Risk of Diabetic Retinopathy According to Subtype of Type 2 Diabetes.

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of ß-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR.

Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Insulinemic potential of lifestyle is associated with depression and anxiety in adults: A large community-based study.

BACKGROUND: We aimed to investigate the association between an empirical lifestyle index for hyperinsulinemia (ELIH), empirical lifestyle index for insulin resistance (ELIR), and depression and anxiety in an adult Iranian population. METHODS: In this cross-sectional study, a total of 6450 participants, aged 35-65 years were recruited as part of the MASHAD cohort study. Dietary intakes were assessed using a validated food frequency questionnaire (FFQ). Depression and anxiety were screened using Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). ELIH and ELIR were calculated using dietary intake, body mass index, and physical activity information. Multivariable ordinal logistic regression models were applied to determine the association between ELIH, ELIR, and depression and anxiety severity. RESULTS: In a fully adjusted model, participants with the highest ELIH quartile had a higher odds of more severe depression and anxiety compared to those in the lowest category (OR = 1.44; 95 % CI = 1.22-1.71 and OR = 1.62; 95 % CI = 1.37-1.25, respectively). Participants with the highest ELIR had higher odds of more severe depression and anxiety compared to those in the lowest category (OR = 1.22; 95 % CI = 1.04-1.43 and OR = 1.21; 95 % CI = 1.03-1.42, respectively). LIMITATIONS: The assessment of dietary intake and mental health by questionnaires may increases the rate of misclassification. Due to the study's cross-sectional nature, causal relationships cannot be established. CONCLUSION: There was a significant positive association between the hyperinsulinemia and insulin resistance potential of lifestyle and severity of depression and anxiety among Iranian adults.

Factors associated with neonatal hyperinsulinemic hypoglycemia, a case-control study.

OBJECTIVES: We aimed to identify perinatal risk factors associated with hyperinsulinemic hypoglycemia in neonates. Secondary objectives included an examination of clinical and biochemical characteristics at the time of diagnosis and an exploration of the duration of diazoxide therapy. METHODS: A case-control study was conducted, involving individual chart reviews of inborn infants diagnosed with hyperinsulinemic hypoglycemia (the HH group) between 2014 and 2021. These cases were paired with controls (the non-HH group) belonging to the same gestational age (GA) strata who did not exhibit HH or only had transient postnatal hypoglycemia. RESULTS: A total of 52 infants with HH were matched with corresponding controls. The mean GA in the HH group was 34.4 ± 3.1 weeks. Notably, the HH group exhibited lower mean minimum plasma glucose (PG) levels and required higher glucose infusion rates in comparison to the non-HH group (26.5 ± 15.6 vs. 49.1 ± 37.7 mg/dL and 12.9 ± 3.8 vs. 5.7 ± 2.1 mg/kg/min, respectively; p<0.001 for both). After adjusting for potential confounding factors, only two variables, fetal growth restriction (FGR) and neonatal sepsis, demonstrated significant associations with HH (adjusted odds ratio [95 % confidence interval]: 8.1 [2.1-31.0], p=0.002 and 6.3 [1.9-21.4], p=0.003, respectively). The median duration of diazoxide therapy for the HH group was 4 months. CONCLUSIONS: FGR and neonatal sepsis emerged as notable risk factors for HH. These infants exhibited lower PG levels and necessitated higher glucose infusion rates compared to their non-HH counterparts. Importantly, a substantial proportion of the HH group received diazoxide therapy, with a median treatment duration of 4 months.

Obesity and obesity-associated metabolic disease conditions in Connemara ponies in Ireland.

