High Blood Sugar and Insulin Resistance

Cancer survival: good evidence of slightly higher mortality among people with solid tumors with diabetes

• 9% higher mortality among people with solid tumors with diabetes compared to those without diabetes in a very large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study²⁶Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.

Cancer risk

Modest evidence of higher risk of cancer as a whole, including invasive cancer, among people with diabetes

Good evidence of higher cancer-specific mortality among people without cancer at baseline with poorer markers of blood sugar balance and insulin sensitivity

• A weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward lower risk of cancer among people with type 2 diabetes with intensive glycemic control compared to standard control in a large meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 3 observational studies²⁷Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia. 2011 Jan;54(1):25-31.
• 84% higher risk of cancer among people with diabetes compared to nondiabetics in a very large observational study²⁸Geraldine N, Marc A et al. Relation between diabetes, metformin treatment and the occurrence of malignancies in a Belgian primary care setting. Diabetes Research and Clinical Practice. 2012 Aug;97(2):331-6.
• 64% higher risk of cancer among people with diabetes compared to nondiabetics in a large observational study²⁹Baur DM, Klotsche J et al. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism. 2011 Oct;60(10):1363-71.
• 13% higher risk of invasive cancer as a whole among postmenopausal women with diabetes (higher HOMA-IR levels) compared to without diabetes in a very large observational study³⁰Gong Z, Aragaki AK, Chlebowski RT, et al. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the Women’s Health Initiative. International Journal of Cancer. 2016;138(8):1915-1927.
• 26% higher cancer-specific mortality among postmenopausal women without cancer at baseline and with higher IGF-1 levels³¹Pan K, Nelson RA et al. Insulin resistance and cancer-specific and all-cause mortality in postmenopausal women: the Women’s Health Initiative. Journal of the National Cancer Institute. 2020 Feb 1;112(2):170-178. or the highest insulin resistance (HOMA-IR levels)³²Gong Z, Aragaki AK, Chlebowski RT, et al. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the Women’s Health Initiative. International Journal of Cancer. 2016;138(8):1915-1927. compared to lower levels in a very large observational study
• Higher mortality from cancer as a whole across 12 years among men without cancer at baseline with higher plasma glucose levels 1 hour after an oral glucose load or for those with diabetes at baseline, and higher mortality from colon, lung, and blood/lymphatic tumors for women, compared to lower levels in a very large observational study³³Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J. Post-load plasma glucose and cancer mortality in middle-aged men and women. 12-year follow-up findings of the Chicago Heart Association Detection Project in Industry. American Journal of Epidemiology. 1990 Feb;131(2):254-62.

Cancer survival: modest evidence of higher rate of cancer progression among people with bladder cancer with diabetes

• 138% higher risk of progression, 51–60% higher cancer-specific mortality, and 40-45% higher risk of recurrence among people with bladder cancer and diabetes compared to people without diabetes in 3 large observational studies³⁴Rieken M, Xylinas E et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU International. 2013 Dec;112(8):1105-12; Rieken M, Xylinas E et al. Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma. Urologic Oncology. 2014 Jan;32(1):49.e7-14; Rieken M, Xylinas E et al; UTUC Collaboration. Diabetes mellitus without metformin intake is associated with worse oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. European Journal of Surgical Oncology. 2014 Jan;40(1):113-20.
• Higher rate of cancer progression among people with non-muscle invasive bladder cancer with diabetes with high blood sugar levels (HbA1c 7.0% or higher) compared to lower levels or people without diabetes in a mid-sized observational study³⁵Ahn JH, Jung SI et al. Impact of glycemic control and metformin use on the recurrence and progression of non-muscle invasive bladder cancer in patients with diabetes mellitus. Journal of Korean Medical Science. 2016 Sep;31(9):1464-71.

Cancer recurrence: preliminary evidence of higher risk of cancer recurrence among people with non-muscle invasive bladder cancer with diabetes

• Higher risk of cancer recurrence among people with non-muscle invasive bladder cancer with diabetes compared to people without diabetes in a mid-sized observational study³⁶Ahn JH, Jung SI et al. Impact of glycemic control and metformin use on the recurrence and progression of non-muscle invasive bladder cancer in patients with diabetes mellitus. Journal of Korean Medical Science. 2016 Sep;31(9):1464-71.

