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Microvascular Consequences of Obesity and Diabetes

H Glenn Bohlen

10.1002/cphy.cp020419

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Major Differences in Insulin‐Dependent and‐Independent Diabetes
2 Consequences of Obesity
3 Insulin Receptor‐no Production in Obesity and Diabetes
4 Functional Studies of no Mechanisms in Obesity, Hyperglycemia, and Diabetes
5 Blood Lipids and Endothelial Function
6 Vascular Smooth Muscle Function in Obesity and Diabetes
6.1 Leptin and C‐peptide influences on vascular regulation in obesity and diabetes
6.2 Hyperglycemia as a major threat to vascular function
6.3 Hyperglycemia, PKC, and NO
6.4 Oxygen radical formation during hyperglycemia
7 Conclusions
7.1 The state of affairs
7.2 The future
Figure 1. Figure 1.

Photograph of the small intestinal microcirculation of normal and streptozotocin diabetic rats to illustrate the growth of the bowel and maintenance of the vascular branching pattern of major microvessels. Using higher power microscopy, studies revealed that only new capillaries were formed as the bowel enlarged in normal and diabetic rats. The addition of new capillaries was particularly large in diabetic animals due to the hypertrophy of their small intestine (from figure 1 of Ref. 15).
Figure 2. Figure 2.

Scanning electron photomicrographs of the vascular smooth muscle cells in intestinal arterioles of normal (A) and streptozotocin (B) diabetic rats that had been diabetic for 6 months. The vascular smooth muscles of equivalent arterioles were much larger in diabetic than normal animals, as were the endothelial cells. The spindle shape of the vascular muscle cells was preserved in the diabetic animal's intestine (from figure 2 in Ref. 20).
Figure 3. Figure 3.

Scanning electron photomicrographs of the vascular smooth muscle cells of comparable larger arterioles form the cerebral cortex of normal (A) and streptozotocin (B) diabetic rats. The diabetic rats had been diabetic about 4 weeks. The abnormal shape of the vascular muscle in diabetic animals was consistent throughout the cerebral cortical vasculature; normal arterioles have spindle‐shaped muscle cells much like those shown in figure 3 of Ref. 25. Arrows are to typical muscle cells in normal and diabetic rats.
Figure 4. Figure 4.

Transmission electron photomicrographs of cerebral cortical arterioles cut longitudinally. Comparable branch orders of arterioles in normal (A) and strepotozotocin diabetic (B) rats which had been diabetic for 4 weeks are shown. The degeneration of the endothelial and vascular smooth muscle intracellular structures is very evident in the diabetic animals. The large arrows in the upper and lower figures are to call attention to the rectangular cross section of the normal vascular smooth muscle cells compared to the abnormally shaped cells of diabetic animals. In diabetic rats, mitochondria (M) are swollen and the cisternae (arrow head) of the endoplasmic reticulum is swollen. Endothelial necrosis (EN) was common in diabetic rats, as were platelet adhesions (P) to the endothelium. The asterisk represents an unknown cell type between the endothelial and vascular muscle cells in the diabetic arteriole (approximately x6200) (from figure 5 of Ref. 25).
Figure 5. Figure 5.

Relationship between body mass index in humans and the fasted blood glucose. A body mass index higher than about 25 would indicate obesity yet many individuals have normal blood glucose (from figure 1 of Ref. 26).
Figure 6. Figure 6.

Nitric oxide (NO) was measured with an NO‐sensitive microelectrode over cultured human umbilical vein endothelial cells as the insulin concentration was increased in the culture media. NO concentrations in excess of 1000 nM occurred at very high insulin concentrations. These data demonstrate that physiological and pharmacological concentrations of insulin can stimulate endothelial cells to produce increased NO and maintain NO production as long as insulin is present (from figure 1b of Ref. 44).
Figure 7. Figure 7.

Blood flow in the leg of lean, obese, and Type II diabetic humans is compared at rest and during endothelial‐dependent dilation caused by methacholine in the left panels. Both obese and Type II diabetic patients have suppressed flow and resistance responses to methacholine. After acute blockade of endothelin‐1 receptors with BQ123, the vascular responses in obese and diabetic humans became essentially normal (from figure 5 of Ref. 50). * Different from control.
Figure 8. Figure 8.

The change in NO concentration measured with a microelectrode and blood flow in the intestine of lean and obese Zucker rats was followed during a protocol to increase flow by forcing increased collateral flow or decreasing flow by downstream occlusion. The responses in obese rats were subnormal but after blockade of the endothelial PKC system with LY333531, the responses of arterioles in obese animal were essentially normal. The PKC blockade did not significantly impact responses of normal arterioles (from figure 2 of Ref. 72). * Different from control. ** Different from PKC blockade.
Figure 9. Figure 9.

