Exploring Prediabetes: Seizing the Reversal Golden Window and Building a Healthier Community
- Yan Yan
- Feb 13, 2024
- 10 min read
Updated: Nov 20, 2024
Prediabetes is a significant health concern characterized by elevated blood sugar levels that are below the diagnostic threshold for type 2 diabetes (T2D). According to the Centers for Disease Control and Prevention (CDC)[1], approximately 38% of American adults (Figure 1), 1 in 5 adolescents aged 12-18 years, and 1 in 4 young adults aged 19-34 years have prediabetes. It is crucial to note that prediabetes substantially increases the risk of developing T2D, heart disease, and stroke [1].
Figure 1. 38% of US adult with prediabetes. Source data:
the Journal of the American Medical Association (JAMA).
September 8, 2015, Vol 314, No.10.
Prediabetes, characterized by insulin resistance, often arises from dietary habits high in empty calories, rapidly absorbed sugars, and refined carbohydrates such as bread and rice, as well as liquid calories from sodas and sports drinks [2]. Additionally, disruptions in mitochondrial response within cells play a critical role in cellular energy balance. This can lead to uncontrolled mitochondrial biogenesis and mitophagy, thereby contributing to insulin resistance in important insulin-targeted tissues such as skeletal muscle and liver cells [3].
As a consequence, cells reduce responsiveness to insulin, prompting increased insulin production to stabilize blood sugar levels—a condition termed insulin resistance. This leads to excess glucose accumulation and elevated blood sugar levels. Over time, pancreatic beta cells producing insulin may diminish, resulting in inadequate insulin production to counter cellular resistance. This progression can ultimately lead to prediabetes, which, if untreated, may advance to T2D [4].
To manage insulin resistance, dietary adjustments and regular physical activity are vital in preventing disease progression. For more comprehensive information on managing prediabetes, please refer to the 'Portfolio' post on Reversing Prediabetes.
Signs, Symptoms and Calculation of Insulin Resistance:
The specific signs that may indicate you have or are likely to develop insulin resistance include:
• A Large Waist:
To measure your waist:
Find the top of your hip bone and the bottom of your ribcage. Measure in the middle of these two points.
What is a healthy waist size ?
This depends on your gender and ethnicity. For a healthy measurement, aim to be less than:
80cm (31.5in) for all women
94cm (37in) for most men
A waist measuring more than the above-mentioned healthy measurements increases the odds of insulin resistance and metabolic syndrome[5].
• Dark Skin Patches -Acanthosis Nigricans[6]:
Severe insulin resistance can manifest in noticeable skin changes, such as darkened patches on the neck, elbows, knees, knuckles, or armpits, a condition known as acanthosis nigricans.
• Homeostatic Model Assessment of Insulin Resistance (HOMA-IR):
The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is a tool utilized to assess insulin resistance in suspected patients. The normal reference range for HOMA-IR is 1[7], with higher values indicating increased insulin resistance. Optimal insulin sensitivity is reflected by a HOMA-IR less than 1. Levels above 1.9 suggest early insulin resistance, while levels exceeding 2.9 indicate significant insulin resistance[8]. HOMA-IR is calculated using the formula[7]:
HOMA-IR = (fasting insulin in mU/L) × (fasting glucose in mmol/L)/22.5.
Numerous studies have revealed the correlation between prediabetes,T2D, hypertension, and certain cancers. A significant study involving nearly 900,000 participants found that prediabetes increases the risk of developing stomach, colon, liver, pancreas, and breast cancer [9].
A joint report by the American Diabetes Association (ADA) and the American Cancer Society[10] confirms the association between T2D and heightened risk of ovarian cancer [11,12]. Mechanisms such as hyperinsulinemia, hyperglycemia, and inflammation underscore the importance of prediabetes screening in cancer prevention.