• Lower overall survival among people with glioblastoma and with high blood sugar levels (hyperglycemia) compared to people without hyperglycemia in 10 of 12 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies in a review³⁷Montemurro N, Perrini P, Rapone B. Clinical risk and overall survival in patients with diabetes mellitus, hyperglycemia and glioblastoma multiforme. a review of the current literature. International Journal of Environmental Research and Public Health. 2020 Nov 17;17(22):8501.

Elevated insulin levels may promote breast cancer. Reducing elevated fasting blood sugar levels or increasing insulin sensitivity in people with insulin resistance may be helpful not only in reducing breast cancer risk, but also in reducing risk of recurrence and breast cancer-related death among people diagnosed with breast cancer.³⁸Cazzaniga M, Bonanni B. Relationship between metabolic disorders and breast cancer incidence and outcomes. Is there a preventive and therapeutic role for berberine? Anticancer Research. 2018 Aug;38(8):4393-4402.

Cancer proliferation or mortality 

Modest evidence of worse survival among people with breast cancer with diabetes

Preliminary evidence of lower overall and cancer-specific mortality among people eating a diet for diabetes risk reduction before and after a diagnosis of breast cancer

• 32% higher mortality among people with breast cancer with diabetes compared to those without diabetes in a very large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study³⁹Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
• Worse survival after 8 years but no evidence of an effect on overall survival at 5 years and time to next treatment at 1 year among people with breast cancer with diabetes compared to no diabetes in a mid-sized observational study⁴⁰Cheung Y-MM, Hughes M et al. (RF28 | PSUN185) The effects of diabetes and glycemic control on cancer outcomes in individuals with metastatic breast cancer. Presentation at ENDO 2022. Viewed August 13, 2022.
• No evidence of an effect on overall survival at 5 years but a weak trend towards shorter time to next treatment—an indication of cancer growth—at 1 year among people with breast cancer with poor diabetes control compared to good diabetes control in a mid-sized observational study⁴¹Cheung Y-MM, Hughes M et al. (RF28 | PSUN185) The effects of diabetes and glycemic control on cancer outcomes in individuals with metastatic breast cancer. Presentation at ENDO 2022. Viewed August 13, 2022.

Cancer risk

Good evidence of higher risk of breast cancer among people with diabetes, including gestational diabetes

Modest evidence of higher risk of breast cancer diagnosis, recurrence, possibly mortality among people with higher levels of insulin-like growth factor 1

• Higher risk of breast cancer among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of observational studies⁴²Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.
• 23% higher risk of breast cancer among women with diabetes, and especially postmenopausal women, compared to other women in a meta-analysis of 16 observational studies⁴³Liao S, Li J et al. Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. Asian Pacific Journal of Cancer Prevention. 2011;12(4):1061-5.
• Higher risk of breast cancer, and especially ER-positive breast cancer, among women having at least 2 pregnancies with gestational diabetes mellitus compared to other women in a very large observational study⁴⁴Park YM, O’Brien KM et al. Gestational diabetes mellitus may be associated with increased risk of breast cancer. British Journal of Cancer. 2017 Mar 28;116(7):960-963.
• 27% higher risk of breast cancer among postmenopausal women with self-reported treated diabetes compared to people without diabetes in a very large observational study⁴⁵Luo J, Chlebowski R et al. Diabetes and lung cancer among postmenopausal women. Diabetes Care. 2012 Jul;35(7):1485-91.
• Higher risk of breast cancer diagnosis, recurrence, and possibly mortality among people with higher levels of insulin-like growth factor-1 (IGF-1) compared to lower levels in a review of studies⁴⁶Djiogue S, Nwabo Kamdje AH et al. Insulin resistance and cancer: the role of insulin and IGFs. Endocrine-Related Cancer. 2013 Jan 7;20(1):R1-R17.

