|Year : 2021 | Volume
| Issue : 1 | Page : 1-9
Sweetening sixteen: Beyond the ominous octet
Sanjeev R Phatak, Banshi Saboo, Shivangi Dwivedi, Padmanabh Zinzuwadia, Dharmendra Panchal, Abhilasha Ganguli, Dhruvi Hasnani
Vijayratna Diabetes Diagnosis & Treatment Centre, Ahmedabad, Gujarat, India
|Date of Submission||02-Feb-2020|
|Date of Decision||17-Mar-2020|
|Date of Acceptance||11-May-2020|
|Date of Web Publication||25-Dec-2020|
Dr. Sanjeev R Phatak
Vijayaratna Diabetes Diagnosis & treatment Centre, Sumeru Centre, Near Parimal Underbridge, Paldi, Ahmedabad, Gujarat.
Source of Support: None, Conflict of Interest: None
As the epidemic of type 2 diabetes continues to grow, newer pathophysiologic mechanisms of diabetes are being unraveled in quick succession. From a simplistic model of insulin deficiency and insulin resistance, researchers have moved to a multipronged explanation of the disease. In addition to the ominous octet, eight other players, such as catecholamines, vitamin D deficiency, renin–angiotensin system, testosterone deficiency, melatonin, renal gluconeogenesis, intestinal sodium-glucose cotransporter 1, and gut microbiota, seem to participate in the etiopathogenesis of glucose intolerance and type 2 diabetes. Collectively, these 16 players comprise a cluster of interrelated etiologies implicated in the pathogenesis of diabetes, prompting the authors to address them as the “sweetening sixteen.” While exploring these factors, the authors wish to emphasize that diabetes treatment should focus on the reversal of these proposed pathogenetic defects and not simply reduction of hemoglobin A1C.
Keywords: Gut microbiota, melatonin, metabolic syndrome, obesity, pathophysiology, renal gluconeogenesis, SGLT1, sweetening sixteen, testosterone, type 2 diabetes
|How to cite this article:|
Phatak SR, Saboo B, Dwivedi S, Zinzuwadia P, Panchal D, Ganguli A, Hasnani D. Sweetening sixteen: Beyond the ominous octet. J Diabetol 2021;12:1-9
| Introduction|| |
From the ominous octet to the sweetening sixteen
Even as currently available antidiabetic agents target the ominous octet to effectively combat hyperglycemia in diabetes, various studies conducted across India indicate that more than 50% of people with type 2 diabetes (T2DM) have poor glycemic control (hemoglobin A1C [HbA1c] >8%),, uncontrolled hypertension, and dyslipidemia, resulting in a higher incidence of diabetes-related vascular complications. This suggests the need to consider concomitant nontraditional mechanisms underlying the occurrence, progression, and complications of T2DM. This review examines the pathogenesis of T2DM in greater depth and novel therapeutic options in light of the same.
| Role of Catecholamines in Diabetes|| |
In humans, the target tissue response to insulin is regulated via circadian rhythms in the monoamine neurotransmitter systems within the hypothalamus. Serotonin level and activity increases, whereas the dopamine level and activity decreases in the insulin-resistant state., Patients with T2DM probably have an early morning dip in the dopaminergic tone, leading to an increased sympathetic activity and thereby increased insulin resistance in the morning., This perhaps explains blood glucose excursions being significantly higher at breakfast than at lunch and dinner.
Therapeutic role of catecholamine modulation
Administration of bromocriptine, a D2 receptor agonist, mediates a decrease in the inappropriately elevated hypothalamic noradrenergic and serotonergic levels, with a resultant decline in hepatic glucose production and adipose tissue lipolysis, therefore improving insulin sensitivity. The promising efficacy of bromocriptine as a novel therapeutic agent for T2DM has been affirmed in four phase 3 trials, wherein bromocriptine was administered as monotherapy or add-on to other oral antidiabetic drugs, within 2h of awakening. Results of these studies consistently showed a placebo-subtracted decline of 0.5%–0.7% in HbA1c.
| Vitamin D Deficiency|| |
Sunlight is the primary source of vitamin D3, which is now known to perform multiple extra-skeletal functions. It plays a crucial role in preserving β-cell function, insulin secretion, and insulin sensitivity, via both direct and indirect mechanisms.