BACKGROUND: Equine obesity combined with insulin dysregulation (ID) is a major risk factor associated with laminitis. Some pony breeds appear to be at increased risk. However, little is known regarding the prevalence of obesity or hyperinsulinaemia as evidence of ID in Irish ponies. OBJECTIVE: To investigate the prevalence of obesity and associated endocrine/metabolic disease conditions in Connemara ponies and to determine if hyperinsulinaemia in these ponies could be predicted by morphometric or metabolic markers. STUDY DESIGN: Cross-sectional study. METHODS: The study population included registered Connemara ponies recruited through public and veterinary social media posts. Ponies underwent a physical examination and information on their management and clinical history was obtained via owner questionnaire. The body condition score (BCS) was measured using the Henneke system; cresty neck score (CNS) and regionalised adiposity were also assessed. Hyperinsulinaemia was confirmed by measuring serum basal insulin concentration (BIC) or insulin concentration after an oral sugar test (OST). Blood glucose and triglyceride concentrations were measured. Characteristics of hyperinsulinaemic and insulin-sensitive ponies were compared by logistic regression. RESULTS: Two hundred ponies were included; 59 ponies (29.5%) had a BCS ≥7, 58 (29.0%) had a CNS ≥2.5 and 135 (67.5%) had regionalised adiposity; 137 (68.5%) ponies had at least one of these abnormalities. Owner-reported history or clinical evidence of chronic laminitis was found in 92 ponies (46.0%). Hyperinsulinaemia was confirmed in 32 ponies (16.0%), including 23 of 91 (25.3%) detected by OST and 9 of 109 (8.3%) by BIC. Hypertriglyceridaemia was observed in 12 of 198 ponies (6.1%) ponies and hyperglycaemia in 11 of 197 ponies (5.6%) ponies. The odds of hyperinsulinaemia increased by a factor of 6.53 (95% confidence interval: 2.95, 15.21) when BCS was ≥7. MAIN LIMITATIONS: The OST was not performed in all ponies. CONCLUSIONS: Increased adiposity, laminitis and metabolic derangements are prevalent in this native Irish pony breed.

Dietary and lifestyle indices for hyperinsulinemia and colorectal cancer risk: a case-control study.

BACKGROUND: The incidence of colorectal cancer (CRC) has increased in Iran, and determining the dietary patterns that can contribute to reducing or increasing the risk of CRC will help better control this disease. Therefore, in the current study, we assessed the association between the empirical lifestyle index for hyperinsulinemia (ELIH) and the empirical dietary index for hyperinsulinemia (EDIH) with the CRC odds. METHODS: The present case (n = 71)-control (n = 142) study was carried out in several CRC surgical units of hospitals in Tehran, Iran. A semi-quantitative food frequency questionnaire containing 168 items was used to assess participants' dietary intakes. The EDIH and ELIH scores were calculated by food groups and some variables such as body mass index and physical activity. Logistic regression models were applied to evaluate the association between the EDIH and ELIH scores with CRC odds. RESULTS: According to baseline features of the study participants, there were significant differences between the controls and cases in ELIH score, fiber intake, taking aspirin, and family history of CRC in first- and second-degree relatives. Also, we found that the odds of CRC increased significantly in the last tertile compared to the first tertile in EDIH and ELIH in the adjusted model (odds ratio (OR) = 3.12; 95% confidence interval (CI): 1.30-7.48 and OR = 4.72; 95% CI: 1.15-19.39, respectively). CONCLUSIONS: In conclusion, the result of this study indicated that CRC odds was significantly greater in subjects with higher EDIH and ELIH scores. Also, according to the results of this study, lifestyle and diet with insulinemic potential can influence the CRC risk.

The Rising Incidence of Hyperinsulinemic Hypoglycemia: Connection With Maternal Health.

OBJECTIVE: Due to a perceived rise in hyperinsulinemic hypoglycemia (HH) cases over time, notably during the COVID-19 pandemic, institutional experiences between 2013 and 2021 were reviewed to evaluate trends, characteristics, and outcomes in children with HH. METHODS: Charts of all children diagnosed with HH during the study period and evaluated by Pediatric Endocrinology were reviewed. HH was defined per Pediatric Endocrine Society guidelines. Regression analysis compared rates of change in HH cases and maternal risk factors over time. RESULTS: The incidence of HH began to rise in April 2016 and became significant in March 2017 (P < .001), with a more rapid rate of rise during the first year of the COVID-19 pandemic (P < .001). Seventy-four children with HH were identified over 9 years; 43% (n = 32) were diagnosed in 2020-2021. Maternal hypertensive disorders demonstrated longitudinal association with hyperinsulinism cases (P < .001). CONCLUSION: While HH diagnoses were on the rise for much of the 9-year study period, nearly half of all infants were diagnosed during the COVID-19 pandemic in 2020 to 21. The trends in HH diagnoses correlated with maternal hypertensive disorders. More studies exploring the roles of maternal health, hypertension, and stress and development of HH in offspring are needed.

The Relationship between Insulin Resistance and Thyroid Volume in Georgia.

