Eamj jan type 2

East African Medical Journal Vol. 85 No. 1 January 2008TYPE 2 DIABETES MELLITUS: CLINICAL AND AETIOLOGIC TYPES, THERAPY AND QUALITY OF GLYCAEMICCONTROL OF AMBULATORY PATIENTSC. F. Otieno, MBChB, MMed, Senior Lecturer, Department of Clinical Medicine and Therapeutics, A. N. Huho, MBChB,MMed, Department of Clinical Chemistry, E. O. Omonge, MBChB, MMed, Lecturer, Department of Clinical Medicineand Therapeutics, A. A. Amayo, MBChB, MMed, Department of Clinical Chemistry and E. Njagi, MBChB, MSc(Immunology), Lecturer, Department of Immunology, College of Health Sciences, University of Nairobi, P. O. Box 19676-00202, Nairobi, Kenya Request for reprints to: Dr. C.F. Otieno, Department of Clinical Medicine and Therapeutics, College of Health Sciences,University of Nairobi, P. O. Box 19676-00202, Nairobi, Kenya TYPE 2 DIABETES MELLITUS: CLINICAL AND AETIOLOGIC TYPES, THERAPY
AND QUALITY OF GLYCAEMIC CONTROL OF AMBULATORY PATIENTS
C. F. OTIENO, A. N. HUHO, E. O. OMONGE, A. A. AMAYO and E. NJAGI ABSTRACT
Background: Type 2 diabetes is a heterogeneous disease with multiple causes revolving
around beta cell dysfunction, insulin resistance and enhanced hepatic glucose output.
Clinical judgement based on obesity status, age of onset and the clinical perception of
residual beta cell insulin secretory function (hence insulin-requiring or not), has been
used to determine therapeutic choices for each patient. Further laboratory testing of the
clinically defined type 2 diabetes unmasks the various aetiologic types within the
single clinical group.
Objective: To determine the aetiological types of the clinically defined type 2 diabetic
patients, their chosen therapies at recruitment and the quality of glycaemic control
achieved.
Design: Descriptive cross-sectional study.
Setting: Diabetes out-patient clinic of Kenyatta National Hospital, Nairobi, Kenya.
Results: A total of 124 patients with clinical type 2 diabetes were included, 49.2% were
males. The mean duration of diabetes in males was 26.09 (20.95) months and that of
females was 28.68 (20.54) months. The aetiological grouping revealed the following
proportions: Type 1A-3.2%, Type lB-12.1%, LADA-5.7%, and “true” type 2 diabetes
79.0%. All the patients with Type lA were apparently, and rightly so, on “insulin-only”
treatment even though they did not achieve optimal glycaemic control with HbA c %
= 9.06. However the study patients who were type lB and LADA were distributed all
over the treatment groups where most of them did not achieve optimal glycaemic
control, range of HbA c of 8.46 -10.6%. The patients with “true” type 2 were also
distributed all over the treatment groups where only subjects on ‘diet only’ treatment
had good HbA c of 6.72% but those in other treatment groups did not achieve optimal
glycaemic control of HbA c, 8.07 - 9.32%.
Conclusion: Type 2 diabetes is a heterogeneous disease where clinical judgement alone
does not adequately tell the various aetiological types apart without additional
laboratory testing of C-peptide levels and GAD antibody status. This may partly
explain the inappropriate treatment choices for the various aetiological types with
consequent sub-optimal glycaemic control of those patients.
