Limits...
Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass.

Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, Lussier R, Pineda M, Jetton TL, Madiraju SR, Joly E, Prentki M - Diabetes (2010)

Bottom Line: The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR.Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only.Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets. beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition.

View Article: PubMed Central - PubMed

Affiliation: Montreal Diabetes Research Center and CRCHUM, Montreal, QC, Canada. marie-line.peyot@crchum.qc.ca.

ABSTRACT

Objective: C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about beta-cell failure in these mice.

Research design and methods: DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced beta-cell mass or function and studied islet metabolism and signaling.

Results: HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced beta-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.

Conclusions: beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition.

Show MeSH

Related in: MedlinePlus

Model depicting the possible mechanisms of β-cell failure to compensate for insulin resistance in HDR mice. In normal mice, an elevation of glucose leads to an increase in ATP/ADP ratio and intracellular Ca2+ and a decrease in fatty acid oxidation that allows long-chain-acyl-CoA (fatty acid-CoA) availability for glycerolipid/fatty acid (GL/FA) cycling, which produces lipid signaling molecules (LSMs), such as diacylglycerol, necessary for insulin secretion. Enhanced GL/FA cycling is an “on” signal for insulin secretion that contributes to the amplification arm of GSIS. Enhanced fat oxidation is an “off” signal for insulin secretion because it removes molecules from the cycle (46). In HDR mice, to adapt to the elevation of circulating FFA and postprandial glucose and to prevent β-cell glucolipotoxicity and steatosis, fatty acid esterification processes and lipolysis are simultaneously decreased in association with enhanced FFA oxidation. The increase in fatty acid oxidation, in parallel to depleting LSM, reduces fatty acid-CoA availability for cholesterol ester (CE) synthesis, contributing with elevated blood cholesterol to free cholesterol accumulation and β-cell dysfunction with reduced secretion. Besides the amplification arm of GSIS, the classical triggering ATP/Ca2+ pathway is also affected in HDR versus LDR mice due to reduced glucose-stimulated ATP production and a lack of compensatory increase in the rise in Ca2+ promoted by high glucose. GPR40 activation by FFA may contribute to maintain high level of secretion and hyperinsulinemia. However, in the absence of insufficient insulin secretion for the demand due to the marked insulin resistance, HDR mice become hyperglycemic. Black arrows indicate a difference between DIO group (LDR and HDR) and normal diet group. Striped arrows indicate a difference between HDR and LDR groups.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2927940&req=5

Figure 6: Model depicting the possible mechanisms of β-cell failure to compensate for insulin resistance in HDR mice. In normal mice, an elevation of glucose leads to an increase in ATP/ADP ratio and intracellular Ca2+ and a decrease in fatty acid oxidation that allows long-chain-acyl-CoA (fatty acid-CoA) availability for glycerolipid/fatty acid (GL/FA) cycling, which produces lipid signaling molecules (LSMs), such as diacylglycerol, necessary for insulin secretion. Enhanced GL/FA cycling is an “on” signal for insulin secretion that contributes to the amplification arm of GSIS. Enhanced fat oxidation is an “off” signal for insulin secretion because it removes molecules from the cycle (46). In HDR mice, to adapt to the elevation of circulating FFA and postprandial glucose and to prevent β-cell glucolipotoxicity and steatosis, fatty acid esterification processes and lipolysis are simultaneously decreased in association with enhanced FFA oxidation. The increase in fatty acid oxidation, in parallel to depleting LSM, reduces fatty acid-CoA availability for cholesterol ester (CE) synthesis, contributing with elevated blood cholesterol to free cholesterol accumulation and β-cell dysfunction with reduced secretion. Besides the amplification arm of GSIS, the classical triggering ATP/Ca2+ pathway is also affected in HDR versus LDR mice due to reduced glucose-stimulated ATP production and a lack of compensatory increase in the rise in Ca2+ promoted by high glucose. GPR40 activation by FFA may contribute to maintain high level of secretion and hyperinsulinemia. However, in the absence of insufficient insulin secretion for the demand due to the marked insulin resistance, HDR mice become hyperglycemic. Black arrows indicate a difference between DIO group (LDR and HDR) and normal diet group. Striped arrows indicate a difference between HDR and LDR groups.

