Referat: Varjehanda om diabetes
- Gestational diabetes may account for common "idiopathic" birth defects
- Diabetesmellitus appears to inhibit the formation of colloateral coronoary vessels
- New diagnostic criteria for Diabetes
- Lovande medel mot diabetes från svamp
- Encapsulated pancreatic islet cells control diabetes in pregnant mice
- Ny metod kan varna diabetiker
- Natural history of diabetic gastroparesis
- Gene knockout prevents insulin resistance, doesity in mice
- Insulin- like growth factor plus insulin improves glycemic control in type 1 diabetes
- Tight control of Diabetes
- Food with high glycemic index may trigger overeating
- Matpreferenser programmeras tidigt
- Metformin and bedtime insulin best
Gestational diabetes may account for common ”idiopathic” birth defects
Gestational diabetes and birth defects
Am J Med Genet 1999;83:402-408. Apr 23 Reuters Health.
- Gestational diabetes may be teratogenic in humans, according to the results of a study conducted at the University of South Florida in Tampa.
In the April 23rd issue of the American Journal of Medical Genetics, Dr. Boris G. Kousseff reports that, among 152 children of mothers with gestational diabetes, 24 had no anomalies, 41 had a primary diagnosis that accounted for an anomaly, and 87 ”...had a constellation of anomalies or solitary structural defects as seen in diabetic embryopathy.”
The latter set of anomalies could not be explained by chromosomal, monogenic or other teratogenic causes, the investigator found. None of the mothers of these children had class B1 gestational diabetes. Even so, Dr. Kousseff reports, the phenotypes observed ”...matched those seen in offspring of mothers with diabetes mellitus classes B2 to T.”
He adds that the phenotypes ”...corroborated...animal studies, indicating that the embryopathy of gestational diabetes has a pathogenesis similar to that in classes B2 to T, and recent epidemiological studies showing a statistically significant increase of anomalies as in diabetic embryopathy in the offspring of gestational diabetes mothers.”
Dr. Kousseff concludes that common birth defects thought to be idiopathic may ”...actually [be] caused by undiagnosed maternal gestational diabetes.”
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Diabetes mellitus appears to inhibit the formation of collateral coronary vessels.
Circulation 1999;99:2224-2225, 2239-2242.
In the May 4th issue of Circulation: Journal of the American Heart Association, Dr. Adnan Abaci and colleagues, of Erciyes University School of Medicine in Kayseri, Turkey, describe a study of 205 patients with diabetes mellitus and 205 without, all of whom underwent coronary angiography at the university.
According to the article, the investigators detected a higher average number of diseased vessels in diabetic patients than in nondiabetics. When they used the Rentrop scoring system, they found that the prevalence of collateral circulation was significantly lower in the diabetic group than among nondiabetics.
”This investigation is the first study with a large number of patients to show the relationship between [diabetes mellitus] and collateral vessel development,” the authors note. ”We can speculate that [diabetes mellitus] is an important factor...affecting the development of coronary collaterals.”
In an accompanying editorial, Drs. Wolfgang Schaper and Ivo Buschmann, of the Max-Planck Institute for Physiological and Clinical Research in Bad Nauheim, Germany, comment that the Turkish researchers’ finding is ”surprising.” They point out that diabetes ”...is known to stimulate angiogenesis, at least in the retina of the eye.”
”This article...is a good example [of] drawing attention to the recently appreciated fact that not all vascular growth should be called angiogenesis,” Drs. Schaper and Buschmann remark. ”The functionally more important collateral vessels of the heart are not the product of angiogenesis but rather of ’arteriogenesis.’”
The editorialists conclude that the findings by Dr. Abaci’s group ”...should stimulate basic scientists to unravel the...mechanisms that increase angiogenesis but decrease arteriogenesis in [diabetes mellitus].”
