had never smoked. There was no association of pancreatic cancer with coffee drinking.

Cancer Epidemiol Biomarkers Prev. 1993 Nov-Dec;2(6):513-8.

Dietary intake as a risk factor for cancer of the exocrine pancreas.

Lyon JL, Slattery ML, Mahoney AW, Robison LM.

Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City.

Data from 149 cases with pancreatic cancer and 363 control subjects in Utah were obtained from proxy respondents to assess the associations between dietary intake and the development of pancreatic cancer. After adjusting for cigarette smoking status and alcohol and coffee consumption, we observed that foods containing large amounts of fat from all sources increased risk of pancreatic cancer in men [odds ratio (OR), 3.41; 95% CI, 1.59-7.29]. Further division of fat by source of food showed that high intake of bacon and sausages (OR for upper tertile, 2.77; 95% CI, 1.34-5.72) as well as large intakes of fatty foods other than meat or dairy products (OR for upper tertile, 2.80; 95% CI, 1.33-5.89) increased risk of pancreatic cancer in men; high levels of intake of red meat, chicken, fish, and dairy foods did not increase risk of pancreatic cancer in either men or women. In women, fat from nonmeat and nondairy sources also increased risk of pancreatic cancer (OR for upper tertile, 3.44; 95% CI, 1.35-8.78). Although no protective effect was observed among men who consumed large amounts of fruits, vegetables, or high fiber foods, we did observe a protective effect in women for these foods (OR for upper tertile of fruit consumption, 0.37; 95% CI, 0.18-0.81; OR for upper tertile of vegetable consumption, 0.32; 95% CI, 0.13-0.74; and OR for upper tertile of fiber consumption, 0.28; 95% CI, 0.12-0.67). Findings from this study support the hypothesis that diets high in fat contribute to the development of pancreatic cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer Epidemiol Biomarkers Prev. 1995 Dec;4(8):895-9.

Food habits and pancreatic cancer: a case-control study of the Francophone community in Montreal, Canada.

Ghadirian P, Baillargeon J, Simard A, Perret C.

Hôpital Hôtel-Dieu de Montréal, Department of Nutrition, Faculty of Medicine, University of Montreal, Quebec, Canada.

In a population-based case-control study of pancreatic cancer and nutrition among the Francophone population of Montreal (Quebec, Canada), a total of 179 cases and 239 controls matched for age, sex, and language (French) were interviewed between 1984 and 1988. Data on food habits, methods of food preparation and preservation, and related information were obtained through a questionnaire. The study found an increased risk of pancreatic cancer associated with a high consumption of salt [relative risk (RR) = 4.28; 95% confidence interval (CI) = 2.20-8.36], smoked meat (RR = 4.68; CI = 2.05-10.69), dehydrated food (RR = 3.10; 95% CI = 1.55-6.22), fried food (RR= 3.84; 95% CI = 1.74-8.48), and refined sugar (RR = 2.81; 95% CI = 0.94-8.45). An inverse association was found with the consumption of food with no preservatives or additives (RR = 0.08; 95% CI = 0.01-0.59), raw food (RR = 0.28; 95% CI = 0.10-0.75), and food prepared by presto or high-pressure cooking (RR = 0.35% 95% CI = 0.15-0.81), electricity (RR = 0.30; 95% CI = 0.90), or microwave oven (RR = 0.56; 95% CI = 0.34-0.92). Cooking with firewood was associated with a significantly higher risk for pancreatic cancer (RR = 4.63; 95% CI = 1.15-16.52). The results of this study suggest that food habits may play an important role in the etiology of cancer of the pancreas among French Canadians in Montreal, whereas other food habits may reduce the risk of this disease.

PMID: 8634663 [PubM

J Am Diet Assoc. 2000 Jan;100(1):43-51, quiz 49-50.

Food sources of added sweeteners in the diets of Americans.

Guthrie JF, Morton JF.