INTRODUCTION
classification (2) sought to replace the previouscategories with a functional measure based on insulin classification (1) subdivided diabetes according to Type 2 diabetes is a heterogeneous disease perceived need for insulin therapy. The WHO (1997) with multiple causes revolving around beta cell dysfunction and insulin resistance, the latter process consecutively because they are relatively fewer in is largely determined by obesity (3,4). However the this clinic. Each recruited study participant was re- cut-off level of obesity and the proportions thereof evaluated for weight and height in the standard way vary in populations. C-peptide is considered a good to ascertain the BMI. A detailed history of diabetes marker of insulin secretion because of its equimolar including date of onset, family history, the secretion with insulin, negligible hepatic extraction contemporary and past treatment modality or profile (5-7) and constant peripheral clearance at different were obtained and recorded. Family history of plasma concentrations and in the presence of diabetes was recorded as present or absent; treatment alterations in plasma glucose concentrations (7,8).
choices as; diet-only, oral glucose lowering agents- Fasting C-peptide alone is easy to obtain and correlates only, insulin only and combined insulin and oral agents. There were multiple generics of the oral agents (both sulphonylureas and metformin) in use largely guided by the perceived class of insulin by the study patients either as single or combination requiring or non-insulin requiring types, this oral agents therefore no further attempts were made classification being informed by clinical judgement to define them in details beyond their categories as based on age of onset and obesity status. It is unclear oral glucose lowering agents. The information was whether the defects in insulin- sensitivity and insulin captured as the number (proportion) of study patients secretion occur in parallel and progress at the same on each treatment modality/choice. Laboratory work- velocity through the time course of the disease once up of fasting C-peptide levels, GAD antibody status, the diagnosis has been made (9-12) and particularly glycated haemoglobin (HbAIc) and fasting glucose when the diabetes is being treated by mono or were done. A sample of 8mls of venous blood was multiple drug strategies. Suffice to say that glycaemic withdrawn from antecubital vein. C-peptide was control of diabetes has remained largely an elusive determined by Elisa (human bioassay technique, US goal in many regions of the world even where biological, a solid two-site enzyme immunoassay with resources are considered to be relatively abundant.
a lowest detection limit of 0.3 ng/ml and precision Hattersley (13), opines that treatment decisions in CV<10%. GAD antibody status was also determined diabetes should depend on genetic aetiology of by Elisa technique (diaplets anti-GAD plus, Roche diabetes and not just on age of onset, Body Mass Applied Science Division for Quantitative Index (BMI) and severity of hyperglycaemia. He Determination of Antibodies to GAD-65). Data on C- admits that high costs remain a deterrent to detailed peptide and GAD antibody status were used to re- testing in diabetes care. This study first classified categorise patients as type lA autoimmune, type IB- patients with type 2 diabetes on clinical grounds, idiopathic, latent autoimmune diabetes of adults then re-categorised them using laboratory tests and (LADA) and “true’ type 2 diabetes. Upon re- evaluated the therapeutic choices they were using categorisation the study participants were evaluated that had been initiated based on clinical judgement.
for clinical characteristics, current therapeutic choicesin use and respective levels of glycaemic control MATERIALS AND METHODS
achieved. The data were summarised in categorieswhere appropriate and continuous variables were Subjects: Patients with clinically defined type 2 summarised in means and standard deviation and diabetes were recruited and included in the study.
proportions. Differences in means between males Type 2 diabetes was defined as diabetes mellitus of and females and various treatment modalities were onset at age 40 years and above or if less than 40 years tested by students t-test where indicated. The level of the person had been on oral glucose lowering agents statistical significance was taken at p<0.05.
for at least six months. Furthermore, the patientswho were classified as obese by body mass index (BMI); ( BMI > 25kg m2) were systematically sampledwhere every other patient fitting the inclusion criteria A total of 124 subjects were included in the study.
was enrolled on each clinic day. This clinic conducts Their clinical and laboratory characteristics are only one major diabetes clinic each week. The non- obese (BMI <25kg/m2) patients were recruited Characteristics of the study subjects by gender Treatment choicesproportion of patients Diet-only Statistically significant differences between males and females Characteristics of the study population by their aetiologic types Aetiologic types, therapy at enrolment and mean glycated haemoglobin of the study subjects Virtually all patients categorised as type IA were on treatment with insulin only, howeverthey were not reaching glycaemic targets.
Other types (lB and LADA) of diabetes were on various therapies but did not achieveoptimal glycaemic control.
“True” Type 2 diabetes were also receiving multiple therapies without reaching desiredtargets except those on “diet - only” therapy.