Cancer survival or progression

Modest evidence of higher mortality among people with colorectal cancer with the highest insulin index or insulin load

Preliminary evidence of higher local tumor load among people with colorectal cancer with higher blood glucose levels

• 66–82% higher cancer-specific mortality among people with colorectal cancer with the highest insulin index or insulin load in their diets compared to those with the lowest in a large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁴⁷Yuan C, Bao Y et al. Influence of dietary insulin scores on survival in colorectal cancer patients. British Journal of Cancer. 2017 Sep 26;117(7):1079-1087.
• 87% higher mortality among people with nonmetastatic colorectal cancer with the highest markers of insulin compared to those with the lowest in a mid-sized observational study⁴⁸Wolpin BM, Meyerhardt JA et al. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. Journal of Clinical Oncology. 2009 Jan 10;27(2):176-85.
• Higher local tumor load (larger tumor diameters and lower tumor differentiation) among people with colorectal cancer with higher blood glucose levels compared to those with normal blood glucose levels in a mid-sized observational study⁴⁹Cui G, Zhang T et al. High blood glucose levels correlate with tumor malignancy in colorectal cancer patients. Medical Science Monitor. 2015 Dec 8;21:3825-33.

Cancer risk

Good evidence of higher risk of colorectal cancer among people with type 2 diabetes

Preliminary evidence of higher risk of recurrence among people with stage 3 colorectal cancer with high blood glucose

Preliminary evidence of higher risk of left-side colorectal adenoma among people with higher levels of insulin-like growth factor 1

• Higher risk of colorectal cancer among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of observational studies⁵⁰Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.
• Higher risk of recurrence (lower disease-free survival) among people with stage 3 colorectal cancer with high blood glucose (126 mg/dl or higher) compared to lower blood glucose levels in a mid-sized observational study⁵¹Yang IP, Miao ZF et al. High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy. Therapeutic Advanced in Medical Oncology. 2019 Aug 20;11:1758835919866964.
• Higher risk of left-side colorectal adenoma among people with higher levels of insulin-like growth factor 1 compared to lower levels in a mid-sized observational study⁵²Gao Y, Katki H et al. Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma. International Journal of Cancer. 2012 Jul 15;131(2):E105-13.

Gallbladder cancer: good evidence of higher risk of gallbladder cancer among people with type 2 diabetes

• Higher risk of hepatocellular carcinoma among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁵³Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.

Liver cancer (hepatocellular carcinoma)

Preliminary evidence of worse survival after radiofrequency ablation among people with early hepatocellular carcinoma (HCC) with diabetes

• Worse survival at 1, 3, and 5 years after radiofrequency ablation among people with early hepatocellular carcinoma (HCC) with diabetes compared to without diabetes in a mid-sized observational study; people with diabetes treated with metformin had better survival than those not treated with metformin⁵⁴Chen TM, Lin CC, Huang PT, Wen CF. (2011). Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. Journal of Gastroenterology and Hepatology. 2011 May; 26(5):858–865.

Preliminary evidence of higher risk of recurrence of hepatocellular carcinoma after initial liver resection among people with diabetes and with HbA1c higher than 9%

• 143% higher cancer mortality among people with hepatocellular carcinoma and diabetes compared to no diabetes in a meta-analysis of 7 observational studies⁵⁵Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2012 Feb;28(2):109-22.
• Higher risk of recurrence of hepatocellular carcinoma after initial liver resection among people with diabetes compared to no diabetes and among people with HbA1c higher than 9% compared to lower values in a mid-sized observational study⁵⁶Cho WR, Wang CC et al. Impact of metformin use on the recurrence of hepatocellular carcinoma after initial liver resection in diabetic patients. PLoS One. 2021 Mar 4;16(3):e0247231.

Good evidence of higher risk of hepatocellular carcinoma among people with type 2 diabetes

• Higher risk of hepatocellular carcinoma among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analyses of observational studies⁵⁷Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.
• More than 25% higher risk of hepatocellular carcinoma among adults with chronic hepatitis B infection with diabetes compared to no diabetes in a meta-analysis of 19 observational studies⁵⁸Campbell C, Wang T, McNaughton AL, Barnes E, Matthews PC. Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis. Journal of Viral Hepatitis. 2021 Mar;28(3):493-507.

• Higher risk of endometrial cancer among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁵⁹Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.
• Higher fasting insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) among women with endometrial cancer compared to women without endometrial cancer in a meta-analysis of 25 observational studies⁶⁰Hernandez AV, Pasupuleti V et al. Insulin resistance and endometrial cancer risk: a systematic review and meta-analysis. European Journal of Cancer. 2015 Dec;51(18):2747-58.