Center for Food Safety and Applied Nutrition, US Food and Drug Administration, Washington, DC 20204, USA.

OBJECTIVE: To identify food sources of added sweeteners in the US diet. DESIGN: A descriptive study using data from the US Department of Agriculture (USDA) 1994-1996 Continuing Survey of Food Intakes by Individuals. Each subject provided one 24-hour dietary recall. Intake of added sweeteners was calculated using the USDA Food Guide Pyramid servings database. SUBJECTS/SETTING: A national sample of noninstitutionalized persons aged 2 years and older (N = 15,010). STATISTICAL ANALYSES: Mean intakes of added sweeteners from all food sources and from specific food categories; percentage contribution of added sweeteners to total energy intake; and percentage contribution of each food category to total intake of added sweeteners. All analyses were conducted for the total sample and for 12 age-gender groups. RESULTS: During 1994 to 1996, Americans aged 2 years and older consumed the equivalent of 82 g carbohydrate per day from added sweeteners, which accounted for 16% of total energy intake. In absolute terms, adolescent males consumed the most; as a percentage of energy, male and female adolescents had the highest intakes (averaging 20% of total energy from added sweeteners). The largest source of added sweeteners was regular soft drinks, which accounted for one third of intake. Other sources were table sugars, syrups, and sweets; sweetened grains; regular fruitades/drinks; and milk products. APPLICATIONS/CONCLUSIONS: Intakes of added sweeteners exceed levels compatible with meeting current dietary recommendations. Knowing food sources of added sweeteners for the overall population and for specific age-gender groups can help dietitians provide appropriate nutrition education.

J Sch Nurs. 2008 Feb;24(1):3-12.

The role of sugar-sweetened beverage consumption in adolescent obesity: a review of the literature.

Harrington S.

Wayne State University School of Nursing, Detroit, MI, USA.

Soft drink consumption has increased by 300% in the past 20 years, and 56-85% of children in school consume at least one soft drink daily. The odds ratio of becoming obese among children increases 1.6 times for each additional can or glass of sugar-sweetened drink consumed beyond their usual daily intake of the beverage. Soft drinks currently constitute the leading source of added sugars in the diet and exceed the U.S. Department of Agriculture's recommended total sugar consumption for adolescents. With the increase in adolescent obesity and the concurrent increase in consumption of sugar-sweetened beverages (SSB), the assumption infers a relationship between the two variables. SSB, classified as high-glycemic index (GI) liquids, increase postprandial blood glucose levels and decrease insulin sensitivity. Additionally, high-GI drinks submit to a decreased satiety level and subsequent overeating. Low-GI beverages stimulate a delayed return of hunger, thereby prompting an increased flexibility in amounts and frequencies of servings. Single intervention manipulation, elimination, or marked reduction of SSB consumption may serve to decrease caloric intake, increase satiety levels, decrease tendencies towards insulin resistance, and simplify the process of weight management in this population.

Nutr Res Rev. 2008 Dec;21(2):134-47.

Sugar-sweetened soft drinks and obesity: a systematic review of the evidence from observational studies and interventions.

Gibson S.

Sig-Nurture Ltd, 11 Woodway, Guildford, Surrey GU1 2TF, UK. sigrid@sig-nurture.com