Research indicates a significant overlap between prediabetes and prehypertension, as well as between T2D and hypertension [13,14]. The prevalence of their coexistence is 11%, with men having a higher rate than women (14.2% vs. 8.4%; P < 0.0001) [13]. Common risk factors and pathophysiological mechanisms, including insulin resistance and activation of renin-angiotensin-aldosterone system, link T2D and hypertension.
Summary: Studies demonstrate the coexistence of prediabetes, T2D, hypertension, and cancers (Figure 2). Chronic hyperglycemia, a key factor, drives physiological changes and metabolic distortions, contributing to organ dysfunction and cancer progression [15]. According to ADA, up to 70% of individuals with prediabetes will eventually develop T2D [16].
Figure 2. Illustrates prediabetes, T2D, hypertension, and cancer coexistence. About 70% of individuals with prediabetes progress to T2D. The key question: How fast is this progression?
Progressive beta (β) cell failure, resulting in insulin deficiency, is the primary mechanism in the transition from prediabetes to T2D [17]. T2D development is driven by two key factors: insulin resistance and impaired insulin secretion worsening over time. Without intervention, β cell function continues to decline, reaching approximately 50% of normal at diagnosis (indicated by the dashed red line) (Figure 3) [17,18]. The decline in β cell function starts about 10-12 years pre-diagnosis, decreasing by about 5% per year, reaching less than 25% within 6 years post-diagnosis [19].
Leading up to diabetes, many individuals are unaware of having prediabetes. A CDC report states that over 80% of those with prediabetes are unaware. Without intervention, many people with prediabetes could develop T2D in around 5 years [20]. It is essential to seize this golden window of opportunity for intervention, aiming to prevent the progression to T2D!
Figure 3. Timeline of prediabetes progression to diabetes without intervention. Upon diagnosis, pancreatic β cell function was approximately 50% of the normal level, as indicated by the red dashed line. The blue dashed line, derived from the HOMA data of UKPDS, illustrates the progressive decline in β cell function characteristic of T2D.
HOMA = Homeostasis Model Assessment; IGT = Impaired Glucose Tolerance.
CDC reports 1 in 4 U.S. young adults has prediabetes, with factors in schools including sedentary behavior, lack of exercise, obesity, poor dietary habits, challenging transitions, and peer influence [21,22,23].
However, there is limited exploration into the potential impact of academic, mental, work-related, social, and overall stress on prediabetes in school. Our small-scale survey revealed the presence of prediabetes and hypertension among young adults in university settings. We infer that intense academic, social, and work-related pressures, coupled with insufficient stress relief, may disrupt lifestyle patterns, such as irregular eating and sleeping, thereby increasing the risk of prediabetes (Figure 4). The lack of physical activity due to academic pressures and sedentary learning environments may further contribute to this risk.
Figure 4. Potential sources of stress within the school environment.
So, how does stress contribute to prediabetes?
Stress, a natural response to challenging situations, affects mental and physical well-being [24]. Prolonged stress triggers the hypothalamus to signal the adrenal glands, producing high levels of glucocorticoids like cortisol [25]. Elevated glucocorticoid levels stimulate glycogen release, leading to increased blood glucose. Prolonged elevation of the cortisol and adrenaline may contribute to insulin resistance, potentially leading to prediabetes (Figure 5)[26]. In essence, higher cortisol levels can result in elevated blood sugar.
Figure 5. A schematic diagram of the process of 'How does Stress Affect Prediabetes?'
Glycosylated hemoglobin (HbA1c) is a 3-month average blood sugar test, commonly used for prediabetes and diabetes diagnosis. It also serves as a valuable biomarker predicting both physiological and psychological health. Elevated HbA1c levels in prediabetics correlate with faster memory decline and adverse cognitive function [27]. Higher HbA1c predicts psychological distress as well [28] and is associated with prediabetes causing organ dysfunction through chronic hyperglycemia-induced damage to micro and macrovascular structures.