The elevation of diacylglycerol (DAG) during hyperglycemia can occur by de novo synthesis of DAG beginning with glucose 6‐phosphate (G6P) as well as activation of phospholipase D (PLD) acting on phosphatidylcholine (PC) to liberate phosphatidic acid (PA). In either case, protein kinase C (PKC) would be activated by DAG. DHAP, dihyroxyacetone phosphate; G3P, glucose 6‐phosphate; LysoPA, lysophosphatidic acid (from figure 1 of Ref. 152).
Figure 10. Figure 10.

Control and post‐protein kinase C inhibition, nitric oxide concentration, and arteriolar diameter. The in vivo nitric oxide concentration and inner diameter of large arterioles of the lean and obese Zucker rats was measured under control conditions and after local suppression of endothelial PKC with LY333531. Under control conditions, arterioles are constricted and their [NO] is less than normal in obese rats but both of these increase with 1h after PKC blockade begins (from figure 1 of Ref. 92). * Different from control.
Figure 11. Figure 11.

The in situ gastrocnemius muscle blood flow and contractile tension were measured in lean and obese Zucker rats before and after polyethylene glycol complexed superoxide dismutase and the alpha adrenergic blocker phentolamine were given systemically. In Obese rats, the combined drug blockade lowered vascular resistance to the muscle at rest (Panel C) in obese rats, improved the blood flow during muscle contractions, and allowed the muscle to maintain higher tensions during contractions for longer periods. Effects in lean rats were minimal (from figure 3 of Ref. 246). * Different from control, *** Different from lean treated group.
Figure 12. Figure 12.

The diameter response of small arteries from the rat heart were exposed to 5 mM normal (NG) and 23 mM D‐glucose (HG) glucose concentrations as well as 5 mM D‐glucose and 17 mM L‐glucose (LG) for 24 h. Superoxide dismutase and catalase did not effect the contraction to 4‐aminopyridine (4‐AP) that activates voltage‐sensitive potassium channels at NG and LG, but did increase contraction in HG vessels. This would indicate oxygen radicals are impairing the function of Kv channels during hyperglycemia (from figure 7 of Ref. 113). * Different from control.
Figure 13. Figure 13.

These are pooled data in a review of diabetic nephropathy and hypertension by Bakris et al. 262 (figure 3 of that review). With increasing mean arterial pressure, the decline in glomerular filtration rate per year is approximately linearly increased. These data are based on hypertensive patients with and without diabetes.


Figure 1.

Photograph of the small intestinal microcirculation of normal and streptozotocin diabetic rats to illustrate the growth of the bowel and maintenance of the vascular branching pattern of major microvessels. Using higher power microscopy, studies revealed that only new capillaries were formed as the bowel enlarged in normal and diabetic rats. The addition of new capillaries was particularly large in diabetic animals due to the hypertrophy of their small intestine (from figure 1 of Ref. 15).



Figure 2.

Scanning electron photomicrographs of the vascular smooth muscle cells in intestinal arterioles of normal (A) and streptozotocin (B) diabetic rats that had been diabetic for 6 months. The vascular smooth muscles of equivalent arterioles were much larger in diabetic than normal animals, as were the endothelial cells. The spindle shape of the vascular muscle cells was preserved in the diabetic animal's intestine (from figure 2 in Ref. 20).



Figure 3.

Scanning electron photomicrographs of the vascular smooth muscle cells of comparable larger arterioles form the cerebral cortex of normal (A) and streptozotocin (B) diabetic rats. The diabetic rats had been diabetic about 4 weeks. The abnormal shape of the vascular muscle in diabetic animals was consistent throughout the cerebral cortical vasculature; normal arterioles have spindle‐shaped muscle cells much like those shown in figure 3 of Ref. 25. Arrows are to typical muscle cells in normal and diabetic rats.



Figure 4.

Transmission electron photomicrographs of cerebral cortical arterioles cut longitudinally. Comparable branch orders of arterioles in normal (A) and strepotozotocin diabetic (B) rats which had been diabetic for 4 weeks are shown. The degeneration of the endothelial and vascular smooth muscle intracellular structures is very evident in the diabetic animals. The large arrows in the upper and lower figures are to call attention to the rectangular cross section of the normal vascular smooth muscle cells compared to the abnormally shaped cells of diabetic animals. In diabetic rats, mitochondria (M) are swollen and the cisternae (arrow head) of the endoplasmic reticulum is swollen. Endothelial necrosis (EN) was common in diabetic rats, as were platelet adhesions (P) to the endothelium. The asterisk represents an unknown cell type between the endothelial and vascular muscle cells in the diabetic arteriole (approximately x6200) (from figure 5 of Ref. 25).