Sugar-sweetened soft drinks (SSD) are a special target of many obesity-prevention strategies, yet critical reviews tend to be more cautious regarding the aetiological role of SSD in promoting excess body weight. Since ongoing evaluation of this issue is important, the present systematic review re-examined the evidence from epidemiological studies and interventions, up to July 2008. Database searches of Medline, Cochrane reviews, Google scholar and a hand search of cross-references identified forty-four original studies (twenty-three cross-sectional, seventeen prospective and four intervention) in adults and children, as well as six reviews. These were critically examined for methodology, results and interpretation. Approximately half the cross-sectional and prospective studies found a statistically significant association between SSD consumption and BMI, weight, adiposity or weight gain in at least one subgroup. The totality of evidence is dominated by American studies where SSD consumption tends to be higher and formulations different. Most studies suggest that the effect of SSD is small except in susceptible individuals or at high levels of intake. Methodological weaknesses mean that many studies cannot detect whether soft drinks or other aspects of diet and lifestyle have contributed to excess body weight. Progress in reaching a definitive conclusion on the role of SSD in obesity is hampered by the paucity of good-quality interventions which reliably monitor diet and lifestyle and adequately report effect sizes. Of the three long-term (>6 months) interventions, one reported a decrease in obesity prevalence but no change in mean BMI and two found a significant impact only among children already overweight at baseline. Of the six reviews, two concluded that the evidence was strong, one that an association was probable, while three described it as inconclusive, equivocal or near zero. Reasons for some discrepancies are presented.

Cancer Epidemiol Biomarkers Prev. 2010 Feb;19(2):447-55.

Soft drink and juice consumption and risk of pancreatic cancer: the singapore chinese health study.

Mueller NT, Odegaard A, Anderson K, Yuan JM, Gross M, Koh WP, Pereira MA.

Corresponding Author: Mark A. Pereira, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South Second Street, Suite 300, Minneapolis, MN 55454. map@umn.edu.

BACKGROUND: Sugar-sweetened carbonated beverages (called soft drinks) and juices, which have a high glycemic load relative to other foods and beverages, have been hypothesized as pancreatic cancer risk factors. However, data thus far are scarce, especially from non-European descent populations. We investigated whether higher consumption of soft drinks and juice increases the risk of pancreatic cancer in Chinese men and women. METHODS: A prospective cohort analysis was done to examine the association between soft drink and juice consumption and the risk of pancreatic cancer in 60,524 participants of the Singapore Chinese Health Study with up to 14 years of follow-up. Information on consumption of soft drinks, juice, and other dietary items, as well as lifestyle and environmental exposures, was collected through in-person interviews at recruitment. Pancreatic cancer cases and deaths were ascertained by record linkage of the cohort database with records of population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths. RESULTS: The first 14 years for the cohort resulted in cumulative 648,387 person-years and 140 incident pancreatic cancer cases. Individuals consuming >/=2 soft drinks/wk experienced a statistically significant increased risk of pancreatic cancer (hazard ratio, 1.87; 95% confidence interval, 1.10-3.15) compared with individuals who did not consume soft drinks after adjustment for potential confounders. There was no statistically significant association between juice consumption and risk of pancreatic cancer. CONCLUSION: Regular consumption of soft drinks may play an independent role in the development of pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 447-55.

Schernhammer ES, Hu FB, Giovannucci E, Michaud DS, Colditz GA, Stampfer MJ, Fuchs CS. Sugar-sweetened soft drink consumption and risk of pancreatic cancer in two prospective cohorts. Cancer Epidemiol Biomarkers Prev. 2005 Sep;14(9):2098-105.

Am J Clin Nutr. 2006 Nov;84(5):1171-6.

Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study.

Larsson SC, Bergkvist L, Wolk A.

Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. susanna.larsson@ki.se

BACKGROUND: Emerging evidence indicates that hyperglycemia and hyperinsulinemia may be implicated in the development of pancreatic cancer. Frequent consumption of sugar and high-sugar foods may increase the risk of pancreatic cancer by inducing frequent postprandial hyperglycemia, increasing insulin demand, and decreasing insulin sensitivity. OBJECTIVE: The objective of the study was to examine prospectively the association of the consumption of added sugar (ie, sugar added to coffee, tea, cereals, etc) and of high-sugar foods with the risk of pancreatic cancer in a population-based cohort study of Swedish women and men. DESIGN: A food-frequency questionnaire was completed in 1997 by 77 797 women and men aged 45-83 y who had no previous diagnosis of cancer or history of diabetes. The participants were followed through June 2005. RESULTS: During a mean follow-up of 7.2 y, we identified 131 incident cases of pancreatic cancer. The consumption of added sugar, soft drinks, and sweetened fruit soups or stewed fruit was positively associated with the risk of pancreatic cancer. The multivariate hazard ratios for the highest compared with the lowest consumption categories were 1.69 (95% CI: 0.99, 2.89; P for trend = 0.06) for sugar, 1.93 (1.18, 3.14; P for trend = 0.02) for soft drinks, and 1.51 (0.97, 2.36; P for trend = 0.05) for sweetened fruit soups or stewed fruit. CONCLUSION: High consumption of sugar and high-sugar foods may be associated with a greater risk of pancreatic cancer.

