Cardiovascular Diabetology - Latest Comments

Addressing predisease conditions (clinical triggers for chronic disease): A pathway for primary prevention of disease.

Alok Kumar Gupta — 2013-03-09T16:38:51Z

Birth is usually followed by natural death. A disease can often hasten death. Predisease conditions, covertly present decades earlier [1], have been thought to promote early death, by insidiously converting into overt disease over time. It is, however, also being recognized that predisease conditions like prediabetes and prehypertension, do not only have a high prevalence among healthy adults in the United States [2,3], but also place these healthy individuals on an accelerated pathway for cardiovascular adverse events [4]. This risk appears to begin with an enlargement of the waist circumference, deposition adipose tissue in ectopic locations (visceral, liver and muscle), and adipose tissue dysfunction leading to worsening insulin resistance and/or systemic inflammation [5,6]. The early functional consequences of these changes,upon the cardiovascular system, can be elucidated with non-invasive assessment of circadian blood pressure variability and resting endothelial function [7]. While altered variability of blood pressure increases the risk for stroke, endothelial dysfunction places one at risk for a heart attack. Assessing functional measures (circadian blood pressure variability and resting endothelial function) along with adipose tissue dysfunction (systemic inflammation and insulin resistance) in at risk, but otherwise healthy individuals, can provide avenues for primary prevention of disease [6]. These assessments can let us get beyond the lifestyle measures (diet, increase in exercise to sustain weight loss) currently reserved for intervention with predisease conditions. Abnormal circadian blood pressure variability could be reset with bromocriptine, increased systemic inflammation could be treated with salicylates and insulin resistance could be reversed with a biguanide (metformin) or thiazolidinedione (pioglitazone).
1Preis SR, et al.Diabetes Care. 2013 Jan 22.
Gupta AK, et al. 2Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome. Elsevier Inc.: Academic Press; 2012. p. 57¿75. 3Hypertens Res. 2010; 33(9):905-10. 4Hypertens Res. 2011; 34(4):456-61. 5J Inflamm (Lond). 2010; 7:36. Highly accessed. 6Cardiovasc Diabetol. 2013 Jan 24; 12(1):23. 7Cardiovasc Diabetol. 2010; 9:58. Highly accessed.
8WHO: Noncommunicable diseases. Fact sheet. September 2011.

Corrigendum

Christa Buechler — 2012-03-21T11:00:10Z

Fig. 1B on page 3:
We meanwhile recognized that an error had occurred during preparation part of figure 1 (i.e. figure 1B). This error, however, had no effect on scientific content and conclusions. In figure 1B the lower immunoblot is an erroneously duplication of the lower panel of figure 2B. The original adiponectin immunoblot looks quite similar and shows that LMW adiponectin is not altered 2 h after oral glucose uptake. Original blot can not be posted here and can be send upon request.
We deeply regret that these error occurred and are sorry for this inconvenience.

Correction

Rudolf de Boer — 2012-03-21T10:36:55Z

The authors would like to correct that the drug substances used in this study was the vildagliptin analog PKF275-055. The authors apologize for the error.

A mistake in the unit of fasting plasma glucose

Alexandra Kautzky-Willer — 2011-07-05T17:08:41Z

Please note that the unit of Fasting plasma glucose in Table 2 and in Figure 2 is in (mg/dl) and not in (gm/dl).

Correction

Enrique Fisman — 2011-06-13T05:24:22Z

Correction (posted on behalf of the authors):

After publication of this work [1], we noted an error in the results section of the abstract. The results for heart rate and the LF component of AP variability for the SHR sample were omitted from the list. The corrected results section appears below.

Results
Higherglycemia (p lesser than 0.05) and lower mean AP were observed in diabetics vs. nondiabetics (p lesser than 0.05). Heart rate was higher in renal-denervated hypertensive and lower in diabetic-hypertensive rats (384.8± 37, 431.3 ±36, 316.2 ±5, 363.8 ±12 bpm in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively). Heart rate variability was higher in renal-denervated diabetic-hypertensive rats (69.84 ±37.91, 55.75 ± 25.21, 73.40 ± 53.30, 148.4 ± 93 in SHR, RD-SHR, STZ-SHR- and RD-STZ-SHR, respectively, p lesser than 0.05), as well as the LF component of AP variability (5.17 ± 5.24, 1.62 ± 0.9, 2.12 ± 0.9, 7.38 ± 6.5 in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively, (p lesser than 0.05). GLUT2 renal content was higher in all groups vs. SHR.