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New diagnostic criteria for diabetes Appropriateness of new diagnostic criteria for diabetes debated JAMA 1999;281:1203-1210,1222-1224
New diagnostic criteria advocated by the National Diabetes Data Group and the World Health Organization may be too inclusive, resulting in the potentially harmful misclassification of many nondiabetic patients as diabetic.
Using data collected on more than 11,000 patients through the third National Health and Nutrition Examination Survey (NHANES III) and the Meta-Analysis Research Group (MRG), Dr. Mayer B. Davidson and colleagues, from the University of California Los Angeles, examined the accuracy of new diabetes diagnostic criteria.
The new criteria reduced the diagnostic threshold for fasting plasma glucose from 7.8 mmol/L to 7.0 mmol/L, according to a report in the April 7th issue of The Journal of the American Medical Association. Among individuals diagnosed with diabetes according to the new criteria alone—fasting plasma glucose between 7.0 and 7.8 mmol/L—59.6% (MRG data) and 60.9% (NHANES data) had normal glycosylated hemoglobin levels, and only 3.4% (NHANES) and 7.6% (MRG) had elevated glycosylated hemoglobin levels.
By comparison, 16.7% (MRG) and 18.6% (NHANES) of patients diagnosed as diabetic according to the old criteria had normal glycosylated hemoglobin levels and 48.9% (NHANES) to 62.3% (MRG) had high glycosylated hemoglobin levels. ”Since treatment is linked to measures of excessive glycosylation, we believe that giving individuals with normal glycosylated hemoglobin levels the diagnosis of diabetes will lead to more harm than benefit (eg, employment, insurance and possibly social and psychological disadvantages),” Dr. Davidson and colleagues explain in the journal.
Based on this assumption, the authors recommend alternative diabetes diagnostic criteria. They suggest a diagnosis of diabetes for patients with fasting plasma glucose of 7.8 mmol/L and higher ”...unless excessive glycosylation is evident.” Patients with fasting plasma glucose between 7.0 to 7.7 mmol/L and normal glycosylated hemoglobin, who would be given a diagnosis of diabetes according to the new National Diabetes Data Group and World Health Organization criteria, should be classified as having impaired fasting glucose, Dr. Davidson and others suggest, and treated with diet and exercise.
The authors stress that these changes would not adversely affect patient treatment options. ”We have not changed the therapy in either group, only their diagnoses.” Elsewhere in the journal, editorialist Dr. Frank Vinicor disagrees with the investigators’ conclusions, noting that it is as important to avoid underdetecting diabetes as it is to avoid overdiagnosis.
The Centers for Disease Control and Prevention investigator recommends that further research is needed, ”...including prospective information establishing the glycohemoglobin levels that are associated with the early development of microvascular complications vs. those that are only statistical abnormalities; and qualification of the actual benefit and harm of receiving a diagnosis of diabetes and its subsequent treatment.”
Until this information is available, Dr. Vinicor recommends adhering to the revised diagnostic criteria for diabetes.
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Lovande medel mot diabetes från svamp
Science May 7 1999: 974-977
Bei Zhang, Merck Research Laboratories i Rahway, New Jersey och kollegor från USA, Spanien och Sverige har funnit ett nytt ämne som kan ersätta insulinets effekter hos möss som lider av diabetes.
Forskarna presenterar sina resultat från en genomgång av över 50 000 ämnen som binder till insulinreceptorer in vitro på celler och sätter igång en kaskad som leder till att glukos tas upp. Man fokuserade särskilt på ett ämne som kunde tas upp i blodet via munnen. Den mest lovande kandidaten, L-783,281, kommer från en svamp som finns på blad i Kongo, och har egenskaper som liknar insulin.
Den fastnar på insulinreceptorer och sätter igång mekanismer som gör så att glukos tas upp av behövande celler. Forskarna provade ut L-783,281 på möss som lider av diabetes och resultaten visade att ämnet sänker blodsockerhalten hos mössen. Den fortsatta utvecklingen av det nyfunna ämnet till en fungerande medicin för människor kräver mycket forskning då man vill försäkra sig om att det inte finns några risker med att inta ämnet oralt.