Patients with insulin resistance (IR) have a higher thyroid volume therefore the aim of our study is to examine the correlation between IR and thyroid volume in the residents of Georgia. METHODS: 413 patients with a mean age of 37.3 ± and 11.4 years were included in this study. Out of those, 120 were males, and 293 were females who were studied retrospectively. They had hyperinsulinemia and were referred to the clinic from 2017 to 2019. The factors studied were age, sex, body mass index (BMI), clinical signs, thyroid ultrasound, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids, fasting insulin, fasting glucose, thyroid stimulating hormone (TSH), Free thyroxine (FT4), and Zinc (Zn). RESULTS: IR was detected in 252 individuals. The frequency of men with insulin resistance was significantly higher than in the control group - 72.50%, and 56.31%, respectively (F = 9.55, p= 0.0021). Mean thyroid volume in the patients with IR was significantly higher compared to the controls 20.52 + 6.39 cm3 and 15.25 + 6.55 cm3, respectively (p < 0.001). Hyperinsulinemia had a significant positive correlation with Goiter r = 0.445, p < 0.0001. The associated factors for hyperinsulinemia are: Goiter (1) - OR = 5.12 (95% CI:3.02-8.69); Cholesterol - OR = OR = 3.31 (95% CI: 1.54-7.14); Triglycerides - OR = 3.23 (95% CI:1.02-10.28); Obesity (1)- OR = 3.94 (95% CI: 2.23-6.98); Thyroid structural changes (1) - OR = 2.01 (95% CI: 1.12-3.60); ALT/AST-OR = 4.53 (95% CI: 2.33-8.80); Zn decreased Odds Ratio hyperinsulinemia - OR = 0.95 (95% CI: 0.94-0.97). CONCLUSION: Hyperinsulinemia is the most common cause of diffuse goiter and the heterogeneous structure of the thyroid. The volume of the thyroid gland shows a significant positive association with the characteristics of metabolic syndrome and increased thyroid volume predictors of metabolic syndrome.

High insulinemic potential of diet and lifestyle is associated with increased risk of chronic kidney disease incident in adults.

BACKGROUND: The role of higher insulinemic effects of dietary pattern and lifestyle factors on the risk of chronic kidney disease (CKD) is not well-studied. In the current study, we aimed to investigate the relationship between the insulinemic potential of diet and lifestyle with the risk of CKD in adults. METHODS: A total of 6044 individuals without CKD, aged>18 years, were recruited from among participants of the Tehran Lipid and Glucose Study (third and fourth surveys) and followed a mean of 6.03 years(follow-up rate:94.95%). The dietary intake data were collected using a food frequency questionnaire. The insulinemic potential of diet and lifestyle was determined based on four empirical indices, including the empirical dietary index for hyperinsulinemia (EDIH), the empirical dietary index for insulin resistance (EDIR), the empirical lifestyle index for hyperinsulinemia (ELIH), and the empirical lifestyle index for insulin resistance (ELIR). RESULTS: Mean ± SD age of all study participants (54.3% women) was 37.8 ± 12.8 years. During the 6.03 years of follow-up (46,889.8 person-years), 1216(20.1%) new cases of CKD were identified. According to the multivariable-adjusted model, the risk of CKD incident is increased across quintiles of EDIR (OR = 1.29;95% CI: 1.06-1.57), ELIH (OR = 1.35; 95%CI: 1.10-1.67), and ELIR (OR = 1.24; 95%CI:1.02-1.51). However, no significant relationship was found between the EDIH score and the risk of CKD. CONCLUSION: Results of the current study showed that dietary pattern with a high EDIR score and a lifestyle with higher ELIH and ELIR scores may be related to increasing the risk of CKD incident. However, no significant association was observed between EDIH score and CKD incident.

Inflammatory and insulinemic dietary patterns and risk of endometrial cancer among US women.

BACKGROUND: Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. METHODS: We followed 48 330 women from the Nurses' Health Study (1984-2016) and 85 426 women from the Nurses' Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. RESULTS: We documented 1462 type I endometrial cancer cases over 2 823 221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; Ptrend < .001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; Ptrend < .001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P < .001) and 71.8% (95% CI = 41.0% to 90.4%; P < .001) of the association of endometrial cancer with EDIP and EDIH, respectively. CONCLUSIONS: In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity.

Dietary and lifestyle indices for hyperinsulinemia with the risk of obesity phenotypes: a prospective cohort study among Iranian adult population.