Stopping prediabetes can interrupt the cascade that eventually leads to organ failures and impaired cognitive function. However, the challenge lies in the fact that most people are unaware of their prediabetes due to the absence of symptoms [29]. Thus, emphasizing awareness about prediabetes within school communities becomes crucial.
Diagnosis Criteria for Prediabetes(ADA)
Prediabetes is diagnosed with fasting blood glucose levels ranging from 100mg to 125 mg/dl, an Oral Glucose Tolerance Test (OGTT) two-hour blood glucose level of 140 to 199 mg/dl, and an HbA1C level equal to or greater than 5.7% to 6.4%.
Fasting Plasma Glucose (FPG)
Oral Glucose Tolerance Test (OGTT)
HbA1C
Glucose Units – Conversion between mmol/L and mg/dl [30]
Blood glucose concentration is internationally expressed in either mmol/L (millimoles per liter) or in the United States and continental Europe in mg/dl (milligrams per deciliter). Conversion between these units is straightforward, with 1 mmol/L equaling 18 mg/dl. The conversion formulas are:
1. To calculate mmol/L from mg/dl: mmol/L = mg/dl ÷18.
2. To calculate mg/dl from mmol/L: mg/dl = 18 × mmol/L.
Glucose Units - Convert HbA1c (%) to Estimated Average Glucose(mg/dl) [31,32]
Estimated average glucose (eAG), based on your A1C test, estimates your average blood sugar levels over 2-3 months, providing insight into your diabetes control. For example, an HbA1c level of 5.6% translates to an eAG of 114 mg/dl over the past 3 months.
Click the link for instant conversion: https://professional.diabetes.org/glucose_calc.
To gain a basic understanding of the onset of prediabetes, we will briefly introduce the basic concepts of metabolism and insulin.
1.Metabolism
Metabolism, a complex set of biochemical processes within living organisms, sustains life by converting food into essential energy molecules like ATP and reduced nicotinamide adenine dinucleotide (NADH) [33, 34]. This vital process comprises two main phases: catabolism, breaking down complex substances to release energy, and anabolism, synthesizing simpler molecules to build cellular structures. Regulating energy balance, supporting growth, and ensuring proper cellular and organ functioning are crucial roles played by metabolism (Figure 6) [34]. Insulin plays a significant role in synthesis within this intricate metabolic system.
Metabolism converts four classes of substrate into energy or other usable products. These substrates include:
Carbohydrates
Lipids and fatty acids
Proteins and amino acids
Nucleotides
2. Insulin
The pancreas, located behind the stomach, functions as both an endocrine and exocrine gland. Its endocrine activity involves the release of hormones, such as insulin and glucagon.
Insulin, produced by the β cells of the islets of Langerhans (Figure 7), is a pivotal anabolic polypeptide hormone that facilitates tissue growth. Proinsulin undergoes processing to transform into active insulin (Figure 8). Additionally, alpha cells secrete glucagon. The hormonal orchestration of glucose homeostasis occurs within the islet cells (Figure 9) [35].
FIGURE 9. Hormonal regulation of glucose homeostasis in the islet cells. This diagram illustrates the metabolic effects of glucagon and insulin. Blood glucose levels influence secretion of insulin and glucagon. Insulin deficiency leads to elevated lipolysis, increased proteolysis, and decreased glucose utilization, while excess glucagon leads to decreased glycogen synthesis, increased ketogenesis, elevated glycogenolysis, and gluconeogenesis. Red arrows refer to a stimulatory effect, while blue arrows refer to an inhibitory effect.
Insulin regulates blood sugar levels, triggered by carbohydrate and nutrients intake, while factors such as epinephrine inhibit insulin release. The pancreas is vital for glucose metabolism regulation, and imbalances can lead to conditions like prediabetes and diabetes.
Finally, let us extend our honor to the discoverers of insulin: Sir Frederick Grant Banting and Charles Best!
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