• Higher overall and cancer-specific mortality among people with head and neck cancer and diabetes compared to people without diabetes in a large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁶¹Kwon M, Roh JL et al. Effect of metformin on progression of head and neck cancers, occurrence of second primary cancers, and cause-specific survival. Oncologist. 2015 May;20(5):546-53.

• A lower circulating marker of insulin sensitivity (adiponectin) among people with renal cell carcinoma compared to healthy controls in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 8 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁶²Fang J, Xu X et al. Lower circulating adiponectin is associated with higher risk of renal cell carcinoma: a meta-analysis. International Journal of Biological Markers. 2020 Mar;35(1):57-64.
• Higher risk of kidney cancer during 3 years of follow up among people with diabetes compared to no diabetes in a very large observational study⁶³Tseng CH. Type 2 diabetes mellitus and kidney cancer risk: a retrospective cohort analysis of the National Health Insurance. PLoS One. 2015 Nov 11;10(11):e0142480.

• A weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward higher risk of lung cancer among people with diabetes, which was significant among women but not men, in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁶⁴Yi ZH, Luther Y et al. Association between diabetes mellitus and lung cancer: meta-analysis. European Journal of Clinical Investigation. 2020 Oct;50(10):e13332.
• Higher risk of lung cancer among people with diabetes compared to those without diabetes in a very large observational study⁶⁵Kim J, Hyun HJ et al. Diabetes, metformin, and lung cancer: retrospective study of the Korean NHIS-HEALS Database. Clinical Lung Cancer. 2020 Nov;21(6):e551-e559.
• 16% lower mortality among people with lung cancer with diabetes compared to those without diabetes in a very large observational study⁶⁶Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
• 27% higher overall mortality among women with lung cancer and diabetes compared to no diabetes in a large observational study⁶⁷Luo J, Hendryx M, Qi L, Ho GY, Margolis KL. Pre-existing diabetes and lung cancer prognosis. British Journal of Cancer. 2016 Jun 28;115(1):76-9.
• Roughly double the risk of lung cancer among men with higher fasting serum insulin levels and insulin resistance (HOMA-IR) compared to the lowest levels in a mid-sized observational study⁶⁸Argirion I, Weinstein SJ, Männistö S, Albanes D, Mondul AM. Serum insulin, glucose, indices of insulin resistance, and risk of lung cancer. Cancer Epidemiology, Biomarkers & Prevention. 2017 Oct;26(10):1519-1524.

• Weak trendsan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward higher overall and lymphoma-specific mortality among people with diabetes not treated with metformin compared to people without diabetes after adjusting for several potential confounders in a large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁶⁹Wang Y, Maurer MJ et al. Impact of metformin use on the outcomes of newly diagnosed diffuse large B-cell lymphoma and follicular lymphoma. British Journal of Haematology. 2019 Sep;186(6):820-828.

• More progression of melanoma among people with lower levels of insulin-like growth factor binding protein (IGFBP-3) in a small observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁷⁰Panasiti V, Naspi A et al. Correlation between insulin-like growth factor binding protein-3 serum level and melanoma progression. Journal of the American Academy of Dermatology. 2011; 64:865–872.
• 61% lower risk of malignant melanoma among people without a history of non-melanoma skin cancer with higher levels of IGF-I compared to lower levels, but a higher risk among people with a history, in a mid-sized observational study⁷¹Park SL, Setiawan VW et al. Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma. Cancer Causes and Control. 2011 Sep;22(9):1267-75.

• 64% higher risk of ovarian cancer among people with diabetes compared to nondiabetics in a very large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁷²Baur DM, Klotsche J et al. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism. 2011 Oct;60(10):1363-71.
• Higher risk of developing cancer in any organ with high levels of estrogen receptors, including ovaries, among people with decreased levels of estrogen as a result of insulin resistance in a review⁷³Eketunde AO. Diabetes as a risk factor for breast cancer. Cureus. 2020 May 7;12(5):e8010.

Cancer survival: modest evidence of worse survival of pancreatic cancer among people with diabetes

• Worse survival among people with pancreatic cancer with diabetes undergoing chemotherapy compared to those without diabetes in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 6 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁷⁴Ma J, Wang J, Ge L, Long B, Zhang J. The impact of diabetes mellitus on clinical outcomes following chemotherapy for the patients with pancreatic cancer: a meta-analysis. Acta Diabetologica. 2019 Oct;56(10):1103-1111.

