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. 2023 Jun 1;324(6):E577-E588.
doi: 10.1152/ajpendo.00087.2023. Epub 2023 May 3.

Maternal Western-style diet in nonhuman primates leads to offspring islet adaptations including altered gene expression and insulin hypersecretion

Darian T Carroll  1 , Joseph M Elsakr  1 , Allie Miller  2 , Jennifer Fuhr  3   2 , Sarah Rene Lindsley  4 , Melissa Kirigiti  4 , Diana L Takahashi  4 , Tyler A Dean  4 , Stephanie R Wesolowski  5 , Carrie E McCurdy  6 , Jacob E Friedman  7 , Kjersti M Aagaard  8 , Paul Kievit  4 , Maureen Gannon  1   3   2   9
Affiliations

Maternal Western-style diet in nonhuman primates leads to offspring islet adaptations including altered gene expression and insulin hypersecretion

Darian T Carroll et al. Am J Physiol Endocrinol Metab. .

Abstract

Maternal overnutrition is associated with increased susceptibility to type 2 diabetes in the offspring. Rodent models have shown that maternal overnutrition influences islet function in offspring. To determine whether maternal Western-style diet (WSD) alters prejuvenile islet function in a model that approximates that of human offspring, we utilized a well-characterized Japanese macaque model. We compared islet function from offspring exposed to WSD throughout pregnancy and lactation and weaned to WSD (WSD/WSD) compared with islets from offspring exposed only to postweaning WSD (CD/WSD) at 1 yr of age. WSD/WSD offspring islets showed increased basal insulin secretion and an exaggerated increase in glucose-stimulated insulin secretion, as assessed by dynamic ex vivo perifusion assays, relative to CD/WSD-exposed offspring. We probed potential mechanisms underlying insulin hypersecretion using transmission electron microscopy to evaluate β-cell ultrastructure, qRT-PCR to quantify candidate gene expression, and Seahorse assay to assess mitochondrial function. Insulin granule density, mitochondrial density, and mitochondrial DNA ratio were similar between groups. However, islets from WSD/WSD male and female offspring had increased expression of transcripts known to facilitate stimulus-secretion coupling and changes in the expression of cell stress genes. Seahorse assay revealed increased spare respiratory capacity in islets from WSD/WSD male offspring. Overall, these results show that maternal WSD feeding confers changes to genes governing insulin secretory coupling and results in insulin hypersecretion as early as the postweaning period. The results suggest a maternal diet leads to early adaptation and developmental programming in offspring islet genes that may underlie future β-cell dysfunction.NEW & NOTEWORTHY Programed adaptations in islets in response to maternal WSD exposure may alter β-cell response to metabolic stress in offspring. We show that islets from maternal WSD-exposed offspring hypersecrete insulin, possibly due to increased components of stimulus-secretion coupling. These findings suggest that islet hyperfunction is programed by maternal diet, and changes can be detected as early as the postweaning period in nonhuman primate offspring.