BACKGROUND: Previous studies have cited insulin-related disorders, including hyperinsulinemia, as one of the main causes of obesity risk and metabolic disorders. We aimed to investigate the association of the Empirical Dietary Index for Hyperinsulinemia (EDIH) and Empirical Lifestyle Index for Hyperinsulinemia (ELIH) with the risk of obesity phenotypes among Iranian adults. METHODS: Present study was conducted on 2705 subjects, including 1604 metabolically healthy normal weights (MHNW) and 1101 metabolically healthy obesity (MHO) individuals. Obesity phenotypes, including MHNW, MHO, metabolically unhealthy normal weights (MUNW), and metabolic unhealthy obesity (MUO), were determined using the criteria of the Joint International statement (JIS) for metabolic syndrome. Dietary intake data from the previous year was gathered using a food frequency questionnaire. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals (HRs and 95% CIs) of obesity phenotypes incident across tertiles of EDIH and ELIH scores. RESULTS: The mean ± SD of age and BMI of all participants were 33.5 ± 12.2 years and 24.3 ± 3.8 kg/m2, respectively. In the multivariable-adjusted model, a higher ELIH score was associated with a greater risk for incidence of MUO (HR: 3.47, 95%CI: 2.54-4.74; Ptrend = < 0.001) and MHO (HR: 3.61, 95%CI: 2.73-4.77; Ptrend = < 0.001). Also, a higher score of EDIH was related to an increased risk of MUO incidence (HR: 1.35, 95%CI: 1.02-1.79; P for trend = 0.046). However, there was no significant association between a higher score of EDIH and the risk of MHO. CONCLUSION: Our findings revealed that a high insulinemic potential of diet and lifestyle, determined by EDIH and ELIH indices, may be related to an increase in the simultaneous occurrence of obesity with metabolic disorders in Iranian adults.

Higher scores of dietary and lifestyle inflammatory indices are associated with increased risk of insulin-related disorders in Iranian adults.

BACKGROUND/OBJECTIVES: The roles of potential inflammation of diet and lifestyle in the risk of insulin-related disorders are unclear. In the current study, we aimed to assess the relationship between dietary inflammation scores (DIS), lifestyle inflammation scores (LIS), and dietary and lifestyle inflammation score (DLIS) and the risk of insulin resistance (IR) and hyperinsulinemia in Tehranian adults. SUBJECTS/METHODS: A total of 1,244 participants, aged ≥20 years, who were free of insulin-related disorders at baseline (2006-08), were followed for 3.2 years (2009-11) to ascertain the incidence of hyperinsulinemia and IR. A food frequency questionnaire was used to determine the score of DIS, LIS, and DLIS at baseline. Logistic regression models were used to determine the odds ratio (ORs) of insulin-related disorders across tertiles of DIS, LIS, and DLIS. RESULTS: Mean ± SD age of participants (42.7% men) was 43.0 ± 13.0 years. During the 3.2 years follow-up, the incidence of IR and hyperinsulinemia was 30.0% and 20.0%, respectively. In the multivariable model, there was a direct association between the higher score of DLIS (OR = 2.10; 95% CI: 1.17-3.74) and DIS (OR = 1.84; 95% CI: 1.09-3.11) with the risk of IR incident (P for trend <0.05). Also, the higher score of LIS was related to increased risk of IR (OR = 2.28; 95% CI: 1.19-4.37) and hyperinsulinemia (OR = 1.69; 95% CI: 1.02-2.85) (P for trend <0.05). However, no significant association was observed between the higher score of DLIS and DIS with risk of hyperinsulinemia CONCLUSION: The higher inflammatory potential of diet and lifestyle, determined by DLIS, DIS, and LIS scores, were associated with a higher risk of IR. Also, individuals with a higher score of LIS are more prone to hyperinsulinemia risk.

Cancer and its predictors in Chinese adults with newly diagnosed diabetes and impaired glucose tolerance (IGT): a 30-year follow-up of the Da Qing IGT and Diabetes Study.

BACKGROUND: We aimed to explore if hyperglycaemia and hyperinsulinemia in the diabetes and prediabetes population were associated with increased risk of cancer occurence. METHODS: Overall, 1700 participants with different glycaemic statuses were screened from the 110,660 residents of Da-Qing, China, in 1985. They were followed up to 30 years to access cancer outcomes. RESULTS: Cancer was identified in 15.2% (259/1700) of the participants. The incidence of cancer in the normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes groups was 6.06, 6.77, and 7.18 per 1000 person-years, respectively (P = 0.02). In the Fine-Gray model with all cause death as competing risk, compared with the NGT controls, both IGT and diabetes groups demonstrated significantly higher risk of cancer (for the IGT group, adjusted hazard ratio (aHR) = 1.77, 95% CI 1.38-2.27, P < 0.0001; for the diabetes, aHR = 3.34, 95% CI 2.64-4.22, P < 0.0001). Among the IGT participants, progress to diabetes (aHR = 2.28, 95%CI 1.24-4.20, P = 0.008) and insulin-area under the curve at baseline (for 1 SD increase, aHR = 1.39, P = 0.02) were also associated with the risk of cancer after adjustment of covariables. CONCLUSIONS: Hyperglycaemia in patients with diabetes, hyperinsulinemia, and progression to diabetes in people with IGT is significantly associated with the long-term increased risk of cancer occurrence.