References
1. Dias LD, Casali KR, Leguisamo NM, Azambuja F, Souza MS, Okamoto M, Machado UF, Irigoyen MC, Schaan BD. 2011. Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy. Cardiovasc Diabetol. 10(1):33.

Mistake in Table 2

Manuel A Gomez-Marcos — 2011-06-13T05:23:27Z

In title "Bivariate correlations between IMT, risk factors and arterial stiffness measures (ambulatory arterial stiffness index, augmentation index and pulse wave velocity) in subjects with and without type 2 diabetes.

In second row, first column, delete "Univariate

Correction

Kei Nakajima — 2011-06-01T14:32:36Z

Figure 2
Q1 is highest quartile and Q4 is lowest quartile.

Figure 3 and Figure 4
Q1 is lowest quartile and Q4 is highest quartile.

Carbohydrate-rich Diet Is The Likely Culprit For Insulin Resistance

Robert Su — 2010-11-28T07:46:15Z

I thoroughly enjoyed reading this excellent article, “Hyperinsulinemia improves ischemic LV function in insulin resistant subjects” by Patrick M. Heck et al. Furthermore, the use of hyperinsulinemic euglycemic clamp (HEC) in this study prompts me to share my thought on the possible cause of insulin resistance.

Insulin resistance is a situation when the body, or more specifically, the cell, has built up resistance to the (endogenous) insulin produced by its pancreas, and cannot use the endogenous insulin for taking up and metabolizing the circulating glucose to produce energy, metabolites of glucose, glycogen, and fats. At the same time, the patient with insulin resistance continues to consume carbohydrates; his blood glucose level will rise accordingly. The more he consumes carbohydrates, the higher his blood glucose level will be. Despite that the unused insulin continues to accumulate in the circulation, more insulin is produced and released into the circulation by the pancreas in response to the rising blood glucose level. Thus, the patient suffers from hyperglycemia and hypeinsulinemia at the same time under this detrimental circumstance. [1, 2]

Insulin resistance is often observed in the patient who is pre-diabetic or type 2 diabetic. It is also observed in the patient with metabolic syndrome along with several pathological biomarkers such as increases in inflammatory factors, blood glucose LDLs, and fibrinogen, and a decrease in HDLs. Because one of the prevalence of insulin resistance is obesity, studies have claimed factors(s) of the adipose (fatty) tissue as the cause(s) of insulin resistance. But, interestingly, the fact that improvement in the blood glucose level of the diabetics decreased in a few days after bariatric surgery or gastric bypass surgery, even before the obese diabetics began to lose weight, should contradict the claims. [3, 4, 5]

While several situations have been brought up as the causes of insulin resistance, the consensus blames hyperinsulinemia for desensitizing the insulin receptors of the cells to insulin. In other words, hyperinsulinemia with unknown reason(s) is supposed to be the culprit. Therefore, discovering the cause(s) of hyperinsulinemia and confirming the causative role of hyperinsulinemia in insulin resistance should be the foci of future studies. [6]

To make insulin help the cell take in and utilize glucose, the cellular membrane has insulin receptors, which take up insulin in coupling like the combination between a key and a lock. Logically, if the key does not fit the lock, insulin cannot be coupled with the cellular insulin receptors, As a result, both hyperinsulinemia and hyperglycemia are observed. Setting aside the blame on the insensitivity of the insulin receptors to the endogenous insulin, two possible issues should be considered in insulin resistance. One is with the insulin receptors, and the other is with the endogenous insulin.

Despite the belief of the consensus that accumulation of insulin or hyperinsulinemia desensitizes the cellular insulin receptors to endogenous insulin, one of the treatments for insulin resistance (hyperinsulinemia and hyperglycemia) is to use a large amount of exogenous insulin. The same technique was observed in a recent study, in which a hyperinsulinemia euglycemia (keeping the blood glucose level within the normal range) clamp improved the left ventricular functions in the patients with insulin resistance and coronary artery disease. In this approach, the patients received more exogenous insulin along with glucose to improve the uptake of glucose by the cardiac muscle cells. [7] How could one situation with hyperinsulinemia cause insulin resistance, and the other with hyperinsulinemia improve insulin resistance?