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Encapsulated pancreatic islet cells control diabetes in pregnant mice
ASAIO J 1999;45:13-17
Encapsulating pancreatic islet cells in a gelatin before transplanting them is a promising strategy for controlling diabetes during pregnancy, according to murine studies conducted at the University of Iowa.
The technique kept islet cells alive long enough to control glucose levels during pregnancy in mice, according to a report by Dr. Stephen K. Hunter and colleagues in the current issue of the American Society for Artificial Internal Organs Journal, dated January 1999.
”Transplanted animals had significantly lower [blood glucose] levels throughout pregnancy, compared with [untreated diabetic] animals, but also had levels that were often lower than those seen in control nondiabetic animals,” Dr. Hunter’s team writes. Malformations were significantly less common among offspring of mice that received transplants than among offspring of untreated diabetic mice, the research team found. In fact, in the offspring of mice that received transplants, the rate of major malformations did not differ significantly from that in the offspring of nondiabetic control mice.
Among the offspring from animals that received transplants, the major malformations observed were three cases of isolated anencephaly. At the time of publishing the report, the team had not determined whether a specific teratogen was responsible. The investigators acknowledge that there are limitations to the new technology, principally a short survival time for the cells. They point out that pregnancy ”...is one of the situations in which a short-term treatment could have a critical benefit.”
An unexpected outcome of the study was the fact that a number of the animals with transplants experienced episodes of hypoglycemia. Dr. Hunter’s group proposes several possible explanations for this finding, including ”...the inability of isolated, encapsulated islets to communicate and coordinate the total insulin secreted between them.
” The authors caution that ”...the possible role these encapsulated islets may play in producing increased episodes of hypoglycemia and/or specific congenital malformations must be thoroughly investigated before any clinical use.”
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Ny metod kan varna diabetiker
Mikroalbuminuri ökar risken för graviditetspreklampsi
Från Dagens Medicin 990316
Var femte kvinnlig diabetiker drabbas av preklampsi, havandeskapsförgiftning, under graviditeten, skriver Dagens Medicin 990316.
Enligt en ny dansk studie kan ett mikroalbuminuri-urinprov (MA) förutsäga med ganska stor säkerhet vilka diabetiker som kommer att drabbas.
Tillståndet uppstår efter den tjugonde graviditetsveckan och orsakerna är inte helt klarlagda, berättar Elisabeth R Mathiesen, avd läk vid medicinsk-endokrinoligksa kliniken vid Rigshospitalet i Köpenhamn. De danska forskarna följde 68 kvinnor med typ 1 diabetes. Ingen hade diabetisk njursjukdom eller förhöjt blodtryck.
Upplysningar om MA och blodtryck under 2 år före graviditeten inhämtades och kvinnorna följdes regelbundet genom graviditeten. Av de 68 kvinnorna utvecklade 8 preklampsi, definierat som blodtryck över 140/90 och proteinutsöndring över 0.3 gram per 24 timmar i urinen efter den tjugonde graviditetsveckan.
MA en riskfaktor
En närmare analys visade att 60% av de kvinnor som redan före graviditeten hade haft MA drabbades av preeklampsi, mot endast 4% av de gravida som inte hade utsöndrat MA. Den senare siffran är lika låg som hos andra kvinnor. - Våra resultat tyder på att MA innan knvinnan blir gravid utgör en väsentlig riskfaktor för att utveckla preeklampsi, säger dr Mathiesen.
