SouthWest Diabetes Symposium 2019 - Part II

Having gone through the statistics about diabetes and pre-diabetes, the second part of the symposium related to current standard-of-care treatment of the disease.

Blood sugar control depends upon a multitude of factors, all of which must function correctly in order to maintain a stable blood glucose level. Obesity is one of those factors. In conventional medicine, we tend to blame diabetes mainly on obesity and lack of exercise both causing insulin resistance and the attendant downstream morbidities (illnesses).

  1. Glucose is absorbed by the large intestine. So the large intestine must be functioning adequately in order for blood sugar absorption to occur.
  2. The pancreas secretes insulin to regulate blood sugar uptake into muscle tissue.
  3. Skeletal muscle takes up glucose to use a fuel for muscle activity – this activity is dependent on mitochondrial function. Mitochondria must be healthy, and the skeletal muscle must be activated – hence the importance of movement and exercise.
  4. The liver converts glucose into glycogen and triglycerides for future use. The liver must be healthy, not overloaded with toxins.
  5. Adipose tissue stores glucose as triglycerides, fats. There must be some adipose tissue, again not overloaded with fat-soluble toxins.
  6. The kidney filters blood glucose and returns it to the blood stream, until its filtering capacity is overwhelmed, at which point glucose spills into the urine. Kidney function is essential – diabetics typically have poor kidney function. Which came first?
  7. The brain requires large amounts of glucose to function. Hence the need to eat while doing intellectual work, to provide “food for thought”.

Some theorize that the primary defect occurs at the level of skeletal muscle, which becomes insulin-resistant and unable to take up glucose from the peripheral blood.[1]

Another explanation for the diabetes epidemic is that accumulation of fat is a driver – the current obesity epidemic is clearly related (at least temporally) to the diabetes epidemic. When fat is mobilized from the tissues, insulin sensitivity increases, and diabetes parameters improve.[2]

As early as 2007 a proposal was made that offered a potential treatment of metabolic syndrome (which Medicare does not recognize as a “real” diagnosis) incorporating the treatment of hypertension, dyslipidemia and overweight along with the dysglycemia all in one package, by treating insulin resistance, the common denominator among all those dysfunctions.[3] This was an excellent step in beginning to treat the whole body, rather than just the manifestation of elevated fasting glucose.

The large intestine and its microbiome have enormous influence over our entire metabolic system. Some authors suggest that these factors may play a part in the development of diabetes.[4], [5], [6], [7] And in rats, at least, fecal transplantation from lean healthy rats to obese diabetic rats resulted in improvement of the diabetic state.[8]

At the present time, diabetes care appears to be focused on obesity (“lifestyle factors”) and drugs to reduce blood glucose levels. Interestingly, the treatment of kidney and liver dysfunction is placed into the “ancillary” or “co-morbid” conditions. It is recommended that these co-morbid conditions also be treated, as though they were separate and not an integral part of the whole body dysfunction that manifests in the disease we call diabetes.[9], [10]

The American Medical Association in 2005 declared obesity to be a chronic disease involving impairment of a normal function of the body (satiety hormone regulation of energy intake, and adipose tissue dysfunction) resulting in harm or morbidity (cardiometabolic and structural complications like painful knees and hips).

The pathway to “normal” or “obese” weight can be explained by considering the balance between hormones that make you feel hungry (“orexigenic hormones”) and hormones that tell you that you have eaten enough (“anorexigenic hormones”). Some of us grew up in the era when we were told “finish what is one your plate, there are starving children in China who would love to eat that food” as though the two halves of the sentence had some relationship to one another. We believed our parents and teachers and did our best to polish off whatever was on the plate, whether we were hungry or not. And thus we learned that food can be a measure of approval – even of love – irrespective of its nutritional content and caloric value. Bad lesson to learn for those of us who have genetics that predispose us to obesity.

It is clear that our bodies have a finely tuned system aimed at keeping our weight stable. So what goes wrong? That question was never answered during this symposium. Why does our body suddenly decide that a higher weight is preferable for our survival? Why do some of us store fat for the winter that never comes? And how can we persuade our bodies that a lower weight is actually beneficial and should be our “set point”?

The answer given at the symposium was to use pharmacology to overcome physiology, with the understanding that obesity is a life-long disease and requires life-long pharmacologic treatment, just like type 2 diabetes, or asthma, or inflammatory bowel disease. Mechanisms of action of the different drugs was never very well explained – the mechanisms have something to do with interfering with different components of the hunger/satiety pathways.