Cancer risk: good evidence of higher risk of pancreatic cancer among people with diabetes

• Higher risk of pancreatic cancer among people with type 2 diabetes compared to no diabetes in an umbrella review of the evidence across meta-analyses of observational studies⁷⁵Pearson-Stuttard J, Papadimitriou N et al. Type 2 diabetes and cancer: an umbrella review of observational and mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention. 2021 Jun;30(6):1218-1228.
• Substantially higher risk of pancreatic cancer among people with diabetes, and especially recently diagnosed diabetes, compared to people without diabetes in a large meta-analysis of 26 observational studies⁷⁶Zhang JJ, Jia JP, Shao Q, Wang YK. Diabetes mellitus and risk of pancreatic cancer in China: a meta-analysis based on 26 case-control studies. Primary Care Diabetes. 2019 Jun;13(3):276-282.

Cancer survival

Good evidence of higher mortality among people with prostate cancer with diabetes

Preliminary evidence of higher mortality among people with advanced prostate cancer with higher levels of insulin-like growth factor-1 (IGF-1)

• Higher mortality at 8.7 years after external-beam radiation therapy among people with localized prostate cancer and diabetes compared to nondiabetics in a large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁷⁷Spratt DE, Zhang C et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. European Urology. 2013 Apr;63(4):709-16.
• 19% higher mortality among people with prostate cancer with diabetes compared to those without diabetes in a very large observational study⁷⁸Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
• 64% higher mortality among people with advanced prostate cancer with higher levels of IGF-1 compared to lower levels in a mid-sized observational study⁷⁹Rowlands MA, Holly JM et al. Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer. Cancer Causes Control. 2012 Feb;23(2):347-54.

Cancer risk

Preliminary evidence of higher risk of biochemical recurrence among people with prostate cancer and diabetes or with high blood sugar levels

Modest evidence of higher risk of prostate cancer among people with high serum levels of insulin-like growth factor

Modest evidence of a link between higher fasting insulin levels and homeostasis model assessment of insulin resistance and prostate cancer

• 55% higher risk of biochemical recurrence among people with prostate cancer and diabetes compared to people without diabetes in a mid-sized observational study⁸⁰Patel T, Hruby G, Badani K, Mckiernan J. The impact of diabetes and metformin use in clinically localized prostate cancer treated by radical prostatectomy. Journal of Urology. 2010;183:e102.
• Roughly double the risk of biochemical recurrence and higher pathologic Gleason scores among people with prostate cancer and high blood glucose levels (HbA1c 6.5% or higher) compared to lower levels in a mid-sized observational study⁸¹Lee H, Kuk H, Byun SS, Lee SE, Hong SK. Preoperative glycemic control status as a significant predictor of biochemical recurrence in prostate cancer patients after radical prostatectomy. PLoS One. 2015 Apr 21;10(4):e0124761.
• Higher risk of prostate cancer among people with high serum levels of IGF-1 compared to low levels in a review of 2 observational studies⁸²Perdana NR, Mochtar CA, Umbas R, Hamid AR. The risk factors of prostate cancer and its prevention: a literature review. Acta Medica Indonesiana. 2016 Jul;48(3):228-238.
• Weak trends toward higher risk of prostate cancer among people with advanced prostate cancer with higher IGF-1 and lower IGF-binding proteins (IGFBP-3) compared to lower levels in a mid-sized observational study⁸³Rowlands MA, Holly JM et al. Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer. Cancer Causes Control. 2012 Feb;23(2):347-54.
• Higher fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) levels among men with prostate cancer age 65 or older in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 10 observational studies⁸⁴Saboori S, Rad EY, Birjandi M, Mohiti S, Falahi E. Serum insulin level, HOMA-IR and prostate cancer risk: a systematic review and meta-analysis. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2019 Jan-Feb;13(1):110-115.

• Higher risk of thyroid cancer among people with insulin resistance (59% higher risk) or unbalanced blood sugar levels (dysglycemia, 40% higher risk) compared to other people in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 42 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁸⁵Yin DT, He H et al. The association between thyroid cancer and insulin resistance, metabolic syndrome and its components: a systematic review and meta-analysis. International Journal of Surgery. 2018 Sep;57:66-75.

