While insulin is often produced by the insulin resistant patient/diabetic, they lack a strong first phase insulin response which is typical in healthy subjects (9, 10, 11, 12). Without this strong first phase insulin release with oscillating insulin pulses, the liver fails to receive the signal to produce enzymes and cofactors for aerobic oxidation by the mitochondria.
Interestingly, insulin resistant patients progressively lose the ability to produce this first phase insulin release over time with the pancreas attempting to compensate by producing more and more insulin. Eventually, their pancreas loses the ability to produce insulin requiring insulin therapy in some patients.
As mentioned earlier, insulin’s actions are far more complex than control of blood glucose levels alone. Catabolic hormones like insulin work through activation of protein kinase A and the ensuing phosphorylation of key enzymes. Insulin activates protein phosphatases and dephosphorylates these enzymes (Table 2).
Table 3: Enzyme Regulation by Insulin and Glucagon
Some of these are activated by phosphorylation, other are inactivated through the same mechanism. Insulin activates glycogen synthetase and pyruvate dehydrogenase, and inactivates phosphofructokinase 2 and hormone-sensitive lipase (16).
Glucose uptake by muscle and fat cells is dependent upon activation of glucose transporter type 4 (GLUT4) by insulin. GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Glucose uptake and GLUT4 activation fails when insulin secretion or the body’s responsiveness to insulin (insulin resistance) is no longer coupled to blood glucose levels. After reduction or loss of the insulin signal, liver gluconeogenesis progresses in spite of high blood glucose levels. In the words, the body reacts as though glucose is not even present.
To meet this “perceived low glucose” crisis, lipolysis and hepatic gluconeogenesis are activated by glucagon, growth hormone and catecholamines. Massive amounts of fatty acids are released to the circulation and the liver converts these to ketone bodies as the body is unable to utilize glucose. The high blood glucose levels lead to diuresis with loss of water, sodium, potassium and glucose, while the “ketone” build-up (actually carboxy acids) leads to a pronounced drop in blood pH (16). In the worst cases, ketoacidosis can lead to diabetic coma and death if left untreated.
Glucagon performs the opposite function of insulin in blood glucose regulation, as it increases blood glucose levels when deficient. Glucagon is also produced by the pancreas but in pancreatic alpha-cells. Glucagon is the hormone responsible for:
- Breakdown of glycogen into glucose (glycogenolysis)
- Promote the synthesis of glucose from lactic acid, fatty acids and amino acids (gluconeogenesis)
Glucose produced in the liver flows from the liver into general circulation. Glycogen is the body’s way of storing glucose for later use, and is primarily stored in the liver. Although most tissues have the ability to hydrolyze glycogen, only the liver and kidneys contain glucose-6 phosphatase, the enzyme necessary for the release of glucose into the circulation (6).
In the diabetic state, there is inadequate biofeedback suppression of glucagon excretion following a meal resulting in elevated liver glucose production (both gluconeogenesis and glycogenolysis). Notably, administering insulin by syringe or insulin pump is unable to both restore normal insulin pulse concentrations to the portal vein and to suppress glucagon secretion inside the pancreas as glucose levels rise. This results in an abnormally high glucagon-to-insulin ratio in the portal vein and liver that favors the release of glucose from the liver.
GLP-1, and Glucose-dependent insulinotropic peptide (GIP)
Insulin and glucagon effect blood glucose control by decreasing or storing “blood” glucose levels (insulin), or increasing “blood” glucose levels by releasing glucose stored as glycogen or synthesizing glucose from lactic acid, fatty acids and amino acids.
The peptides GLP-1 and GIP are incretin hormones that work in concert with insulin and glucagon. Both GIP and GLP-1 are stimulated by ingestion of a mixed meal or meals enriched with fats and carbohydrates. GIP is the more potent hormone of the two and stimulates insulin secretion and regulates fat metabolism, but does not inhibit glucagon secretion or gastric emptying (6).
In the pancreas, GLP-1 stimulates insulin secretion and suppresses postprandial glucagon secretion. GLP-1 slows gastric emptying, reducing the availability of glucose and other nutrients from the intestines following a meal. While GLP-1 is significantly reduced postprandially in those with type 2 diabetes or impaired glucose tolerance (6).