- Preeklampsi är av de vanligaste orsakerna till att en gravid diabetiker måste inläggas på sjukhus eller förlösas långt före förväntat förlossning. De flesta gravida diabetiker har typ 1 diabetes, men antalet gravida med typ 2 diabetes ökar, särksilt bland kvinnor från andra etniska grupper
Jerk W Langer
Dagens Medicin
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Natural history of diabetic gastroparesis
From Diabetes Care May 1999. Natural History of Diabetic Gastroparesis. Diabetes Care 22(3):503-507,
1999 by Kong, Horowitz, Jones, Wishart, and Harding, Adelaide, Australia.
Abstract
Objective:
The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. Research Design and Methods: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbA1c and blood glucose concentrations during gastric emptying measurement).These patients were followed up in 1998.
Results:
Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50%´emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups.
Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death.
Conclusions:
In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis.
Introduction
Until relatively recently, gastroparesis was thought to be an infrequent complication of diabetes, occurring only in patients with long-standing diabetes who had severe microvascular complications.[1-3] We now know that this is not the case. Although there are no true population-based studies of gastric emptying in diabetic patients, cross-sectional studies using radioisotopic methods have established that gastric emptying of solid and/or nutrient liquid meals is delayed in about 50% of outpatients with long-standing type 1 or type 2 diabetes.[4-11] Previous methods used to measure gastric emptying in patients with diabetes (e.g., radiographic methods using liquid barium sulfate) are much less sensitive than scintigraphic methods.[1,2]
Diabetic gastroparesis is clinically important because it may be associated with gastrointestinal symptoms, alterations in glycemic control, and changes in oral drug absorption.[12] Gastrointestinal symptoms, however, correlate relatively poorly with measurements of gastric emptying, so that up to 50% of patients with marked delay in gastric emptying have few or no upper gastrointestinal symptoms.[4-7,10,11,13]
Both symptomatic and asymptomatic gastroparesis may be associated with poor glycemic control by causing a mismatch between the action of insulin (or oral hypoglycemic drug) and absorption of nutrients.[8,12] There is relatively little information about the natural history of diabetic gastroparesis;[1,14] although it has been considered to be associated with a poor prognosis,[1,3,15] its high prevalence suggests that this assumption may be incorrect.
Between 1984 and 1989 we performed radioisotopic measurements of solid and liquid gastric emptying in 86 randomly selected diabetic outpatients; we have reported some of these data previously.[4-6,16] We attempted to determine whether these patients were alive or deceased 9 years after their gastric emptying measurement, primarily to evaluate the relationship between delayed gastric emptying and mortality.
Those results are reported in this study. See full text online:
http://www.medscape.com/ADA/DC/1999/v22.n03/dc2203.02.kong/dc2203.02.kong-01.html
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Gene knockout prevents insulin resistance, obesity in mice
Science 1999;283:1423-1425,1544-1548
Mice lacking the gene for protein tyrosine phosphatase-1B (PTP-1B) are protected against insulin resistance and obesity.
Dr. Brian P. Kennedy, of the Merck Frosst Center for Therapeutic Research in Quebec, Canada, and multicenter colleagues disrupted the gene that encoded for the mouse homolog of PTP-1B in a series of mice. The knockout rendered the mice resistant to obesity, even when fed a diet of 50% fat. Knockout mice also had improved insulin sensitivity compared with their wild-type littermates, which appeared to be the result of increased phosphorylation of the insulin receptor in muscle and liver cells in the knockout mice.
”Administration of a bolus of glucose to PTP-IB [homozygous knockout] mice resulted in a more rapid clearance of glucose than was observed in wild-type mice,” Dr. Kennedy and his team say in the March 5th issue of Science. ”The reason for the obesity resistance observed in the PTP-1B [homozygous knockout] mice is unclear at this time,” the scientists explain in the report, ”...but analysis of triglyceride concentrations indicates that fat metabolism has been affected in these animals.”
The scientists conclude that the study implicates PTP-1B as a major player in ”...the insulin signaling pathway.” They speculate that the protein may represent a new ”...therapeutic target for the treatment of type 2 diabetes and obesity.” Dr. Barry Goldstein, of Thomas Jefferson University in Philadelphia, agrees with this conclusion elsewhere in the journal, calling PTP-1B ”...a very exciting drug target.”