• Increased blood clotting (hypercoagulation) and platelet activation among people with type 2 diabetes and cardiovascular disease compared to healthy people in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁹¹Pretorius L, Thomson GJA et al. Platelet activity and hypercoagulation in type 2 diabetes. Cardiovascular Diabetology. 2018 Nov 2;17(1):141.

• The insulin resistance of type 2 diabetes occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. The authors of a review conclude that insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with type 2 diabetes.⁹²Malone JI, Hansen BC. Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite? Pediatric Diabetes. 2019 Feb;20(1):5-9.

See High Blood Sugar and Insulin Resistance ›

Metabolic hormones: The hormone glucagon is important in maintaining your body’s sugar and fuel balance. It also promotes the breakdown of fat in fat cells. It is usually released overnight and between meals, when blood sugar levels from food drop. Typically, levels of glucagon fall immediately after a meal. However, in individuals with diabetes, glucagon levels rise after a meal, which causes blood sugar levels to rise. This deviation is linked to imbalances in other hormones, specifically glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and amylin.⁹³Diabetes Education Online. Blood Sugar & Other Hormones. Diabetes Teaching Center at the University of California, San Francisco. Viewed September 15, 2022.

Sex hormones 

Both male and female sex hormones may be linked to high blood sugar  and insulin resistance.⁹⁴Lau LHY, Nano J et al. Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study. BMJ Open Diabetes Research & Care. 2021 Feb;9(1):e001951.

Testosterone

Preliminary evidence of high rates of testosterone deficiency among men with type 2 diabetes

Preliminary evidence of a link between low testosterone levels and insulin resistance among men with either type 1 diabetes or type 2 diabetes

• High rates of testosterone deficiency among men with type 2 diabetes, and low testosterone levels independently associated with insulin resistance among men with either type 1 diabetes or type 2 diabetes in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁹⁵Grossmann M, Thomas MC et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. Journal of Clinical Endocrinology and Metabolism. 2008 May;93(5):1834-40.

Type 2 diabetes is linked to disruptions in immune function, leading to higher risk—and more complicated cases—of infections.⁹⁶Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020 Jul 22;11:1582; Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunology & Medical Microbiology. 1999 Dec;26(3-4):259-65.

Modest evidence of impaired immune function among people with diabetes or high blood sugar

• Disrupted immune response and cellular immunity due to insulin deficiency and high blood sugar (hyperglycemia), leading to increased susceptibility to infection among people with diabetes compared to nondiabetic people in a review⁹⁷Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 diabetes and its impact on the immune system. Current Diabetes Reviews. 2020;16(5):442-449.
• A weak trend toward lower levels of natural killer (NK) cells in adults with type 2 diabetes compared to nondiabetic controls in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 3 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies at low risk of bias⁹⁸Mxinwa V, Dludla PV et al. Natural killer cell levels in adults living with type 2 diabetes: a systematic review and meta-analysis of clinical studies. BMC Immunology. 2020 Sep 9;21(1):51.
• Impaired immune responses among people experiencing high blood sugar (hyperglycemia) compared to normal blood sugar in a review article⁹⁹Ieronymaki E, Daskalaki MG, Lyroni K, Tsatsanis C. Insulin signaling and insulin resistance facilitate trained immunity in macrophages through metabolic and epigenetic changes. Frontiers in Immunology. 2019 Jun 12;10:1330.

High blood sugar (hyperglycemia) is pro-inflammatory.¹⁰⁰Sun Q, Li J, Gao F. New insights into insulin: the anti-inflammatory effect and its clinical relevance. World Journal of Diabetes. 2014 Apr 15;5(2):89-96.