Mentions: The results point to a role of alterations in the classical ATP/Ca2+ signaling and lipid amplification pathways as well as free cholesterol deposition, in the failure of the HDR β-cells to compensate for the marked insulin resistance (Fig. 6). Thus, LDR islets displayed an amplified Ca2+ response to glucose that was not apparent in the HDR group, together with reduced rise in ATP content at high glucose, with the latter, however, also being reduced in LDR islets. The reason for the enhanced Ca2+ response in the LDR group that should favor compensating insulin secretion remains to be determined. Furthermore, LDR and HDR mice showed altered lipid metabolism and signaling that may explain reduced glucose-, KCl- and arginine-induced insulin secretion. Thus, exogenous palmitate partially restored GSIS and KSIS in islets of both DIO groups. Importantly, the differences that were found between the compensating pre-diabetic LDR and decompensating (here defined as insufficient compensation) HDR groups were enhanced fat oxidation and elevated intracellular NEFA at basal glucose in HDR islets, in association with an increased free cholesterol content, as well as a more pronounced reduction of fatty acid esterification into cholesterol esters and SCD-1 expression (Table 2). Our previous work indicated that both the balance of fat oxidation versus esterification, β-cell lipolysis and GL/FFA cycling play a role in GSIS (13,14). As shown in Fig. 6, in HDR mice, impaired glucose-stimulated lipolysis and fatty acid esterification should reduce the production of lipid signaling molecules such as diacylglycerol (33), which has been linked to the activation of C-kinase enzymes (38) and the exocytotic protein Munc13-1 (39), whereas enhanced fat oxidation should simultaneously cause their removal. Increased fatty acid oxidation should also reduce fatty acid-CoA availability for cholesterol ester formation (a protective mechanism against the toxic effects of excess cholesterol) (40) leading to free cholesterol accumulation.


Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass.

Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, Lussier R, Pineda M, Jetton TL, Madiraju SR, Joly E, Prentki M - Diabetes (2010)

Model depicting the possible mechanisms of β-cell failure to compensate for insulin resistance in HDR mice. In normal mice, an elevation of glucose leads to an increase in ATP/ADP ratio and intracellular Ca2+ and a decrease in fatty acid oxidation that allows long-chain-acyl-CoA (fatty acid-CoA) availability for glycerolipid/fatty acid (GL/FA) cycling, which produces lipid signaling molecules (LSMs), such as diacylglycerol, necessary for insulin secretion. Enhanced GL/FA cycling is an “on” signal for insulin secretion that contributes to the amplification arm of GSIS. Enhanced fat oxidation is an “off” signal for insulin secretion because it removes molecules from the cycle (46). In HDR mice, to adapt to the elevation of circulating FFA and postprandial glucose and to prevent β-cell glucolipotoxicity and steatosis, fatty acid esterification processes and lipolysis are simultaneously decreased in association with enhanced FFA oxidation. The increase in fatty acid oxidation, in parallel to depleting LSM, reduces fatty acid-CoA availability for cholesterol ester (CE) synthesis, contributing with elevated blood cholesterol to free cholesterol accumulation and β-cell dysfunction with reduced secretion. Besides the amplification arm of GSIS, the classical triggering ATP/Ca2+ pathway is also affected in HDR versus LDR mice due to reduced glucose-stimulated ATP production and a lack of compensatory increase in the rise in Ca2+ promoted by high glucose. GPR40 activation by FFA may contribute to maintain high level of secretion and hyperinsulinemia. However, in the absence of insufficient insulin secretion for the demand due to the marked insulin resistance, HDR mice become hyperglycemic. Black arrows indicate a difference between DIO group (LDR and HDR) and normal diet group. Striped arrows indicate a difference between HDR and LDR groups.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927940&req=5