Larsson SC, Bergkvist L, Wolk A. Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study. Am J Clin Nutr. 2006 Nov;84(5):1171-6.

Am J Clin Nutr. 2007 Nov;86(5):1495-501.

Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study.

Nöthlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN.

Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA. ute.noethlings@difr.de

BACKGROUND: Because elevated blood glucose concentrations have been shown to be associated with greater risk of pancreatic cancer, a high dietary glycemic load, which is based on an empirical measure of blood glucose response after food consumption, has been hypothesized as a pancreatic cancer risk factor. However, results so far are scarce and inconsistent. OBJECTIVE: We analyzed data for 162 150 participants in the Hawaii-Los Angeles Multiethnic Cohort Study to investigate associations between glycemic load, dietary carbohydrates, sucrose, fructose, total sugars, and added sugars and the risk of pancreatic cancer. DESIGN: Dietary intake was assessed at baseline by using a quantitative food-frequency questionnaire. During 8 y of follow-up, 434 incident pancreatic cancer cases occurred. RESULTS: Glycemic load and added sugars were not significantly associated with pancreatic cancer risk. The risk increased with higher intakes of total sugars, fructose, and sucrose, and the association with fructose was significant when the highest and lowest quartiles were compared (relative risk: 1.35; 95% CI: 1.02, 1.80; P for trend = 0.046). A significant association was found with fruit and juices intake (1.37; 1.02, 1.84; P for trend = 0.04) but not with soda intake. Statistical evidence of a significant interaction with body mass index was present only for sucrose intake (P = 0.04). A comparison of the highest and lowest quartiles of sucrose intake in overweight or obese participants gave a relative risk of 1.46 (0.95-2.25; P for trend = 0.04), but the comparison was not significant in normal-weight participants. CONCLUSIONS: High fructose and sucrose intakes may play a role in pancreatic cancer etiology. Conditions such as overweight or obesity in which a degree of insulin resistance may be present may also be important.

Nöthlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr. 2007 Nov;86(5):1495-501.

Bao Y, Stolzenberg-Solomon R, Jiao L, Silverman DT, Subar AF, Park Y, Leitzmann MF, et al. Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study. Am J Clin Nutr. 2008 Aug;88(2):431-40.

Am J Clin Nutr. 2008 Aug;88(2):431-40.

Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study.

Bao Y, Stolzenberg-Solomon R, Jiao L, Silverman DT, Subar AF, Park Y, Leitzmann MF, Hollenbeck A, Schatzkin A, Michaud DS.

Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. ybao@hsph.harvard.edu

BACKGROUND: Although it has been hypothesized that hyperglycemia, hyperinsulinemia, and insulin resistance are involved in the development of pancreatic cancer, results from epidemiologic studies of added sugar intake are inconclusive. OBJECTIVE: Our objective was to investigate whether the consumption of total added sugar and sugar-sweetened foods and beverages is associated with pancreatic cancer risk. DESIGN: In 1995 and 1996, we prospectively examined 487 922 men and women aged 50-71 y and free of cancer and diabetes. Total added dietary sugar intake (in tsp/d; based on the US Department of Agriculture's Pyramid Servings Database) was assessed with a food-frequency questionnaire. Relative risks (RRs) and 95% CIs were calculated with adjustment for total energy and potential confounding factors. RESULTS: During an average 7.2 y of follow-up, 1258 incident pancreatic cancer cases were ascertained. The median intakes for the lowest and highest quintiles of total added sugar intake were 12.6 (3 tsp/d) and 96.2 (22.9 tsp/d) g/d, respectively. No overall greater risk of pancreatic cancer was observed in men or women with high intake of total added sugar or sugar-sweetened foods and beverages. For men and women combined, the multivariate RRs of the highest versus lowest intake categories were 0.85 (95% CI: 0.68, 1.06; P for trend = 0.07) for total added sugar, 1.01 (0.82,1.23; P for trend = 0.58) for sweets, 0.98 (0.82,1.18; P for trend = 0.49) for dairy desserts, 1.12 (0.91,1.39; P for trend = 0.35) for sugar added to coffee and tea, and 1.01 (0.77,1.31; P for trend = 0.76) for regular soft drinks. CONCLUSION: Our results do not support the hypothesis that consumption of added sugar or of sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.

PMID: 18689380 [PubMed - indexed for MEDLINE]

Cancer Causes Control. 2009 Aug;20(6):835-46. Epub 2009 Mar 11.

Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case-control study.

Chan JM, Wang F, Holly EA.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. june.chan@ucsf.edu

OBJECTIVE: We examined the associations between sweets, sweetened and unsweetened beverages, and sugars and pancreatic cancer risk. METHODS: We conducted a population-based case-control study (532 cases, 1,701 controls) and used multivariate logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Because associations were often different by sex, we present results for men and women combined and separately. RESULTS: Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk (total sweets: OR = 1.9, 95% CI: 1.0, 3.6; sweet condiments: OR = 1.9, 95% CI: 1.2, 3.1; chocolate candy: OR = 2.4, 95% CI: 1.1, 5.0; other mixed candy bars: OR = 3.3, 95% CI: 1.5, 7.3 for 1 + servings/day versus none/rarely). Sweets were not consistently associated with risk among women. Sweetened beverages were not associated with increased pancreatic cancer risk. In contrast, low-calorie soft drinks were associated with increased risk among men only; while other low-/non-caloric beverages (e.g., coffee, tea, and water) were unassociated with risk. Of the three sugars assessed (lactose, fructose, and sucrose), only the milk sugar lactose was associated with pancreatic cancer risk (OR = 2.0, 95% CI: 1.5, 2.7 comparing extreme quartiles). CONCLUSION: These results provide limited support for the hypothesis that sweets or sugars increase pancreatic cancer risk.

Cancer Causes Control. 2009 Nov 29. [Epub ahead of print]

Dietary habits and risk of pancreatic cancer: an Italian case-control study.

Polesel J, Talamini R, Negri E, Bosetti C, Boz G, Lucenteforte E, Franceschi S, Serraino D, La Vecchia C.

Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, IRCCS, Via Franco Gallini, 2, 33081, Aviano, Pordenone, Italy, polesel@cro.it.

OBJECTIVE: To investigate the association between dietary habits and pancreatic cancer. METHODS: Between 1991 and 2008, we conducted a hospital-based case-control study in northern Italy. Cases: 326 patients (median age 63 years) with incident pancreatic cancer admitted to general hospitals in the areas of Milan and Pordenone, northern Italy. Controls: 652 patients (median age 63 years) with acute non-neoplastic conditions admitted to the same hospital network of cases. Diet was assessed using a validated food frequency questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI). RESULTS: Frequent meat consumption was associated to a twofold increased risk of pancreatic cancer (95% CI: 1.18-3.36); the risk was significant for meat cooked by boiling/stewing or broiling/roasting. Added table sugar (OR = 2.23; 95% CI: 1.34-3.71) and potatoes (OR = 1.79; 95% CI: 1.12-2.86) were related to pancreatic cancer. An inverse association emerged for non-citrus fruits (OR = 0.41; 95% CI: 0.24-0.69), cooked vegetables (OR = 0.57; 95% CI: 0.36-0.92), and, possibly, for pulses (OR = 0.59; 95% CI: 0.35-1.00). CONCLUSIONS: The present study supports an inverse association between fruits and vegetables and pancreatic cancer risk, and it confirms a direct relation with meat. The increased risk for table sugar suggests that insulin resistance may play a role in pancreatic carcinogenesis.