Effect on β-cell function and insulin secretion
In addition to increasing insulin secretion via nongenotropic rapid responses, vitamin D exerts an antiapoptotic effect and promotes β-cell survival by mitigating the generation and action of cytokines and by downregulating fetal alcohol syndrome (Fas)-related pathways (Fas/Fas-L).
Calcium flux is a significant modulator of depolarization-stimulated insulin release. Vitamin D regulates calbindin, a cytosolic calcium-binding protein, and participates in the regulation of the intracellular calcium concentration, thereby indirectly affecting and enhancing insulin secretion.
Effect on insulin sensitivity
Vitamin D modulates the lipid homeostasis in the skeletal muscle and adipose tissue, by increasing the expression of insulin receptors and/or by activating peroxisome proliferator-activated receptor-δ (PPAR-δ), thereby enhancing insulin sensitivity.
Owing to the crucial role of calcium in the target tissue response to insulin, cytosolic calcium concentration is required to be maintained within a narrow range for optimum cellular function. Vitamin D regulates the calcium flux through the cell membrane and thus the intracellular calcium levels. It also suppresses renin formation and local pancreatic renin–angiotensin system (RAS), which is known to adversely affect insulin secretion as well as peripheral action.,
Therapeutic role of vitamin D supplementation
Various observational studies and randomized controlled trials (RCTs) have shown that vitamin D supplementation plays a therapeutic role in type 1 diabetes (T1DM) as well as T2DM., In a study on subjects with T2DM treated with cholecalciferol daily for 1 month, significant increments were noted in the first-phase and the second-phase insulin secretion. In another study, patients who received oral vitamin D3 for 8 weeks showed a significant reduction in fasting plasma glucose (FPG), fasting insulin, and insulin resistance. In the Nurses’ Health Study, a 33% lower risk of T2DM was observed with a combined daily intake of >1200 mg/day calcium and >800 IU vitamin D/day, compared to 600 mg/day calcium and 400 IU/day vitamin D.
In the D2D trial, 2423 adults with prediabetes across 22 medical centers in the United States were randomized to receive 4000 IU per day of vitamin D3 or to receive placebo, regardless of baseline serum 25-hydroxyvitamin (25-OH) vitamin D level. After a median follow-up of 2.5 years, incident type 2 diabetes occurred in 293 of the 1211 participants in the vitamin D group and 323 of the 1212 participants in the placebo group, corresponding to a hazard ratio (HR) of 0.88 (95% confidence interval 0.75–1.04, P = 0.12). The addition of vitamin D has shown mixed results.
| Local and Systemic Renin–Angiotensin System|| |
The physiological role of systemic RAS in maintaining blood pressure, fluid, and electrolyte homeostasis is well established. Pathologically, alterations in RAS activity are being increasingly acknowledged as contributory to seemingly unrelated conditions, such as altered glucose metabolism and systemic inflammation. Parallel to systemic RAS, there is mounting evidence regarding the tissue-specific effects of local RAS in skeletal muscles, adipocytes, heart, vasculature, and pancreas, expanding our understanding of activated tissue RAS influencing the development and progression of T2DM.,
Renin–angiotensin system in insulin secretion
Pancreatic RAS is proposed to affect both endocrine and exocrine functions in the pancreas. In the β-cell, angiotensin II (ANGII) produces both hemodynamic effects (AT1 receptor-mediated impaired islet blood flow) and direct inhibitory effects on insulin synthesis and glucose-mediated insulin secretion (independent of AT1 receptor)., In addition, it induces oxidative stress and resultant pancreatic inflammation and fibrosis, potentially contributing to progressive β-cell dysfunction in diabetes.