Good evidence of higher inflammation among people with type 2 diabetes

• Higher incidence of chronic pro-inflammatory immune (natural killer cell) activation among people with type 2 diabetes and cardiovascular disease compared to nondiabetic people with CVD in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 15 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies¹⁰¹Mxinwa V, Dludla PV et al. Natural killer cell levels in adults living with type 2 diabetes: a systematic review and meta-analysis of clinical studies. BMC Immunology. 2020 Sep 9;21(1):51.
• A link between raised immune activation (pro-inflammatory Th1/Th2 cytokines such as interferon-gamma (IFN-γ)/interleukin (IL)-5 and IL-2/IL-5 ratios) and type 2 diabetes in a review of clinical and preclinical studies¹⁰²Mahlangu T, Dludla PV et al. A systematic review on the functional role of Th1/Th2 cytokines in type 2 diabetes and related metabolic complications. Cytokine. 2020 Feb;126:154892.
• More chronic inflammation from several causes, including impaired endothelial function, oxidative stress, impaired macrophage function, lipid imbalance (dyslipidemia) among people with type 2 diabetes compared to nondiabetic people in a review¹⁰³Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020 Jul 22;11:1582.
• Upregulation of circulating inflammatory markers among people with type 2 diabetes and cardiovascular disease compared to healthy people in a mid-sized observational study¹⁰⁴Pretorius L, Thomson GJA et al. Platelet activity and hypercoagulation in type 2 diabetes. Cardiovascular Diabetology. 2018 Nov 2;17(1):141.

• Higher incidence of oxidative stress leading to vascular complications and inflammation among people with type 2 diabetes compared to nondiabetic people in a review¹⁰⁵Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020 Jul 22;11:1582.

High blood sugar (hyperglycemia) and the subsequent inflammation promote gut microbiome dysbiosis, increased intestinal permeability, and fatty liver disease.¹⁰⁶Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020 Jul 22;11:1582.

• Increased insulin sensitivity and gut microbial diversity among males with metabolic syndrome treated with small intestinal infusions of microbiota from lean donors (allogenic) compared to baseline in an observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods analysis within a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹⁰⁷Vrieze A, Van Nood E et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7.
• Lower levels of beneficial butyrate-producing bacteria, Roseburia and Faecalibacterium prauznitzii, in the gut microbiota of people with type 2 diabetes compared with healthy people in mid-sized observational studies¹⁰⁸Karlsson FH, Tremaroli V et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013 Jun 6;498(7452):99-103; Qin J, Li Y et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012 Oct 4;490(7418):55-60.
• Higher risk of insulin resistance among postmenopausal obese Caucasian females with higher fecal concentrations of Lactobacillus gasseri, Streptococcus mutans, or Escherichia coli in an observational study¹⁰⁹Hartstra AV, Bouter KE, Bäckhed F, Nieuwdorp M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care. 2015 Jan;38(1):159-65.
• More marked insulin resistance among people with low bacterial richness (number of gut microbial genes) compared with people with high bacterial richness in a mid-sized observational study¹¹⁰Le Chatelier E, Nielsen T et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013 Aug 29;500(7464):541-6.

Cardiovascular symptoms: modest evidence of higher levels of vascular injury and risk of cardiovascular disease, heart attack (myocardial infarction), stroke, and peripheral artery disease among people with type 2 diabetes

• Higher levels of vascular injury and risk of cardiovascular disease, heart attack (myocardial infarction), stroke, and peripheral artery disease among people with type 2 diabetes compared to nondiabetic people in a review¹¹¹Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020 Jul 22;11:1582.

Cognitive difficulties: modest evidence of higher risk of cognitive dysfunction among people with diabetes or increased insulin resistance

• Worse measures of executive function including inhibition, working memory, set-shifting, and overall executive function performance among people with type 1 diabetes compared to people without diabetes in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 26 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies¹¹²Broadley MM, White MJ, Andrew B. A systematic review and meta-analysis of executive function performance in type 1 diabetes mellitus. Psychosomatic Medicine. 2017 Jul/Aug;79(6):684-696.
• 2 to 3 times higher risk of dementia among people with diabetes compared to no diabetes in 7 of 10 studies in a review of observational studies¹¹³Li J, Shao YH et al. Diabetes mellitus and dementia—a systematic review and meta-analysis. European Review for Medical and Pharmacological Sciences. 2014;18(12):1778-89.
• Much higher risk of cognitive dysfunction after gastrointestinal surgery among people with increased insulin resistance (HOMA-IR > 2.6) compared to lower HOMA levels in a small observational study¹¹⁴He X, Long G et al. Insulin resistance predicts postoperative cognitive dysfunction in elderly gastrointestinal patients. Frontiers in Aging Neuroscience. 2019 Aug 8;11:197.