PMID: 20091114 [PubMed - as supplied by publisher]

http://emedicine.medscape.com/article/280605-overview

emedicine. Medscape

Pancreatic Cancer

Richard A Erickson,

Coauthor(s): Claire R Larson, MD, Mohsen Shabahang,

Apr 7, 2009

Diabetes. 1985 Oct;34(10):980-6.

The insulin-pancreatic acinar axis.

Williams JA, Goldfine ID.

Recent studies indicate that insulin directly regulates the acinar pancreas. Morphologic and hemodynamic studies indicate the presence of a portal system that conveys islet blood to acinar cells. Studies both in humans with diabetes mellitus and in animals given beta cell toxins indicate that insulin is necessary for normal acinar cell function. Studies in the perfused rat pancreas indicate that endogenous insulin potentiates zymogen release. Isolated rat and mouse acini have insulin receptors, and in these cells, after binding to its receptors, insulin regulates a number of functions including: sugar transport, protein synthesis, and the number of cholecystokinin receptors. These in vivo and in vitro studies suggest, therefore, that there is an insulin-pancreatic acinar axis that plays a major role in pancreatic function.

PMID: 2412

Gut. 1981 Feb;22(2):158-67.

The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland.

Henderson JR, Daniel PM, Fraser PA.

PMID: 6111521 [PubMed - indexed for MEDLINE]

Cancer Res. 2007 Aug 15;67(16):7923-8.

Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer.

Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS.

Department of Medical Oncology, Dana-Farber Cancer Institute, MA 02115, USA. bwolpin@partners.org

Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk. IGF binding protein-1 (IGFBP-1) is a downstream target of insulin and inhibits IGF-I activity. To investigate whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective, case-control study nested within the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative. We assayed circulating IGFBP-1 among 144 pancreatic cancer cases that occurred >or=4 years after plasma collection and in 429 controls, matched for date of birth, prospective cohort, smoking status, and fasting status. When compared with participants in the three highest quartiles of plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR) for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26-3.39], after adjusting for other risk factors, including circulating IGF-I, IGF binding protein-3, and C-peptide. Only participants in the lowest quartile of plasma IGFBP-1 showed an elevated risk of pancreatic cancer. The influence of low plasma IGFBP-1 became progressively stronger with time; among cases diagnosed >or=8 years after blood collection, the adjusted RR was 3.47 (95% CI, 1.48-8.14), comparing the bottom versus the top three quartiles. The influence of plasma IGFBP-1 was most marked among participants who never smoked cigarettes (RR, 3.30; 95% CI, 1.48-7.35). Among participants in four U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly predicted an increased risk of pancreatic cancer.

Br J Cancer. 2007 Jul 2;97(1):98-104. Epub 2007 May 29.

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts.

Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. bwolpin@partners.org

Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case-control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60-1.48), 0.96 (95% CI, 0.61-1.52), and 1.21 (95% CI, 0.75-1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54-1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.

PMID: 17533398 [PubMed - indexed for MEDLINE]

Mueller et al. 2010.

Diabetologia. 2009 Sep;52(9):1766-77. Epub 2009 Jul 2.

The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.

Currie CJ, Poole CD, Gale EA.

School of Medicine, Cardiff University, The Pharma Research Centre, Cardiff MediCentre, Cardiff, CF14 4UJ, UK. currie@cardiff.ac.uk

Comment in:

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.

Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2435-40.

The effect of modifiable risk factors on pancreatic cancer mortality in populations of the Asia-Pacific region.