Renin–angiotensin system in insulin resistance
Presence of local RAS in the adipose tissue has been described, along with its role in obesity and insulin resistance. Local ANGII is known to augment inflammation and also disturb the adipogenesis and lipolysis processes in adipocytes.,
In skeletal muscles, it leads to the following:
- (1) hemodynamic effect: decreased microvascular blood flow
- (2) nonhemodynamic effects:
- a. decreased GLUT-4 translocation and resultant diminished insulin-stimulated glucose uptake
- b. impaired intracellular insulin signaling pathway.
These ultimately result in insulin resistance in the peripheral tissues.
Therapeutic role of renin–angiotensin system blockade
Multiple recent large-scale clinical studies have consistently reported a significant reduction in the incidence of T2DM in patients with arterial hypertension or congestive heart failure treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for 3–6 years. This beneficial action of RAS inhibition was seen uniformly against placebo as well as comparators including β-blockers, thiazides, and amlodipine. A meta-analysis of several recent RCTs concluded that the mean risk for developing T2DM was reduced by 27% with ACE inhibitor-based treatment, 23% with AT1 receptor blocking-based treatment, and 25% overall in a pooled analysis of RAS blockers.
| Testosterone Deficiency|| |
The manifestations of low testosterone are not confined merely to male reproductive and sexual functions. Testosterone is postulated to impart a profound effect on insulin sensitivity and its deficiency alters several metabolic parameters linked with the emergence of T2DM, metabolic syndrome, and cardiovascular disease.,,, After 30 years of age, the average annual decline in serum testosterone in men is approximately 1%–2%, with free testosterone declining more steeply with aging., The Third National Health and Nutrition Examination Survey (NHANES III) found that men in the lowest free testosterone tertile were four times more likely to have T2DM than those in the highest free testosterone tertile.
Testosterone in insulin resistance
Testosterone inhibits lipoprotein lipase and reduces associated uptake of triglycerides into visceral adipose cells, thereby reducing the size of these highly insulin-resistant cells. Testosterone deficiency thus promotes excess adiposity. Through the action of leptin, adipose tissue aromatase, the hypothalamic–pituitary–gonadal feedback loop, and inflammatory cytokines, excess adiposity eventually results in reduced testosterone and luteinizing hormone (LH) production [Figure 1].
|Figure 1: Interrelationship between testosterone deficiency and insulin resistance|
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Therapeutic role of testosterone administration
In a study on hypogonadal men with T2DM, intramuscular testosterone administration for 3 months significantly reduced the Homeostatic Model Assessment (HOMA) index (–1.73 ± 0.67, P = 0.02), HbA1c (–0.37% ± 0.17%, P = 0.03), and fasting blood glucose (–1.58 ± 0.68 mmol/L, P = 0.03), compared to placebo, with simultaneous reduction in visceral adiposity (waist circumference –1.63 ± 0.71cm, P = 0.03; waist/hip ratio –0.03 ± 0.01, P = 0.01). In the TIMES2 Study conducted on hypogonadal men with T2DM or metabolic syndrome, 2% testosterone gel reduced of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). Furthermore, it showed a beneficial effect, albeit inconclusive, on the glycemic control in patients with –T2DM (HbA1c treatment difference at 9 months: −0.446%; P = 0.035, at 12 months: −0.49%, P = 0.066).
| Role of Melatonin|| |
Endogenous melatonin release is synchronized with the light/dark cycle via a multisynaptic pathway involving the retina, hypothalamus, and pineal gland. Its diurnal pattern is regulated by an endogenous clock (hypothalamus), with plasma melatonin levels peaking at 3:00–4:00 AM, declining sharply before awakening. Lower nocturnal secretion of melatonin is recognizably associated with insulin resistance. A study on over 17,000 nurses compared the association of rotating vs. fixed shifts with T2DM. The risk of T2DM was seen to progressively increase with increasing years of rotating shift work (20%, 40%, and approximately 60% after 3–9 years, 10–19 years, and >20 years of rotating shifts).