DISCUSSION
that BMI does not seem to influence treatmentresponse with either class of drugs (15-17) even though At recruitment of subjects into this study, the defining BMI is used to inform treatment choices. Whatever characteristics were clinically defined type 2 diabetes factors that are considered in making choices of with a body mass index of either < 25 Kg/m2 or above therapy adequate glycaemic control is the main goal 25 Kg/m2. Other clinical and laboratory parameters of therapy in diabetes both in type 1 (18) and type 2 were subsequently determined which unmasked a previously unknown heterogeneity within those The significance of this study is that all study patients who were clinically defined as type 2 participants were clinically defined to have type 2 diabetes and followed up as such. Hence their therapeutic choices were essentially those designed patients with type 2 diabetes and obesity (BMI >25 for such patients. It is therefore no wonder that the Kg/m2) should be treated with metformin as first subjects who were later found to fit the category of line and the non-obese (BM1< 25Kg/m2) should be type 1 B diabetes were on oral agents with or without given either sulphonylurea alone and/or combination insulin. The oral glucose lowering agents included with metformin. The message implied is that BMI metformin and sulphonylureas (either glibenclamide or chlorpropamide) in various dosages.
Probably BMI of our study patients was used On re-categorising the patients by laboratory to inform the primary clinicians of the perceived testing (C-peptide levels and GAD antibody status) appropriate choices of treatment. Some studies have the patients fell into the various types of diabetics looked at what factors including BMI ( as a measure shown including type lA (autoimmune) and IB of obesity) may predict response to treatment with (idiopathic), latent autoimmune diabetes of adults sulphonylureas or metformin and they suggested (LADA) and ‘true’ type 2 diabetes.
The glycaemic control remained sub-optimal higher BMI than the other aetiologic types. We did in all those patients who remained ‘true’ type 2, recognise that poor glycaemic control may not wholly LADA and even those who were coincidentally type be attributable to beta cell and/or insulin resistance 1 and supposedly on rightful insulin- therapy at the factors but the mind of the patients may also be time of enrolment (Table 3). Indeed only ‘true’ type 2 involved .The patients’ attitudes and perceptions and diabetic patients on diet-only therapy had good their participation in self-care are particularly glycaemic control. The better glycaemic control in important in improving therapeutic goals of glycaemia the diet-only treatment group has been observed (22), although they were not evaluated in the subjects before in this clinic although we did not do C-peptides in that study (20). A significant contribution from Type 2 diabetes is a progressive disease (11) in their adequate endogenous beta cell function, read spite of therapies that are in use at onset of the disease high C-peptide levels, explains the superior control (23). There are no immediate therapeutic answers to declining beta cell function of type 2 diabetes. ADOPT Achieving glycaemic targets in type 2 diabetes study (24) was a step towards this direction where remains a major challenge during their clinical care.
preservation of beta cell was an outcome measure.
Cook et al (21) demonstrated that delayed or Similarly there is no consensus, so far, on definition insufficient intensification of pharmacological (25) and management (26) of LADA. Pozzilli et al (26) management is a cause of failure to attain glycaemic have suggested that therapy which would influence goals in their urban African-American- population.
the speed of progression towards insulin dependency Our study has revealed the limitation of clinical and in the process protect residual C-peptide secretion judgement for telling the type of diabetes with preferable for latent auto-immune diabetes of adults certainty so that therapy can be optimised. However clinical judgement has not been condemned Insulin availability and accessibility to those wholesome by this study. Rather it seems to suggest who need it, especially in sub-Sahara Africa, is still the need for early insulin therapy in the lean (BMI< precarious (27). Even where insulin is already 25 Kg/m2) type 2 diabetic patients in this population available, there is inertia in initiating patients with who are likely to be the more heterogeneous group type 2 diabetics on it (28). Our study patients had with higher proportion of aetiologic type 1 diabetes.
