Episode 20 – Sweet, sweet insulin and you

Show notes:

Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion (Kyriazis et al. 2012)

Background

  • Beta-cell metabolized nutrients (e.g. amino acids & glucose) stimulate insulin secretion whilst GLP-1 interacts with the beta-cell’s cell-surface GPCRs to stimulate insulin secretion [G-protein coupled receptor]
  • There are many more Non-metabolizable insulin secretagogues than Metabolizable ones
  • TRPM5 (Transient receptor potential cation channel subfamily M member 5) is found on surface of beta-cells, transducing taste for bitter, sweet, umami & maybe fat
  •  T1R2 (Taste receptor type 1 member 2) is a GPCr widely distributed in the mouth, transducing taste for sucrose and fructose, and artificial sweeteners saccharin, acesulfame potassium (Ace K), dulcin & guanidinoacetic acid (maybe aspartame)
  • T1R3 Taste receptor type 1 member 2 = a GPCr also widely distributed in the mouth, not important as T1R2 for transducing taste but working in concert with it and T1R3, possibly to differentiate between natural sugars and artificial sweeteners
  • Are natural and artificial sweet compounds agonists for beta-cell specific surface receptors?

Methods

  • In vivo
    • double-knockout mice (-/-) of TRPM5, T1R2, T1R3
    • 8 – 10 week old mice on standard chow diet (16% protein/4% fat/80% carbs, no animal protein)
    • Plasma insulin, GLP-1 and blood glucose
      • baseline: “morning-fasted for 5 h to achieve glycemic levels of approximately 160 mg/ dL (9.0 mM), which corresponds with the glucose concentration (8.3 mM) used in the majority of the in vitro experiments”
      •  “bolus of glucose (0.5 g/kg body weight), fructose (0.3 g/kg body weight), or a combination of the two”
  • In vitro
    • Calcium imaging of MIN6 beta-cells
    • IRF imaging (Total Internal Reflection Microscopy) of MIN6 beta-cells [same microscope & procedures as for calcium imaging]
      • This study used 5 – 20 passaged MIN6 cells = good! As MIN6 cells passaged 60 – 70 times lose GSIS, specifically 1st phase & some 2nd phase insulin secretion [1]

Results

  • “fructose potentiation is glucose-dependent” above a (>3mM glucose threshold) (in vitro)
  • “the physiological role of fructose is to enhance the effects of glucose”
  • “closure of KATP channels by glucose is necessary to reach the depolarizing threshold, and fructose signaling positively modulates global membrane depolarization, thus enhancing calcium influx and insulin release”
  • “ablation of T1R1 or T1R2 is adequate to obliterate umami or sweet taste respectively, whereas ablation of T1R3 eliminates both taste responses”
  • “the lack of fructose response in T1R2−/− islets is not caused by defects in glucose metabolism”
  • “The rapid increase in plasma insulin cannot be explained by changes in plasma glucose or GLP-1, but rather can be attributed to the direct effects of fructose on pancreatic islets
  • “a moderate increase in circulating fructose alone is not sufficient to stimulate insulin release”
  • “[PLC and taste receptors] are converging to amplify known downstream steps required for insulin secretion, such as membrane depolarization and VDCC- dependent calcium influx“
  • TRPM5 is required for taste receptor signaling in beta cells and that its activation is the likely step that contributes to the global membrane depolarization and induction of calcium influx”
  • the authors confirmed “the significance of taste receptor signaling in human islet physiology”
  • low physiological concentrations of fructose were adequate to potentiate GSIS in mouse and human islets, and in vivo
  • because of “heterogeneous taste perception among species […], it is not apparent whether these findings are relevant to human physiology”
  • “beta cells secrete insulin by integrating signaling cues that emanate from several independent mechanisms. Because the metabolism of glucose is the unequivocal principal mechanism for insulin release
  • “Although in vivo human studies have failed to show an effect of consumed artificial sweeteners on insulin or blood glucose levels […], an oral solution of sucrose (disaccharide of glucose and fructose) can potentiate insulin release compared with equimolar glucose alone […], and can cause a sustained increase in insulin levels starting short after ingestion

FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans (Søberg et al. 2017)

