Postglucose Hyperinsulinemia in Black Women Is Not What We Thought

Abstract

Chung et al. present data showing altered insulin secretion and metabolism in black women across the lifespan. This work is critical to move our field toward personalized patient-centered care.

In the current era of a push for personalized medicine based on genetic background, we may be putting the cart before the horse. There is still much to learn in terms of basic endocrinologic variation secondary to racial, ethnic, sex, and life-phase differences. In “Postprandial Insulin Response and Clearance Among Black and White Women: The Federal Women’s Study” by Chung et al. (1), the authors write about their investigation of key insulin responses to glucose and how they vary on the basis of race and menopausal status in women.

Women without diabetes underwent three different, provocative glucose tests—an oral glucose tolerance test, an insulin-modified IV glucose test, and a mixed-meal test—to assess a true physiologic response. The test data were mathematically modeled to assess more complex measures, including initial dynamic insulin responsiveness to change in glucose and hepatic insulin clearance (1). Confirming previous work, the authors found that compared with white women, black premenopausal women had lower peripheral insulin sensitivity with compensatory higher insulin concentrations after a glucose load. However, the increased insulin concentrations in black women were not due to increased total insulin secretion, as previously thought; rather, they were the result of a combination of increased early, dynamic β-cell responsivity and decreased hepatic insulin clearance. These findings were confirmed with both the IV and mixed-meal tests and via multiple models. Similar results were found comparing white vs black postmenopausal women. Same-race postmenopausal women had greater impairment of early, dynamic β-cell responsivity and hepatic insulin clearance than did premenopausal women, demonstrating that racial differences persisted through life-stage transitions (1).

Despite decades of study on glucose and insulin dynamics, this is the first time that racial differences in women have been so comprehensively studied and mathematically modeled. The findings of Chung et al. (1) contrast with the dogma that black women have hyperinsulinemia secondary to persistent excess insulin secretion. However, the modeling needed to distinguish the difference between dynamic β-cell responsivity and overall total secretion had not been performed from a race perspective in women, nor had responses to a meal (in this case, a bagel with cream cheese and orange juice) been studied. The Endocrine Society released a statement in 2012 that identified “a need for basic science, population based, translational and health services studies to explore underlying mechanisms contributing to endocrine health disparities” (2). This work by Chung et al. (1) directly responds to this call and is the kind of work needed to better understand the biological contribution toward the higher incidence of type 2 diabetes in black women (3, 4).

Limited study on racial differences in insulin secretion and clearance as individuals progress through different life stages has been performed. As women transition through menopause, the rates of diabetes and metabolic disease increase, are thought to be related to several factors, and those with early menopause are at highest risk (5). Black women have a higher rate of early menopause compared with white non-Hispanic and Hispanic women, and menopausal age in blacks was most associated with excess body mass index (6). Larger studies examining differences in insulin resistance by race in postmenopausal women found that insulin resistance predicted postmenopausal weight gain in all races or ethnicities except black women, who were the heaviest at time of menopause (7). Using just the IV glucose tolerance test in women across the lifespan, Chandler-Laney et al. (8) found similar differences by race that persisted as women aged.

With the relatively recent increase in incidence of type 2 diabetes in youth, there has also been a focus on understanding racial differences in pubertal insulin dynamics. After using a hyperglycemic clamp in a study of healthy, normal-weight, normoglycemic youth, Arslanian and Suprasongsin (9) also found decreased peripheral insulin sensitivity and decreased hepatic insulin clearance in black youth relative to that in white youth, indicating that this pattern is present early in life. However, in contrast to the adult data, they found increased total insulin secretion in the black youth. This group also documented similar findings in obese adolescents with type 2 diabetes, using the same methods (10). We have recently shown that adolescents have twofold to fourfold higher insulin secretion in response to either an oral glucose or a hyperglycemic clamp compared with similarly obese and dysglycemic adults (11, 12). The extreme physiologic alterations from puberty may overwhelm the subtle differences seen by Chung et al. (1). Regardless, the difference by race is clinically relevant to type 2 diabetes in youth, as the Treatment Options for Type 2 Diabetes in Adolescents and Youth study found that the adolescents in whom metformin therapy was most likely to fail were black teens (13). Thus, it is important to examine the effect of race, sex, and ethnicity at all stages of life.

In addition to focusing on the insulin response to oral and IV glucose excursions, Chung et al. (1) also examined the relationship between hepatic insulin clearance and hepatic fat percentage. Increased serum triglyceride levels and lower rates of hepatic steatosis in black individuals relative to white non-Hispanic and Hispanic people have been well documented (14). Fatty liver disease is described as a strong predictor of future development of cardiovascular disease and type 2 diabetes, yet these analyses are based on liver disease in nonblack populations (14, 15). Still unclear is how this alteration in hepatic lipid metabolism relates to the relative increase in serum insulin concentrations. Chung et al. (1) showed that whereas there was a very strong relationship with fasting hepatic insulin extraction and hepatic fat in white women, this relationship did not exist in black women. Their findings provide an explanation for the previous work that demonstrated the paradox in black men and women of a high degree of insulin resistance, as assessed by the homeostatic model assessment for insulin resistance measure, which includes fasting insulin concentration, yet low levels of hepatic steatosis (16). It is critical as the field moves forward to understand the relationship between fatty liver disease and diabetes or cardiovascular disease risk, so that paradox in black individuals is not forgotten.

It is crucial that we apply what we know about differences in racial, ethnic, sex, and life-phase physiology to how we treat our patients today. Recommendations for personalized, patient-centered treatment of type 2 diabetes were just released by the American Diabetes Association/European and the European Association for the Study of Diabetes (17). These guidelines are a huge step forward and call for patient-centered culturally sensitive and comorbidity-specific selection of treatments and medications. However, the role of race and ethnicity are notably missing because of insufficient, high-quality translational and clinical research in this area. Additional work like the study by Chung et al. (1) in this issue of the journal is desperately needed so we can better treat all types of patients in a manner best suited for who they are as individuals. The new guidelines recommend escalation of glycemic management at time of metformin failure with a sodium-glucose cotransporter-2 inhibitor in the setting of cardiovascular disease (17). However, one could envision that because black women with diabetes have disproportionally worse heart disease than do white women, would they do better with a sodium-glucose cotransporter-2 inhibitor, which has good cardiovascular disease secondary outcomes, at the time of need for escalation of diabetes therapy, even before the development of cardiovascular disease? Conversely, should the treatment of a Hispanic man with obesity who is at high risk for fatty liver disease include the addition of a glucagon-like peptide-1 receptor agonist at time of glycemic deterioration on metformin because secondary analysis has indicated that this class of medications may improve fatty liver disease (18)? These are all questions to be investigated, provoked by this much-needed thorough work into understanding the basic physiology of insulin responses in black women, conducted only 97 years after Banting discovered insulin.