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Diabetes Mellitus Type 2
Diabetes mellitus type 2 (formerly called diabetes mellitus type II, non insulin-dependent diabetes (NIDDM),
obesity related diabetes, or adult-onset diabetes) is a metabolic
disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and
hyperglycemia. It is often managed by engaging in exercise and modifying one's diet. It
is rapidly increasing in the developed world, and there is some evidence that this pattern will be followed in much of the rest of the world in coming years. The CDC has characterized
the increase as an epidemic.
Unlike Type 1 diabetes, there is little tendency toward ketoacidosis in Type 2 diabetes, though it is not unknown. Complex and multifactorial metabolic changes lead to damage and
function impairment of many organs, most importantly the cardiovascular system in both types. This leads to substantially increased morbidity and mortality in both Type 1 and Type
2 patients, but the two have quite different origins and treatments despite the similarity in complications.
Current Research
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Pathophysiology
Genetic factors, usually polygenic, are present in most patients. However, environmental factors such as
obesity, lack of exercise and a sedentary lifestyle are thought by most
observers to lead to insulin resistance. Certainly not all type 2 diabetics have a family history of the condition.
Insulin resistance means that body cells do not respond appropriately when insulin is present.
Other important contributing factors:
- Increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times
- Decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects)
- Impaired beta-cell function—loss of early phase of insulin release in response to hyperglycemic stimuli
- Cancer survivors who received allogenic Hematopoeitic Cell Transplantation (HCT) are 3.65 times more likely to report type 2 diabetes than their siblings. Total
body irradiation (TBI) is also associated with a higher risk of developing diabetes.
This is a more complex problem than type 1, but is sometimes easier to treat, especially in the initial years when insulin is often still being produced internally. Type 2 may go
unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (no ketoacidosis) and can be sporadic. However, severe complications can result from
unnoticed type 2 diabetes, including renal failure, blindness, wounds that fail to heal, and coronary artery disease. The onset of the disease is most common in middle age and
later life.
Diabetes mellitus type 2 is presently of unknown etiology (i.e., origin). Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defects, trauma
or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus. Examples include diabetes mellitus caused by hemochromatosis, pancreatic
insufficiency, or certain types of medications (e.g. long-term steroid use).
About 90–95% of all North American cases of diabetes are type 2, and about 20% of the population over the age of 65 has diabetes mellitus type 2. The fraction of type 2 diabetics
in other parts of the world varies substantially, almost certainly for environmental and lifestyle reasons, though these are not known in detail. There is also a strong inheritable
genetic connection in type 2 diabetes: having relatives (especially first degree) with type 2 is a considerable risk factor for developing type 2 diabetes. About 55 percent of type 2
are obese[2] —chronic
obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissue is a (recently identified) source of chemical
signals (hormones and cytokines). Other research shows that type 2 diabetes causes
obesity.
Diabetes mellitus type 2 is often associated with
obesity and
hypertension and
high cholesterol (combined hyperlipidemia), and with the condition Metabolic syndrome (also
known as Syndrome X, Reavan's syndrome, or CHAOS). It is also associated with acromegaly, Cushing's syndrome and a number of other endocrinological disorders.
Screening and Prevention
Interest has arisen in preventing diabetes due to research on the benefits of treating patients before overt diabetes. Although the U.S. Preventive Services Task Force (USPSTF)
concluded that "the evidence is insufficient to recommend for or against routinely screening asymptomatic adults for type 2 diabetes, impaired glucose tolerance, or impaired
fasting glucose"[4][5], this was a grade I recommendation when published in 2003.
Since publication of the USPSTF statement, a randomized controlled trial of prescribing acarbose to patients with "high-risk population of men and women between the ages of
40 and 70 years with a body mass index (BMI), calculated as weight in kilograms divided by the square of height in meters, between 25 and 40. They were eligible for the study if
they had IGT according to the World Health Organization criteria, plus a fasting plasma glucose concentration of between 100 and 140 mg/dL (5.5 and 7.8 mmol/L)" found a
number needed to treat of 44 (over 3.3 years) to prevent a major cardiovascular event.