Figure 5.

Relationship between body mass index in humans and the fasted blood glucose. A body mass index higher than about 25 would indicate obesity yet many individuals have normal blood glucose (from figure 1 of Ref. 26).



Figure 6.

Nitric oxide (NO) was measured with an NO‐sensitive microelectrode over cultured human umbilical vein endothelial cells as the insulin concentration was increased in the culture media. NO concentrations in excess of 1000 nM occurred at very high insulin concentrations. These data demonstrate that physiological and pharmacological concentrations of insulin can stimulate endothelial cells to produce increased NO and maintain NO production as long as insulin is present (from figure 1b of Ref. 44).



Figure 7.

Blood flow in the leg of lean, obese, and Type II diabetic humans is compared at rest and during endothelial‐dependent dilation caused by methacholine in the left panels. Both obese and Type II diabetic patients have suppressed flow and resistance responses to methacholine. After acute blockade of endothelin‐1 receptors with BQ123, the vascular responses in obese and diabetic humans became essentially normal (from figure 5 of Ref. 50). * Different from control.



Figure 8.

The change in NO concentration measured with a microelectrode and blood flow in the intestine of lean and obese Zucker rats was followed during a protocol to increase flow by forcing increased collateral flow or decreasing flow by downstream occlusion. The responses in obese rats were subnormal but after blockade of the endothelial PKC system with LY333531, the responses of arterioles in obese animal were essentially normal. The PKC blockade did not significantly impact responses of normal arterioles (from figure 2 of Ref. 72). * Different from control. ** Different from PKC blockade.



Figure 9.

The elevation of diacylglycerol (DAG) during hyperglycemia can occur by de novo synthesis of DAG beginning with glucose 6‐phosphate (G6P) as well as activation of phospholipase D (PLD) acting on phosphatidylcholine (PC) to liberate phosphatidic acid (PA). In either case, protein kinase C (PKC) would be activated by DAG. DHAP, dihyroxyacetone phosphate; G3P, glucose 6‐phosphate; LysoPA, lysophosphatidic acid (from figure 1 of Ref. 152).



Figure 10.

Control and post‐protein kinase C inhibition, nitric oxide concentration, and arteriolar diameter. The in vivo nitric oxide concentration and inner diameter of large arterioles of the lean and obese Zucker rats was measured under control conditions and after local suppression of endothelial PKC with LY333531. Under control conditions, arterioles are constricted and their [NO] is less than normal in obese rats but both of these increase with 1h after PKC blockade begins (from figure 1 of Ref. 92). * Different from control.



Figure 11.

The in situ gastrocnemius muscle blood flow and contractile tension were measured in lean and obese Zucker rats before and after polyethylene glycol complexed superoxide dismutase and the alpha adrenergic blocker phentolamine were given systemically. In Obese rats, the combined drug blockade lowered vascular resistance to the muscle at rest (Panel C) in obese rats, improved the blood flow during muscle contractions, and allowed the muscle to maintain higher tensions during contractions for longer periods. Effects in lean rats were minimal (from figure 3 of Ref. 246). * Different from control, *** Different from lean treated group.



Figure 12.

The diameter response of small arteries from the rat heart were exposed to 5 mM normal (NG) and 23 mM D‐glucose (HG) glucose concentrations as well as 5 mM D‐glucose and 17 mM L‐glucose (LG) for 24 h. Superoxide dismutase and catalase did not effect the contraction to 4‐aminopyridine (4‐AP) that activates voltage‐sensitive potassium channels at NG and LG, but did increase contraction in HG vessels. This would indicate oxygen radicals are impairing the function of Kv channels during hyperglycemia (from figure 7 of Ref. 113). * Different from control.



Figure 13.

These are pooled data in a review of diabetic nephropathy and hypertension by Bakris et al. 262 (figure 3 of that review). With increasing mean arterial pressure, the decline in glomerular filtration rate per year is approximately linearly increased. These data are based on hypertensive patients with and without diabetes.

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Article Title: Microvascular Consequences of Obesity and Diabetes
 

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H Glenn Bohlen. Microvascular Consequences of Obesity and Diabetes. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 896-930. First published in print 2008. doi: 10.1002/cphy.cp020419