Diabetes as an Insulin Signaling Issue
One can demonstrate that insulin resistance is linked to incomplete insulin signaling following the work of Dr. T Aoki and his pulsed insulin treatment (13, 14, 15) with Type 1 diabetics. Both Type 1 and Type 2 diabetic patients lose the ability to properly burn glucose and rely more and more heavily on lipid metabolism for energy. Aoki explained that the liver was getting insufficient signal from the diabetic pancreas, and was unable to “turn on” enzyme production (“For induction and maintenance of insulin-dependent fuel-processing enzyme synthesis… …the hepatocytes require a defined insulin level (200-500 μU/ml in the portal vein) concomitant with high glucose levels…”) (13). This glucose/lipid metabolic phenomenon is easily measurable using a standard metabolic cart by measuring the resting respiratory quotient (R/Q).
By pulsing insulin intravenously every 4-6 minutes and at concentrations in the portal vein approximating a healthy pancreas, he was able to “wake up” the patient’s liver. The diabetic patient could be shifted from abnormal lipid metabolism to glucose metabolism as the liver got the correct signal from the “IV pulsed insulin.” The moral of the story is that insulin resistance is not that cells lose sensitivity to insulin; rather it is improper insulin delivery that causes the inability to synthesize and activate enzymes to metabolize glucose properly. All the many severe diabetic complications are symptoms stemming from the same glucose metabolism issue.
After reading Part 1 of Diabetes and Nutrition you should understand that:
- Diabetes is a state of improper glucose metabolism primarily caused by improper insulin production and/or release
- The CDC estimates that 1/3 of the U.S. population has prediabetes (84.1M), undiagnosed diabetes (7.2M) or diagnosed diabetes (23.1M)
- Glucose-processing enzyme synthesis in the liver requires a defined insulin level in the portal vein concomitant with high glucose levels (13)
- Insulin is a signaling hormone that is released as oscillating pulses in the non-diabetic pancreas at 5-7 times levels found in peripheral blood
- Insulin resistance is associated with a reduced first phase insulin release and deficient pulsed insulin levels released to the portal vein
- Abnormally high glucagon-to-insulin ratio in the portal vein and liver favors the release of glucose from the liver in diabetes
- People with prediabetes can delay or prevent the onset of Type 2 diabetes through lifestyle changes, such as diet and exercise (17)
- “… it will be helpful for all individuals with newly diagnosed type 2 diabetes to know that they have a metabolic syndrome that is reversible. They should know that if it is not reversed, the consequences for future health and cost of life insurance are dire… …must be balanced against the difﬁculties and privations associated with a substantial and sustained change in eating patterns.” (17)
In Part 2 of Diabetes and Nutrition, we will cover sugar metabolism, minerals in metabolism, the glycemic food index and diet.
Know Precisely What Your Body Needs
Learn more about how to rebalance your vitamins and minerals to naturally improve carbohydrate metabolism by referring to your BioCorrect Nutrition™ Analysis (BNA) report or order your BNA today. The BioCorrect Nutrition™ Analysis is a medically-proven, clinical laboratory test that measures 36 trace and toxic minerals in a patient’s hair sample; which correspond to an individual’s biochemical and metabolic status. With these test results; a personalized food and supplement plan is designed to safely biocorrect each person’s unique biochemistry into metabolic balance by eliminating the excesses and building up the deficiencies.
Stop Guessing… It’s In Your BNA!
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- https://www.medscape.org/viewarticle/438374. Arun S. Rajan, MD, MBA. Medscape CME. Regulation of Glucose Uptake Web sourced: January 2, 2018
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- Kahn SE, Montgomery B, Howell, Ligueros-Saylan M, Hsu CH, Devineni D, McLeod JF, Horowitz A, and Foley JE. Importance of Early Phase Insulin Secretion to Intravenous Glucose Tolerance in Subjects with Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2001;86(12):5824–5829
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- Aoki TT, Benbarka MM, Okimura MC, Arcangeli MA, Walther RM Jr, Willison LD, Truong MP, Barber AR, Kumagai LF. 1993. LONG TERM INTERMITTENT INTRAVENOUS INSULIN THERAPY AND TYPE 1 DIABETES MELLITUS. Lancet. 342:515-517
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- American Diabetes Association. http://www.diabetes.org/are-you-at-risk/?loc=atrisk-slabnav (Sourced: January 3, 2018)
- Taylor, R. Type2 Diabetes Etiology and reversibility. DIABETES CARE. 2013;36(4): 1047-1055
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- DiNicolantonio JJ, Bhutani J, OKeefe JH, et al. Postprandial insulin assay as the earliest biomarker for diagnosing pre-diabetes, type 2 diabetes and increased cardiovascular risk. Open Heart 2017;4:e000656. doi:10.1136/openhrt-2017-000656
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