Depression

Good evidence of higher incidence of depression among people with higher levels of blood sugar or type 2 diabetes

Preliminary evidence of a link between depression and high blood sugar, but no evidence specific to people with cancer

• Higher emotional intensity and lower emotional intelligence among people with type 2 diabetes with higher markers of blood sugar (HbA1c levels) in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹¹⁵Coccaro EF, Drossos T, Phillipson L. HbA1c levels as a function of emotional regulation and emotional intelligence in patients with type 2 diabetes. Primary Care Diabetes. 2016 Oct;10(5):334-41.
• Substantially higher incidence of depression among people with diabetes compared to people without diabetes in a review¹¹⁶Bădescu SV, Tătaru C et al. The association between diabetes mellitus and depression. Journal of Medicine and Life. 2016 Apr-Jun;9(2):120-5.
• Higher markers of blood sugar and insulin responses among people with depression than among controls in a small observational study¹¹⁷Winokur A, Maislin G, Phillips JL, Amsterdam JD. Insulin resistance after oral glucose tolerance testing in patients with major depression. American Journal of Psychiatry 1988; 145:325-30.
• Higher incidence of insulin resistance among people with depression compared to controls in small observational studies¹¹⁸Nathan RS, Sachar EJ, Asnis GM, Halbreich U, Halpern FS. Relative insulin insensitivity and cortisol secretion in depressed patients. Psychiatry Research. 1981;4:291-300; Weber B, Schweiger U, Deuschle M, Heuser I. Major depression and impaired glucose tolerance. Experimental and Clinical Endocrinology & Diabetes. 2000;108(3):187-90; Okamura F, Tashiro A et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism. 2000 Oct;49(10):1255-60.

Neuropathy and other neurological symptoms: modest evidence of slower progression of neuropathy among some people with type 2 diabetes or delay of the development of neuropathy among patients with type 1 diabetes practicing tight glycemic control

• Slower progression of neuropathy among some people with type 2 diabetes or delay of the development of neuropathy among patients with type 1 diabetes practicing tight glycemic control in a review of RCTs¹¹⁹Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Current Diabetes Reports. 2014;14(9):528.

Surgery outcomes

Modest evidence of higher risk of infection and other complications, including short-term mortality, after surgery among people with poor glycemic control and/or insulin resistance

Modest evidence of longer hospital and/or intensive care unit (ICU) stays after surgery among people with diabetes with poor glycemic control

• Lower risks of total infection and wound infection, shorter stays in the ICU, lower risk of short-term mortality, and a weak trend toward shorter hospital stays and acute renal failure, but higher risks of hypoglycemia, after surgery among people with tight glycemic control compared to conventional glycemic control in a meta-analysis of 15 RCTs¹²⁰Wang YY, Hu SF et al. Postoperative tight glycemic control significantly reduces postoperative infection rates in patients undergoing surgery: a meta-analysis. BMC Endocrine Disorders. 2018 Jun 22;18(1):42.
• Higher incidence of major complications and minor infections, longer stays in the ICU and the hospital after cardiac surgery among people with diabetes with poor glycemic control compared to people without diabetes in a mid-sized observational study¹²¹Sato H, Carvalho G et al. The association of preoperative glycemic control, intraoperative insulin sensitivity, and outcomes after cardiac surgery. Journal of Clinical Endocrinology and Metabolism. 2010 Sep;95(9):4338-44.
• Higher risk of complications and poor glycemic control after major colorectal surgery within an enhanced-recovery protocol among people without diabetes and with a preoperative HbA1c level over 6.0% compared to people with levels 4.5-6.0% in a mid-sized observational study¹²²Gustafsson UO, Thorell A, Soop M, Ljungqvist O, Nygren J. Haemoglobin A1c as a predictor of postoperative hyperglycaemia and complications after major colorectal surgery. British Journal of Surgery. 2009 Nov;96(11):1358-64.
• Higher rates of wound complications among people with high blood glucose (>200 mg/dl) or elevated A1C levels (> 6.5%) compared to lower levels in a small observational study¹²³Endara M, Masden D et al. The role of chronic and perioperative glucose management in high-risk surgical closures: a case for tighter glycemic control. Plastic and Reconstructive Surgery. 2013 Oct;132(4):996-1004.