Based on the compatibility between the key and the lock, the ability of cells to couple with the exogenous insulin but to not couple with the endogenous, means the possible issue is not necessarily with the receptors. Rather, the issue should be with the difference between the exogenous and endogenous insulin. And, the difference may well be in the structures of the endogenous and the exogenous. In other words, the amino acid sequence of the insulin in the case of insulin resistance and of the insulin in the normal state may be different.

Having realized the potential of mutations by hyperglycemia, mutation of the ß cells in the environment of hyperglycemia is a reality that has yet to be further explored. [8, 9] Studies have shown hyperglycemia is responsible for damage, death, and mutations of cells including ß cells. A study, “Chronic Exposure of ß-TC-6 Cells to Supraphysiologic Concentrations of Glucose by Poitout V, et al., demonstrated that exposing the ß cells to supraphysiological concentration of glucose solution (199.8 mg%) for up to 41 weeks could decrease the production of insulin by changing (decreasing) their genetic factors. [10] With the findings of mutations of the ß cells, gene or genes, which are normally responsible for keeping a normal sequence of amino acids of insulin produced by ß cells, could be mutated when the ß cells are exposed to hyperglycemia. If that indeed happens as thought, the sequence of amino acids of the insulin produced by the mutated ß cells could be different from that of the insulin produced by the normal ß cells. The defective insulin with an abnormal amino acid sequence, despite its accumulation in the circulation, cannot help the cellular insulin receptors take up and metabolize glucose in the circulation, thus, results in both hyperinsulinemia and hyperglycemia.

Undoubtedly, consuming carbohydrates is positively linked to the blood glucose level. Consequently, excess carbohydrate intake results in hyperglycemia. Restricting carbohydrates is the best way for reversing hyperinsulinemia and hyperglycemia in insulin resistance, by returning the blood glucose level to normal, as no addition of glucose from the dietary carbohydrate; and allow the normal insulin from the normal ß cells to have the time help the cells take up and metabolize glucose, which has already in the circulation. When the blood glucose level stays within the normal range, the demand for insulin will decline and hyperinsulinemia will subside. [11, 12, 13, 14, 15]

Hopefully, the future studies will focus on the sequence of amino acids of insulin in the cases of insulin resistance to substantiate the author’s claim that carbohydrate-rich diet is the likely culprit for insulin resistance.

1. Reusch JE. “Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome.” The American Journal Of Cardiology. Volume 90, Issue 5, Supplement 1, Pages 19-26 (5 September 2002) http://www.ncbi.nlm.nih.gov/pubmed/12231075

2. National Diabetes Information Clearinghouse (NDIC) “Insulin Resistance and Pre-diabetes.” http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/

3. Gumbs AA, et al. “Changes in insulin resistance following bariatric surgery: role of caloric restriction and weight loss” Obes Surg. 2005 Apr;15(4):462-73. http://www.ncbi.nlm.nih.gov/pubmed/15946423

4. van Dielen FM, et al. “Insulin sensitivity during first months after restrictive bariatric surgery, inconsistency between HOMA-IR and steady-state plasma glucose levels.” Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2009 Dec 11. http://www.ncbi.nlm.nih.gov/pubmed/20096645

5. Kormer J. et al. “Bariatric Surgery in Diabetic Adults Improves Insulin Sensitivity Better than Diet.” The Endocrine Society. June 19, 2010. http://www.endo-society.org/media/press/2010/BariatricSurgeryinDiabeticAdults.cfm?RenderForPrint=1

6. Shanik, MH, et al. “Insulin Resistance and Hyperinsulinemia Is hyperinsulinemia the cart or the horse?” Diabetes Care 31 (Suppl. 2):S262–S268, 2008. http://care.diabetesjournals.org/content/31/Supplement_2/S262.full.pdf+html

7. Heck, PM, et al. “Hyperinsulinemia improves ischemic LV function in insulin resistant subjects.” Cardiovascular Diabetology 2010, 9:27. http://www.cardiab.com/content/9/1/27

8. Olson LK, et al. “Chronic Exposure of HIT Cells to High Glucose Concentrations Paradoxically Decreases Insulin Gene Transcription and Alters Binding of Insulin Gene Regulatory Protein.” Journal of Clinical Investigation. Volume 92, July 1993, 514-519. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC293640/

9. Lee, AT, et al. “Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo.” DIABETES, VOL. 48, FEBRUARY 1999. http://diabetes.diabetesjournals.org/content/48/2/371.full.pdf+html