Effect on β-cell function
Oxidative stress offers a plausible explanation for the tissue damage induced by chronic hyperglycemia. This is noteworthy in the context of pancreatic islets, which have much lower intrinsic antioxidant capacity compared to other metabolic tissues. Melatonin is a potent and unique antioxidant. Hence, reduction in melatonin levels produces increased oxidative stress in the β cells.
Role in insulin resistance
The cellular action of insulin at the target tissues begins with insulin-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Melatonin possibly acts in conjunction with insulin at this level, via membrane-bound MT1/MT2 melatonin receptors, accelerating the phosphorylation of IRS-1. This, in turn, triggers the cascade of intracellular reactions which eventually promote cellular glucose uptake and glycogen synthesis, inhibit lipolysis, and thereby increase insulin sensitivity.
Therapeutic role of melatonin supplementation
In an Israel-based crossover study, effects of 3 weeks each of prolonged-release melatonin and placebo were observed for an extended period of 5 months. Despite unsubstantial changes in glucose, fructosamine, insulin, or C-peptide levels at 3 weeks, the mean HbA1c was significantly lower after 5 months than at baseline following extended treatment with melatonin, compared to placebo (9.13% ± 1.55% vs. 8.47% ± 1.67%, respectively, P = 0.005). Another crossover study reflected the potential antioxidant function of melatonin through significant reduction of plasma malondialdehyde levels (a marker of oxidative stress), following melatonin supplementation (–6.25 ± 2.10 nmol/mL) compared to placebo (0.72 ± 3.30, P = 0.028). This was accompanied by a significant total improvement of 0.33% in HbA1c with melatonin over placebo. Meanwhile, an Indian study observed that melatonin administration not only reduced fasting blood glucose and low-density lipoprotein (LDL) levels, but also improved high-density lipoprotein (HDL) levels among patients with T2DM. It also seemed to render a favorable hormone balance by reducing serum insulin, cortisol, adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH) levels while increasing serum gastrin levels. Melatonin has been considered as a nutraceutical by the Food and Drug Administration (FDA).
| Sodium-Glucose Cotransporter 1 in the Intestine|| |
The small intestine is the major site for the absorption and systemic delivery of dietary sugars, the rate of absorption being a crucial determinant of the resultant blood glucose concentration. Intestinal glucose transport and luminal uptake are primarily mediated by sodium-glucose cotransporter 1 (SGLT1) situated at the brush-border membrane, which absorbs glucose derived from the hydrolysis of larger dietary carbohydrates. Studies of duodenal biopsies revealed that in diabetes, the intestine’s capacity to absorb monosaccharides is greatly enhanced, perhaps because of significantly enhanced expression and activity of glucose transporters such as SGLT1, GLUT5, and GLUT2, multiplying by over fourfold compared to nondiabetic subjects. This mechanism appears as a distinct and independent contributor to the composite pathogenesis of T2DM, suggesting intestinal SGLT1 inhibition as a potential target for devising future antihyperglycemic therapies.
Therapeutic role of intestinal sodium-glucose cotransporter 1 inhibition
Duodenal glucose uptake stimulates the release of glucagon-like peptide 1 (GLP-1) and other pancreatic enzymes. GLP-1, in turn, suppresses pancreatic glucagon secretion and reduces appetite. However, the second, sustained phase of GLP-1 secretion involves the L-cells in the distal colon and seems unrelated to glucose directly. Experimental studies concede that SGLT1 inhibition in the proximal intestine increases glucose availability more distally, which indirectly induces and augments the sustained release of GLP-1,, thus enhancing the incretin effect. Furthermore, leptin is theorized to minimize luminal glucose uptake by suppressing intestinal SGLT1 expression and activity [Figure 2].