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Insulin-like growth factor plus insulin improves glycemic control in type 1 diabetes Diabetes Care
1999;22:585-592.
Cotherapy with recombinant human insulinlike growth factor 1 (rhIGF-1) and insulin is superior to optimal insulin therapy alone for glycemic control in patients with type 1 diabetes mellitus.
Researchers led by Dr. Kathryn M. Thrailkill of the University of Kentucky, Lexington, randomized 233 patients with type 1 diabetes, between the ages of 11 and 66, to receive 12 weeks of twice-daily injections of either a placebo or one of three dosages of rhINF-1 while they continued with standard insulin therapy. Patients tested their blood glucose levels four times a day and adjusted their insulin dose to maintain optimal blood glucose levels.
Dr. Thrailkill and the multicenter team report in the April issue of Diabetes Care that patients on combination therapy had a decrease in hemoglobin A1c levels of 1.2% over baseline compared with a drop of 0.7% for patients on intensive insulin therapy alone. Patients on combination therapy required 11% to 19% less insulin during the 12-week study while those on insulin alone increased their use by 7%.
The incidence of hypoglycemia was similar in both combination therapy and insulin-only groups. Investigators tested morning/evening doses of rhIGF-1 of 40/40 micrograms/kg, 80/40 micrograms/kg and 80/60 micrograms/kg. The lowest dose of rhIGF-1 was as effective as higher doses and was better tolerated. Higher doses were associated with increased adverse events including edema, jaw pain and exacerbation of retinopathy. The latter is a concern to the investigators. They note that ”...it remains unclear whether IGF-1-induced retinal changes resulted directly from a toxic IGF-1 effect or are the indirect result of a progressively greater effect of high-dose rhIGF-1 on glycemic control.”
Therefore more research is needed to establish the risk-benefit balance of using rhIGF-1 in treating diabetes.
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Tight control of diabetes.
AHA and ACC call for aggressive measures to prevent CVD in women Circulation 1999;99:2480-2484
Statins or other cholesterol-lowering agents, not hormone replacement therapy, should be considered the first-line therapy for postmenopausal women with elevated lipid levels.
This and other recommendations appear in a consensus statement on heart disease in women drafted by the American Heart Association and American College of Cardiology and produced in conjunction with four other medical societies.
Dr. Lori Mosca of the University of Michigan in Ann Arbor, the chair of the consensus panel, notes in an ACC press release that trials of hormone replacement have not shown conclusively that such therapy lowers the risk of cardiovascular disease. ”The typical woman who takes HRT has a healthy lifestyle, which may confound the clinical trial results,” she said. The consensus report cautions that current lipid targets might not be aggressive enough for women. Blood levels of 150 mg/dL for triglycerides and 45 mg/dL for HDL cholesterol may be more appropriate for women, Dr. Mosca’s group writes.
According to the results of one study the group reviewed, diabetes increases a woman’s risk of heart disease 3- to 7-fold compared with a 2- to 3-fold increased risk among men. The panelists call for tight control of diabetes risk factors and pharmacotherapy with oral agents or insulin when needed. According to the results of a previous study, physicians counsel women less often than men about the importance of nutrition, exercise and weight loss, the panel comments. ”The problem may result in part from the perception that these recommendations for reducing risk factors apply to men and may not apply to women,” Dr. Mosca suggests in the ACC statement.
”Although more women die from coronary heart disease than from cancer or any other disease, we are missing many opportunities to reduce the risk of heart disease in women,” she concludes. The consensus document is published in the April 30th issue of the Journal of the American College of Cardiology and the May 11th issue of Circulation: Journal of the American Heart Association.
The collaborating organizations are the American College of Nurse Practitioners, the American College of Obstetricians and Gynecologists, the American Medical Women’s Association and the Canadian Cardiovascular Society.