Other studies have shown that life-style changes and metformin can delay the onset of diabetes.
Treatment
Diabetes mellitus type 2 is a chronic, progressive disease that cannot now be cured. There are two main goals of treatment of the disease:
- Reduction of mortality and concomitant morbidity (from assorted diabetic complications)
- Preservation of quality of life
The first goal can be achieved through close glycemic control (i.e., blood glucose levels); the reduction effect in diabetic complications has been well demonstrated in several
extensive clinical trials and is thus well established. The second goal is often addressed (in developed countries) by support and care from teams of diabetic health workers
(physician or PA, nurse, dietitian, certified diabetic educator, ...). Knowledgeable patient participation is vital and so patient education is a crucial aspect of this effort.
Type 2 is initially treated by adjustment in diet and exercise, and by weight loss, especially in obese patients. The amount of weight loss which improves the clinical picture is
sometimes modest (5–10 lb); this is almost certainly due to currently poorly understood aspects of fat tissue chemical signalling (especially in visceral fat tissue in and around
abdominal organs). In many cases, such initial efforts can substantially restore insulin sensitivity.
Antidiabetic Drugs
The next step, if necessary, is treatment with antidiabetic drugs (all are oral agents "OA"s, with the exception of the GLP analogues, which are injected):
- Sulfonylureas
- Biguanides (metformin)
- Thiazolidinediones (rosiglitazone and pioglitazone)
- α-glucosidase inhibitors (acarbose, miglitol)
- Meglitinides (nateglinide, repaglinide, and their analogs)
- Peptide analogs
- Incretin mimetics (insulin secretagogues)
- Glucagon-like peptide (GLP) analogs (subcutaneous administration)
- Exenatide
- Liraglutide (not FDA approved)
- Gastric inhibitory peptide (GIP) analogs
- Incretin enhancers
- Amylin agonist analog (slows gastric emptying and suppresses glucagon)
The initial choice of anti-diabetic drug has been compared in a randomized controlled trial which found "cumulative incidence of monotherapy failure at 5 years of 15% with
rosiglitazone, 21% with metformin, and 34% with glyburide." Rosiglitazone had more weight gain and edema.[9] Rosiglitazone may increase risk of death from cardiovascular
causes. Pioglitazone and rosiglitazone may increase the risk of fractures.
Insulin Preparations
If antidiabetic drugs fail to help (or stop helping), insulin therapy may be necessary, usually as an adjunct to oral medication therapy, to maintain normal glucose levels. Thus,
the term non-insulin-dependent diabetes is inaccurate and misleading. The classification, or type, of diabetes is determined by the underlying cause of the diabetes, not the
type of therapy that is used to treat the diabetes. Many patients with type 2 diabetes will progress to insulin therapy to control of blood glucose levels, but these patients are still
type 2 diabetics.
Long Acting Insulins
A meta-analysis of randomized controlled trials by the international Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues
for patients with diabetes mellitus type 2."
- Insulin glargine
- Insulin detemir
Other Treatments
Carnitine has been shown to increase insulin sensitivity in humans[citation needed]. Taurine has also shown a similar effect, but only in rats thus far.
(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Type_2_Diabetes)
Intra-Uterine Origins of Type 2 Diabetes
Authors: Jones RH, Ozanne SE
Department of Clinical Biochemistry, Addenbrookes Hospital, University of Cambridge. Cambridge. UK
Epidemiological studies have linked low birth weight with an increased risk of type 2 diabetes in later life. This finding has been observed in many populations worldwide, in many
different ethnic and socio-economic groups. These studies led to the proposal of the 'thrifty phenotype hypothesis' that suggests that the foetal environment plays a major role in
mediating this relationship. Here we review the human studies and those in animal models which support the 'thrifty phenotype hypothesis'. Molecular pathways underlying the
mechanisms by which a suboptimal foetal environment leads to increased risk of type 2 diabetes are discussed, along with future directions outlining how these pathways and
programming events can be further dissected to discover plausible intervention strategies to reduce type 2 diabetes.