In order to understand these mechanisms, it is important to understand the fine balancing act that our bodies go through in order to maintain homeostasis – a stable weight. Certain hormones regulate these pathways.[11]

We have Orexigenic pathways that encourage us to increase our caloric intake. These pathways are controlled mostly by Ghrelin, a peptide (small protein) produced in the stomach. Production is inhibited by feeding or by elevated blood sugar.

We have Anorexigenic pathways that encourage us to decrease our caloric intake. These pathways are controlled by a multitude of hormones, suggesting that it is constitutionally more difficult for us to LOSE weight than it is to GAIN weight – as any woman over the age of 35 could confirm.

Leptin appears to function on both sides of the fence. Its primary function appears to be the conveyance of information on adequacy of energy reserves to the brain and peripheral organs.

Leptin (Greek leptin = thin). Leptin is produced in fat cells. It acts on the hypothalamus suppressing food intake, stimulating energy expenditure (raising body temperature). Paradoxically, obese individuals often have increased leptin concentrations – perhaps due to a desensitization process akin to loss of sensitivity to insulin in type 2 diabetics. Leptin affects both the central nervous system and the peripheral nervous system, and both the orexigenic and the anorexigenic pathways. Leptin receptors are found all over the body. They are particularly concentrated in the feeding section of the hypothalamus. However, treatment of obese animals or people does not necessarily result in weight loss, as the subjects appear to develop resistance to leptin. Genetic mutations in the leptin gene can lead to extreme pathological obesity.

  • Leptin secretion is stimulated (at least temporarily) by:
    • Overfeeding
    • Insulin
    • Stress (glucocorticoids)
  • Leptin secretion is suppressed by
    • Fasting - Decreasing leptin concentrations in response to starvation suppresses the HPA/gonadal axis (who needs to make children if you are starving to death?).
    • cAMP – this messenger is a metabolite of ATP, the cell’s unit of energy. cAMP promotes the mobilization of energy sources, both carbohydrate and protein, in response to stimulation by epinephrine (the fight or flight hormone), thus explaining why stress often causes weight gain, in those who are not sensitive to insulin and glucose levels. cAMP also enhances release of insulin from the pancreas, thus providing the means for our bodies to use the glucose which has been mobilized.[12]
    • excitatory stimulation by epinephrine, stress-related hormones
  • Leptin suppresses neuropeptide Y (NPY). NPY is a strong appetite stimulator and also a growth hormone suppressor.
  • Obese subjects have elevated leptin levels, and clearly their appetite is not suppressed, or they would stop eating, stop being obese, and return to normal weight levels.
  • Leptin is also influenced by the Circadian rhythm, peaks around 2:00 am. When the Circadian rhythm is disrupted, we begin to see leptin resistance – at least in mice.[13]

The peptide signals from the GI tract represent the “feeding state” for our central nervous systems, while the hormones Leptin and insulin give us information on our nutritional state.[14]

Ghrelin – produced by the stomach, sends information to the hypothalamus and the stomach, increases gastric motility and acid secretion, to promote digestion of food. Ghrelin stimulates release of growth hormone from the anterior pituitary. It affects appetite and energy balance. It stimulates lactation and secretion of corticosteroids by the adrenal gland. Ghrelin levels double before a meal and decrease within 1 hour of eating. Ghrelin concentrations are increased with low-calorie diets, heavy exercise and with both cancer anorexia and anorexia nervosa. Obviously in the latter two conditions it is not stimulating food intake so much, so something else must also be happening in those two conditions to counteract its effect. Reduction in body weight in obese patients increases ghrelin levels – again reflecting the apparent elevated set point in obesity. Ghrelin crosses the blood-brain barrier intact. Insulin concentrations are inversely correlated with ghrelin concentrations.  

Adiponectin – produced by fat cells, decreases insulin resistance and blood glucose concentrations. There is a negative correlation between obesity and adiponectin levels. Decreased concentrations are associated with insulin resistance and are seen in patients with type II diabetes. Adiponectin levels are modulated by PPAR gamma, a protein which regulates gene expression of adiponectin (among other hormones). Adiponectin function goes a long way toward explaining the relationship between heart disease, diabetes and obesity.[15]

Adiponectin decreases lipid synthesis and glucose production in the liver, and increases oxidation of fats in the muscle. It improves glucose tolerance by increasing insulin sensitivity. Adiponectin protects against cancer and myocardial infarction.[16], [17] Low adiponectin levels are correlated with various cancers including colorectal cancer.

AMPK is a protein kinase which acts as a sensor of cellular energy status. It also promotes the assemblage of adiponectin molecules into a large molecule called a “multimer” which is very metabolically active, promoting insulin sensitivity in peripheral tissues. Different multiples of adiponectin have different functions in the body.