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Foods with high glycemic index may trigger overeating
Pediatrics 1999;103:e26
The rapid absorption of glucose that follows consumption of foods with a high glycemic index may trigger hormonal changes that lead to overeating, researchers report in the electronic pages of the March issue of Pediatrics.
Dr. David S. Ludwig of Tufts University in Boston, Massachusetts, and colleagues offered 12 obese teenage boys unlimited snacks for 5 hours after giving them meals with low-, medium-, or high-glycemic indexes. The low-glycemic index meal consisted of a vegetable omelet and fruit, the medium was unprocessed oatmeal, and the high-glycemic index meal was processed ”instant” oatmeal. All meals contained an equal number of calories.
The boys who had eaten the high-starch instant oatmeal ate 81% more snacks than those who had eaten the low-starch omelet and fruit, the researchers found. The investigators also found that the blood glucose levels in these boys had risen sharply and then dropped, triggering hunger. Although more work needs to be done to determine the optimal healthy diet, the study authors write that ”...this study suggests possible advantages for treatment of obesity... with abundant quantities of vegetables, legumes, and fruits; decreased amounts of... carbohydrates; and moderate intake of protein and fats.”
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Matpreferenser programmeras tidigt
Av Mette Axelsen, Göteborg
Referatet är gjort på uppdrag av DiabetologNytt från ”Lukt och smaksinnenas betydelse för matupplevelsen”, kurs 27/4 1999 i Uppsala, arrangerad av Livsmedelsverket.
Inget är lika minnesrikt som en doft. Den kan vara oväntad, dröja kvar endast en sekund och sedan förflyktigas, men ändå trolla fram en barndomssommar eller andra gamla minnen som legat djupt begravda. Marcel Proust beskrev hur “charlottenkakor” doppade i Lindblomste hos honom framkallade barndomen. Coca-cola company är ett av många företag som framgångsrikt utnyttjar våra lukt- och smak minnen. Genom massiv ungdomsreklam får många redan i barn- och ungdomen tidiga positiva associationer. Associationer som man sedan vill återvända till.
Kan vi i hälsosektorn använda samma programmering för prevention och beteendeförändring?
Luktsinnet
Luktsinnet har alltid varit det minst studerade av våra sinnen men intresset har ökat markant under senare år. Ett stort antal av våra gener, mer än 1%, ansvarar för att vi skall kunna känna igen lukter, vilket innebär att detta är den hitintills största identifierade genfamiljen hos däggdjur. Denna mycket stora mängd av genetiskt material speglar sannolikt luktsinnets betydelse för överlevnad och reproduktion hos de flesta högre stående arterna.
Till skillnad från vad man skulle kunna tro verkar lukt- och smakpreferenser ej vara medfödda. Istället är våra preferenser baserat på erfarenhet och programmeringen sker till stor del omedvetet. Luktsinnet är också anatomiskt kopplat till den sk. limbiska systemet, området för känslolivet. Våra känslor och upplevelser i samband med en lukt och smak bidrar därför till en programmering av våra preferenser. Tvärsnittsstudier av personer från 3 till 20 år visar att i 3-4-års åldern tycker vi att banan, avföring och svett doftar lika behagligt, och ganska gott faktiskt! I 5-års åldern och framåt rapporterar vi dock större och större skillnad mellan dessa dofter och endast banan fortsätter att vara behagligt. Det är troligt att yttre påtryckning och uppfostran lär oss att tycka illa om vissa lukter.
Luktminne
Minnet för lukter är anatomiskt integrerat med hippocampus och amygdala vilket innebär att det är svårt att ändra luktminnen när de väl är befästa! Men
kunskaperna
om möjligheten till omprogrammering, beteendemodifiering är fortfarande
rudimentära. Man vet att när vuxna testas i två sitationer, dels utan
information om livsmedlet och dels med upplysning om att maten är nyttig, rankas smaken som mycket bättre när de fått veta att den är nyttig.