Pathophysiological Characteristics Linking Type 2 Diabetes Mellitus and Colorectal Neoplasia.

A substantial body of literature has provided evidence that type 2 diabetes mellitus (T2DM) and colorectal neoplasia share several common factors. Both diseases are among the leading causes of death worldwide and have an increasing incidence. In addition to usual risk factors such as sedentary lifestyle, obesity, and family history, common pathophysiological mechanisms involved in the development of these diseases have been identified. These include changes in glucose metabolism associated with adipose tissue dysfunction including insulin resistance resulting to hyperinsulinemia and chronic hyperglycemia. In addition to altered glucose metabolism, abdominal obesity has been associated with accented carcinogenesis with chronic subclinical inflammation. An increasing number of studies have recently described the role of the gut microbiota in metabolic diseases including T2DM and the development of colorectal cancer (CRC). Due to the interconnectedness of different pathophysiological processes, it is not entirely clear which factor is crucial in the development of carcinogenesis in patients with T2DM. The aim of this work is to review the current knowledge on the pathophysiological mechanisms of colorectal neoplasia development in individuals with T2DM. Here, we review the potential pathophysiological processes involved in the onset and progression of colorectal neoplasia in patients with T2DM. Uncovering common pathophysiological characteristics is essential for understanding the nature of these diseases and may lead to effective treatment and prevention.

Association of the insulinemic potential of diet and lifestyle with risk of diabetes incident in Tehranian adults: a population based cohort study.

BACKGROUND: We aimed to assess the associations between insulinemic potential of diet and lifestyle and the risk of diabetes incident, using four empirical indices including the empirical dietary index for hyperinsulinemia (EDIH), the empirical dietary index for insulin resistance (EDIR), empirical lifestyle index for hyperinsulinemia (ELIH), and empirical lifestyle index for insulin resistance (ELIR). METHODS: A total of 3734 individuals, aged ≥ 20 years old, who were free of diabetes at baseline (2008-2011), were followed for 6.2 years (2015-2018) to ascertain incident diabetes. The food frequency questionnaire was used to collect dietary intakes at baseline. Odds ratio (OR) of diabetes were calculated across quartiles of EDIH, EDIR, ELIH, and ELIR using logistic regression, which controlled for confounding factors. RESULTS: The mean ± SD age and BMI of individuals (45.1 % male) were 40.9 ± 12.0 years and 27.1 ± 4.1 kg/m2, respectively. At the end of follow-up, 253 (6.8 %) diabetes cases were identified. In the multivariable-adjusted model, individuals in the highest quartile of EDIR (1.58;95 %CI:1.03-2.44, P for trend = 0.025), ELIH (1.89;95 %CI:1.20-2.97, P for trend = 0.004), and ELIR (1.74; 95 %CI:1.11-2.72, P for trend = 0.031) had increased the risk of diabetes. However, no significant associations were found between the score of EDIH and diabetes incident. CONCLUSIONS: Higher adherence to EDIR, ELIH, and ELIR scores were associated with increased risk of diabetes, while no significant association was found between EDIH score and diabetes incident.

Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study.

AIMS/HYPOTHESIS: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanineaminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.

Dietary Patterns of Insulinemia, Inflammation and Glycemia, and Pancreatic Cancer Risk: Findings from the Women's Health Initiative.