Ansary-Moghaddam A, Huxley R, Barzi F, Lawes C, Ohkubo T, Fang X, Jee SH, Woodward M; Asia Pacific Cohort Studies Collaboration.

The George Institute, University of Sydney, Australia.

BACKGROUND: Pancreatic cancer accounts for about 220,000 deaths each year. Known risk factors are smoking and type 2 diabetes. It remains to be seen whether these risk factors are equally important in Asia and whether other modifiable risk factors have important associations with pancreatic cancer. METHODS: An individual participant data analysis of 30 cohort studies was carried out, involving 420,310 Asian participants (33% female) and 99,333 from Australia/New Zealand (45% female). Cox proportional hazard models, stratified by study and sex and adjusted for age, were used to quantify risk factors for death from pancreatic cancer. RESULTS: During 3,558,733 person-years of follow-up, there were 324 deaths from pancreatic cancer (54% Asia and 33% female). Mortality rates (per 100,000 person-years) from pancreatic cancer were 10 for men and 8 for women. The following are age-adjusted hazard ratios (95% confidence interval) for death from pancreatic cancer: for current smoking, 1.61 (1.12-2.32); for diabetes, 1.76 (1.15-2.69); for a 2-cm increase in waist circumference, 1.08 (1.02-1.14). All three relationships remained significant (P < 0.05) after adjustment for other risk factors. There was no evidence of heterogeneity in the strength of these associations between either cohorts from Asia and Australia/New Zealand or between the sexes. In men, the combination of cigarette smoking and diabetes more than doubled the likelihood of pancreatic cancer (2.47; 95% confidence interval, 1.17-5.21) in both regions. CONCLUSIONS: Smoking, obesity, and diabetes are important and are potentially modifiable risk factors for pancreatic cancer in populations of the Asia-Pacific region. Activities to prevent them can be expected to lead to a major reduction in the number of deaths from this cancer, particularly in Asia with its enormous population.

Gut. 1987;28 Suppl:51-5.

Do insulin and the insulin like growth factors (IGFs) stimulate growth of the exocrine pancreas?

Mössner J, Logsdon CD, Goldfine ID, Williams JA.

Cell Biology Research Laboratory, Mount Zion Hospital and Medical Center, San Francisco.

Previous in vivo studies have suggested a long term regulatory role for insulin in the exocrine pancreas. Furthermore, we reported that pancreatic acini have specific receptors for IGF I and II, and using different techniques (acid washing, trypsinisation, electron microscope autoradiography), that CCK8 reduces the internalisation of IGF II. To now directly study the long term role for IGF and insulin in the exocrine pancreas we used AR42J cells, a rat cell line that is derived from a transplantable tumour of the acinar pancreas. Hormone binding studies with 125I-labelled hormones indicated that those cells have insulin receptors, relatively fewer receptors for IGF II but in contrast with normal acini no detectable IGF I receptors. Insulin at concentrations as low as 1 nm stimulated the growth of AR42J cells, as measured by an increase in cell number, DNA and protein content. At 100 nM insulin had maximal effects stimulating the growth by about 50%. IGF I and II had only very weak growth promoting effects probably due to their interaction with the insulin receptor. Additionally insulin increased amylase synthesis over the same concentration range that it stimulated growth. But immunoprecipitation studies revealed that insulin induced a selective increase of amylase synthesis over general protein synthesis. These studies indicate, therefore, that insulin is a growth promoting hormone for AR42J cells and that additionally it seems to specifically regulate amylase synthesis. The role for the IGFs in the exocrine pancreas, however, still remains to be determined.

Diabetologia. 2009 Sep;52(9):1766-77. Epub 2009 Jul 2.

The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.

Currie CJ, Poole CD, Gale EA.

School of Medicine, Cardiff University, The Pharma Research Centre, Cardiff MediCentre, Cardiff, CF14 4UJ, UK. currie@cardiff.ac.uk

Comment in:

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.