Detta är ett exempel på hur attityder påverkar matpreferenserna i positiv riktning. Det förefaller dock som om information att mat är nyttig kan ha motsatt effekt hos barn. Här är det andra attityder som får starkare genomslag, tex. idolpåverkan, kompistryck eller att ordet nyttigt ofta används med ambvivalent attityd från de vuxna. Prevention av hög konsumtion av socker och fett bör sannolikt därför addressera de breda sociala och kulturella attityderna för att åstadkomma förändring. Det torde däremot också finnas en potential för individuell beteendemodifiering.
Åldrande
En annan aspekt av lukt- och smak är dess relation till nutritionsstatus hos äldre. När man åldras mister man större delen av luktcellerna och mister motivationen och glädjen i samband med ätandet. Forskning behövs sålunda också för att finna hur man kan komponera smaker, kryddor så att även de äldre får en god nutrition. Kanske kommer vi att i framtiden i butikshyllan att finna särskilda livsmedelsprodukter för de ädre.
Fördragshållare vid ovanstående kurs var
Steven Nordin,
Åke Bruce
Ebba Hedén-Blomkvist
Einar Risvik
Lisbeth Johansson
Tore Stenström
Sven Lindgren
Mette Axelsen
E-post mette.axelsen@medicine.gu.se
www.sdn.nu
Nätverket för dietister och näringsfysiologer
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Metformin and bedtime insulin best
Editorials Annals of Internal Medicine March 2 1999 angående:
Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus- a randomized, controlled trial. Annals of Internal Medicine, 2 March 1999. 130:389-396 by Yki-Järvinen, Ryysy, Nikkilä, Tulokas, Vanamo and Marjatta Heikkilä.
Treating Type 2 Diabetes with Respect
Until recently, typ 2 diabetes received little respect from clinicians or patients, especially compared with its subling, type 1 diabetes ... ... The ”adult-onset” form has often been treated dismissively as a mild form of diabetes that does not cause the litany if severe complications associated with type 1 diabetes.
We have finally awakened to the fact that type 2 diabetes, whose very designation suggests second-class citizenship, is actually the predominant form of diabetes and is a major public health problem in the USA and elsewhere. Epidemiologic surveys reveal that type 2 diabetes is one of the most common chronic severe disease in the world, affecting an estimated 12% of the adult population over 40 to 74 years in the United States.
Moreover, the clinical characteristics of type 2 diabetes belie any suggestion that it is mild. As the increased human life span results in longer exposure to type 2 diabetes, all of the complications that occur in type 1 diabetes are increasingly seen in typ2 diabetes. Type 2 diabetes is a major cause of kidney disease, vision loss, and amputation in most countries in which its prevalence exceeds 5%.
Type 1 vs Typ 2
Type 2 diabetes differs from typ 1 in several fundamental ways. In addition to causing retinopathy, nephropathy, and neuropathy and their attendant long-term clinical sequelae, type 2 diabetes is accompanied by a twofold to fivefold increase in the occurrence of macrovascular disease. Most patients with type 2 diabetes are obese and have hypertension, dyslipidemia, and cardiovascular disease; cardiovascular disease accounts for as much as 75% of all mortality among patients with type 2 diabetes.
Given the magnitude of the publich health problem created by this highly prevalent disease, identification of the most benefecial therapies for type 2 diabetes should be high priority. The pathophysiology of type 2 diabetes - insulin resistance compounded by failing insulin secretion - lends itself to many therapeutic strategies. Insulin resistance can be decreased with diet, weight loss, and exercise or with medications, and insulin levels can be increased with agents that increase endogenous insulin secretion or with insulin injections. However, until recently, neither the appropriate metabolic goals of therapy nor the most advantageous therapy or combinations of therapies to achieve those goals had been clealy defined.