Background

  • hepatokine FGF21 (fibroblast growth factor 21) in primates and rodents decrease consumption of sweet foods
  • hepatokine FGF21 is the ‘endocrine version’ of FGF21, lacking a heparin binding domain allowing it to circulate more freely
  • in vitro, acetoacetate induces FGF21 (maybe via a SIRT1)
  • in mice, PPARα regulates FGF21 expression, FGF21 rises during a ketogenic diet and fasting whilst in humans it takes a 7 to 10 day fast
  • “high doses of FGF21 analogs do not lower blood glucose in obese type 2 diabetic patients, despite improving markers of insulin sensitivity, suggesting that some of [FGF21] biological effects in model organisms do not extend to humans
  • What’s the molecular basis for our ‘sweet tooth’?
    • authors think “that FGF21 mediates a hormonal liver-to-brain feedback loop whereby sugar consumption negatively autoregulates sugar appetite

Methods

  • Observational
    • 18-39 years old with a BMI between 19-25 kg/m2 and without any medical conditions
    • 6,514 Danish self-reporting participants were genotyped
    • Lipid profile + OGTT at 30min and 120min
    • two FGF21 SNPs (rs838133 and rs838145), both obeyed Hardy-Weinberg equilibrium (p >0.025) [frequency of this allele in this population hasn’t remained constant = possible selection pressure]
    • 1 month diet recall FFQ for estimating total kcals, macros and micros
      • ⇒ total carbohydrates, simple carbohydrates, complex carbohydrates, protein, total fat, SFA, MUFA, PUFA and omega-3 fatty acids comprising the daily energy intake (in %)
      • ⇒ number of servings per week of ⇒ candy, cake, total sweets (candy plus cake), salty snacks, and foods with a high content of complex carbohydrates
    • A health and lifestyle questionnaire additionally provided information regarding alcohol intake (units per week), coffee consumption (cups per day), and smoking habits
      • Categories of smokers ⇒ i) never smoked, ii) former smoker, iii) occasional smoker, and iv) daily smoker
      • Summary score ⇒ normal beer, strong beer, glass of red wine, glass of white wine, spirits)
    • “The 1st tertile was used as a reference to test effect of the FGF21 SNPs on the odds of being in the 2nd and 3rd tertile”
    • Plasma glucose, insulin, proinsulin, serum trigs, total cholesterol and HDL cholesterol
  • Clinical study
    • PrefQuest questionnaire of 143 items on sweet, fatty-sweet, fatty-salt, and salt
    • “Those in the highest (4.1 – 5.7) and lowest (2.5 – 3.5) quartiles by score were defined as sweet-likers (n = 25) and sweet-dislikers (n = 26), respectively”
    • “A 5hr 75g sucrose challenge test was performed within 2 days to 3 weeks after the pre-examination”
    • “a total 45% of participants drink soda less than once a week, 12% never drink soda, 25% less than once a month, 12% once a week, 4% every other day and only 2% once a day. No participants claimed to drink soda twice or more a day
    • Sweet-preference and sweet-taste perception test questionnaires
    • FGF21 and many more more tested

Results

  • “Surprisingly, despite the association of the rs838133 A-allele with increased intake of sweets, this allele did not correlate with increased total energy intake (Table 2) and was associated with lower BMI and waist circumference in the Inter99 cohort (Table S3)”
  • no difference in the sex distribution between the sweet-liker and sweet-disliker groups”

  • OR 1.01 (0.97-1.06) for T2DM risk with FGF21 A-allele
  • “plasma FGF21 was markedly increased by sucrose (mean 193% above baseline, p < 0.0001) in both groups, reaching maximum levels after 120 min”
  • “The large variation in inter-subject FGF21 levels is also notable and consistent with prior reports”
  • strongest association observed in our study was with sweet snacking, candy in particular […] FGF21 may regulate hedonic sugar craving, as opposed to homeostatic sugar appetite”
  • “FGF21 increases with a hormone-like profile in humans after oral fructose and glucose ingestion”
  • this study “does not experimentally demonstrate that FGF21 regulates sweet appetite and reward seeking, an outcome that awaits future interventional trials”

 

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