Keywords: developmental origins of health and disease; developmental programming; maternal overnutrition; mitochondrial respiration; pancreatic β cell.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Schematic of experimental design. Female Japanese macaques were assigned to a control diet (CD) or Western-style diet (WSD) for 4–7 yr before pregnancy and maintained on the same diet throughout gestation and lactation. On weaning, offspring were all maintained on WSD. One-year-old offspring were necropsied at 14 mo of age. Created with Biorender.com.
Figure 2.
Figure 2.
Maternal Western-style diet is associated with hypersecretion of insulin in 1-yr-old offspring. A: perifusion of isolated islets demonstrates that WSD/WSD offspring secreted significantly more insulin when stimulated with 16.7 mM glucose. B: basal insulin secretion during the first 15 min of perifusion assay on isolated islets was increased in WSD/WSD offspring. Each color corresponds to a different offspring and open symbols denote female offspring in B. **P < 0.001. CD/WSD (n = 14, 9 M/5 F), WSD/WSD (n = 10, 5 M/5 F). CD, control diet; F, female; M, male; WSD, Western-style diet.
Figure 3.
Figure 3.
Maternal Western-style diet feeding has no effect on insulin granule density or maturity. A: representative images of β cells from 1-yr-old female offspring. In total, 20 β cells were analyzed per offspring. n: nucleus; orange arrow: mature insulin granule; purple arrow: immature insulin granule. B: insulin granule density, quantified as the number of insulin granules per β-cell cytoplasmic area, was not changed in islets of male or female WSD/WSD offspring. C: insulin granule maturity, calculated based on average gray value within an insulin granule, was not influenced by maternal WSD consumption. D: expression of PDX1 trends to be increased in WSD/WSD offspring. Each color corresponds to a different offspring and open symbols denote female offspring. TEM image magnification 2.7 kx, scale bars = 2 μm. CD, control diet; TEM, transmission electron microscopy; WSD, Western-style diet.
Figure 4.
Figure 4.
Expression of calcium and potassium channel components is elevated in islets from offspring of Western-style diet fed dams. CACNA1C (A), CACNA1D (B), KCNJ11 (C), and ABCC8 (D) transcripts were increased in male and female WSD/WSD offspring. E: insulin area under the curve during perifusion assay was positively correlated with the fold-change expression of KCNJ11, ABCC8, CACNA1C, and CACNA1D in offspring. n = 8 per maternal diet group, *P < 0.05, **P < 0.001. Each color corresponds to a different offspring and open symbols denote female offspring in A–D. CD, control diet; WSD, Western-style diet.
Figure 5.
Figure 5.
Maternal Western-style diet feeding is associated with altered expression of cell stress markers in offspring islets. Offspring of dams fed a WSD showed no change in expression of DDIT3 (A) or ATF6 (B) but showed increased expression of NQO1 (C) and reduced expression of SOD2 (D) and HSPA5 (E). Each color corresponds to a different offspring and open symbols denote female offspring. CD, control diet; WSD, Western-style diet.
Figure 6.
Figure 6.
No evidence for increased mitochondrial density in β cells from offspring exposed to maternal Western-style diet. A: representative images of β cells from male offspring. 2× zoom factor insets show β-cell mitochondria. In total, 20 β cells were analyzed per offspring. n: nucleus. B: mitochondrial density relative to total β-cell area was not changed in WSD/WSD offspring. C: the ratio of expression of the mitochondrial gene ND1 relative to nuclear-encoded GAPDH was not altered in islets of WSD/WSD offspring. D: transcript expression of PPARGC1A was not changed in islets from WSD/WSD offspring. Each color corresponds to a different offspring and open symbols denote female offspring. TEM image magnification 2.7 kx, scale bars = 2 μm. CD, control diet, TEM, transmission electron microscopy; WSD, Western-style diet.
Figure 7.
Figure 7.
Hallmarks of glycolysis are not altered in islets from offspring exposed to maternal Western-style diet. Transcript expression of SLC2A1 (GLUT1; A) was not altered in islets of WSD/WSD offspring, whereas SLC2A2 (GLUT2; B) is increased. C: there was no difference in transcript expression of GCK. D: extracellular acidification rate (ECAR) for isolated islets in Agilent Seahorse Cell Mito Stress Test showed no difference between treatment groups. E: basal ECAR rate before the addition of oligomycin was not changed in islets from offspring exposed to maternal Western-style diet. Each color corresponds to a different offspring and open symbols denote female offspring in A and C. P < 0.05; n = 11–13/group. CD, control diet; WSD, Western-style diet.
Figure 8.
Figure 8.
Spare respiratory capacity is increased in male offspring of dams fed a Western-style diet. Isolated islets were subjected to Agilent Seahorse Cell Mito Stress Test. A: oxygen consumption rate (OCR) profiles of islets assessed ex vivo. Basal respiration (B), maximal respiration (C), and ATP-linked respiration (D) were not changed in male or female WSD/WSD offspring. E: spare respiratory capacity was increased in islets of male WSD/WSD offspring. *P < 0.05, n = 9–13 per maternal diet group. Each color corresponds to a different offspring and open symbols denote female offspring in B and C. CD, control diet; WSD, Western-style diet.
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