Journal: Arch Physiol Biochem. 2007 Feb;113(1):25-29
Adapted from PubMed; click here to access full journal article.
Progression and Remission of Nephropathy in Type 2 Diabetes: New Strategies of Treatment and Monitoring
Authors: Rossing K
Malmrosevej 81B, 2830 Virum, Copenhagen, Denmark. karo@steno.dk.
Type 2 diabetes is one of the fastest growing epidemics World-wide and diabetic nephropathy has become the single most common cause of ESRD in the Western world. Without
specific intervention, 20 to 40% of all diabetic patients will develop diabetic nephropathy characterized clinically by
hypertension, a progressive increase in albuminuria and a
relentless decline in GFR leading towards ESRD. In addition diabetic nephropathy is associated with a greatly increased cardiovascular morbidity and mortality. During the past
decades substantial improvements have been achieved in the prevention and treatment of the diabetic nephropathy primarily through antihypertensive treatment which reduces
the risk of ESRD and improves survival. Nevertheless, in spite of aggressive antihypertensive treatment some patients still rapidly progress to ESRD. Therefore it is essential to
identify early risk factors for enhanced progression for prompt treatment of high risk individuals and for identifying new targets for intervention. In a long-term observational follow-up
study of a large cohort of type 2 diabetic followed early in the course of nephropathy several modifiable risk factors for enhanced renal function loss were identified. They include;
albuminuria, elevated blood pressure, poor glycemic control and smoking. In addition and as a novel finding moderate reductions of hemoglobin even within the normal range
were also predictive of an adverse renal outcome. It was also demonstrated that increased albuminuria, elevated blood pressure and poor glycemic control are associated with
increased mortality. In the past, diabetic nephropathy was progressive and irreversible and a particular poor prognosis was described for patients with the most advanced stages
of the disease with albuminuria in the nephritic range. Recent studies have, however, shown that aggressive antihypertensive treatment not only slows progression of renal disease
but can even in some cases reverse the course of disease and induce remission of renal structural and functional impairment. Among patients in the previously described cohort
of 227 type 2 diabetic patients with nephropathy it was found that nephritic range albuminuria is still frequent, occurring in approximately 35% of our patients but aggressive lowering
of blood pressure in particular with agents that block the RAAS results in sustained remission (albuminuria < 600 mg/24-hour for at least one year) in a substantial proportion
of the patients (25%). Such remission is associated with a greatly improved renal outcome and survival. These observations are in close agreement with recent studies
demonstrating that albuminuria is not only a marker of glomerular lesions, but also a powerful predictor (surrogate endpoint) of the long-term beneficial effect of blood
pressure-lowering therapy i.e. the more albuminuria is reduced the better the long-term renal and cardiovascular outcome. Intrarenal RAAS activity is elevated in diabetic
nephropathy and plays an important role in both hemo- and nonhemodynamic pathogenetic mechanisms. Numerous clinical trials have demonstrated specific renoprotective
effects of treatment with an ACE-I or an ARB in diabetic nephropathy. In spite of such treatment many patients still progress to ESRD. In part, this can be due to incomplete RAAS
blockade with the present use of ACE-I and ARB either because doses are too low or because effective blockade of the system requires combinations of several agents that block
the system at different levels. Currently used doses for ACE-I and ARB are based on dose-response studies of the blood pressure lowering effect in patients with essential
hypertension whereas the optimal dosing for renoprotection have previously been unknown. In two dose-response studies with two different ARBs we found a clear dissociation
between the optimal dose for blood pressure reduction and for lowering of albuminuria with higher doses needed to maximally reduce albuminuria. Moreover, additional
antiproteinuric effects can be obtained without additional side-effects by increasing the dose of the ARB irbesartan to ultrahigh doses (900 mg o.d.) exceeding by far the currently