10. Poitout V, et al. “Chronic Exposure of ß-TC-6 Cells to Supraphysiologic Concentrations of Glucose Decreases Binding of the RIPE3b1 Insulin Gene Transcription Activator.” Journal of Clinical Investigation. Volume 97, Number 4, February 1996, 1041–1046 http://www.jci.org/articles/view/118496/pdf

11. Samaha FF, et al. “A Low-Carbohydrate as Compared with a Low-Fat Diet in Severe Obesity.” New England Journal of Medicine. Volume 348:2074-2081. May 22, 2003. http://www.contentnejmorg.zuom.info/cgi/content/full/348/21/2074

12. Plodkowski R. “Cutting Carbs is More Effective than Low-Fat Diet for Insulin-Resistant Women.” The Endocrine Society’s 92nd Annual Meeting in San Diego. June 19, 2010. http://www.endo-society.org/media/press/2010/CuttingCarbsisMoreEffective.cfm

13. Gannon MC and Nuttal FQ. “Effect of a High-Protein, Low-Carbohydrate Diet on Blood Glucose Control in People With Type 2 Diabetes.” Diabetes, Volume 53, Number 9, Pages 2375-2382. 2004. http://diabetes.diabetesjournals.org/content/53/9/2375.full.pdf+html

14. Nuttall FQ and Gannon MC. “The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 iabetes mellitus.” Metabolism. Volume 55, Issue 2, Pages 243-251. February 2006. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WN4-4J2N7WW-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4ab451c21a4f6af24c243cf0a9325cce

15. Gannon MC and Nuttal FQ. “Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.” Nutrition and Metabolism. Volume 3, Number 1, Pages 16. 2006. http://www.nutritionandmetabolism.com/content/3/1/16

Erratum:

Alok Kumar Gupta — 2010-10-06T15:48:12Z

Table 3 compares the seven obese participants with normal circadian BP variability with the eight obese participants who had abnormalities. The seven obese participants (BMI 32 kg/m2) who had normal circadian BP variability had normal glucose, hs-CRP, fibrinogen, triglycerides, HDL-C and cardiac risk ratios. In contrast the eight obese subjects with abnormal circadian BP variability exhibited (REPLACE majority WITH all) all of the CVD risk parameters outside of the desirable range.

The results from this study show that latent CVD risk in disease-free (healthy) obese adults assessed with no or low risk by conventional risk assessment methods, can be unmasked by simple non-invasive measures. The obese participants exhibiting normal circadian BP variability had normal endothelial function, (REMOVE normotension) normoglycemia and were within the desirable limits for systemic inflammation, triglycerides, HDL-C, and cardiac risk ratios.

In Figure 5, Figure 6,
Subjects with No Abnormalities (n=7) (Not n=2).

It is the time to revisit dietary therapy for diabetes mellitus.

Robert Su — 2010-09-17T15:06:01Z

Congratulations to Kurukulasuriya LR & Sowers JR of University of Missouri on their excellent analysis, “Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors”, to detail the desirable therapeutic and undesirable effects of each antidiabetes agent of each category, in terms of glycemic control, body weight, lipid level, and blood pressure parameters, all of which are significant cardiovascular risk factors. However, selecting a perfect antidibetes agent is hardly an easy decision, even equipped with such an excellent analysis. Both Kurukulasuriya & Sowers, as well as many physicians including the diabetes experts have continued to ignore an excellent therapeutic alternative to the pharmacotherapy.

Glycemic control is the key to treating diabetes mellitus and its concurrent complications, because the higher the glycemic concentration, the worse the outcome of the diseases will be. Besides, hyperglycemia is causal to gaining weight, dyslipidemia or atherosclerosis, and vasoconstriction or hypertension, in addition to inflammation, thrombosis, and glycation. Tight glycemic control is unequivocally the most important measure in preventing and treating diabetes mellitus and many concurrent diseases. [1]

All physicians must understand the sources of glycemia that the major supply for glycemia is the carbohydrate foods especially those with high in glycemic indices and glycemic loads. The more the intake of carbohydrate foods, the greater the excursion of postprandial glycemia is. The focus of preventing and treating hyperglycemia is the same --- keeping a normal glycemic level. However, preventing hyperglycemia is far more superior to treating the disorder, because the former takes one step ahead of the development of disease, and the latter trails behind the course of disease.