|Figure 2: Factors modulating sodium-glucose cotransporter 1 (SGLT1) expression and activity in the proximal intestine and the effect of SGLT1 inhibition on intestinal glucose absorption and glucagon-like peptide 1 (GLP-1) release. FFA = free fatty acids, FFAR2/3 = free fatty-acid receptor 2/3|
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Drugs such as phlorizin, canagliflozin, sotagliflozin, LP-925219, GSK-1614235, and KGA-2727, with varying selectivity for SGLT1 and SGLT2, are being evaluated as potential tools for SGLT1 inhibition. KGA-2727 is the first selective SGLT1 inhibitor under development., Both canagliflozin and KGA-2727 show reductions in intestinal glucose absorption and consequently lesser postprandial hyperglycemia., Moreover, recent evidence suggests that phlorizin, canagliflozin, GSK-1614235, and sotagliflozin (dual SGLT1 and SGLT2 inhibitor), prompt the sustained release of GLP1 in the intestine.,, Furthermore, in the renal tubules, combined SGLT1 and SGLT2 inhibition generates a promising synergistic effect by producing significantly greater glycosuria than either therapy alone, providing additional pathways to minimize hyperglycemia. Although particulars regarding the cardiovascular and long-term safety of such therapy remain awaited, current evidences certainly endorse the rationale underlying intestinal and/or renal SGLT1 inhibition-based therapy.
| Gut Microbiota|| |
The human intestine is colonized by trillions of bacteria comprising the gut “microbiome,” sizing over 100 times the human genome. Bacteria belonging to Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria groups compose over 90% of the adult gut microbiome., This microbiome influences host fuel metabolism and gut physiology via multiple pathways., Gut microbiota are essential for maintaining an intact intestinal mucus barrier., Therefore, an altered gut microbial balance, particularly an elevated Firmicutes–Bacteroidetes ratio, proposedly disrupts the intestinal barrier, increases gut permeability, and induces persisting metabolic endotoxemia and low-grade systemic inflammation, which characterize T2DM and metabolic syndrome., Emerging evidence testifies that such gut “dysbiosis” is linked with the development of obesity, T2DM, and several metabolic disorders.,, Interestingly, similar disturbances in the gut metagenome are observed to induce subclinical intestinal inflammation and dysregulated host immunity, preceding the clinical onset of T1DM., Similarly, gut microbial aberrations and the resultant triggering of systemic pro-inflammatory pathways are associated with the occurrence and progression of nonalcoholic fatty liver disease (NAFLD), [Figure 3].
|Figure 3: Influence of resident gut microflora on host fuel metabolism, systemic inflammation, obesity, and insulin resistance. IRS = insulin receptor substrate, NF-κB = nuclear factor κ-light-chain-enhancer of activated B cells, TLR-4 = toll-like receptor 4, LPS = lipopolysaccharide|
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Therapeutic role of gut microbial modulation
The past decade has provided considerable evidence supporting gut dysbiosis as a distinct pathogenetic factor for obesity, insulin resistance, and diabetes. Finer inspection of the gut microbiome–host interactions shall offer avenues for developing ingenious treatment strategies aiming to restore intestinal microbial symbiosis and minimize chronic systemic inflammation and metabolic dysregulation.