Figure 6: Model depicting the possible mechanisms of β-cell failure to compensate for insulin resistance in HDR mice. In normal mice, an elevation of glucose leads to an increase in ATP/ADP ratio and intracellular Ca2+ and a decrease in fatty acid oxidation that allows long-chain-acyl-CoA (fatty acid-CoA) availability for glycerolipid/fatty acid (GL/FA) cycling, which produces lipid signaling molecules (LSMs), such as diacylglycerol, necessary for insulin secretion. Enhanced GL/FA cycling is an “on” signal for insulin secretion that contributes to the amplification arm of GSIS. Enhanced fat oxidation is an “off” signal for insulin secretion because it removes molecules from the cycle (46). In HDR mice, to adapt to the elevation of circulating FFA and postprandial glucose and to prevent β-cell glucolipotoxicity and steatosis, fatty acid esterification processes and lipolysis are simultaneously decreased in association with enhanced FFA oxidation. The increase in fatty acid oxidation, in parallel to depleting LSM, reduces fatty acid-CoA availability for cholesterol ester (CE) synthesis, contributing with elevated blood cholesterol to free cholesterol accumulation and β-cell dysfunction with reduced secretion. Besides the amplification arm of GSIS, the classical triggering ATP/Ca2+ pathway is also affected in HDR versus LDR mice due to reduced glucose-stimulated ATP production and a lack of compensatory increase in the rise in Ca2+ promoted by high glucose. GPR40 activation by FFA may contribute to maintain high level of secretion and hyperinsulinemia. However, in the absence of insufficient insulin secretion for the demand due to the marked insulin resistance, HDR mice become hyperglycemic. Black arrows indicate a difference between DIO group (LDR and HDR) and normal diet group. Striped arrows indicate a difference between HDR and LDR groups.
Mentions: The results point to a role of alterations in the classical ATP/Ca2+ signaling and lipid amplification pathways as well as free cholesterol deposition, in the failure of the HDR β-cells to compensate for the marked insulin resistance (Fig. 6). Thus, LDR islets displayed an amplified Ca2+ response to glucose that was not apparent in the HDR group, together with reduced rise in ATP content at high glucose, with the latter, however, also being reduced in LDR islets. The reason for the enhanced Ca2+ response in the LDR group that should favor compensating insulin secretion remains to be determined. Furthermore, LDR and HDR mice showed altered lipid metabolism and signaling that may explain reduced glucose-, KCl- and arginine-induced insulin secretion. Thus, exogenous palmitate partially restored GSIS and KSIS in islets of both DIO groups. Importantly, the differences that were found between the compensating pre-diabetic LDR and decompensating (here defined as insufficient compensation) HDR groups were enhanced fat oxidation and elevated intracellular NEFA at basal glucose in HDR islets, in association with an increased free cholesterol content, as well as a more pronounced reduction of fatty acid esterification into cholesterol esters and SCD-1 expression (Table 2). Our previous work indicated that both the balance of fat oxidation versus esterification, β-cell lipolysis and GL/FFA cycling play a role in GSIS (13,14). As shown in Fig. 6, in HDR mice, impaired glucose-stimulated lipolysis and fatty acid esterification should reduce the production of lipid signaling molecules such as diacylglycerol (33), which has been linked to the activation of C-kinase enzymes (38) and the exocytotic protein Munc13-1 (39), whereas enhanced fat oxidation should simultaneously cause their removal. Increased fatty acid oxidation should also reduce fatty acid-CoA availability for cholesterol ester formation (a protective mechanism against the toxic effects of excess cholesterol) (40) leading to free cholesterol accumulation.

Bottom Line: The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR.Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only.Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets. beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition.

View Article: PubMed Central - PubMed

Affiliation: Montreal Diabetes Research Center and CRCHUM, Montreal, QC, Canada. marie-line.peyot@crchum.qc.ca.

ABSTRACT

Objective: C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about beta-cell failure in these mice.

Research design and methods: DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced beta-cell mass or function and studied islet metabolism and signaling.

Results: HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced beta-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.

Conclusions: beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition.

Show MeSH
Related in: MedlinePlus