~Diabetes, Part 3 - Glucose, Insulin, and Glucagon

~Diabetes, Part 3 - Glucose, Insulin, and Glucagon
GLUCOSE, INSULIN, AND GLUCAGON
  • Insulin-Liver Connection
Major control of blood glucose levels is achieved through actions of the hormones insulin and glucagon. The slightest rise in plasma glucose leads to a decrease in glucagon secretion and an increase in insulin secretion. The reverse occurs when plasma glucose levels fall. A network of interrelated responses from the liver, pancreas, pituitary, adrenal, and thyroid glands joins forces to ensure that the rate of glucose entry into the blood is balanced by its rate of withdrawal (Pike et al. 1984).

The pancreas, detecting excess glucose in the bloodstream, takes immediate steps to counter the glucose rise by supplying the hormone insulin. Insulin, in turn, is responsible for marshaling glucose to the receptor site for cellular entry. Stimulating glucose transport into muscle and adipose tissue is a crucial component of the physiologic response to insulin. However, the pancreas demonstrates its diversity by also supplying the hormone glucagon (produced from the alpha cells in the islets of Langerhans). Glucagon has the opposite effect of insulin. Glucagon summons the release of glycogen (the stored form of glucose) from the liver to form glucose when blood sugar levels become too low, a process referred to as glycogenolysis (the breaking down of glycogen). The secretion of glucagon is stimulated by a state of hypoglycemia and the growth hormone from the anterior pituitary gland.

Glycogen (glucose stored in the liver) is a major force in glucose control, but it is the liver (receiving instructions from hormones and neural stimuli) that holds dominion over glycogen pathways. By both supplying glucose when blood levels are low and accepting glucose when blood levels are high, the hepatocytes (liver cells) become key participants in glucose/glycogen homeostatic mechanisms. It should be noted that the muscles stockpile about two-thirds of glycogen but use most of this supply to provide for their own energy requirements. The liver stores the remaining one-third, releasing it when blood levels of glucose are no longer adequate to meet metabolic demand (Hamilton 1988). Normally, an adult will have about three-fourths of a pound of glycogen (340 grams) stored in the liver and muscles at one time (Krause et al. 1984).

The Insulin-Liver Connection

Internal checks and balances, warranting safe blood glucose levels, are as vital as they are amazing. A status favoring neither hyper- nor hypoglycemia occurs through the interaction of hormonal and neural stimuli, as illustrated by the following examples:
  • Insulin's primary action in the hepatic (liver) cell is the inhibition of glucagon-mediated activity by
    1. Blocking glycogenolysis (the degrading of glycogen to form glucose) as well as inhibiting gluconeogeneis (the formation of glucose from noncarbohydrate sources, such as lactate, pyruvate, glycerol, and certain amino acids) (Pike et al. 1984).
    2. Removing the glucagon block on liver glycogen synthase. An increased conversion of glycogen synthase to its active form explains a part of the known effect of insulin on glucose uptake by the liver cell (Villar-Palasi et al. 1971; Pike et al. 1984).
  • Another action of insulin is induction of the activity of glucokinase, increasing the uptake of glucose by the liver when plasma glucose levels are elevated (Czech 1980). The Therapeutic Section of this protocol describes how biotin works synergistically with insulin to increase the activity of glucokinase, an enzyme responsible for the first step in glucose utilization (Murray 1996). Glucokinase, with the help of ATP, catalyzes glucose to glucose 6-phosphate, an intermediate in carbohydrate metabolism.
Epinephrine, an adrenal medulla hormone, and thyroxin, a hormone secreted by the thyroid gland, also stimulate glycogenolysis, the breakdown of glycogen to supply a ready source of glucose. Glucocorticoids, particularly cortisol, tend to increase glucose production by the liver cells and decrease glucose utilization in both muscle and fat cells. These actions are inclined to counteract the effects of insulin and subsequently increase blood glucose concentrations.

Comment: In a postabsorptive state, blood glucose concentrations are ideally maintained within a normal range of 80-100 mg/dL by glycogenolysis (the formation of glucose from glycogen) and gluconeogeneis (the formation of glucose from noncarbohydrate sources). Since liver glycogen capacity is rather limited, the ability of liver cells to tap more extensive sources of ultimate glucose (gluconeogenesis) is keenly important. Both mechanisms, glycogenolysis and gluconeogenesis, occur within the liver cell, but under certain circumstances such as starvation, the kidney is equally important in providing glucose from noncarbohydrate sources. In a healthy individual (even during periods of fasting or overeating) blood glucose levels remain remarkably constant because of the efficiency and rapidity of these systems (Unger 1981). It should be noted that the most vital function of glucagon is to maintain plasma glucose at a level adequate for the function of the central nervous system regardless of energy intake or energy expenditure.