Impairment of mitochondrial function and increased oxidative stress within the cell is associated with decreased levels of the HMW form of adiponectin due to decreased production of the hormone in adipocytes.[18]

A 2014 study reports that adiponectin in a trimer form (LMW), hexamer form (MMW) have different functions from the multimer HMW) in adipocytes. The trimeric form of adiponectin is active in the central nervous system, stimulating AMPK activation and increasing food intake.[19] The HMW adiponectin is more metabolically active and closely associated with peripheral insulin sensitivity.[20]

Resistin – produced by fat calls, increases insulin resistance (in rats) – decreasing resistin levels improves glucose metabolism and blood sugar levels.[21] The hormone was originally discovered in mice in 2001 and named for its ability to resist (interfere with) insulin action. Resistin is found mainly in inflammatory cells. It seems to play a part in cardiovascular disease, non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and kidney disease – all the organs which appear to be affected negatively by diabetes. [22]

The last symposium lecture was still very much drug based, but at least thinking a broader approach – although still not a functional approach to the spectrum of diabetes/cardiovascular/renal/neurologic (cognitive) disease.

The speaker discussed the relationship between obesity and diabetes. “Obese patients have more adipocytes, which release leptin, adiponectin, tumor necrosis factor–alpha, and resistin, and these hormones are thought to further contribute to insulin resistance.”[23] With hyperglycemia, glucose is transported into the beta-cells of the pancreas, telling the pancreas to secrete more insulin. With persistent elevation of blood glucose, the pancreas beta-cells fatigue and are able to produce less insulin. Insulin secretion happens in two phases – first, immediately after a meal there is a rapid release lasting a few minutes. Then insulin is released more slowly for a more prolonged period to take care of the glucose that is absorbed after initiation of digestion. Type 2 diabetic patients have a blunted immediate insulin release, resulting in higher post-prandial glucose levels and higher phase 2 insulin release. Eventually the beta cells fatigue, and diabetes ensues.

The discussion largely centered on which drugs to use for which patients with which conditions. The drugs themselves are addressed more fully in the article entitled “Diabetes Drugs – mechanisms of action.” The recommendations[24] and published guidelines[25] by the 2019 AACE Type 2 Diabetes Management Guidelines/Algorithm are mentioned here, and discussed in Part III of this series, entitled “Diabetes Drugs”.

More natural – food and plant based – products to improve glucose metabolism and inflammation are discussed in part IV of this series, entitled: “Natural Solutions to Type 2 diabetes management”.


 

[3] Sharabi, Yehonatan, et al. "Effect of PPAR-γ agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model." American journal of hypertension 20.2 (2007): 206-210.

[5] Giongo, Adriana, et al. "Toward defining the autoimmune microbiome for type 1 diabetes." The ISME journal 5.1 (2011): 82.

[6] Kostic, Aleksandar D., et al. "The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes." Cell host & microbe 17.2 (2015): 260-273.

[7] Hartstra, Annick V., et al. "Insights into the role of the microbiome in obesity and type 2 diabetes." Diabetes care 38.1 (2015): 159-165.

[8] ibid

[9] Sharabi, Yehonatan, et al. "Effect of PPAR-γ agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model." American journal of hypertension 20.2 (2007): 206-210.

[12] Sutherland, Earl W., and G. Alan Robison. "The role of cyclic AMP in the control of carbohydrate metabolism." Diabetes 18.12 (1969): 797-819.

[13] Kettner, Nicole M., et al. "Circadian dysfunction induces leptin resistance in mice." Cell metabolism 22.3 (2015): 448-459.

[14] Székely, Miklós, et al. "Nutritional Impact on Anabolic and Catabolic Signaling." Molecular Basis of Nutrition and Aging. Academic Press, 2016. 189-204.

[16] Sugiyama, Michiko, et al. "Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway." International journal of oncology 34.2 (2009): 339-344.

[17] Ouchi, Noriyuki, Rei Shibata, and Kenneth Walsh. "Cardioprotection by adiponectin." Trends in cardiovascular medicine 16.5 (2006): 141-146.

[18] Liu, Meilian, and Feng Liu. "Regulation of adiponectin multimerization, signaling and function." Best practice & research Clinical endocrinology & metabolism 28.1 (2014): 25-31.

[19] ibid

[22] Jamaluddin, Md S., et al. "Resistin: functional roles and therapeutic considerations for cardiovascular disease." British journal of pharmacology 165.3 (2012): 622-632.

[23] Tran, Kelvin Lingjet, et al. "Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes." American health & drug benefits 10.4 (2017): 178.

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