diabetes for five years and less apparently many of Classification of diabetes is still evolving and so far them, maybe, needed either basal insulin or just inconclusive. Consequently, therapeutic approaches optimisation of the appropriate choice of therapy at to types of diabetes as currently classified (by clinical judgement) provide a lot of room for debate and use In conclusion, successful glycaemic control in of various treatment choices, maybe inappropriately, patients with diabetes mellitus will require more although that is what is universally available to understanding of the disease processes in the various clinicians in routine clinical practice.
classes, the operating clinical-laboratory predictors Our study did cross-sectional fasting C-peptide for the disease class/type and the appropriate and assay where the extent of sulphonylurea stimulation optimal therapeutic choices. Therefore, correctly effect in patients using them could not be under- classifying diabetes at the earliest time of clinical care estimated even though the glycaemic control was sub- would facilitate effective advice to the patient and optimal. Either the beta-cell stimulation was sub- inform the preparation for an individualised optimal with contemporary doses that were in use or treatment programme. This approach will secure the peripheral insulin resistance was the determining maximum participation in self-care of each patient factor that was not addressed in therapy. Alternatively, with diabetes. When patients were more satisfied both beta cell stimulation and peripheral insulin with their physicians’ communication skills (29) and resistance were inadequately addressed, especially participate more in their own treatment (30), they amongst patients re-categorised as “true” type 2 were found to be more adherent to self-care diabetes whose duration of diabetes was five years or recommendations and achieve better health less when they were expected to retain some insulin outcomes. Not all hyperglycaemia is the same, states secretory capability. The contribution of peripheral Fowler (31). The patients living with diabetes and insulin resistance was implied by the relatively high their healthcare providers need to know as much in levels of C-peptide in a significant proportion of our order to embrace the varied therapeutic options and patients with “true” type 2 diabetes and comparatively combinations that may be required often.
REFERENCES
Therapeutic comparison of metformin andsulphonylurea and in various combinations. A National Diabetes Data Group. Classification and double-blind controlled study. Diabetes Care. 1994; diagnosis of diabetes mellitus and other categories of l7: 110 - 1109.
glucose intolerance. Diabetes. 1979; 28: 1039 - 1059.
The DCCT Research Group. The effect of intensive The expert committee on the diagnosis and treatment of diabetes in the development and classification of diabetes mellitus. Report of the expert progression of long-term complications in insulin Committee on the diagnosis and classification of dependent diabetes mellitus. N. Engl. J. Med. 1993; diabetes mellitus. Diabetes Care. 1997; 20:1183-1197.
329: 977 - 986.
Robertson, R. P. Pathophysiological concepts of beta- UK Prospective Diabetes Study (UKPDS) Group.
cell dysfunctional in type 2 diabetes. Medicographia Intensive blood glucose control with sulphonylureas 2005; 27: 320-325.
or insulin compared with conventional treatment Robertson, R. P. Diabetes and Insulin resistance: and risk of complications in patients with type 2 philosophy, sciences and the multiplier hypothesis.
diabetes (UKPDS 33). Lancet. 1998; 352: 837 - 853.
J. Lab. Clin. Med. 1995;125:560 -564.
(Erratum. Lancet 1999; 354:602).
Polonsky, K. S., Japan, J. B., Pugh, W., et al. Metabolism Otieno, C. F., Kariuki, M. and Nganga, L. Quality of of C-peptide in the dog: in vivo demonstration of the glycaemic control in ambulatory diabetics at Kenyatta absence of hepatic extraction. J. Clin. Invest. 1983; 72:
National Hospital. East Afr. Med. J. 2003; 80: 406-410.
Cook, C. B., Lyles, R. H., El-Kebbi, L., et al. The Polonsky, K. S., Pagh, W., Jaspan, J. B., et al. C-peptide potentially poor response to out-patient diabetes and insulin secretion relationship between peripheral care in urban African-Americans. Diabetes Care. 2001; concentrations of C-peptide and insulin and their 24:209 - 215.
secretion rates in the dog. J. Clin. Invest. 1984; 74:
Poyrot, M., Rubin, R. R., Lauritzen, T., et al. International DAWN Advisory Panel. Patient and Lucinio - Paisax, J., Polonsky, K.S., Given, B.D., et al. provider perceptions of care for diabetes; Results of Ingestion of a mixed meal does not affect the metabolic cross- national DAWN study. Diabetologia. 2006; 49:
clearance rate of biosynthetic human C-peptide.