UKPDS
UKPDS - a large, long-term, multicenter clinical trial - and the articles in this issue by Järvinen and colleagues have begun to shed light on these issues. The UKPDS, which ended in 1998 after 20 years, was directed at determing whether intensive therapies aimed at bringing glycemic controls as close to the normal range as possible would affect the long-term outcome of persons with newly diagnosed type 2 diabetes. In addition, the UKPDS compared different intensive therapies to determine which of the available agents was most likely to be beneficial.
Although the UKPDS found an affirmative answer to the first question, demonstrating a clear benefit with regard to microvascular outcomes (but not for macrovascular outcomes), it did not provide a clear answer to help the clinicians choose among therapy with insulin, sulphonylurea, or metformin. The failure of the UKPDS to determine which therapies were most advantageous was predicated, in part, on the design of the study, which allowed intensive interventions to be added over time and resulted in a substantial crossover of therapies.
The result of the UKPDS with regard to the importance of intensive therapy reinforced the results from the Diabetes Control and Complication Trial, in which intensive therapy was demonstrated to have a major salutary effect on microvascular and neurologic complications in type 1 diabetes.
Finnsih study
Results of the randomized trial by Yki-Järvinen and colleagues suggest that for patients in whom in whom sulphonylurea has failed to reduce their glycemic levels, combining insulin with metformin is advantageous compared with other combinations of oral agents and insulin or insulin given twice daily. Combining insulin with metformin resulted in lower hemoglobin A1c levels with less weight gain and fewer episodes of hypoglycemia. Patients adjusted their own bedtime insulin dose on the basis of fasting glucose levels.
Patients who received metformin adjusted their insulin doses more aggressively, using 50% more bedtime insulin than the other treatment groups. It is difficult to explain why patients who received metformin, who were blinded to their oral agent assignment, increased their insulin more aggressively. However, the higher dose of bedtime insulin in this group may explain the relative benefit of this combination with regard to decreased fasting glucose and the hemoglobin A1c levels compared with the other treatment groups.
The authors suggest that the lower frequency of hypoglycemia may explain the willingness or ability of the patients treated with metformin and insulin to increase their insulin dose. Considering the infrequent occurence and mild nature of these episodes - no patient experienced hypoglycemia that required medical assistance - this explanation is not convincing. On the other hand, the weight gain experienced by the other treatment groups may have inhibited them from increasing the insulin dose. The observation that metformin therapy is associated with with less weight gain and less frequent hypoglycemia than sulphonylurea or insulin therapy is not new; it has been seen in other studies of monotherapy and in combinationtherapy.
Weight gain
Whether the use of combined insulin and metformin will spare patients with type 2 diabetes the seemingly inexorable worsening of the metabolic control that occurs over time, an effect that was observed in the UKPDS, remains to be shown. In addition, combination therapy is more expensive than larger doses of insulin, which have been demonstrated in previous studies to result in near-normal glycemia with few, if any, episodes of severe hypoglycemia. Whether the added expense of combination therapy is worth its weight-sparing effect is also open to question. Microvascular complications were decreased with intensive therapy in the UKPDS in the setting of weight gain (mean of 3.1 kg over 10 years), suggesting that the modest weight gain that accompanies nonmetformin intensive therapy is not overly pernicios. However, it is not known whether this degree of weight gain adversely affects macrovascular outcomes.
Conclusion
The study by Yki-Järvinen and colleagues adds the accumulating data supporting the idea that intensive therapy goals can be achieved in type 2 diabetes with relatively low risk for hypoglycemia or weight gain. More aggressively efforts to lower glycemia will provide significant benefit with regard to long-term complications.
Laissez-faire therapy for type 2 is no longer acceptable.
David M Nathan, M.D. Boston
Ann Intern Med 1999;130:440-441.
Hela originalartikeln kan läsas i fulltext online: http://www.acponline.org/journals/annals/02mar99/bedtime.htm
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