recommended dose (300 mg o.d). Similar data suggesting that the full renoprotective effects are not reached within currently recommended doses are now emerging for other
ARBs. Future studies are needed to define the optimal renoprotective doses of ACE-I, which has still not been established. Two studies demonstrated that dual blockade of the
RAAS using both an ACE-I and an ARB is safe and superior to mono RAAS blockade with an ACE-I. Finally, it was shown that blockade of aldosterone by adding spironolactone
on top of conventional antihypertensive treatment including maximally recommended doses of an ACE-I and/or an ARB leads to additional reduction of both albuminuria and
systemic blood pressure. Spironolactone was generally well tolerated but one patient developed severe hyperkalemia highlighting the need for carefully monitoring of plasma
potassium. Overall, three new strategies for improved renoprotection as assessed by short-term reductions of albuminuria can be proposed from these studies. They are: high
dosing of an ARB, combination of an ACE-I and an ARB, and finally aldosterone blockade. Larger studies are needed to establish the long-term safety and efficacy but the
continued lowering of albuminuria is a promising indication. A fourth new strategy for improved renoprotection is the recently developed renin inhibitors which target the RAAS
at its first and rate limiting step. The renoprotective effect of renin inhibitors is presently being evaluated in diabetic nephropathy. Due to recent advances in technology, proteomics
is now emerging as a new field in clinical research allowing a fast and sensitive method for detection of a vast array of protein and protein derivatives for discovering new
pathophysiological mechanisms for disease progression and for monitoring of treatment efficacy. The online-combination of capillary electrophoresis and electrospray mass
spectrometry was used to establish a "diabetic renal damage" pattern consisting of 113 urinary polypeptides that differed significantly between normoalbuminuric patients and
those with diabetic nephropathy. Twelve of these polypeptides had been identified and includes; fragments of albumin, Tamm-Horsfall protein and collagen. Furthermore it was
shown that ARB treatment in patients with diabetic nephropathy significantly changed 15 of these towards levels more closely associated with normoalbuminuria. Future studies
will have to further establish the prognostic value of proteomics in diabetic nephropathy.
Journal: Dan Med Bull. 2007 May;54(2):79-98
Adapted from PubMed; click here to access full journal article.
Metabolic Syndrome: Psychosocial, Neuroendocrine and Classical Risk Factors in Type 2 Diabetes
Authors: Abraham NG, Brunner EJ, Eriksson JW, Robertson RP
Department of Pharmacology, New York Medical College, Basis Science Building/Room 527, Valhalla, New York, 10595, United States
This paper summarizes some aspects of stress in the metabolic syndrome at the psychosocial, tissue and cellular levels. The metabolic syndrome is a valuable research concept
for studying population health and social-biological translation. The cluster of cardiovascular risk factors labeled the metabolic syndrome is linked with low socioeconomic status.
Systematic differences in diet and physical activity contribute to social patterning of the syndrome. In addition, psychosocial factors including chronic work stress are linked with
its development. Psychosocial factors could lead to metabolic perturbations and increase cardiovascular risk via activation of neuroendocrine responses, e.g. in the autonomic
nervous system and in several hormonal pathways. High glucocorticoid levels will promote lipid storage in visceral rather than subcutaneous adipose tissue. Adipocytes secrete
several pro-inflammatory cytokines which considered major contributors to increase in oxidants and cell injury. Upregulation of heme-oxygenase 1 (HO-1) and peroxidase in the
early development of diabetes produces a decrease in oxidative-mediated injury. Increased HO activity is associated with a significant decrease in superoxide, endothelial cell
shedding and blood pressure. Finally, it is proposed that over expression of glutathione peroxidase in beta cells may protect beta cell deterioration from oxidative stress during
development of diabetes and
hyperglycemia and this may result in attenuation of beta cell failure. If this proves to be the case, then the scene will be set to develop glutathione
peroxidase mimetics for use in pre-clinical and clinical trials.