Various experiments evince that treatment with Akkermansia muciniphila, a mucin-degrading bacterium, restores the intestinal mucus barrier, mitigating metabolic endotoxemia, and insulin resistance., Similarly, reconditioning gut microbiota with probiotics and prebiotics not only reduces endotoxemia and improves diabetes risk, but also improves liver function and insulin sensitivity in NAFLD and indirectly stimulates sustained GLP-1 release from the L-cells. Likewise, transplantation of fecal matter containing gut microbiota from healthy individuals to those with obesity or metabolic syndrome has shown to favorably affect fuel metabolism and insulin sensitivity in the recipient, proffering a propitious therapeutic intervention for such conditions.,
| Renal Gluconeogenesis|| |
Maintaining glycemic homeostasis despite the challenging variables of energy demand and supply is determined by the delicate balance between insulin and glucagon. In the postabsorptive state, uninterrupted fuel supply to the brain and other vital organs is ensured by two crucial processes, glycogenolysis and gluconeogenesis, which release glucose into the circulation. Nuclear magnetic resonance (NMR) spectroscopy-based studies identified that hepatic glycogenolysis accounts for 45% ± 6% of the overall glucose released into the circulation, implying that gluconeogenesis furnishes nearly 54% ± 2% of the glucose generated during overnight fasting.,
In humans, the liver and kidneys are the only organs equipped with the enzymes required to perform gluconeogenesis and release glucose into the circulation. However, the assumption that the liver is the exclusive site for both physiologically and pathologically stimulated gluconeogenesis, has been challenged and disproved in multiple studies.,,, Lately, animal experiments have shown the gluconeogenic function of the kidneys under various metabolic conditions.,, Reflecting this, a large volume of recent research focuses on the renal cortex as an important gluconeogenic organ., During liver transplantation, the renal contribution to gluconeogenesis is greatly augmented to compensate for the transient loss of hepatic glucose output in the recipient. A similar net increase in renal gluconeogenesis occurs during prolonged fasting, when hepatic glycogen stores are depleted and the onus of maintaining glucose homeostasis falls chiefly upon gluconeogenesis. Furthermore, in T2DM, the pathological increment in renal glucose production parallels that of the liver,, reinforcing the supposition that the liver may not be the sole culprit for exaggerated gluconeogenesis in T2DM. In fact, the relative increase in renal gluconeogenesis is considerably greater than that in hepatic gluconeogenesis (300% vs. 30%, respectively). Given that renal glucose uptake and release is regulated by insulin, the impaired suppression of renal gluconeogenesis in the postabsorptive state possibly reflects impaired postprandial insulin secretion in T2DM. Moreover, elevated free fatty-acid levels in individuals with T2DM possibly amplify this pathogenetic pathway by stimulating gluconeogenesis, both in the kidneys and the liver.
The recent insights into the paradoxically accelerated renal gluconeogenesis in T2DM, particularly during the postprandial hours,, open up interesting avenues for devising therapies targeting postprandial hyperglycemia and overall glycemic control. In addition, the crucial role of the renal cortex in hypoglycemia counterregulation may explain the heightened tendency of patients with renal failure to develop hypoglycemia. A similar picture is seen in patients with T1DM, because of their blunted glucagon response to hypoglycemia, hence their dependence on catecholamine-mediated counterregulatory mechanisms., Further research requires focus upon the effect of currently available and upcoming pharmacological agents on renal gluconeogenesis, as well as the interplay of these glucose homeostasis mechanisms in pathological states such as hepatic dysfunction, sepsis, and renal insufficiency [Figure 4].
Although the pathogenesis and long-term complications of T2DM appear fairly understood, its satisfactory treatment continues to remain an elusive target. Despite current treatment, regimens addressing all/several of the presently acknowledged pathophysiological mechanisms comprising the ominous octet, glycemic targets, and overall treatment goals are yet unmet in a majority of patients, irrespective of geographical and socioeconomical backgrounds. This fact underscores the need to review T2DM pathogenesis from a fresh perspective, exploring additional factors contributing in a minor yet significant manner. This article highlights such few potentially modifiable pathophysiological defects, which if examined from the therapeutic aspect, may help individualize the treatment process, provide more comprehensive diabetes management, and achieve durable improvements in glycemic control that may delay the onset and progression of diabetes-related complications and maximize the quality of life of patients with T2DM.
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Conflicts of interest
There are no conflicts of interest.
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