BACKGROUND: Pancreatic cancer risk is increasing in countries with high consumption of Western dietary patterns and rising obesity rates. We examined the hypothesis that specific dietary patterns reflecting hyperinsulinemia (empirical dietary index for hyperinsulinemia; EDIH), systemic inflammation (empirical dietary inflammatory pattern; EDIP), and postprandial glycemia [glycemic index (GI); glycemic load (GL)] are associated with pancreatic cancer risk, including the potential modifying role of type 2 diabetes (T2D) and body mass index (BMI). METHODS: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 129,241 women, 50-79 years-old in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate HRs and 95% confidence intervals (95% CI) for pancreatic cancer risk. RESULTS: During a median 19.9 years of follow-up, 850 pancreatic cancer cases were diagnosed. We observed no association between dietary scores and pancreatic cancer risk overall. However, risk was elevated among participants with longstanding T2D (present >3 years before pancreatic cancer diagnosis) for EDIH. For each 1 SD increment in dietary score, the HRs (95% CIs) were: EDIH, 1.33 (1.06-1.66); EDIP, 1.26 (0.98-1.63); GI, 1.26 (0.96-1.67); and GL, 1.23 (0.96-1.57); although interactions were not significant (all P interaction >0.05). Separately, we observed inverse associations between GI [0.86 (0.76-0.96), P interaction = 0.0068] and GL [0.83 (0.73-0.93), P interaction = 0.0075], with pancreatic cancer risk among normal-weight women. CONCLUSIONS: We observed no overall association between the dietary patterns evaluated and pancreatic cancer risk, although women with T2D appeared to have greater cancer risk. IMPACT: The elevated risk for hyperinsulinemic diets among women with longstanding T2D and the inverse association among normal-weight women warrant further examination.

Hyperinsulinemia during pregnancy across varying degrees of glucose tolerance: An examination of the Kraft database.

AIM: Hyperinsulinemia is a known underlying driver of metabolic disease; however, its role in pregnancy complications is less understood due to insulin measurement not being a part of standard clinical assessments. This study aimed to characterize hyperinsulinemia in pregnancy by gestational diabetes (GD) status using Kraft methodology. METHODS: We analyzed historical data from 926 pregnant women who underwent a 100-g oral glucose tolerance test (OGTT), which included insulin measurement. Subjects were grouped by GD diagnosis status ("Normal", "Borderline", "GD") and insulin responses over 3 h were compared between groups. RESULTS: "GD" was diagnosed in 20.3% of the subjects and 13.8% were grouped as "Borderline." The prevalence of hyperinsulinemia using the Kraft algorithm was 33.1% for Kraft IIB and 42.0% for Kraft III. Compared to normal glucose-tolerant mothers, individuals from the "Borderline" group had an exacerbated insulin response, although not to the same magnitude as those with "GD." CONCLUSIONS: Dynamic OGTT insulin measurement during pregnancy may provide a meaningful assessment of metabolic risk among women who would otherwise not be diagnosed with GD.

Bidirectional temporal relationship between obesity and hyperinsulinemia: longitudinal observation from a Chinese cohort.

INTRODUCTION: Although obesity and hyperinsulinemia are closely intercorrelated, their temporal sequence is still uncertain. This study aims to investigate the temporal relationship patterns between obesity measures and hyperinsulinemia in Chinese adults. RESEARCH DESIGN AND METHODS: The longitudinal cohort consisted of 2493 participants (860 males and 1633 female, mean age 56.71 years at follow-up) for whom measurements of obesity and hyperinsulinemia measures were collected twice between 2011 and 2014, with an average follow-up time of 3 years. Cross-lagged panel analysis was used to examine the temporal relationship between obesity measures (body mass index (BMI); waist circumference (WC); hip circumference (HC); waist-to-hip ratio (WHR)) and hyperinsulinemia (insulin, homeostasis model assessment of insulin resistance (HOMA-IR), or homeostasis model assessment of beta cell function (HOMA-%ß)). RESULTS: After the adjustment of age, sex, smoking, drinking and follow-up years, in the BMI-insulin model, the path coefficient (ß2=0.229; p<0.001) of baseline BMI to follow-up insulin was significantly greater than the path coefficient (ß1=0.073; p<0.001) of baseline insulin to follow-up BMI (p<0.001 for ß2>ß1). In the WHR-insulin model, the path coefficient (ß1=0.152; p<0.001) of baseline insulin to follow-up WHR was significantly greater than the path coefficient (ß2=0.077; p<0.001) of baseline WHR to follow-up insulin (p=0.007 for ß1>ß2). In the WC/HC-insulin model, the path coefficients of baseline insulin to follow-up WC or HC (ß1s) were also greater than the path coefficients of baseline WC or HC to follow-up insulin (ß2s), but the difference between ß1s and ß2s were not significant. The similar temporal patterns were founded between obesity measures with HOMA-IR or HOMA-%ß. CONCLUSIONS: These findings indicate that there is a bidirectional relationship between obesity and hyperinsulinemia, and abdominal obesity measures are more sensitive to hyperinsulinemia measures than BMI.