J. Clin. Endocrinol. Metabol. 1986; 63: 401 - 403.
Monnier L., Collette C., Thuan J-F and Lapinski H.
Gumbiner B., Polonsky K.S., Beltz W.F., et al. Effects lnsulin secretion and sensitivity as determinants of of weight loss and reduced hyperglycaemia on the HbAlc in type 2 diabetes. Eur. J. Clin. Invest. 2006; 36:
kinetics of insulin secretion in obese NIDDM. J. Clin. Endocrinol. Metabol. 1990; 70: 1594-1602.
Kahn, S. E., Haffner, S. M., Heise, M. A., et al. ADOPT Le Roith D. Beta cell dysfunction and insulin resistance investigations. Glycemic durability of rosigilitazone, in type 2 diabetes: role of metabolic and genetic metformin of glyburide monotherapy. N. Eng. J. Med. abnormalities. Am. J. Med. 2002; 113: 35-115.
2006; 355; 2427 - 2443.
Khan, S. E. The relative contributions of insulin Palmer, J. P. and Juneja, R. Type 1/2 diabetes. Myth or reality? Autoimmunity. 1999; 29: 65 - 83.
pathophysiology of type 2 diabetes. Diabetologia. 2003; Pozzilli, P. and Di Mario, U. Autoimmune diabetes not requiring insulin at diagnosis (Latent autoimmune UK Progressive Diabetes Study Group l 6; Overview diabetes of the adult. Definition, characterisation of 6 years therapy of type 2 diabetes. Diabetes. and potential prevention. Diabetes Care. 2001; 24:
1995;44:1249-1258.
Levy J., Atkinson A. B., Bell P. M., Melance, D. R.
Beran, D., Yudkin, J.S. and Decourten, M. Access to and Hadden, D.R. Beta cell deterioration determines care for patients with insulin-requiring diabetes in the onset and rate of progression of secondary dietary developing countries. Diabetes Care. 2005: 28:
failure in type 2 diabetes mellitus the 10 year follow up of the Belfast Diet Study. Diabet. Med. 1998; 15:
Peyrot, M., Rubin, R.R., Lauritzen, T., et al. The International DAWN Advisory Panel. Resistance to Hattersley, A. Does genetic subtype of type 2 diabetics insulin therapy among patients and providers: results influence treatment. Medicographia. 2005; 27:354.
of cross-national diabetes, attitudes, wishes and needs UKPDS Group. Effect of intensive blood glucose study. Diabetes Care. 2005; 28: 2673-2679.
control with metformin on complications in Alazri, M. H. and Neal, R. D. The association between overweight patients with type 2 diabetes (UKPDS satisfaction with services provided in primary care 34). Lancet. 1998; 52: 854-865.
and outcomes in type 2 diabetes mellitus. Diabetes Donnelly, L. A., Doney, A. S. F., Hattersley, A. D., Med. 2003; 20: 4486-4490.
et al. The effect of obesity on glycaemic response to van Dam, H. A., van der Horst, F ., van den Borne, B.
metformin or sulphonylureas on type 2 diabetes.
Ryckman, R. and Crebolder, H. Povider - patient Diab. Med. 2005; 23: 128-133.
interaction in diabetes care: effects on patient self- De Fronzo, R. A. and Goodman, A. M. Efficacy of care and outcomes. A systematic review. Patient. metformin in patients with non-insulin dependent Educ. Couns. 2003; 51: 17 - 28.
diabetes. The multi-centered metformin study group.
Fowler M. J. Classification of diabetes: Not all N. Eng. J. Med. 1995; 333: 541-549.
hyperglycaemia is the same. Clinical Diabetes. 2007; Herman L. S., Schersten B., Bitzen P.O., et al. 25:74 -76.

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