Maintaining a healthy liver (capable of fully participating in blood glucose control) is vital. Please consult the Therapeutic Section of this protocol to read about silymarin, a liver protector and hypoglycemic agent.

GUM DISEASE IN DIABETES

The importance of gum health is confirmed in heart disease, but according to data released from the University at Buffalo (UB) School of Dental Medicine, diabetes can be added to the growing list of systemic diseases and conditions associated with bacteria from infected gums (Baker 1999a). Research has emerged suggesting that the relationship between periodontal disease and diabetes goes both ways, that is, periodontal disease may make it more difficult for people who have diabetes to control their blood sugar and poorly controlled Type II diabetic patients are more likely to develop gum disease.

Researchers from UB studied 11,198 nondiabetic subjects (ages 20-90) from the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994 for their evaluation. They assessed the degree of gum detachment from bone, along with fasting-insulin and fasting-glucose levels.

Gram-negative periodontal infections were found to be significantly associated with insulin resistance. Gram-negative bacteria appear to produce a very potent toxin called LPS, which probably interferes with the action of insulin and is responsible for maintaining a chronic state of insulin resistance in individuals with gum infections (Baker 1999a).

As insulin resistance increases, the severity of periodontal disease also increases. Results show that those with severe gum detachment (regardless of weight, smoking status, gender, or age) have a higher index of insulin resistance than those with little or no gum disease.

Note: Researchers used a body mass index (BMI) of 27 as the dividing line between acceptable and unacceptable degrees of obesity (Baker 1999a). See the chart relating to BMI in the next section, How Is Obesity Linked to Hyperinsulinemia and Diabetes?

Another study conducted at the University of Buffalo (involving 168 adults with diabetes) showed that those with severe gum deterioration had the most difficulty controlling blood glucose levels (Millman 2001). Some explain that oral bacteria, fed and nurtured by excesses of sugar, escape from the gums and enter the bloodstream. This summons the immune system into action, and cytokines (proteins that amplify immune reactivity) enter the milieu. In an attempt to kill out the bacteria, cytokines overstep their role and attack pancreatic cells, as well (Reuters Health 2001). An assault on the beta cells compromises their ability to supply insulin, and glucose builds up in the bloodstream. This sequence provides more sugar, perpetuating a classic, vicious cycle.

Note: Poorly controlled diabetics also have more cytokines in the gingival tissue, causing destructive inflammation of the gums. In turn, growth factors are also reduced, interfering with the healing response to infection (Cutler et al. 1999; Strayhorn et al. 1999; AAP 2002)..

In 1997, 113 Pima Indians (having both diabetes and periodontal disease) were treated for their gum conditions. The participants (81 females and 21 males) were divided into 5 groups. All underwent ultrasonic scaling and curettage combined with an antimicrobial regime that consisted of (1) topical water and systemic doxycycline, 100 mg for 2 weeks; (2) topical 0.12% chlorhexidine (CHX) and systemic doxycycline, 100 mg for 2 weeks; (3) topical povidone-iodine and systemic doxycycline, 100 mg for 2 weeks; (4) topical 0.12% CHX and placebo; and (5) topical water and a placebo.

Clinical assessments by probing depth, clinical attachment level, the detection of Porphyromonas gingivalis in subgingival plaque, and the determination of serum glucose and glycated hemoglobin (HbA1c) were performed prior to and at 3 months and 6 months after treatment. All study groups showed clinical and microbial improvement, but the doxycycline-treated groups showed the greatest reduction in probing depth and P. gingivalis infection. All three groups receiving systemic doxycycline showed (at 3 months) significant reductions in mean HbA1c--reaching nearly 10% from the pretreatment value (Grossi 1997).

The control of periodontal infections is essential as a prophylactic against diabetes, as well as for better blood glucose control among confirmed diabetics. If neither a medical nor dental provider has explored the gum disease-diabetes association, a patient should consult a periodontist for an assessment regarding the health of the gums.

Note: A study presented at the International Association for Dental Research concluded that overweight people with the highest levels of insulin resistance were about twice as likely to have severe periodontal disease, compared to overweight people with low insulin resistance. Researchers speculate that bacteria from gum disease may be interfering with fat metabolism, promoting both obesity and hyperlipidemia. The obesity-periodontal disease relationship is particularly significant because both are major factors in Type II diabetes.

Continued . . .


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