Journal: Ann N Y Acad Sci. 2007 May 18
Adapted from PubMed; click here to access full journal article.
Whole-Grain Foods Do Not Affect Insulin Sensitivity or Markers of Lipid Peroxidation and Inflammation in Healthy, Moderately Overweight Subjects
Authors: Andersson A, Tengblad S, Karlstrom B, Kamal-Eldin A, Landberg R, Basu S, Aman P, Vessby B
Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, 751 85 Uppsala, Sweden and 4Department of Food Science, the Swedish
University of Agriculture Sciences (SLU), 750 07 Uppsala, Sweden
High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes, but the mechanisms remain unclear. Our study aimed to
evaluate the effects of a diet rich in whole grains compared with a diet containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and
inflammation. In a randomized crossover study, 22 women and 8 men (BMI 28 +/- 2) were given either whole-grain or refined-grain products (3 bread slices, 2 crisp bread slices,
1 portion muesli, and 1 portion pasta) to include in their habitual daily diet for two 6-wk periods. Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic
clamp tests. 8-Iso-prostaglandin F(2alpha) (8-iso PGF(2alpha)), an F(2)-isoprostane, was measured in the urine as a marker of lipid peroxidation, and highly sensitive C-reactive
protein and IL-6 were analyzed in plasma as markers of inflammation. Peripheral insulin sensitivity [mg glucose . kg body wt(-1) . min(-1) per unit plasma insulin (mU/L) x 100]
did not improve when subjects consumed whole-grain products (6.8 +/- 3.0 at baseline and 6.5 +/- 2.7 after 6 wk) or refined products (6.4 +/- 2.9 and 6.9 +/- 3.2, respectively) and
there were no differences between the 2 periods. Whole-grain consumption also did not affect 8-iso-PGF(2alpha) in urine, IL-6 and C-reactive protein in plasma, blood pressure,
or serum lipid concentrations. In conclusion, substitution of whole grains (mainly based on milled wheat) for refined-grain products in the habitual daily diet of healthy moderately
overweight adults for 6-wk did not affect insulin sensitivity or markers of lipid peroxidation and inflammation.
Journal: J Nutr. 2007 Jun;137(6):1401-7
Adapted from PubMed; click here to access full journal article.
Inhaled Insulin and the Lung
Authors: Fuso L, Pitocco D, Incalzi RA
Fisiopatologia Respiratoria, Universita Cattolica S. Cuore, Largo A. Gemelli 8, 00168 Roma, Italy. leofuso@rm.unicatt.it
Pulmonary delivery of insulin is more than a promise in the treatment of diabetes mellitus. Inhaled insulin seems at least as efficacious as the conventional regimen of
subcutaneous insulin and/or oral glucose-lowering agents in both type 1 and type 2 diabetes mellitus. Improved metabolic control and the use of a non-invasive route of
administration represent the main benefits of this new treatment. Several physico-chemical factors could reduce the bioavailability of inhaled insulin. Indeed, both deep-lung
deposition and adsorption of insulin variously depend on the type of propellants used, speed of air flow, particle size and velocity, drug deposition into the throat and larger
bronchial tree. These factors, in turn, depend on the pulmonary delivery systems used and on respiratory mechanics and flows. Furthermore, the pharmacokinetics of inhaled
insulin is affected by smoke, which increases its absorption, and by lung diseases, which decrease the available alveolar-capillary surface. Selected abnormalities of
respiratory function complicate both type 1 and type 2 diabetes mellitus and a mild
depression of carbon monoxide lung transfer after a 6-month period of treatment with
inhaled insulin has been reported. Finally, results from some longitudinal studies suggest that diabetes might speed up the age-related decline of lung volumes and probably
alter the pharmacokinetics of inhaled insulin, particularly in the elderly. Clarifying these issues is mandatory in order to define the indications and safety of inhaled insulin.
Journal: Curr Med Chem. 2007;14(12):1335-47
Adapted from PubMed; click here to access full journal article.
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