Having understood the sources of glycemia, to best prevent hyperglycemia is to reduce the supply from carbohydrate foods. Over a century ago, physicians had already discovered the positive relationship between carbohydrate foods, especially sugars and starchy foods, and the increase of glycosuria, which is the namesake of diabetes mellitus. [2] Since the discovery of insulin in 1921, and, more antidibetes agents during the past few decades, physicians have simply forgot the key supplier, carbohydrate foods, for the excursion of postprandial glycemia in a positive relationship. They must realize that the advancement in biotechnology does not and cannot alter the basic physiology and biochemistry.

More than a century after Dr. Williamson' article, the American Diabetes Association, in ADA annual Clinical Practice recommendations at the end of 2007, lukewarmly suggested that individual diabetic patients might be benefited by low carbohydrate diet. [3] On August 24, 2009, the American Heart Association recommended Americans to reduce their daily consumption of added sugar from 22.2 teaspoons to 9 for men and 6 for women. However, It failed to address the need of restricting carbohydrates in its recommendations. [4]

Several studies have revealed that restricting carbohydrates can control the glycemic level, and also can result in weight loss, improve lipid levels, and reduce the cardiovascular risk factors. Up to this date, many physicians continue to embrace several misconceptions that the body cannot live without carbohydrates, that carbohydrates are low in calorie and excellent for weight control, and that fats are causal to obesity, inflammation, coronary syndrome, and many. Refreshing their knowledge in biochemistry would help clear such baseless concerns. [5, 6, 7, 8, 9]

An upcoming study on the effects of the Paleolithic diet on type 2 diabetes mellitus will be conducted by the investigators of University of California, San Francisco. One of the study co-investigator, Dr. Lynda Frassetto, has already found improvement in the diabetic symptoms with the Paleolithic diet, which is carbohydrate-restricted, in just a two short weeks. [10]

With an impossible task in finding an ideal antidiabetes agent or agents for glycemic control, body weight, lipid level, and blood pressure parameters, it is the time to revisit the dietary therapy for diabetes mellitus.

References:

1. Su RK. “Carbohydrates Can Kill: Hyperglycemia is problematic but preventable by restricting carbohydrates.” The Blog Carbohydrates Can Kill. August 16, 23, 30, 2010. http://www.carbohydratescankill.com/497/carbohydrate-can-kill-hyperglycemia-problematic-but-preventable-by-restricting-carbohydrates-of

2. Williamson RT. ""On The Treatment Of Glycosuria And Diabetes Mellitus With Sodium Salicylate.” The British Medical Journal. Page 760-762. March 30, 1901. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2400585/

3. American Diabetes Association. “Executive Summary: Standards of Medical Care In Diabetes.” Diabetes Care. January 2008 31:S5-S11; doi:10.2337/dc08-S005 http://care.diabetesjournals.org/content/31/Supplement_1/S5.full.pdf+html

4. American Heart Association. “Sugar: Frequently Asked Questions (Consumers.)” Learn and Live. http://www.americanheart.org/presenter.jhtml?identifier=3068663#what_does_AHA_recommend_as_limit_for_added_sugars

5. Boden G, et al. “Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes.” Annals of Internal Medicine, Volume 142, Number 6, Pages 403-11. March 15, 2005. http://www.annals.org/cgi/content/abstract/142/6/403?etoc

6. Nuttall FQ and Gannon MC. “The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 iabetes mellitus.” Metabolism. Volume 55, Issue 2, Pages 243-251. February 2006. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WN4-4J2N7WW-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4ab451c21a4f6af24c243cf0a9325cce

7. Gannon MC and Nuttal FQ. “Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.” Nutrition and Metabolism. Volume 3, Number 1, Pages 16. 2006. http://www.nutritionandmetabolism.com/content/3/1/16

8. Arora SK and McFarlane SI. “The case for low carbohydrate diets in diabetes management.” Nutrition & Metabolism, (Lond), 2005; Volume 2, Number 16. 2005. Published online 2005 July 14. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1188071

9. Nielsen JV and Joensson E. “Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up.” Nutrition & Metabolism, (Lond), Volume 3, Number 22. 2006 Published online June 14, 2006. http://www.nutritionandmetabolism.com/content/3/1/22

10. News Article. “Hunter-Gatherer Diet May Help Prevent And Treat Type 2 Diabetes.” Diabetes Center, University of California, San Francisco. Wednesday, June 25, 2008. http://www.diabetes.ucsf.edu/about-us/news-events/news/200806/hunter-gatherer-diet-may-help-prevent-and-treat-type-2-diabetes